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BackgroundGlioblastoma (GBM) is a devastating brain tumor with poor prognosis, characterized by rapid growth and invasion into surrounding brain tissue. It is a hard-to-treat cancer and represents an unmet medical need. In recent years, there has been a growing interest in developing novel approaches to improve the outcomes of GBM patients; among these, drug repurposing. Our preclinical studies identified the antipsychotic chlorpromazine (CPZ) as an important modulator of signal transduction and energy metabolism in GBM cells, so we embarked on a Phase II clinical trial in which CPZ has been added to the standard disease treatment.MethodsWith these assumptions, we started a multicenter phase II clinical trial on newly diagnosed GBM patients carrying hypo-/un-methylatedMGMTgene promoter by adding CPZ to temozolomide (TMZ) in the adjuvant phase of the standard first-line therapeutic protocol RACTAC schedule. Primary endpoints: Progression-Free Survival (PFS) and Combination treatment toxicity. Secondary endpoints: Overall Survival (OS) and Quality of Life (QoL)ResultsThe RACTAC schedule showed an overall clinical benefit in GBM patients carrying hypo-/un-methylatedMGMTgene promoter. When compared with historical cohorts, these patients displayed longer PFS, with toxicity described as a dose-dependent sedation and liver toxicity, both expected. One case of severe liver toxicity has been reported. OS and QoL are still under evaluation.ConclusionsThis clinical trial confirms the anticancer properties of CPZ, as described in several preclinical studies. In addition, the RACTAC study can be considered at least as a proof-of-concept in demonstrating the effectiveness of interfering with the well-described oncogenic monoamine signaling between neurons and GBM.

Objective Peripherally inserted central catheters (PICC) guarantee a stable and safe vascular access to administer irritants or vesicants therapies. However, they may occasionally be affected by relevant thrombotic complications especially in patients with hypercoagulability such as oncological patients. Among the identification of independent risk factors, the role of body mass index (BMI) ≥25 kg/m2 is now emerging in literature with conflicting results. The aim of this systematic review is to analyze the available scientific literature in order to determine whether BMI could represent a risk factor in the development of thromboembolic event among cancer patients with PICCs. Data sources and review methods A scientific literature review was performed in Pubmed, Embase and Cinahl from Jan 1, 2010 to September 10, 2020 in which we identified 100 records. Of these, 88 were excluded and 14 were reviewed in full text. Among the reviewed records, 6 articles satisfied the inclusion criteria for analysis. These criteria included the English language, oncological patients with PICCs, the evaluation of catheter-related thrombosis as well as the stratification of patients according to BMI. Studies off topic and lacking data on PICC related complications among overweight and underweight patients were excluded. The includedstudies, judged with Newcastle-Ottawa Scale, was fair-lower quality. The primary endpoint was the relative risk (RR) of PICC-related thrombosis of overweight/obese vs normal weight/underweight (i.e., BMI ≥25 vs Results A total of 2431 patients were included in the analysis. Overall, 15.1% of patients developed PICC-related thrombosis within a median time of 23.2 days (range 11.0-42.5) after PICC implantation. Concerning BMI, 52.6% of the entire population was overweight/obese. We assessed the proportion of patients with PICC-related thrombotic events in the two groups, with 28% (95% CI, 12%-45%) of events registered in the overweight/obese patients cohort, and 13% (95% CI, 6%-19%) in the normal weight/underweight cohort. The pooled relative risk (RR) was 2.06 (95% CI, 1.21-3.49, p Conclusion This review showed a two-fold risk of thrombosis in overweight/obese compared to normal weight/underweight oncological patients with PICCs. Underweight condition could also play a role in thrombosis development, especially in nasopharyngeal and digestive system cancer. Future prospective studies are needed to achieve reliable results and produce useful conclusion.

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.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.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.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.

The use of central venous catheters with peripheral insertion (PICC) has increased rapidly in recent years, particularly in cancer patients. The benefits provided may occasionally be affected by relevant complications, such as infections and thrombotic events, especially in neuro-oncological patients. To date, the risk of PICC-related complications in this subset of patients is unknown, as is tolerability. As a primary objective, this study aimed to collect complications related to PICCs in primary neuro-oncological patients. As a secondary objective, the study aimed to evaluate PICC tolerability. Neuro-oncological patients with PICCs that were placed as part of normal clinical practice at IRCCS Neurologico C. Besta were consecutively enrolled in the study. PICC-related complications were recorded immediately (during the procedure), early (within 1 week after PICC insertion), and late (1–3-5 months after PICC placement). At the same time points, all patients were also evaluated for tolerability through interviews with semi-structured, open-ended questions. Sixty patients were enrolled (41 males and 19 females, with a median age of 56.2 years). Excluding loss to follow-up, 33/49 patients developed at least one complication related to the PICC. Immediate complications mainly included hematoma (8), accidental arterial puncture (4), and primary malpositioning (3). Regarding early and late complications, 3 device-related infections, 8 thrombotic events, and 20 mechanical complications were registered. Semi-structured interviews revealed an overall positive experience with the device. The most negative impact was on hygiene habits, with 34 patients becoming caregiver-dependent. Over time, almost all patients became used to the device and perceived greater security during chemotherapy. A strongly negative issue was the difficulty of relying on competently trained healthcare personnel in outpatient setting. The results showed a nonnegligible increased thromboembolic risk in neuro-oncological patients with PICCs, almost double that in historical oncological populations. It is essential to extend the study to a greater number of patients to achieve reliable results and to identify patients at high risk. The device seems to be positively accepted by the majority of patients, without affecting activities of daily living.

BACKGROUND Venous thromboembolism (VTE) is a frequent and potentially fatal event in cancer patients. Patients with brain tumors in particular have one of the highest risk of developing VTE among cancer patients (25–39%), contributing significantly to mortality and morbidity. VTE is particularly high in the postoperative period, with almost half of the events occurring at that time, but it also persists in the first 12 months, with a risk ranging between 7–28%. Despite the high incidence of VTE in patients with brain tumors, to date there are no sufficient data to predict teh real risk or to lead to a standardized approach in the management of these patients. We conducted a retrospective analysis to assess the prevalence of pulmonary embolism complication in patients with brain tumors treated by our Institution in the last 3 years. MATERIAL AND METHODS Clinical data, treatment modalities, and patients outcome were analyzed and described. In particular, In particular, the dosages of D-dimer performed in the clinical suspicion of thromboembolic complication were reviewed, and the data of patients with pulmonary embolism confirmed by chest CT scan were recorded. RESULTS Overall 372 patients were treated at our Institute in the last 3 years for brain tumors. 14 patients (3.7%) 9 males and 5 females, with a median age of 62 years and a median KPS of 80, affected by glioblastoma (69%), cerebral lymphoma (23%) and low-grade gliomas (8%) had pulmonary embolism during the course of treatment. None of the 14 patients was on prophylactic anticoagulant treatment. One patient developed the embolic event during radio and chemotherapy concomitant treatment, 5 patients during chemotherapy only (2 with PCV scheme and 3 with fotemustine scheme), 2 patients with primary nervous system lymphoma during methotrexate infusion. Six patients were not receiving any chemotehrapy treatment at the onset of pulmonary embolism. At the time of pulmonary embolism diagnosis, more than half of the patients had clinical signs suggestive of deep venous thrombosis, confirmed by echocolor Doppler, 10/14 patients were treated with high-dose enoxaparin, the others with fondaparinux and calcium nadroparin. CONCLUSION Despite the high incidence of VTE in patients with brain tumors, there is currently no gold standard in the prevention and treatment of this complication. In fact, many questions are still open, for example the efficacy of low molecular weight heparins vs oral anticoagulants as a prophylactic treatment, the timing of onset and the real risk of bleeding. Future prospective studies should be designed to identify parameters for optimize stratification of thrombotic / haemorrhagic risk in this group of patients. This could allow patients at high risk to undergo more aggressive prophylactic therapy or closer clinical-instrumental surveillance, without incurring the opposite risk of bleeding.

Introduction Meningiomas are usually considered benign lesions, however a proportion of them shows a more aggressive behavior, defined high-grade meningiomas (HGM). Effective medical treatments are lacking, especially at the time of recurrence. Methods Through a retrospective analysis, we examined epidemiological, diagnostic, therapeutic, recurrence information and survival data of HGM treated at our institution between 2010 and 2018. Results 183 patients (105 females and 78 males), with median age of 58 years (25–88), were included; 168 were atypical, 12 anaplastic, 3 rhabdoid. Overall, m-PFS was 4.2 years, and m-OS was 10.3 years. Gross-total resection had a 5-year survival rate of 95% compared with subtotal/partial resection (86% and 67%) (p = 0.002). Higher expression of Ki-67/MIB-1 seems associated with higher risk of death (HR:1.06 with 95% CI, 1.00–1.12, p = 0.03). No statistically significant differences were seen in survival between the group managed with a wait-and-see strategy vs the group treated with RT while a difference on PFS was seen (4.1 years vs 5.2 years p = 0.03). After second recurrence, the most employed treatments were systemic therapies with a very limited effect on disease control. Conclusions Data confirmed the aggressive behavior of HGM. The extent of resection seems to correlate with a favorable outcome regardless histological subtypes. The role of RT remains controversial, with no statistically significant impact on OS but a possible role on PFS. Recurrent HGM remains the real challenge, to date no chemotherapies are able to achieve disease control. Future research should focus on biological/molecular predictors in order to achieve a patient-tailored treatment.

BACKGROUND Meningiomas are usually considered benign lesions, however a part of them can show very aggressive behavior with tendency to metastasize. This subgroup is known as high-grade meningiomas (HGM). Due to the rarity of the disease, effective medical treatments are lacking, especially at the time of recurrence. We aim to describe the clinical, radiological and molecular features of a large population of HGM diagnosed between 2010 and 2018. The secondary aim was to evaluate survival (PFS) and overall survival (OS). MATERIAL AND METHODS We collected clinical and survival data from primitive WHO grade II and III meningioma patients treated at Fondazione IRCCS Istituto Neurologico Carlo Besta from January 2010 to December 2018. Records were collected on a web-based platform (Microsoft Excel) that was customized for this study. The database, contained epidemiological, diagnostic (radiological and histological/molecular), surgical, therapeutic and recurrence information, as well as survival data. RESULTS 183 patients (105 females and 78 males), with median age of 58 years (25–88), were included; 168 were atypical, 12 anaplastic, 3 rhabdoid. Overall, m-PFS was 4.2 years, and m-OS was 10.3 years. Gross-total resection had a 5-year survival rate of 95% compared with subtotal/partial resection (86% and 67%) (p=0.002). Higher expression of Ki-67/MIB-1 seems associated with higher risk of death (HR:1.06 with 95% CI, 1.00–1.12, p=0.03). No statistically significant differences were seen in survival between the group managed with a wait-and-see strategy vs the group treated with RT/SRS while a difference on PFS was seen (4.1 years vs 5.2 years p=0.03). After second recurrence, the most employed treatments were systemic therapies with a very limited effect on disease control. CONCLUSION Data confirmed the aggressive behavior of HGM. The extent of resection seems to correlate with a favorable outcome regardless histological subtypes. The role of RT/SRS remains controversial, with no statistically significant impact on OS but a possible role on PFS. At relapse, no chemotherapies are able to achieve disease control and recurrent HGM remains the real challenge for future research, focusing on biological/molecular predictors in order to achieve a patient-tailored treatment.This retrospective study allowed to analyzed the largest national recent series of aggressive meningiomas with the purpose of identify relevant outcome measures for future prospective studies. Our findings could be important to give a snapshot of the current attitude to treat aggressive meningiomas but also to inspire national and international collaboration in order to provide evidence-based management strategies trying to obtain a standard of care.

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. To evaluate the risk of recurrente myelotoxicity during adjuvant chemotherapy (CT) in patients who recovered from severe myelotoxicity during CRT. We retrospectively collected data on patients with MG who developed and recovered from severe myelotoxicity during CRT from eight Italian neuro-oncology centers. 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. 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 (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. 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. 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. 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.

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.

BACKGROUND The use of central venous catheter with peripheral insertion (PICC) has increased rapidly in recent years particularly in cancer patients because they represent a stable and safe vascular access to administer irritants or vesicants therapies. However, the benefit provided may occasionally be affected by severe complications. An observational study conducted at our Institute, showed a significant increase of thromboembolic risk in neuro-oncological patients compared to general cancer population (16.3% vs 6.7% respectively). For this reason, it is essential to identify independent risk factors in order to avoid preventable harm. MATERIAL AND METHODS Neuro-oncological patients with PICC that developed a thromboembolic event were retrospectively analyzed. We evaluated clinical data, BMI, KPS, steroid therapies and anticoagulants at the time of positioning of the PICC and at the onset of the thrombotic event. RESULTS A total of 90 neuro-oncological patients have been analyzed. The most common histology was represented by glioblastoma, followed by anaplastic astrocytoma, primary central nervous system lymphoma, grade II glioma. 17.6% of patients were at first diagnoses, 41.6% were at the first recurrence, and the remaining patients were at the second or third recurrence. The median KPS was 90 (range 80–100), and the median ECOG was 0 (range 0–2). Overall, 14% patients developed thromboembolic events within a median time of 34.5 days (range 5–146) after PICC implantation. Among these, 64% of patients was considered overweight. No patients were on anticoagulant therapy but all were treated with a median dose of 5.5 mg of steroids (range 3,5-12), stable between PICC insertion and onset of adverse event. CONCLUSION 64% of patients who developed a thromboembolic event had BMI >28 at the time of PICC insertion, suggesting a possible trend towards a risk of developing PICC related thrombosis in overweight/obese patients. Other independent risk factors for PICC associated complications seems to be amount of previous chemotherapies administered: 82% of patients who developed thrombotic complications had already undergone at least one line of chemotherapy before PICC placement, suggesting this condition as a possible risk factor for the onset of the event. Also failed positioning attempts could damage vascular endothelium, contributing to the onset of thrombotic complications. An accurate anamnesis and a physical evaluation with particular attention to the presence of malnutrition could help in the in the early identification of independent risk factors that could farther negatively influence the outcome of neuro-oncological patients.

BACKGROUND Some (elderly) patients present a communicating (normal pressure) hydrocephalus (NPH) in association with or secondary to vestibular schwannoma (VS). We aim to investigate the usefulness ventriculo-peritoneal shunt (VPS) without tumor removal. MATERIALS AND METHODS 8 patients aged from 50 to 78 years received both diagnosis of VS (mean maximum diameter 21 mm, range 13–28 mm) and NPH. None presented the classical Hakim’s triad. They presented isolated ataxia with gait impairment and loss of equilibrium. It was hard to distinguish if these symptoms were due to NPH or to VIII cranial nerve compression. They underwent TAP test, through a lumbar puncture with a very slow whithdrawal of at least 30 ml of cerebrospinal fluid (CSF). RESULTS None of the 8 patients presented improvement after lumbar puncture. Despite this, we decided to proceed with VPS in 4 patients because of a high risk of falls.... All these 4 patients showed clinical improvement after VPS.. The VS were treated as follows: 4 surgery, 2 radiosurgery, 2 observation. CONCLUSIONS Although some authors indicate VS removal as the best option to improve also NPH symptoms, some patients present high risk of falls in the presence of a small VS. These clinical features are more likely to be relayed related to NPH instead of VS.. VPS carries lower postoperative risks compared to VS removal. For this reason, VPS has to be considered, even without a positive response to a TAP test, as a good alternative to improve quality of life in patient affected by NPH associated with VS.

BACKGROUND Insomnia linked to therapeutical intake of intravenous (IV) megadoses of steroid (Mgds, 8–16 mg) is a common side effect in neuro-oncology patients. Hypno-inducing drugs (IP) and Benzodiazepines (BDZ) can provoke drug interference and daytime sedation. Trazodone (Trz) is an atypical antidepressant with poor liver metabolism; it has moderate histamine-1 (H1) receptor antagonism and possesses some anxiolytic and hypnotic properties. We tested the use of the Trz retard (RP) formulation as a hypnotic drug in patients undergoing a therapeutic regimen with IV Mgds. To evaluate anxiety and side effects. MATERIAL AND METHODS 10 patients (6 females and 4 males) admitted to the Neuro-oncology Department of the Neurological Institute “Carlo Besta” treated with Mgds IV. The average age was 55 years and the mean HAM-A score was 25. Instruments included the Hamilton Anxiety Scale (HAM-A), the Clinical Global Impression (CGI), and the Pittsburgh Sleep Quality Index (PSQI). Trz RP was administered at a dosage of 25-50-75 mg/day in the evening. RESULTS All 10 patients reported improved hypnotic profiles within the third day of Trz RP administration. Four patients improved on the first day. Reduction of the HAM-A score was found on the third day. No adverse events (epilepsy, daytime sedation, incontinence) were observed in 3 weeks. CONCLUSIONS Trz RP proved to have a swift beneficial effect on sleep and anxiety without side effects in the short term. Trz may be preferred to IP and BDZ in patients receiving IV Mgds, considering the lack of daytime sedation and the reduced pharmacological inference. Larger samples will enable future research to better describe the characteristics and the indication of Trz.

BACKGROUND Pleomorphic xanthoastrocytoma (PXA) represent an astrocytic neoplasm that is typically well circumscribed and can have a relatively favorable prognosis. Tumor progression to anaplastic PXA (WHO grade III), however, is associated with a more aggressive biologic behavior and worse prognosis. The factors that drive anaplastic progression are largely unknown. The activating BRAF mutation is a genetic alteration that could be present in both PXA and anaplastic PXA; Identification of the mutation can be important as BRAF V600E mutant protein could be targeted therapeutically by small molecule inhibitors of both RAF and MEK. The low frequency of these tumors has fostered heterogeneity of therapeutic approaches, particularly in adult patients. We performed a monocentric, retrospective study on adult patients with a PXA diagnosis treated by our Institution, in order to search for markers of diagnosis and prognosis. MATERIAL AND METHODS All consecutive patients older than 18 years with a histological diagnosis of a primary grade II and III pleomorphic xanthoastrocytoma operated and treated by our Institution from 2011 to 2021 were consecutively and retrospectively included in the study. All pathological diagnoses and PXA cases were reviewed according to the WHO classification. Histological and molecular characteristics, including BRAF mutation status, as well as clinical data, treatment modalities, and patient outcome were analyzed and described. RESULTS 21 patients were included, 10 males and 11 females, with a median age of 40 years old (range 18–66). In 10 patients the histology showed an anaplastic PXA and in 11 patients a grade II tumor. Genetic features, including IDH status were available to all patients and BRAF mutation study was available in 8/10 anaplastic PXA. All patients underwent main surgery. Anaplastic features were associated with minimal PFS, whereas BRAF mutation tended to be associated with a better PFS. CONCLUSION Anaplastic features and BRAF mutation can lead to identify subgroups with distinct prognosis. These results should be validated in a larger and prospective study.

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.

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.

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 (p0.003), radiotherapy (p0.0001), chemotherapy (p0.0001) 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 p0.0001) 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.

BACKGROUND Primary Central nervous system (CNS) lymphomas (PCNSL) are extranodal, malignant non- Hodgkin lymphomas of the diff use large B-cell type, confined to CNS. It accounts for up to 1% of all lymphomas and about 3% of all CNS tumours. The incidence continues to rise in immuno- competent elderly patients.Although the prognosis of PCNSL remains poor, it has improved in the past two decades as a result of better treatment strategies. However, treatment recommendations still result mainly from retrospective series or single-arm phase 2 studies and a few three completed randomised trials. We described a series of patients with newly diagnosis of PCNSL treated with modified-schedula published by Omuro MATERIAL AND METHODS Patients was treated with HD-MTX, procarbazine, vincristine, received four 28-day cycles of chemotherapy, on schedule: HD-MTX (3·5 g/m²) days 1 and 15; Procarbazine (100 mg/m²) on days 1–7. Vincristine (1·4 mg/m²) on days 1 and 15. Toxicity was assessed with Common Terminology Criteria for Adverse Events version 4. The International PCNSL Collaborative Group Response Criteria were used for response assessment. Endpoints include overall survival (OS) and adverse events (AE). RESULTS 21 immunocompetent patients (12 females and 9 males) were retrospectively studied, among 2014 to 2019. Median age at diagnosis 61 years (range 41–76). Median KPS at diagnosis was 70 (range 40–100). Clinical and radiological data and treatment related toxicity were described CONCLUSION Present combination regimen is effective; however, AE incidence is high, and often induces schedule modification

INTRODUCTION: Glioblastoma (GBM) remains the most aggressive brain tumor; even with current standard of care for newly diagnosed GBM, the majority of patients recur within a year. Therapeutic options are lacking and the development of more effective therapeutic approaches is imperative. Ortataxel, another second-generation taxane, showed to be active in different tumor. It was hypothesize a potential therapeutic activity of ortataxel against glioblastoma and led us to design a phase two study in patients with glioblastoma recurring after surgery and first line treatment. PATIENTS AND METHODS: A single arm, phase II trial on the efficacy of ortataxel in recurrent glioblastoma was performed to evaluate the activity of ortataxel in in terms of PFS-6. PFS, overall survival at 9 months (OS-9) after the enrolment, objective response rate (ORR), compliance, tolerability and safety were evaluated as secondary endpoints. RESULTS: A total of 40 GBM patients were recruited. PFS-6 was 11.4 %: four patients were alive and progression free at 6 months after the enrolment. One additional patient progressed at 5.5 months with the appearance of a new lesion but his clinical status was considered stable and therefore the clinician decided to continue the treatment with ortataxel receiving up to 18 cycles until the further disease progression. All other patients progressed in a range from 1.0 to 5.5 months from the study entry. The median follow-up was 19.9 months (IQR 12.0–32.0). Median PFS was 1.7 months (IQR 1.4–3.8). Regarding the OS-9, 29 patients out of 35 (OS-9 %: 12.8; 95%CI: 21.8–53.8) died before 9 months from the enrolment, in a range from 0.99 to 7.70 months from study enrolment. The best response to treatment was PR in only one patient that was still on treatment when the analysis was performed and SD in 9 patients (29.0%). The most important toxicities were neutropenia, hepatotoxicity and leukopenia that occurred in 5 patients (13.2%), 5 patients (13.2%) and 6 patients (15.8%) respectively. CONCLUSION: The finding that two cases responded to the drug for a long time invite us to speculate that ortataxel might be effective in a limited fraction of GBM patients with some peculiar molecular features associated to high sensitivity to the drug.

INTRODUCTION Malignant gliomas are aggressive primitive brain tumor in adults. Today, the standard of care is Temozolomide (TMZ) administered daily with radiation therapy, followed by adjuvant TMZ. TMZ treatment has been considered to have a low toxicity profile. However, during concomitant treatment some patient may develop a severe myelosuppression. This toxicity may be in some cases prolonged and lead to treatment discontinuation. METHODS We have retrospectively collected data from 5 Italian neuro-oncological centers, about glioma patients who developed severe and prolonged hematological toxicity during concomitant chemoradiotherapy with TMZ. The purpose of this study is to evaluate: percentage of patients receiving adjuvant chemotherapy after severe myelotoxicity; rate of toxicity observed during adjuvant chemotherapy. RESULTS 54 glioma patients who developed myelosuppression of grade 3 or 4 were considered. Histology was Glioblastoma in 45 patients (83%); 63% of patients were female. Myelotoxicity during concomitant phase occurred at a median of 4 weeks (range 1–8) from the start of treatment. After recovery of myelotoxicity 19 patients did not received any treatment while 35 (65%) were treated with chemotherapy (28 received standard TMZ, one TMZ with metronomic schedule, 2 lomustine and 4 other agents). Among patients treated with TMZ, 13 patients presented hematological toxicity grade 3–4 which required treatment discontinuation in 7 cases (20%). CONCLUSION the results of our study show that 80% of glioma patients presenting severe myelotoxicity during concomitant radiochemotherapy may be treated with maintenance TMZ after recovery of myelosuppression.

Medulloblastoma is a rare disease in adult patients, it accounts for 6 % of the Posterior Fossa Tumors. Large, trials are often impossible and also access to biospecimens may be problematic Two years ago, during the spring meeting of AINO in Turin we planned an online web-data base on rare tumours of CNS. We decided to start our work with medulloblastoma, as example of multidisciplinary treatment for a rare tumour without codified guidelines. To simplify data collection we chose to include in the data base only the patients treated over the past five years Of the 225 clinicians- centres emailed; 32 (14 %) responded, 27 respondents identified their medical specialties: 11 medical neuro-oncologists, 8 radiation oncologists, 7 neurosurgeons, 1 neurologist 11 centres entered the data in the dbase During the last 5 years, 11 centres reported treated patients for a total of 53 patients 31 Male. Median age at surgery was 35 (17–80). Symptomatic hydrocephalus was found in 50 % of patients. Postoperative residual tumour was found in 10 patients, in 6 pts the residual tumor was less than 1.5 cm square, In 2 pts more than 1,5 cm square Fore other two patients the residue volume was missing. VPS was placed on 3 pts. Positive CFS was found in 3 patients but post op spinal tap was performed only in 20 pts. In eight patients the histological definition was limited to the diction of medulloblastoma non other specified In six patients SHH mutation was found High-risk disease defined as residual disease, metastatic dissemination or large cell- anaplastic histology we defined 14 patients but we have incomplete staging or missing information in 5 pts. After surgery Craniospinal radiotherapy was given to 92 % patients and only 2 had only cranial radiotherapy due to their low PS and the 85 years old patient was not treated. A boost into the posterior fossa was given to almost all patients. X Patients were treated also by chemotherapy and regimens used varied considerably. Recurrence take place in 25 patients, in 10 out of these patients as leptomenigeal dissemination. At recurrence 4 Pts were re-operated on. The radiotherapy re-treatment was administered in one patient. Six Patient were treated with Temozolomide as salvage treatment, plus intrathecal chemotherapy. The data collected on patients and their disease characteristics were consistent with the literature. Similar also relative incidence of different histological subtypes, risk status and tumour surgery. The data are partial due to quite low number of patients included at the moment in d-base. We have extended the observation period up to 10 years and we also have started to insert patients in a prospective way opening the study to the SIN and SINCH members.

The purpose of this study was to analyze the psychological well-being, quality of life, and cognitive strategies activated by patients with high-grade glioma. We hypothesized that the self-perceived quality of life is modulated by physical and psychological factors and that in order to understand this modulation more psychometric approaches are necessary. Data were collected from a sample of 73 consecutive patients with a histological diagnosis of primary malignant brain cancer (grade IV glioblastoma and grade III anaplastic astrocytoma) hospitalized in a specialized Italian center. The Functional Assessment of Cancer Therapy (FACT) scale and the Schedule of Evaluation of Individual Quality of Life-Direct Weighting (SEIQoL-DW) scale were used to assess quality of life. The mean FACT-Brain (Br) score was 122.37. Similarly, the median SEIQoL-DW score was 72.9 out of a maximum value of 100. No gender effect was found in relation to overall quality of life. Patients with high depression and/or anxiety scores reported lower quality of life (QoL) scores in all the instruments considered. We did not find any gender effect concerning depression and anxiety levels. However, we found that men and women, though having similar physical and functional well-being, reported different QoL determinants, since men seem to rely more on physical adjustment, while women activate more introspective strategies. Positive actions, family issues, negative thoughts, health, and positive thoughts were found to be the most reported themes. In conclusion, the present study strongly suggests that a positive psychological adjustment is possible also in the event of a severe diagnosis and during aggressive treatments, but QoL determinants might be considered too in order to help health professionals to understand patients' experience and to meet their needs.

Introduction: Extra cranial metastasis of glioblastoma (GBM) are fairly rare event: they occur in only 1% of all GBM patients. The most frequent sites of colonization are generally cervical lymph nodes, lungs, liver, bones and the spine. The most common way of metastasis spread is hematogenous but also through lymph nodes, especially in patients undergoing surgical resection. METHODS: We report the case of a 38 year old male that in 2012 underwent to surgical resection of GBM (methylated MGMT, negative IDH1, MIB1 20%), followed by radiotherapy (RT) (60 Gy) and subsequently treated with concomitant and adjuvant Temozolomide (TMZ) up to 6 cycles. The patient remained stable over the year when he was re-operated due to recurrence. Because of the extremely good response to prior TMZ schedule, it was decided to try a rechallenge with adjuvant TMZ for 6 months. The sudden onset of of paresthesia and hypoesthesia on the right upper limb, induced physicians to performed an MRI that showed an increase of the lesion with nodular component parasagittal. After surgery, the patient was treated with anti-angiogenic treatment achieving a good radiological response and stabilization of disease. In February 2016, due to a neck pain associated with weakness of upper right limb, MRI found significant reduction of the lesion but revealed the presence of pathological enhancement at C4- C7. In suspicion of dissemination of the disease, chest-abdomen CT scan was performed showing 3 suspected pulmonary nodules metastasize. Results: Biopsy confirmed the presence of compatible tissue with GBM metastases and PET TC total body highlighted a mass effect in highly hypermetabolic character that stretched from C4 to C6-C7. Also it showed accumulations in the lymph nodes, lungs, and in the right iliac crest, and multiple thoracic vertebrae. The patient was radiated on bone localization and promptly started a new chemotherapy treatment with etoposide and oncocarbide but he died on 09.04.2016. CONCLUSION: Despite the peculiar tendency of GBM to remain confined within the central nervous system, a low percentage of them may metastasize. The biological-genetic mechanisms involved in the pathogenesis remain unclear but risk factors seems to include long survival, surgery procedures and vascular involvement. Therapeutic experience is limited making the management of GBM an even greater challenge.

Extra-cranial metastases of glioblastoma (GBM) represent a rare event, and the biological-genetic mechanisms involved in the pathogenesis have not yet been determined. We report the case of a young patient with multiple visceral and osseous metastases occurred after 4 years after first diagnosis of GBM. The strangeness as well as the rarity of this event does not allow to identify an effective treatment for GBM metastases, making the management of this ominous tumor an even greater challenge.

Anaplastic gliomas (AG) include 6-10% of all newly diagnoses of primary brain tumors. They have an unfavourable prognosis and, to date, there is not an established treatment universally recognized. Four recent randomized clinical trials were identified for a total of 1,170 patients (anaplastic-astrocytomas, anaplasticoligoastrocytoma, anaplastic-oligodendroglioma), in order to define the better sequence and timing of chemo-radiotherapy, Three studies compared radiotherapy (RT) treatment vs. radio-chemotherapy with procarbazine-lomustine-vincristine (PCV) or temozolomide (TMZ) or dibromodulcitol and bichloroethylnitrosurea (DBD/BCNU) and only one compared RT vs chemotherapy (CT) with PCV or TMZ. Results show no significant differences in terms of PFS/OS between RT/CT alone or combined treatment although a trend toward an improvement of OS was observed after RT + CT treatment (m-OS in RT + adjuvant PCV was 42.3 vs. 30.6 months in RT alone p=0.0003). Grade 3-4 mielotoxicity has been observed in almost all cases of patients treated with PCV + RT. None of four studies reviewed conducted a head to head comparison between PCV vs. TMZ. Only a study randomized patients to PCV/TMZ without however providing data in terms of PSF and OS between the two treatments. It found no significant differences in PFS from initial RT and adjuvant CT (PCV-TMZ) at progression compared to initial CT followed by RT at progression. The optimal treatment of AG should reasonably consider not only the histology as well as the molecular markers of the tumor, but also clinical conditions, age of patients, life expectancy, Karnofsky-performance-status and tumor resection to achieve in future the personalization of care.

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.

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.

Neoplastic meningitis (NM) is diagnosed in 1-2 % of patients with primary brain tumors. Standard treatment of NM includes single-agent or combination chemotherapy, with compounds such as methotrexate, thiotepa, and cytarabine (Ara-C) or its injectable, sustained-release formulation Depocyte(®). In this Report, we reported the data of efficacy and tolerability of an intrathecal Depocyte(®) regimen for patients presenting with NM from primary brain tumors. We described 12 patients with NM confirmed at magnetic resonance imaging (MRI) and with a positive cerebrospinal fluid (CSF) cytology. Patients were treated with repeated courses of intrathecal Depocyte(®) (once every 2 weeks for 1 month of induction therapy and as consolidation therapy on a monthly base in responding patients). Twelve patients (10 males and 2 females) were treated by our Institution. The diagnosis of primitive brain tumor was medulloblastoma in six patients, germinoma in two patients, pylocitic astrocytomas with spongioblastic aspects, teratocarcinoma, meningeal melanoma, and ependimoma in the other four patients. The total number of Depocyte(®) cycles ranged from one to nine. In 7/12 patients, there was clinical and/or radiological response after Depocyte(®), and the toxicity was moderate and transient, mainly due to the lumbar puncture procedure. In the two patients with germinoma, we observed a normalization of MRI Imaging and negativization of CSF with disappearance of the tumor cells. OS was 180 days (range 20-300, CI 95 %).

Introduction: Generally considered the model of benign tumors of Central Nervous System (CNS) and associated with a good outcome, meningioma may rarely have an aggressive behavior such as metastatic disease. Unusually, even grade I meningiomas can assume that malignant behavior. We report a case of non-CNS metastases of WHO grade I meningioma, focusing on predisposing factors and predictors of malignant behaviour.

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.

High-grade gliomas are highly vascularized tumors, in which the amount of new blood vessels is closely related with the degree of malignancy. The role of endothelial progenitor cells (EPCs) in the neoangiogenesis of gliomas and the effects of post-surgical therapies (i.e., radiotherapy (RT) and chemotherapy) have not yet been fully elucidated. The aim of the present study was to evaluate the effect of surgery and post-surgical treatment on the levels of circulating EPCs in glioma patients and their correlation with vascular endothelial growth factor (VEGF). In this study, we assessed by flow cytometry the number of EPCs in the peripheral blood of 78 high-grade glioma patients (both untreated and treated with RT and chemotherapy) and 34 age- and sex-matched healthy controls. EPCs were markedly decreased in all treated glioma patients as compared to untreated ones. VEGF levels were significantly higher in patients as compared to controls, and surgery, but not chemotherapy, significantly decreased VEGF concentrations. We found no relationship between VEGF plasma levels and EPCs. In conclusion, the reliability of EPCs as a biomarker for monitoring angiogenesis in glioma patients needs further studies of correlations of this parameter with other markers of tumor-related vasculature.

Quality of life and well-being in caregivers are usually partly neglected since all attention is focused on patients and the way they react to the illness. Carers also usually neglect their own needs, especially when the illness of the patient is as complex as a brain tumor. The aim of this study is to investigate how caregivers deal with a diagnosis of brain tumor in their relatives and how they manage their quality of life and psychosocial well-being. One hundred primary caregivers of patients with brain tumors were interviewed and were asked to fill in self-administered questionnaires detecting multidimensional levels of quality of life, anxiety, depression, and psychosocial reaction to the patient's illness. Data were related with some functional and psychosocial information collected about the patient's disease. Caregivers try to react to the illness of their relatives by mobilizing their physical reaction and growing their self-esteem, but they live with a clinically significant impairment of their quality of life, and experience a deep level of anxiety and depression. The caregivers' burden appears mainly in their ability to provide care and in financial strain. The length of disease and the functional status of patients significantly influence caregivers' psychosocial well-being. Despite the appearance they want to show their affected relatives, caregivers suffer from deep limitation in their quality of life. The relevance of caregivers' burden suggests the importance of psychological support to improve reaction to the illness.

In 1991, a prospective phase II trial was initiated to evaluate the efficacy of treatment for adults with medulloblastoma (MB). After surgery, patients were staged with a neuroradiologic examination of the brain and neuroaxis and by cerebrospinal fluid cytology. All patients received three cycles of upfront cisplatinum (cisplatinum) and etoposide (VP16) chemotherapy followed by cranio-spinal radiation therapy. The current article reports on the long-term results from that trial. After a median follow-up of 14.9 years, among a total of 28 adults with MB, the overall progression-free survival and overall survival (OS) rates at 5 years were 57.6 and 80%, respectively. The median OS for the whole group of patients was 11.3 years. The observed toxicity was mainly hematological, with leukopenia and thrombocytopenia (16% of grades 3 and 4). In summary, in our small series of patients, the role of combination administration of CDDP + VP16 started before the initiation of radiotherapy in reducing recurrences, particularly distant recurrences, remains unclear. To know whether adding chemotherapy to craniospinal radiation in adult therapy increases relapse-free and overall survival, we must await the results of a larger randomized controlled clinical trial.

"Abstract. Purpose. Despite advances in therapies that offer improved. survival rates, clinical course of brain tumours leads to a. progressive functional deterioration in patients with. modifications in their psychological reaction to the. disease. Patients with brain tumours are rarely assessed. for quality of life and psychological variables, and even. fewer studies have assessed patients who have experienced. a recurrence of brain tumours. Therefore, the aim. of the present study is to investigate the patients with. recurrent brain tumours and their reaction to the illness.. Method We enrolled 81 patients with recurrent CNS. tumours. Karnofsky Performance Status scale (KPS) was. used to evaluate functional status of patients; the multidimensional. aspect of quality of life was assessed through. “Functional Assessment of Cancer Therapy-Brain” (FACTBr),. “Hospital Anxiety and Depression Scale” and “Psychological. Distress Inventory”. These were all used as tests. of psychological well-being.. Results Distress and almost all mean FACT-Br subscale. scores seemed to be significantly lower in patients, in. comparison with normative data. Surprisingly, the emotional. well-being mean score was significantly higher in our. recurrence sample than in patients with brain tumours at first. diagnosis. Anxiety seemed not to be influenced by a relapse. diagnosis; instead, depression was higher and differed. significantly from normative data. Low correlation between. KPS and FACT-Br total and some sub-scores was found.. Conclusions Apparent dissociation between patients' judgment. on their quality of life (bad except for emotional) and. their reported distress (low) is the most intriguing finding,. suggesting highly preserved coping strategies in the. emotional sphere, despite intact judgment and disease. awareness."

BACKGROUND: A subset of meningiomas recur after surgery and radiation therapy, no proven effective medical therapy for this sub group of meningioma patients exists. Both recurrent or progressive cases, may exhibit tumor growth involving critical neurovascular structures or diffuse growth, resulting in limited efficacy and higher risk of treatments. MATERIAL AND METHODS: We retrospectively analysed the efficacy and tolerability of systemic chemotherapy with Hydroxyurea (HU) or more complex VAC (Vincristine, Adriamycin and Cyclophosphamide) in a group of recurrent meningioma patients treated at Fondazione IRCCSS Istituto Neurologico Carlo Besta between 2015 and 2017. RESULTS: Twelve patients with high-grade meningioma (8 atypical and 4 anaplastic) were treated with VAC (7) chemotherapy or HU (5). All, patients were heavily pre-treated (median number of 4 recurrences, range 2–7). Responses were assessed using modified Macdonald criteria. The Kaplan-Meier technique was used to estimate PFS and OS. The 95% confidence intervals (CIs) were calculated for all point estimates. The majority of patients came off treatment because of progressive disease. PFS6 rate was 42%. Median PFS was 5.3 months (95% CI: 2.1–9.3 mo), and median overall survival was 19 months (95% CI: 16.5–38.4 mo). No treatment related death occurred. Main treatment-related toxicities were observe in the patients treated by VAC CONCLUSION: HU and VAC chemotherapies are feasible but these treatments have limited activity in recurrent meningiomas. The optimal systemic therapy for meningioma failing surgery and radiation has yet to be identified due to the small number of prospective clinical trials available

It has been demonstrated that sagopilone (ZK-EPO) has antitumor activity in human orthotopic glioma models in vitro and in vivo. The objective of this study was to evaluate the safety and efficacy of ZK-EPO in patients with pretreated, recurrent malignant gliomas. Fifteen patients with recurrent malignant gliomas who had received prior surgery, radiotherapy, andor=2 lines of alkylating chemotherapy were recruited. ZK-EPO (16 mg/m(2)) was administered iv for 3 h every 21 days. The primary end point was six months progression-free survival (PFS-6); secondary end points were safety, toxicity, response rate, and median time to progression (TTP). Magnetic resonance imaging (MRI) evaluations were performed every two cycles and toxicity was evaluated at each cycle using common terminology criteria for adverse events (CTCAE 3.0). A median of four cycles was administered. The median TTP was 13 weeks. PFS-6 was achieved in five patients (33%), three with glioblastoma multiforme and two with anaplastic astrocytoma. The most common treatment-related adverse event was neuropathy, which occurred in 6/15 patients. ZK-EPO had an acceptable safety profile and clinically relevant activity in patients with pretreated, recurrent malignant gliomas.

Brain metastases occur in about 25% of patients who die of cancer. The most common sources of brain metastases in adults are lung, breast, kidney, colorectal cancer and melanoma. The chemokine/receptor system CXCL12/CXCR4 plays a key role in multiple biological functions; among these, homing of neoplastic cells from the primary site to the target and metastasis progression. Recently, an alternative CXCL12 receptor CXCR7 has been discovered. The aim of our study was to investigate the expression of CXCL12 and its receptors CXCR4 and CXCR7 by immunohistochemistry in 56 patients with metastatic brain disease from different non-CNS primary tumors and evaluate their prognostic relevance as well as that of other patient/treatment-related features on patient survival. CXCL12 showed an expression in tumor cells and in tumor vessels; CXCR7 was expressed by tumor and endothelial cells (both within the tumor and in the adjacent brain tissue), while CXCR4 showed a positivity in all samples with a nuclear pattern. Among the investigated immunohistochemical parameters, only CXCL12 expression in tumor endothelial cells showed a statistically significant correlation with shorter survival (p = 0.04 log-rank), perhaps identifying more aggressive tumors. Thus, this is the first study evaluating at the same time the expression of CXCL12 and its two receptors in a cohort of brain metastases.

Neoplastic meningitis from breast cancer often leads to a progressive neurologic deterioration followed by fatal outcome. The therapy is based on the administration of high dose systemic chemotherapy with drugs able to pass through the blood-brain barrier, such as methotrexate (MTX) and cytarabine, cranial or craniospinal irradiation, and intrathecal (IT) administration of MTX and/or cytarabine. However, these approaches only have modest efficacy and are associated with side effects for the patients. A depot formulation of liposomal cytarabine (DepoCyte®) has proven to be useful in clinical trials. We describe the case of a woman with a diagnosis of leptomeningeal carcinomatosis from breast carcinoma who presented cerebrospinal fluid normalization and prolonged complete MRI response to intrathecal chemotherapy with liposomal cytarabine (DepoCyte).

Background The prognosis of patients with glioblastoma is very poor with a mean survival of 10–12 months. Currently available treatment options are multimodal, which include surgery, radiotherapy, and chemotherapy. However, these have been shown to improve survival only marginally in glioblastoma multiforme (GBM) patients. Methylated methylguanine methyltransferase (MGMT) promoter is correlated with improved progression-free and overall survival in patients treated with alkylating agents. Strategies to overcome MGMT-mediated chemoresistance are being actively investigated. Methods A retrospective analysis on 160 adult patients (≥16 years) treated for histologically confirmed GBM between 2003 and 2005 at our Institution was performed. All patients were treated with conventional fractionated radiotherapy and a combined chemotherapy treatment with Cisplatin (CDDP) (100 mg/sqm on day 1) and carmustine (BCNU) (160 mg/sqm on day 2); the treatment was repeated every 6 weeks for five cycles. Toxicity, progression free survival and overall survival were assessed. Results The median number of chemotherapy cycles delivered to each patient was 5 (range 3–6), with no patients discontinuing treatment because of refusal or toxicity. Dose reduction was required in 16 patients (10%), and all patients completed radiotherapy, whereas 5 patients discontinued chemotherapy before completing all planned cycles for disease progression. The primary toxicities were: neutropenia (grade 3–4: 23%), thrombocytopenia (grade 3–4: 18.5%), and nausea and vomiting (13%). Median progression-free survival times and 1-year progression free survival were 7.6 months (95% CI 6.6–8.5) and 17.3%, respectively. OS was 15.6 months (95% CI 14.1–17.1). Conclusions Our results for PFS and overall survival are comparable with those obtained with temozolomide, but the toxicity occurring in our series was more frequent and persistent. The toxicity, and mainly the modalities of administration associated with cisplatin and BCNU combination, argues against future use in the treatment of patients with GBM.

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.

The objective was to evaluate agreement among neurologists for coding stroke, using the International Classification of Diseases 9th Revision - Clinical Modification (ICD-9-CM). Clinical records of 53 consecutive patients (27 stroke or TIA and 26 other diseases) discharged from our general neurology department were coded by four neurology residents, four general neurologists and four neurologists trained in ICD-coding (experts). Inter-coder agreement was evaluated by the kappa statistic. The overall kappa value for coding 430-438 was 0.77 (95% confidence interval 0.70-0.84) for primary (PDx) and 0.82 (0.77-0.88) for PDx+secondary diagnoses (SDx). It was 0.73-0.86 for the residents, 0.78-0.90 for the neurologists and 0.67-0.88 for the experts. The overall kappa values (PDx, SDx) for specific codes were 0.83-0.88 for 431-intracerebral haemorrhage (residents: 0.75-0.89; neurologists: 0.91-0.96; experts: 0.78-0.88) and 0.48-0.51 for 434-occlusion of cerebral arteries) (residents: 0.26-0.26; neurologists: 0.61-0.66; experts: 0.60-0.65). Agreement was substantial for the whole code group 430-438 and higher for code 431 than 434. Reliability was generally improved when both PDx and SDx were considered. Specific training did not increase inter-coders' agreement.

The Fas death receptor is expressed by activated lymphocytes and is involved in switching-off the immune response. Its inherited defects cause auto-immune lymphoproliferative syndrome. Impaired Fas function may also play a role in other auto-immune diseases, such as multiple sclerosis and type 1 diabetes mellitus. The aim of this work was to evaluate Fas function in T cells from patients with chronic inflammatory demyelinating polyneuropathy (CIDP). We evaluated Fas-induced apoptosis in T-cell lines from 27 patients with CIDP, 12 patients with acute inflammatory demyelinating polyneuropathy (AIDP), and 110 controls. CIDP patients displayed lower Fas function than both AIDP patients and controls, whereas no statistically significant difference was found between AIDP patients and controls. Moreover, Fas function was lower in CIDP patients with progressive course than in those with relapsing-remitting course and lower in CIDP patients with axonal damage than in those with pure demyelination. These data suggest that defective Fas function favours CIDP development and aggressive evolution.

The possible relationship between Guillain-Barre syndrome (GBS) and cancer is still controversial and the existence of a paraneoplastic GBS remains unconfirmed. To better define whether there is a relationship between GBS and malignancy, we compared the observed and the expected number of patients with tumours in a population-based cohort of subjects with GBS. Clinical differences between GBS patients with or without malignancies were analysed. Data were obtained from the Piemonte and Valle d'Aosta Register for GBS (PARGBS) (years 1990-1998). GBS was diagnosed according to NINCDS criteria. The number of expected cases of malignancy in the PARGBS population was calculated using the incidence rate of all types of cancer (ICD codes 140-208) in Piemonte [1985-1987], and in the most important town of this region, that is Turin (years 1993-1997). In the nine-year period, 435 incident patients with GBS were found. Nine of them developed cancer in the six months preceding or following GBS; in seven of them, the diagnosis of cancer and GBS was concomitant. The expected number of malignant tumours was 3.7 (using the incidence in Piemonte) and 3.8 (using the incidence in Turin); therefore, the odds ratios were 2.43 (95 % CI, 1.11-4.62) and 2.37 (95% CI, 1.09-4.50), respectively (p