This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
To evaluate disease activity according to rituximab (RTX) induction and maintenance regimens in a... more To evaluate disease activity according to rituximab (RTX) induction and maintenance regimens in a multicenter real-life dataset of NMOSD patients. Methods: This is an observational-retrospective multicentre study including patients with NMOSD treated with RTX in 21 Italian and 1 Swiss centers. Demographics, relapse rate and adverse events over the follow-up were summarized taking into account induction strategy (two-1 g infusions at a 15-day interval (IND-A) vs. 375 mg/ m2/week infusions for one month (IND-B)) and maintenance therapy (regimen A (M-A) with fixed time-points infusions vs. regimen B (M-B) based on cytofluorimetric driven reinfusion regimens, the least further subdivided according to CD19+ B cells (M-B1) or CD27+ memory B cells (M-B2) monitoring). Results: 131 subjects were enrolled, 127 patients completed the induction regimen and 119 patients had at least one follow-up visit and were included in the outcome analysis. Median follow-up was 1.7 years (range 0.1-11.6). Annualized relapse rate (ARR) was 1.7 in the year before RTX start and decreased to 0.19 during the follow-up. Both ARR and Time to first relapse (TTFR) analysis showed a trend toward an increased disease activity for IND-B and M-A. No patients with MT-B2 experienced relapses during the follow-up. Number of relapses in the year before RTX initiation and having received a previous treatment were significantly associated with higher ARR and reduced TTFR in the multivariate analysis. Interpretation: We confirm RTX efficacy in NMOSD patients. Use of specific induction and maintenance protocols is warranted in order to foster RTX efficacy and to reduce costs and side effects.
2027 Background: Bevacizumab has shown activity in recurrent glioblastoma (GBM), and few data are... more 2027 Background: Bevacizumab has shown activity in recurrent glioblastoma (GBM), and few data are available on the combination of bevacizumab and nitrosoureas, that represent the standard cytotoxic option. Fotemustine (FTM) is a nitrosourea with elevated lipophilic properties. METHODS In this phase II study patients with GBM recurrent after surgery, radiation therapy, and concomitant/adjuvant temozolomide were elegible. The treatment consisted of an induction phase with BV at 10 mg/kg intravenously on day 1 and 15 and fotemustine (FTM) at 75mg/m2intravenously on day 1 and 8, followed after 3 week interval by a maintenance phase with BV at 10 mg/kg i.v. and FTM 75mg/ m2 every 3 weeks until tumor progression or unacceptable toxicity. Patients had undergone clinical and MRI assessment 1 month after the start of treatment and thereafter every 2 months. The primary endpoint was progression-free survival at 6 months (PFS6), whereas secondary endpoints were response rate (RR), based on RANO criteria, progression-free (PFS) and overall survival (OS), and safety. RESULTS From April 2008 until November 2010, 54 patients (males 35, females 19, median age 57) were enrolled. PFS6, PFS12 and mPFS were 44%, 21% and 5.29 months respectively. mOS was 9.13 months with 77.4% and 31% of patients surviving at 6 and 12 months respectively. Response rates were as follows: 2CR (4%), 24 PR (44%), 22 SD (41%) and 6 PD (11%). A significant neurological improvement was observed in 57 % of patients, being steroids reduced or interrupted in 64%. 44/54 (81%) patients have progressed and patterns of progression were local in 29/44 (66%), multicentric 10/44 (23%), gliomatosis 3/44 (6%) and isolated leptomeningeal spread 2/44 (5%). 12/54 (22%) patients with grade 3/4 piastrinopenia/leukopenia discontinued fotemustine, whereas 4/54 (7.4%)discontinued bevacizumab (1 stroke, 1 intratumoral haemorrhage, 1 GI perforation and 1 pulmonary embolism). CONCLUSIONS Combination of bevacizumab and fotemustine in glioblastomas recurrent after standard radiotherapy + temozolomide is safe and promising. The analysis of MGMT methylation status is ongoing.
Introduction: neoangiogenesis has recently become a major target for the development of new antin... more Introduction: neoangiogenesis has recently become a major target for the development of new antineoplastic drugs. The most serious adverse events linked to angiogenesis inhibitors are venous or arterial thromboembolism and hemorrhage. Thus, there is a need to define with more certainty the impact of these new drugs in terms of adverse effects in neurological patients. Objective: to assess the risk of venous thromboembolism and bleeding in neuro-oncological patients treated with bevacizumab with or without concomitant anticoagulant therapy. Material and methods: a review of the literature published since 2005 was performed in Medline, from which we identified 476 records. We assessed for eligibility 27 full text articles including retrospective analyses, retrospective reviews, and open label trials. The investigated drugs included bevacizumab alone, bevacizumab plus chemotherapy with or without concomitant radiation therapy, while only two articles dealt with Bevacizumab in association with anticoagulant treatment. Results: a total of 2208 patients with brain tumor were identified and included in the analysis. Data confirmed that patients receiving bevacizumab had a major risk of developing thromboembolic events that increased progressively in association with radiotherapy and chemotherapeutic agents (4.27% vs 7,46%). Regarding bleeding, data showed that patients treated with anticoagulant had a significantly increased risk of severe intracranial bleeding (grades 3,4,5) compared to patients not receiving anticoagulant therapy (0.6% vs 8.2%). Conclusion: The use of bevacizumab combined with chemo and radiotherapy is associated with a higher risk for venous thromboembolism compared to patients receiving antiangiogenic therapy alone. The associated use of anticoagulants and Bevacizumab far increases the risk of developing an intra-extracranial bleeding, higher than grade 3, compared to patients receiving Bevacizumab alone.
ABSTRACT A variety of agents have been investigated with modest results in recurrent grade II and... more ABSTRACT A variety of agents have been investigated with modest results in recurrent grade II and III ependymomas failing surgery and/or radiotherapy. Few data are available on the role of temozolomide (TMZ). We investigated patterns of response, outcome and correlations with MGMT promoter methylation in a cohort of patients with recurrent ependymomas of the adult receiving temozolomide as salvage therapy.
Little information is available regarding the effect of conventional radiotherapy on glioma-relat... more Little information is available regarding the effect of conventional radiotherapy on glioma-related seizures. In this retrospective study, we analyzed the seizure response and outcome following conventional radiotherapy in a cohort of 43 patients with glioma (33 grade II, 10 grade III) and medically intractable epilepsy. At 3 months after radiotherapy, seizure reduction was significant (≥ 50% reduction of frequency compared with baseline) in 31/43 patients (72%) of the whole series and in 25/33 patients (76%) with grade II gliomas, whereas at 12 months seizure reduction was significant in 26/34 (76%) and in 19/25 (76%) patients, respectively. Seizure reduction was observed more often among patients displaying an objective tumor response on MRI, but patients with no change on MRI also had a significant seizure reduction. Seizure freedom (Engel class I) was achieved at 12 months in 32% of all patients and in 38% of patients with grade II tumors. Timing of radiotherapy and duration of seizures prior to radiotherapy were significantly associated with seizure reduction. This study showed that a high proportion of patients with medically intractable epilepsy from diffuse gliomas derive a significant and durable benefit from radiotherapy in terms of epilepsy control and that this positive effect is not strictly associated with tumor shrinkage as shown on MRI. Radiotherapy at tumor progression seems as effective as early radiotherapy after surgery. Prospective studies must confirm and better characterize the response to radiotherapy.
Despite advances in multidisciplinary approaches, the prognosis for most patients with malignant ... more Despite advances in multidisciplinary approaches, the prognosis for most patients with malignant gliomas is poor. Malignant gliomas are highly vascularized tumors with elevated expression of vascular endothelial growth factor (VEGF), an important mediator of angiogenesis. Recent studies of bevacizumab, an anti-VEGF monoclonal antibody, alone or associated with chemotherapy, have demonstrated high response rates and prolongation of median and 6-month progression-free survival. Clinical evaluation of several multitarget small molecule tyrosine kinase inhibitors is ongoing. Other promising antiangiogenic compounds are cilengitide and continuous temozolomide. Toxicity is acceptable. Open issues are represented by patterns of tumor progression, resistance mechanisms and biomarkers.
Angiogenesis has recently become a major target for the development of new antineoplastic drugs. ... more Angiogenesis has recently become a major target for the development of new antineoplastic drugs. The most serious adverse events linked to angiogenesis inhibitors are venous or arterial thromboembolism and haemorrhage. Thus, there is need to define with more certainty the impact of these new drugs in terms of adverse effects in neurological patients. The aim of the study is to assess the risk of venous thromboembolism (VTE) and bleeding in patients with malignant gliomas treated with bevacizumab with or without concomitant anticoagulant therapy. A review of published literature was performed in Medline, from which 476 records were identified. A total of 27 full-text articles, including retrospective analyses, retrospective reviews, and open label trials, were assessed for eligibility. The investigated drugs included bevacizumab alone, bevacizumab plus chemotherapy with/without concomitant radiation therapy; only two articles dealt with bevacizumab in association with anticoagulant treatment. A total of 2,208 patients with malignant gliomas, were identified and included in the analysis. From data it appears that patients receiving bevacizumab had a major risk of developing VTE that increased when bevacizumab is associated with radio-chemotherapy (4.27 vs 7.46 %). Regarding bleeding, data showed that patients treated with anticoagulant had a significantly increased risk of severe central nervous system (CNS) bleeding compared to patients not receiving anticoagulant therapy (0.6 vs 8.2 %). The use of bevacizumab combined with chemo-radiotherapy seems to be associated with a higher risk for VTE compared to patients receiving antiangiogenic therapy alone. The associated use of anticoagulants and bevacizumab far increases the risk of developing CNS and non-CNS bleeding higher than grade 3, compared to patients receiving bevacizumab alone.
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
To evaluate disease activity according to rituximab (RTX) induction and maintenance regimens in a... more To evaluate disease activity according to rituximab (RTX) induction and maintenance regimens in a multicenter real-life dataset of NMOSD patients. Methods: This is an observational-retrospective multicentre study including patients with NMOSD treated with RTX in 21 Italian and 1 Swiss centers. Demographics, relapse rate and adverse events over the follow-up were summarized taking into account induction strategy (two-1 g infusions at a 15-day interval (IND-A) vs. 375 mg/ m2/week infusions for one month (IND-B)) and maintenance therapy (regimen A (M-A) with fixed time-points infusions vs. regimen B (M-B) based on cytofluorimetric driven reinfusion regimens, the least further subdivided according to CD19+ B cells (M-B1) or CD27+ memory B cells (M-B2) monitoring). Results: 131 subjects were enrolled, 127 patients completed the induction regimen and 119 patients had at least one follow-up visit and were included in the outcome analysis. Median follow-up was 1.7 years (range 0.1-11.6). Annualized relapse rate (ARR) was 1.7 in the year before RTX start and decreased to 0.19 during the follow-up. Both ARR and Time to first relapse (TTFR) analysis showed a trend toward an increased disease activity for IND-B and M-A. No patients with MT-B2 experienced relapses during the follow-up. Number of relapses in the year before RTX initiation and having received a previous treatment were significantly associated with higher ARR and reduced TTFR in the multivariate analysis. Interpretation: We confirm RTX efficacy in NMOSD patients. Use of specific induction and maintenance protocols is warranted in order to foster RTX efficacy and to reduce costs and side effects.
2027 Background: Bevacizumab has shown activity in recurrent glioblastoma (GBM), and few data are... more 2027 Background: Bevacizumab has shown activity in recurrent glioblastoma (GBM), and few data are available on the combination of bevacizumab and nitrosoureas, that represent the standard cytotoxic option. Fotemustine (FTM) is a nitrosourea with elevated lipophilic properties. METHODS In this phase II study patients with GBM recurrent after surgery, radiation therapy, and concomitant/adjuvant temozolomide were elegible. The treatment consisted of an induction phase with BV at 10 mg/kg intravenously on day 1 and 15 and fotemustine (FTM) at 75mg/m2intravenously on day 1 and 8, followed after 3 week interval by a maintenance phase with BV at 10 mg/kg i.v. and FTM 75mg/ m2 every 3 weeks until tumor progression or unacceptable toxicity. Patients had undergone clinical and MRI assessment 1 month after the start of treatment and thereafter every 2 months. The primary endpoint was progression-free survival at 6 months (PFS6), whereas secondary endpoints were response rate (RR), based on RANO criteria, progression-free (PFS) and overall survival (OS), and safety. RESULTS From April 2008 until November 2010, 54 patients (males 35, females 19, median age 57) were enrolled. PFS6, PFS12 and mPFS were 44%, 21% and 5.29 months respectively. mOS was 9.13 months with 77.4% and 31% of patients surviving at 6 and 12 months respectively. Response rates were as follows: 2CR (4%), 24 PR (44%), 22 SD (41%) and 6 PD (11%). A significant neurological improvement was observed in 57 % of patients, being steroids reduced or interrupted in 64%. 44/54 (81%) patients have progressed and patterns of progression were local in 29/44 (66%), multicentric 10/44 (23%), gliomatosis 3/44 (6%) and isolated leptomeningeal spread 2/44 (5%). 12/54 (22%) patients with grade 3/4 piastrinopenia/leukopenia discontinued fotemustine, whereas 4/54 (7.4%)discontinued bevacizumab (1 stroke, 1 intratumoral haemorrhage, 1 GI perforation and 1 pulmonary embolism). CONCLUSIONS Combination of bevacizumab and fotemustine in glioblastomas recurrent after standard radiotherapy + temozolomide is safe and promising. The analysis of MGMT methylation status is ongoing.
Introduction: neoangiogenesis has recently become a major target for the development of new antin... more Introduction: neoangiogenesis has recently become a major target for the development of new antineoplastic drugs. The most serious adverse events linked to angiogenesis inhibitors are venous or arterial thromboembolism and hemorrhage. Thus, there is a need to define with more certainty the impact of these new drugs in terms of adverse effects in neurological patients. Objective: to assess the risk of venous thromboembolism and bleeding in neuro-oncological patients treated with bevacizumab with or without concomitant anticoagulant therapy. Material and methods: a review of the literature published since 2005 was performed in Medline, from which we identified 476 records. We assessed for eligibility 27 full text articles including retrospective analyses, retrospective reviews, and open label trials. The investigated drugs included bevacizumab alone, bevacizumab plus chemotherapy with or without concomitant radiation therapy, while only two articles dealt with Bevacizumab in association with anticoagulant treatment. Results: a total of 2208 patients with brain tumor were identified and included in the analysis. Data confirmed that patients receiving bevacizumab had a major risk of developing thromboembolic events that increased progressively in association with radiotherapy and chemotherapeutic agents (4.27% vs 7,46%). Regarding bleeding, data showed that patients treated with anticoagulant had a significantly increased risk of severe intracranial bleeding (grades 3,4,5) compared to patients not receiving anticoagulant therapy (0.6% vs 8.2%). Conclusion: The use of bevacizumab combined with chemo and radiotherapy is associated with a higher risk for venous thromboembolism compared to patients receiving antiangiogenic therapy alone. The associated use of anticoagulants and Bevacizumab far increases the risk of developing an intra-extracranial bleeding, higher than grade 3, compared to patients receiving Bevacizumab alone.
ABSTRACT A variety of agents have been investigated with modest results in recurrent grade II and... more ABSTRACT A variety of agents have been investigated with modest results in recurrent grade II and III ependymomas failing surgery and/or radiotherapy. Few data are available on the role of temozolomide (TMZ). We investigated patterns of response, outcome and correlations with MGMT promoter methylation in a cohort of patients with recurrent ependymomas of the adult receiving temozolomide as salvage therapy.
Little information is available regarding the effect of conventional radiotherapy on glioma-relat... more Little information is available regarding the effect of conventional radiotherapy on glioma-related seizures. In this retrospective study, we analyzed the seizure response and outcome following conventional radiotherapy in a cohort of 43 patients with glioma (33 grade II, 10 grade III) and medically intractable epilepsy. At 3 months after radiotherapy, seizure reduction was significant (≥ 50% reduction of frequency compared with baseline) in 31/43 patients (72%) of the whole series and in 25/33 patients (76%) with grade II gliomas, whereas at 12 months seizure reduction was significant in 26/34 (76%) and in 19/25 (76%) patients, respectively. Seizure reduction was observed more often among patients displaying an objective tumor response on MRI, but patients with no change on MRI also had a significant seizure reduction. Seizure freedom (Engel class I) was achieved at 12 months in 32% of all patients and in 38% of patients with grade II tumors. Timing of radiotherapy and duration of seizures prior to radiotherapy were significantly associated with seizure reduction. This study showed that a high proportion of patients with medically intractable epilepsy from diffuse gliomas derive a significant and durable benefit from radiotherapy in terms of epilepsy control and that this positive effect is not strictly associated with tumor shrinkage as shown on MRI. Radiotherapy at tumor progression seems as effective as early radiotherapy after surgery. Prospective studies must confirm and better characterize the response to radiotherapy.
Despite advances in multidisciplinary approaches, the prognosis for most patients with malignant ... more Despite advances in multidisciplinary approaches, the prognosis for most patients with malignant gliomas is poor. Malignant gliomas are highly vascularized tumors with elevated expression of vascular endothelial growth factor (VEGF), an important mediator of angiogenesis. Recent studies of bevacizumab, an anti-VEGF monoclonal antibody, alone or associated with chemotherapy, have demonstrated high response rates and prolongation of median and 6-month progression-free survival. Clinical evaluation of several multitarget small molecule tyrosine kinase inhibitors is ongoing. Other promising antiangiogenic compounds are cilengitide and continuous temozolomide. Toxicity is acceptable. Open issues are represented by patterns of tumor progression, resistance mechanisms and biomarkers.
Angiogenesis has recently become a major target for the development of new antineoplastic drugs. ... more Angiogenesis has recently become a major target for the development of new antineoplastic drugs. The most serious adverse events linked to angiogenesis inhibitors are venous or arterial thromboembolism and haemorrhage. Thus, there is need to define with more certainty the impact of these new drugs in terms of adverse effects in neurological patients. The aim of the study is to assess the risk of venous thromboembolism (VTE) and bleeding in patients with malignant gliomas treated with bevacizumab with or without concomitant anticoagulant therapy. A review of published literature was performed in Medline, from which 476 records were identified. A total of 27 full-text articles, including retrospective analyses, retrospective reviews, and open label trials, were assessed for eligibility. The investigated drugs included bevacizumab alone, bevacizumab plus chemotherapy with/without concomitant radiation therapy; only two articles dealt with bevacizumab in association with anticoagulant treatment. A total of 2,208 patients with malignant gliomas, were identified and included in the analysis. From data it appears that patients receiving bevacizumab had a major risk of developing VTE that increased when bevacizumab is associated with radio-chemotherapy (4.27 vs 7.46 %). Regarding bleeding, data showed that patients treated with anticoagulant had a significantly increased risk of severe central nervous system (CNS) bleeding compared to patients not receiving anticoagulant therapy (0.6 vs 8.2 %). The use of bevacizumab combined with chemo-radiotherapy seems to be associated with a higher risk for VTE compared to patients receiving antiangiogenic therapy alone. The associated use of anticoagulants and bevacizumab far increases the risk of developing CNS and non-CNS bleeding higher than grade 3, compared to patients receiving bevacizumab alone.
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