A. Botturi

Salvage chemotherapy with procarbazine and fotemustine combination in the treatment of temozolomide treated recurrent glioblastoma patients

The purpose of this study was to evaluate safety and efficacy of Procarbazine (PCB) and fotemustine (FTM) combination in the treatment of pre-temozolomide treated, recurrent GBM patients. The primary end-point was progression free survival at 6xa0months (PFS-6). Secondary end-points were overall survival, response rates (CRxa0+xa0PR) and toxicity. About 54 patients (41 men and 13 women) aged 26–68xa0years (median age, 53.5xa0years) with recurrent GBM were treated. PCB was administered as an oral dosage of 450xa0mg on days 1–2 and a total dose of 300xa0mg on day 3. FTM was administered on day 3, 3xa0h after the last PCB intake at a dose of 110xa0mg/mq/BSA. The treatment was repeated every 5xa0weeks. Treatment was continued for a maximum of six cycles or until disease progression. After two cycles of chemotherapy: 6 patients (11.2%) experienced a neuroradiographic partial response (PR), 29 patients (53.7%) had stable disease (SD), and 19 patients (35.1%) had progressive disease (PD). For the whole group of patients, the median PFS was 19.3xa0weeks (95% CI, 14.1–24.4xa0weeks), and PFS-6 was 26.7% (95% CI, 10.6–42.8%). Overall MST from the beginning of PCBxa0+xa0FTM chemotherapy was 28.7xa0weeks (95% CI, 24.8–32.7xa0weeks). At 6 and 12xa0months, 64.4% (95% CI, 51.5–77.3%) and 23.6% (95% CI, 10.1–37.1%) of patients were alive. The median survival time calculated from the first diagnosis was 20.8xa0months (95% CI, 16.7–24.8). We concluded that the PCBxa0+xa0FTM combination as done in the current trial for patients with recurrent GBM after treatment with TMZ showed some benefit with regards to increased survival and that a Phase III trial is warranted.

The burden of brain tumor: a single-institution study on psychological patterns in caregivers

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.

Treatment of recurrent glioblastoma: can local delivery of mitoxantrone improve survival?

In this study, the records of 276 adult patients with recurrent glioblastoma (GBM) treated at recurrence at our institution between 2004 and 2006 were reviewed for progression-free survival (PFS), overall survival (OS), and toxicity. At recurrence, all patients underwent systemic treatment with temozolomide (200xa0mg/sqm on days 1–5 every 28xa0days) until tumor progression. Patients, whose tumor was judged resectable without risk of adjunctive neurological deficit, underwent a second surgery with or without positioning of a Rickam/Ommaya reservoir. The reservoir was used for locoregional chemotherapy with mitoxantrone. Two hundred seventy-six rGBL patients (pts) were divided into three subgroups: A 161xa0pts treated only with temozolomide, B 50xa0pts re-operated-on +temozolomide, and C 65xa0pts re-operated on +xa0temozolomidexa0+xa0locoregional CHT. For group A, the 6xa0month PFS and 6xa0month survival (ST) were 39.3 and 43%, respectively, with a median survival time (mST) of 5xa0months (range 4–6) and 25% of pts alive at 9xa0months. For group B, the 6xa0month PFS and 6xa0month survivors were 64 and 74.1%, respectively, with a mST of 8xa0months (range 6–10) and 25% of pts alive at 12xa0months. For group C, the 6xa0month PFS and 6xa0month survivors were 70.7 and 87.7%, respectively, with a mST of 11xa0months (range 9–13) and 25% of pts alive at 18xa0months (A vs. B vs. C, log-rank Pxa0<xa00.001) (B vs. C, Pxa0=xa00.041) (A vs. B Pxa0=xa00.009). Cox proportional hazard model was used to obtain Hazard Ratio (HR) for type of treatment corrected by age and time (in months) between diagnosis and first recurrence: second tumor debulking was statistically effective for survival, reducing by 36% the risk of death (HRxa0=xa00.64; 0.46–0.89), but the most significant favorable prognostic factor for survival was the local delivery of mitoxantrone which reduced the risk of death to 50% (HRxa0=xa00.50; 0.38–0.68).

Recurrent brain tumour: the impact of illness on patient's life

PurposeDespite 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.MethodWe 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” (FACT-Br), “Hospital Anxiety and Depression Scale” and “Psychological Distress Inventory”. These were all used as tests of psychological well-being.ResultsDistress 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.ConclusionsApparent 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.

Multidrug resistance proteins expression in glioma patients with epilepsy

Epilepsy occurs in glioma, especially in low-grade glioma (LGG), but also in glioblastoma (GBM). In about 20xa0% of patients pharmacological treatment with anti-epileptic drugs (AEDs) fails. Refractory epilepsy is a multifactorial phenomenon not yet completely understood. The multidrug resistance phenotype was initially associated to P-glycoprotein (Pgp), an ATP-dependent transporter belonging to the same superfamily of multidrug resistance-associated proteins (MRPs). Glutathione-S-transferase-π (GST-π) is also involved in refractory epilepsy. In the present work we investigated the expression of Pgp, MRP1, MRP3 and GST-π in surgical specimens obtained from 35 patients with glioma and epilepsy. We observed MRP1 expression in tumor and endothelial cells (EC), MRP3 and Pgp expression mainly in ECs and GST-π predominantly in tumor cells (TC). MRP1 and MRP3 were more expressed in high grade glioma (HGG) than in LGG. In 6 cases we could compare tumor and periphery detecting the same MRP1 and Pgp expression, while MRP3 was mainly expressed in the tumor. We observed a trend of a better outcome in seizure control associated with a lower expression of MRP1 and MRP3. MRP3 was statistically more expressed in TCs of HGG than LGG (pxa0=xa00.0401) and more expressed in tumor than in periphery, in agreement with recent works that identify MRP3 as a potential target in GBM. Moreover, MRP3 was investigated in association with refractory epilepsy for the first time in our study and it was less expressed in patients with complete response to AEDs (pxa0=xa00.0550). Our preliminary data show an association between multidrug resistance transporters and refractory epilepsy in glioma.

Local drug delivery in recurrent malignant gliomas

In recurrent malignant gliomas, we scheduled a protocol by adding to systemic temozolomide a local treatment delivered through a reservoire positioned in the surgically created cavity, consisting of either mitoxantrone, liposome-loaded doxorubicine or nimustine (ACNU). The progression—free survival (PFS) and survival time (ST) of the whole group of 112 patients were 8.3 and 11 months, respectively, in GBM patients, and 14 and 18 months in AA patients. To limit the selection bias in recruitment we matched locally treated patients with the whole group of patients treated for 3 years and having undergone the same protocol with the exception of local drug delivery. Variables such as age, histology and local chemotherapy delivery were proved to be statistically significant independent factors on adjunctive PFS and ST. Another group of 12 recurrent malignant gliomas with further progression was locally managed according to convection-enhanced delivery (CED) of mitoxantrone; the preliminary results show good tolerability of the schedule.

Systemic sagopilone (ZK-EPO) treatment of patients with recurrent malignant gliomas

It has been demonstrated that sagopilone (ZK-EPO) has antitumor activity in human orthotopic glioma models inxa0vitro and inxa0vivo. 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, and ≥2 lines of alkylating chemotherapy were recruited. ZK-EPO (16xa0mg/m2) was administered iv for 3xa0h every 21xa0days. 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 13xa0weeks. 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.

Meningitis following relapsing painful ophthalmoplegia in aspergillus sphenoidal sinusitis: a case report

We report the case of a 58-year-old woman in whom relapsing painful ophthalmoplegia related to a mycetoma of the sphenoid sinus gave origin to meningitis with markedly depressed glucose levels in the cerebrospinal fluid. Surgical exeresis of the mycetoma allowed aetiological diagnosis (aspergillosis) and—together with antimycotic therapy—led to durable clinical response.

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

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

A novel mutation in the GFAP gene in a familial adult onset Alexander disease

Sirs: Alexander disease is a neurodegenerative disease, belonging to the group of demyelinating disorders [1], which may have its onset in infantile, juvenile or adult age [2, 3]. Infancy-onset cases show megalencephaly, loss/delay of developmental milestones and evolution to mental defficiency and spastic tetraparesis, leading to death in a few years. Patients with onset at a juvenile age generally show bulbar involvement, together with lower limb paraparesis and ataxia, mild cognitive impairment and variable survival. Adult-onset Alexander disease is very rare, with slow progression and a clinical course that may be reminiscent of multiple sclerosis [4]; in some cases, palatal myoclonus has been described [5]. Recurrent cases of Alexander disease have been reported only in a very few families [6]. Disease pathology includes widespread destruction of the white matter with a huge number of intracytoplasmic astrocytic inclusions (Rosenthal fibers) in the glia limitans and periventricular areas, as well as in the brainstem (medulla) and in the optic nerve [7]; the filaments contain GFAP and vimentin [8]. Alterations of the GFAP gene have been reported in 90% of cases subjected to molecular analysis [4, 9]. We describe an Italian family with adult onset Alexander disease and occurrence of a novel GFAP mutation. A 35-year old female presented with a two years history of progressive lower paraparesis, dysarthria and dysphagia. The patient’s mother had died at 49 after a strikingly similar 15-year neurological disease(Fig. 1). Neurological examination showed spastic paraparesis, bilateral Babinski sign, tetrahyperreflexia, dysphagia and pseudobulbar speech. EMG/ENG, EEG and psychometric assessment (M.O.D.A., Milan Overall Dementia Assessment) were normal. MRI showed T2 hyperintensity in bulbar tegmentum, olivary nuclei, superior cerebellar peduncles, dentate nuclei and frontal periventricular white matter (Fig. 2), with slight cervical atrophy. Lysosomal enzyme activity (arylsulphatase A, beta-hexosaminidase, cerebrosidase), Complete CSF analysis, autoimmune tests and serum lactate levels were normal. Molecular analysis of the proband’s DNA, performed by direct sequencing of the whole gene coding region as already reported (Caroli et al., submitted), showed a novel mutation of the GFAP gene (c1178G>T). This finding was not observed in 50 population matched control individuals (100 chromosomes). In our patient, 3 of the 5 MRI criteria reported by Van der Knaap [10] were present, i.e signal hyperintensity in T2-weighted images in the periventricular frontal white matter, swelling and T2-signal hyperintensity in the caudate nuclei, and alterations in the brainstem. The patient’s son (aged 6) at age 2 showed bilateral myoclonic jerks involving the upper limbs, followed, at age 5, by a generalized tonic-clonic seizure and ataxia lasting for a few days; EEG showed subcontinuous paroxysmal spikeswaves and polyspikes on the anterior regions of the hemispheres. Laboratory screening for organic acidurias and brain MRI were negative. The child displays only slight ataxia at neurological follow-up. The c1178G>T mutation found in the mother was also detected in the son; clinical variability can be observed among patients with the same mutation, and modifying genes and other factors may be involved. Although we cannot definitely state the pathogenic role of the mutation detected in our patient, her family history, including a symptomatic mother, and the occeurrence of the mutation in the already mildly symptomatic son (seizures and ataxia have been reported in childhood Alexander’s disease) suggest a diagnosis of adult dominant Alexander disease. In addition, the codon involved in Dr. A. Salmaggi (&) Æ A. Botturi E. Lamperti Æ M. Grisoli Æ A. Boiardi Istituto Neurologico C. Besta Via Celoria 11 20133 Milano, Italy E-Mail: salmaggi@istituto-besta.it