Veronica Biassoni, Maura Massimino, Maria Chiara Oprandi, Carlo Alfredo Clerici, Laura Veneroni, Claudia Corti, Elisabetta Schiavello, Filippo Spreafico & Geraldina Poggi
Rehabilitation for children and young people surviving a brain tumor, and their transition to adult services: the main challenges
Expert Review of Quality of Life in Cancer Care, 2017
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Andrea Anichini
Determinazione della presenza, dei livelli, e della loro evoluzione temporale, in relazione alla terapia, di un ampio spettro di molecole solubili (n=26), appartenenti alle famiglie dei fattori di crescita nei DIPG
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Maura Massimino MD, Veronica Biassoni MD, Rosalba Miceli MD, Elisabetta Schiavello MD, Monika Warmuth – Metz MD, Piergiorgio Modena PhD, Michela Casanova MD, Emilia Pecori MD, Felice Ginagaspero MD, Manila Antonelli MD, Francesca Romana Buttarelli PhD, Paolo Potepan MD, Bianca Pollo MD, Raffaele Nunziata MD, Filippo Spreafico MD, Marta Podda MD, Andrea Anichini PhD, Carlo Alfredo Clerici MD, Iacopo Sardi MD, Loris De Cecco PhD, Udo Bode MD, Ferdinand Bach PhD, and Lorenza Gandola MD.
Results of nimotuzumab and vinolrebine, radiation and re-irradiation for diffuse pontine glioma in childhood
Journal of Neuro-oncology 2014, april 7.
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Giangaspero F.

Brain tumours are the main cause of death due to malignant neoplasia in children. Childhood high-grade gliomas identified with the terms anaplastic astrocytoma and glioblastoma, are 15% of all pediatric brain tumours and have high morbidity and survival rate at three years is less than 20%.
Most of our knowledge concerns malignant gliomas in adults, in particular the glioblastoma (GBM) which is the most frequent primitive neoplasia of the central nervous system.
Recent studies on GBM gene expression in adults, helped to identify oncogenetic molecular events and to
stratify patients into prognostic groups. That is to say, the presence or not of some molecular alterations which enable us to predict the more or less aggressive clinical behaviour of these neoplasms. Childhood GBM are histologically similar to those in adults, but have different molecular features.
Our research projects are aimed at characterizing childhood malignant gliomas. Our results show that molecular mechanisms involved in gliomagenesis and progression are different from those in adults. We observed in particular that, differently from what happens in adults, in which mutation of the oncosuppressor gene p53 has no effect on the clinical trend, in childhood neoplasias TP53 gene mutations are associated to reduced survival.
We have also studied protein YKL-40 expression in child tumours that in adults is associated with a worse
response to radiotherapy and shorter overall survival. Our results showed that the expression of such protein in childhood malignant gliomas is very common but has no effect on prognosis.
Likewise, our studies as well as those of other groups show that IDH1 mutations, present in 80% of glial neoplasias in adults, are practically absent in childhood (Antonelli et al. Prognostic significance of histological grading, p53 status, YKL- 40 expression, and IDH1 mutations in pediatric high grade gliomas, Journal of Neuro-Oncology, in press). Another study we carried out aimed at assessing MGMT mutation in pediatric gliomas. When such gene is inactivated, chemotherapic agents act more effectively on tumour cells. Inactivation of this gene in adult gliomas has proven to be a favourable event with a considerable increase in survival. Our research on pediatric gliomas shows that gene MGMT inactivation is less frequent than in the adult and its correlation with response to treatment is not statistically significant (Buttarelli et al. Evaluation status and prognostic significance of MGMT in pediatric high grade gliomas, submitted).
The results of these studies together with those of others in literature strengthen the concept that, despite histological similarities, molecular mechanisms involved in the pathogenesis and neoplastic progression seem to be totally different in the two age groups. While knowledge of these tumours in adults is advanced, in childhood it is still very scarce. It should be pointed out that understanding such mechanisms is the first step towards the definition of new therapies based on specific molecular targets.
Our future research aims to study the expression of molecules involved in the activation of Ras and Akt molecular pathways which are involved in controlling cell growth, differentiation, and survival. Preliminary results highlight a different behaviour between tumors in which these pathways are activated and those in which activation is absent.

Prof. Felice Giangaspero
Laboratorio Neuropatologia
Policlinico Umberto I, Roma
Università Sapienza Roma
Viale del Policlinico, 155, 00197 Roma
Tel/fax: +390649979175
E mail: felice.giangaspero@uniroma1.it

Iacopo Sardi, *Giancarlo la Marca, *Maria Grazia Giovannini, °Sabrina Malvagia, °Renzo Guerrini, °Lorenzo Genitori, ^Maura Massimino, Maurizio Aricò

Department of Onco-Hematology, Meyer Children’s Hospital, Florence Italy
*Department of Pharmacology, University of Florence Italy
°Department of Neuroscience, Meyer Children’s Hospital, Florence Italy
^Department of Pediatrics, IRCCS Foundation, National Cancer Institute, Milan, Italy

The blood brain barrier discriminates the access of several molecules into the brain. This hampers the use of some drugs, as doxorubicin, potentially active for treatment of brain tumors. We explored the feasibility of active modification of the blood brain barrier protection, by using morphine pretreatment, to allow doxorubicin accumulation into the brain in an animal model. Rats were pretreated with different doses of intraperitoneal morphine before injection of doxorubicin (12 mg/kg). Quantitative analysis of doxorubicin was performed by mass spectrometry. Acute hearth and kidney damage was analyzed by measuring doxorubicin accumulation, LDH activity and malondialdehyde plasma levels. The concentration of doxorubicin was significantly higher in all brain areas of rats pretreated with morphine than in control tissues (P <0.001). This was evident only at therapeutic morphine dose (10 mg/kg, three times over 24 hours), while lower doses (2.5 and 5 mg/kg) were not associated with doxorubicin accumulation. Pretreatment with morphine did not induce an elevation of LDH activity or of lipid peroxidation compared to controls. Our data suggest that morphine pre-treatment is able to allow doxorubicin penetration inside the brain, by modulating the blood-brain barrier. This is not associated with acute cardiac or renal toxicity. These preliminary results will enable us to generate novel therapeutic approaches to refractory or recurrent brain tumors, and might be useful in other human diseases of the central nervous system in which molecules usually stopped by the blood brain barrier may have a therapeutic impact.

Finocchiaro G.

Current standard treatment of glioblastoma multiforme (GBM) is based on the surgical resection of the tumour mass followed by radio- and chemotherapy (Stupp et al., 2005). In spite of novel therapeutic approaches, the prognosis remains dismal and relapse is almost inevitable. We thus clearly need to produce long term, well tolerated and tumourspecific treatments able to eliminate the (remaining) tumour cells infiltrated in the nearby brain areas.
The immune system provides important tools in this direction. Preclinical trials for the development of vaccines against high-grade gliomas, based on the use of potent immune cells i.e. dendritic cells, exposed to a mix of tumour antigens deriving from the glioma (Pellegatta et al., 2005 and 2006), have been carried out in both rat models (Liau et al., 1999; Siesjo et al., 1996; Witham et al., 2002) and mouse models (Akasaki et al., 2001; Heimberger et al., 2000; Insug et al., 2002; Kikuchi et al., 2002; Ni et al., 2001; Okada et al., 1998), showing their capacity to produce a tumour-specific immune response.
Mature DC with autologous tumour lysate have been used to treat patients with relapsed malignant tumours (De Vleeschouwer et al., 2004; Rutkowski et al., 2004; Wheeler et al., 2004; Yamanaka et al., 2003; Yu et al., 2004); no significant adverse effects have been reported. In Italy we have been able to repeat this experience with the treatment of six patients affected by relapsing GBM, using dendritic cells prepared at the Istituto Neurologico Besta. Median survival of these patients from time of relapse is currently of 11,5 months (Finocchiaro et al, manuscript in preparation).
The results of the use of immunotherapy on GBM patients are promising, but further investigation is necessary to identify a safe and more effective combination of immunotherapy with radio- and chemotherapy after tumour resection.

Dott. Gaetano Finocchiaro, M.D.

Director, Unit Neurology 8- Molecular Neuro-Oncology
Director, Department of Neuro-Oncology
Fondazione IRCCS Istituto Neurologico Besta
via Celoria 11, 20133 Milano
Phone +39 02 2394 2769
fax +39 02 2394 2453

Group-leader IFOM-IEO Campus
via Adamello 16, 20139 Milano
Phone +39 02 9437 5113

E mail: finocchiaro@istituto-besta.it

Salsano E.

Medulloblastoma (MB) is the most frequent brain tumour in children. Despite the advances in surgery, radiotherapy and chemoterapy, mortality rate at 5 years is still 50-70% of cases and many children who survive, show damages affecting the central nervous system and other organs due to the adverse effects of the therapies.
The key aim of our project is to generate human medulloblastoma cell lines which can be as faithful as possible to the medulloblastomas they derive from, enabling in this way the creation of a useful in vitro model to study the pathogenesis of the tumour and to find more efficient and targeted therapeutic approaches. To date, obtaining medulloblastoma line cells from the correspondent primary tumour is not easy and the few medulloblastoma cell lines available seem not to be very representative of the tumours they derive from. For example, the DAOY, a cell line commonly used to investigate in vitro the biology of medulloblastomas and to prove the effectiveness of antimedulloblastoma chemiotherapic agents, shows a deletion of the oncosuppressor gene CDNK2A, a non-documented biological feature in human medulloblastomas.
To reach the aim of the project, we try to express a dominant-negative form of the oncosuppressor gene TP53 in human medulloblastoma cells obtained from surgical samples. In fact TP53 was mutated in the most malignant and rare form of medulloblastoma, the so called anaplastic medulloblastoma, and this mutation could be necessary to generate immortalized medulloblastoma cells in vitro, as we observed in our laboratory.
The project should permit to assess: 1) whether and how it is possible to introduce and express genetic material in primary human medulloblastoma cells in vitro; 2) whether TP53 mutations are able to immortalize these tumor cells (normally unable to survive in vitro for more than a few passages).
We suppose that this approach might be a novel strategy to routinely establish human medulloblastoma cell lines, useful for both in vitro and in vivo investigations (the latter after being implanted into laboratory animals).

Dr. Ettore Salsano
Unità Operativa Neurologia 8-Neuro-Oncologia molecolare
Fondazione IRCCS, Istituto Neurologico Carlo Besta
Via Celoria 11, 20133 Milano, Italia
T. +39.02.2394.2285; F. +39.02.2394.2453
E mail: ettore.salsano@istituto-besta.it