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The post-operative pediatric cerebellar mutism syndrome (CMS) affects about one-third of children and adolescents following surgical removal of a posterior fossa tumor (PFT). According to the Posterior Fossa Society consensus working definition, CMS is characterized by delayed-onset mutism/reduced speech and emotional lability after cerebellar or 4th ventricle tumor surgery in children, and is frequently accompanied by additional features such as hypotonia and oropharyngeal dysfunction/dysphagia. The main objective of this work was to develop a diagnostic scale to grade CMS duration and severity. Thirty consecutively referred subjects, aged 1–17 years (median 8 years, IQR 3–10), were evaluated with the proposed Post-Operative Pediatric CMS Survey after surgical resection of a PFT and, in case of CMS, for 30 days after the onset (T0) or until symptom remission. At day 30 (T1), CMS was classified into mild, moderate, or severe according to the proposed scale. CMS occurred in 13 patients (43%, 95% C.I.: 25.5–62.6%), with mild severity in 4 cases (31%), moderate in 4 (31%), and severe in 5 (38%). At T1, longer symptom persistence was associated with greater severity (p = 0.01). Greater severity at T0 predicted greater severity at T1 (p = 0.0001). Children with a midline tumor location and those aged under 5 years at diagnosis were at higher risk of CMS (p = 0.025 and p = 0.008, respectively). In conclusion, the proposed scale is a simple and applicable tool for estimating the severity of CMS at its onset, monitoring its course over time, and providing an early prognostic stratification to guide treatment decisions. What is Known:• Post-operative pediatric Cerebellar Mutism Syndrome (CMS) is a complex phenomenon with a wide spectrum of symptoms that may manifest in children undergoing the resection of a posterior fossa tumor (PFT) and that can result into long-term impairment. What is New:• This study developed and pilot-tested an easily applicable diagnostic and severity scale to grade the duration and the severity of symptoms of the CMS.• The proposed scale was found to be a sensitive instrument to identify even mild CMS presentations.• By scoring not only the duration but also the severity of symptoms the scale allows a more accurate prognostic stratification for an optimal planning of clinical and rehabilitative interventions.

Lateralized/segmental overgrowth disorders (LOs) encompass a heterogeneous group of congenital conditions with excessive body tissue growth. Documented molecular alterations in LOs mostly consist of somatic variants in genes of the PI3KCA/AKT/mTOR pathway or of chromosome band 11p15.5 imprinted region anomalies. In some cases, somatic pathogenic variants in genes of the RAS/MAPK pathway have been reported. We present the first case of a somatic pathogenic variant (T507K) in PTPN11 causing a LO phenotype characterized by severe lateralized overgrowth, vascular proliferation, and cerebral astrocytoma. The T507K variant was detected in DNA from overgrown tissue in a leg with capillary malformation. The astrocytoma tissue showed a higher PTPN11 variant allele frequency. A pathogenic variant in FGFR1 was also found in tumor tissue, representing a second hit on the RAS/MAPK pathway. These findings indicate that RAS/MAPK cascade overactivation can cause mosaic overgrowth phenotypes resembling PIK3CA-related overgrowth disorders (PROS) with cancer predisposition and are consistent with the hypothesis that RAS/MAPK hyperactivation can be involved in the pathogenesis of astrocytoma. This observation raises the issue of cancer predisposition in patients with RAS/MAPK pathway gene variants and expands genotype spectrum of LOs and the treatment options for similar cases through inhibition of the RAS/MAPK oversignaling.

In Italy, 1400 children and 800 adolescents are diagnosed with cancer every year. About 80% of them can be cured but are at high risk of experiencing severe side effects, many of which respond to rehabilitation treatment. Due to the paucity of literature on this topic, the Italian Association of Pediatric Hematology and Oncology organized a Consensus Conference on the role of rehabilitation of motor impairments in children/adolescents affected by leukemia, central nervous system tumors, and bone cancer to state recommendations to improve clinical practice. This paper includes the results on the rehabilitation treatment.

Background A prospective 2002–2014 study stratified 160 patients by resection extent and histological grade, reporting results in 2016. We re-analyzed the series after a median of 119 months, adding retrospectively patients’ molecular features. Methods Follow-up of all patients was updated. DNA copy number analysis and gene-fusion detection could be completed for 94/160 patients, methylation classification for 68. Results Progression-free survival (PFS) and overall survival (OS) at 5/10 years were 66/58%, and 80/73%. Ten patients had late relapses (range 66–126 mo), surviving after relapse no longer than those relapsing earlier (0–5 y). On multivariable analysis a better PFS was associated with grade II tumor and complete surgery at diagnosis and/or at radiotherapy; female sex and complete resection showed a positive association with OS. Posterior fossa (PF) tumors scoring ≥0.80 on DNA methylation analysis were classified as PFA (n = 41) and PFB (n = 9). PFB patients had better PFS and OS. Eighteen/32 supratentorial tumors were classified as RELA, and 3 as other molecular entities (anaplastic PXA, LGG MYB, HGNET). RELA had no prognostic impact. Patients with 1q gain or cyclin-dependent kinase inhibitor 2A (CDKN2A) loss had worse outcomes, included significantly more patients >3 years old (P = 0.050) and cases of dissemination at relapse (P = 0.007). Conclusions Previously described prognostic factors were confirmed at 10-year follow-up. Late relapses occurred in 6.2% of patients. Specific molecular features may affect outcome: PFB patients had a very good prognosis; 1q gain and CDKN2A loss were associated with dissemination. To draw reliable conclusions, modern ependymoma trials need to combine diagnostics with molecular risk stratification and long-term follow-up.

Background More than 40% of patients with intracranial ependymoma need a salvage treatment within 5 years after diagnosis, and no standard treatment is available as yet. We report the outcome after first relapse of 64 patients treated within the 2nd AIEOP protocol. Methods We considered relapse sites and treatments, that is, various combinations of complete/incomplete surgery, if followed by standard or hypofractionated radiotherapy (RT) ± chemotherapy (CT). Molecular analyses were available for 38/64 samples obtained at first diagnosis. Of the 64 cases, 55 were suitable for subsequent analyses. Results The median follow-up was 147 months after diagnosis, 84 months after first relapse, 5-year EFS/OS were 26.2%/30.8% (median EFS/OS 13/32 months) after relapse. For patients with a local relapse (LR), the 5-year cumulative incidence of second LRs was 51.6%, with a 5-year event-specific probability of being LR-free of 40.0%. Tumor site/grade, need for shunting, age above/below 3 years, molecular subgroup at diagnosis, had no influence on outcomes. Due to variation in the RT dose/fractionation used and the subgroup sizes, it was not possible to assess the impact of the different RT modalities. Multivariable analyses identified completion of surgery, the absence of symptoms at relapse, and female sex as prognostically favorable. Tumors with a 1q gain carried a higher cumulative incidence of dissemination after first relapse. Conclusions Survival after recurrence was significantly influenced by symptoms and completeness of surgery. Only a homogeneous protocol with well-posed, randomized questions could clarify the numerous issues, orient salvage treatment, and ameliorate prognosis for this group of patients.

Few reports exist about reirradiation (RT2) for recurrent brain tumors in pediatric patients.A monocentric retrospective analysis of 22 patients with reirradiated CNS neoplasms was conducted with the objective to describe clinical outcomes and toxicities associated with RT2. Median age at diagnosis and RT2 was 8.5 years and 11.5 years respectively. Primary diagnoses included ependymoma (n=7, 32%), medulloblastoma (n=5, 23%), DIPG (n=4, 18%), glioblastoma (N=2, 9%), and others (N=4, 18%). The median interval between the first radiotherapy and RT2 was 16.5 months. Two patients underwent in-field RT2 for a secondary tumor. RT2 was administered with a curative intent in 13 patients, with a palliative-only treatment in the remaining 9. Sixteen patients received brain RT2 and 3 patients spine RT2, with a median cumulative dose of 19.9 Gy and 30 Gy respectively. Three patients received combined RT2. Volumetric Modulated Arc Therapy(VMAT) was the most frequent technique used (60%). Eight patients showed neurological symptoms before RT2, 6 had clinical benefit with RT2. Among patients who were asymptomatic before RT2, 5 later showed progressive neurological symptoms (at least partly attributable to RT2). Radionecrosis was radiologically detected in 6 patients, but accompanied by symptoms only in 3. Median event-free survival (EFS) and overall survival(OS) after RT2 was 4.7 and 8.7 months respectively, similarly to previous results. One-year EFS and OS was 13% and 36% respectively. As previously reported, OS appeared to be longer for patients with >12 months elapsed time between first irradiation and RT2 (1-year OS=45% versus 0%, p=0.07). In our cohort RT2 appeared feasible and provided short-term disease control with tolerable short-term toxicity, while providing relief in most symptomatic patients. Larger prospective studies are needed to understand which subsets of patients may benefit from either curative or palliative reirradiation, to provide respectively a longer survival and a significantly improved symptom control.

BACKGROUND: The post-operative Pediatric Cerebellar Mutism Syndrome (CMS) affects about one-third of children and adolescents following surgical removal of a posterior fossa tumor (PFT). According to the Posterior Fossa Society consensus working definition, CMS is characterized by delayed onset mutism/reduced speech and emotional lability after cerebellar or 4th ventricle tumor surgery in children, with additional common features that include hypotonia and oropharyngeal dysfunction/dysphagia. The main objective of this work was to propose a diagnostic scale to grade CMS duration and severity.METHOD: Thirty consecutive subjects, aged 1-17 years (median 8 years, IQR 7) were evaluated with the proposed Post-Operative Pediatric CMS Survey after surgical resection of a PFT and, in cases of CMS, for the next 30 days after the onset (T0) or until symptom remission. At day 30th (T1), CMS was classified into mild, moderate, or severe according to the proposed Scale.RESULTS: CMS occurred in 13 patients (43.3%, 95% C.I.: 25.5-62.6%), with mild severity in 4 cases (31%), moderate in 4 (31%), and severe in 5 (38%). At T1, longer symptom persistence was associated with greater severity (p=0.01). Greater severity at T0 predicted greater severity at T1 (p=0.0001). Children with a midline tumor location and those aged under 5 years at diagnosis were at higher risk of CMS (p=0.025 and p=0.008, respectively).CONCLUSIONS: The proposed scale is a simple and applicable tool for estimating the severity of CMS at its onset, monitoring its course over time, and providing an early prognostic stratification to guide treatment decisions.

Because of increasing survival rates in pediatric oncology, attention is focusing on cancer and its treatment-related side effects. Rehabilitation may reduce their impact. However, the literature does not provide strong evidence regarding rehabilitation pathways. Therefore, the Italian Association of Pediatric Hematology and Oncology organized a consensus conference on the role of rehabilitation of motor impairments in children/adolescents affected by leukemia, central nervous system, and bone tumors to define recommendations for daily practice. The grading of recommendation assessment, developing and evaluation (GRADE) method was used in order to formulate questions, select outcomes, evaluate evidence, and create recommendations. This paper includes the results on the rehabilitation assessment.

BACKGROUND This 2002–2014 Italian prospective study stratified 160 patients by surgical resection (complete=NED/incomplete=ED) and centrally-reviewed grade. Grade2/NED patients received focal radiotherapy (RT) up to 59.4Gy, Grade3/NED received 4 courses of VEC(vincristine,etoposide,cyclophosphamide) after RT.ED patients received 1–4 VEC courses, second-look surgery, 59.4 Gy+8Gy boost on measurable residue. METHODS We re-analyzed data at 115 months follow-up including methylation profile on available samples. RESULTS Global PFS/OS at 5/10 years were 66/59% and 80/74%, respectively. Of the 64 relapsers at median 20 months, 53 died at median 37/18 months after diagnosis/relapse, respectively.10/64 relapsed after 5 years (66–126 months); 4 died, relapse was local in 8/10, metastatic 1, combined 1;5/10 patients were below age 3, 5 females, 8 PF tumors. Their survival post-relapse was not longer than earlier relapsers’. At univariable analysis, age over 3 years, female sex, complete surgery, grade 2, no shunt confirmed better PFS/OS. 66/95 analyzed tumors received a score >0.80 through the DNA methylation-based central nervous system tumor classifier: 41/8 as PFA/PFB, respectively,14/17 ST as RELA-positive (3 scored for other molecular entities i.e. anaplastic PXA, LGG MYB, HGNET). Prognostic factors were equally distributed among PFA/PFB groups,1 only group B patient relapsed locally at 96 months. CONCLUSIONS Already published prognostic factors remained at long-term follow-up;6.2% patients had late relapses. OS after relapse was not better in late relapsers. Group B confirmed better prognosis but all patients had received «at least» adjuvant RT. Modern ependymoma trials need long follow-up to draw firm conclusions.

Purpose: The aims of the present study were to: 1- critically assess the utility of L-3,4- dihydroxy-6-18Ffluoro-phenyl-alanine (18F-DOPA) and O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET) Positron Emission Tomography (PET)/Computed Tomography (CT) in patients with high grade glioma (HGG) and 2- describe the results of 18F-DOPA and 18F-FET PET/CT in a case series of patients with recurrent HGG. Methods: We searched for studies using the following databases: PubMed, Web of Science and Scopus. The search terms were: glioma OR brain neoplasm and DOPA OR DOPA PET OR DOPA PET/CT and FET OR FET PET OR FET PET/CT. From a mono-institutional database, we retrospectively analyzed the 18F-DOPA and 18F-FET PET/CT of 29 patients (age: 56 ± 12 years) with suspicious for recurrent HGG. All patients underwent 18F-DOPA or 18F-FET PET/CT for a multidisciplinary decision. The final definition of recurrence was made by magnetic resonance imaging (MRI) and/or multidisciplinary decision, mainly based on the clinical data. Results: Fifty-one articles were found, of which 49 were discarded, therefore 2 studies were finally selected. In both the studies, 18F-DOPA and 18F-FET as exchangeable in clinical practice particularly for HGG patients. From our institutional experience, in 29 patients, we found that sensitivity, specificity and accuracy of 18F-DOPA PET/CT in HGG were 100% (95% confidence interval- 95%CI - 81-100%), 63% (95%CI: 39-82%) and 62% (95%CI: 39-81%), respectively. 18F-FET PET/CT was true positive in 4 and true negative in 4 patients. Sensitivity, specificity and accuracy for 18F-FET PET/CT in HGG were 100%. Conclusion: 18F-DOPA and 18F-FET PET/CT have a similar diagnostic accuracy in patients with recurrent HGG. However, 18F-DOPA PET/CT could be affected by inflammation conditions (false positive) that can alter the final results. Large comparative trials are warranted in order to better understand the utility of 18F-DOPA or 18F-FET PET/CT in patients with HGG.

Purpose: The aims of patients’ radiological surveillance are to: ascertain relapse; apply second-line therapy; accrue patients in phase 1/2 protocols if second-line therapy is not standardized/curative; and assess/treat iatrogenic effects. To lessen the emotional and socioeconomic burdens for patients and families, we ideally need to establish whether scheduled radiological surveillance gives patients a better outcome than waiting for symptoms and signs to appear. Methods: We analyzed a prospective series of 160 newly-diagnosed and treated pediatric/adolescent patients with intracranial ependymoma, comparing patients with recurrent disease identified on scheduled MRI (the RECPT group; 34 cases) with those showing signs/symptoms of recurrent disease (the SYMPPT group; 16 cases). The median follow-up was 67 months. Results: No significant differences emerged between the two groups in terms of gender, age, tumor grade/site, shunting, residual disease, or type of relapse (local, distant, or concomitant). The time to relapse (median 19 months; range 5–104) and the MRI follow-up intervals did not differ between the SYMPPT and RECPT groups. The presence of signs/symptoms was an unfavorable factor for overall survival (OS) after recurrence (5-year OS: 8% vs. 37%, p = 0.001). On multivariable analysis, an adjusted model confirmed a significantly worse OS in the SYMPPT than in the RECPT patients. Conclusions: Symptomatic relapses carried a significantly worse survival for ependymoma patients than recurrences detected by MRI alone. It would therefore be desirable to identify recurrences before symptoms develop. Radiological follow-up should be retained in ependymoma patient surveillance because there is a chance of salvage treatment for relapses found on MRI

In the event of large crises (earthquakes, typhoons, floods, ...), a primordial task of the fire and rescue services is the search for human survivors on the incident site. This is a complex and dangerous task, which - too often - leads to loss of lives among the human crisis managers themselves. This book explains how unmanned search can be added to the toolkit of the search and rescue workers, offering a valuable tool to save human lives and to speed up the search and rescue process. The introduction of robotic tools in the world of search and rescue is not straightforward, due to the fact that the search and rescue context is extremely technology-unfriendly, meaning that very robust solutions, which can be deployed extremely quickly, are required. Multiple research projects across the world are tackling this problem and in this book, a special focus is placed on showcasing the results of the European Union ICARUS project on this subject. The ICARUS project proposes to equip first responders with a comprehensive and integrated set of unmanned search and rescue tools, to increase the situational awareness of human crisis managers, so that more work can be done in a shorter amount of time. The ICARUS tools consist of assistive unmanned air, ground, and sea vehicles, equipped with victim-detection sensors. The unmanned vehicles collaborate as a coordinated team, communicating via ad hoc cognitive radio networking. To ensure optimal human-robot collaboration, these tools are seamlessly integrated into the command and control equipment of the human crisis managers and a set of training and support tools is provided to them in order to learn to use the ICARUS system.

Background The management of children with cancer during the end-of-life (EOL) period is often difficult and requires skilled medical professionals. Patients with tumors of the central nervous system (CNS) with relapse or disease progression might have additional needs because of the presence of unique issues, such as neurological impairment and altered consciousness. Very few reports specifically concerning the EOL period in pediatric neuro-oncology are available. Procedure Among all patients followed at our center during the EOL, we retrospectively analyzed data from 39 children and adolescents with brain tumors, in order to point out on their peculiar needs. Results Patients were followed-up for a median time of 20.1 months. Eighty-two percent were receiving only palliative therapy before death. Almost half the patients (44%) died at home, while 56% died in a hospital. Palliative sedation with midazolam was performed in 58% of cases; morphine was administered in 51.6% of cases. No patient had uncontrolled pain. Conclusions The EOL in children with advanced CNS cancer is a period of active medical care. Patients may develop complex neurological symptoms and often require long hospitalization. We organized a network-based collaboration among the reference pediatric oncology center, other pediatric hospitals and domiciliary care personnel, with the aim to ameliorate the quality of care during the EOL period. In our cohort, palliative sedation was widely used while no patients died with uncontrolled pain. A precise process of data collection and a better sharing of knowledge are necessary in order to improve the management of such patients. Pediatr Blood Cancer 2014;61:2004–2011. © 2014 Wiley Periodicals, Inc.

Patients with diffuse intrinsic pontine glioma (DIPG) have a very poor prognosis. Only radiotherapy (XRT) has proven to be effective in delaying the disease progression. Several chemotherapy schedules have been applied so far, but none demonstrated significant improvements in progression and survival. We retrospectively analyzed the clinical data of children diagnosed with DIPG at our center (Pediatric Hospital “Regina Margherita,” Turin, Italy) between 1999 and 2013. Progression-free survival (PFS) and overall survival (OS) were used to describe the outcomes. Twenty-four children were included in our report. Patients diagnosed before March 2003 (n = 12) were treated with XRT and vincristine (VCR); the remaining 12 patients received XRT and temozolomide (TMZ). Progression-free survival was 18.8 % at 1 year (SE = 7.6 %), while overall survival was 44.1 % at 1 year (SE = 9.9 %). Median PFS was 8.1 months, whereas median OS was 11.2 months. No statistically significant difference in PFS or OS was evidenced between the two treatment groups. Radiotherapy followed by VCR or TMZ allows obtaining results that are in line with previous reports, with no advantages over other similar treatment schedules. DIPGs are challenging tumors with a dismal outcome. Further research and newer therapies are urgently needed in order to achieve improvements in survival.

Aims of patient follow-up are: discovering relapse to apply second-line therapy for possible cure, accruing patients in phase 1/2 protocols if second-line therapy is not standardized/curative, evaluating/treating iatrogenic effects. To lessen the patient/family emotional and social economic burdens, we should ideally understand if scheduled radiological follow-up has a better rationale/outcome than the symptomatic relapse. We analyzed the Italian series of 2016 (doi:10.1093/neuonc/now108) comprehending 160 newly diagnosed pediatric/adolescent patients with intracranial ependymoma (EPD) according to relapse status (recurrence at scheduled exam [RECPT]/sign-symptomatic recurring [SYMPPT]). RECPT and SYMPPT were assessed in Cox model as time-dependent variables for overall survival (OS). Differences in characteristics between RECPT and SYMPPT subgroups were assessed by Wilcoxon-Mann-Whitney or Fisher Exact tests. Kaplan-Meier curves depicted event-free survival (EFS) and OS after recurrence according to signs/symptoms. There were 16 SYMPPT /34 RECPT, at a median follow-up of 55 months. No significant differences were found between SYMPPT/RECPT for gender, age, tumor grade/site, shunt, residual disease, radiation boost, type of relapse (local/distant/combined). Time-to-relapse (median:19 months, range 5–104) and treatment adoption did not differ between SYMPPT/RECPT while signs/symptoms depicted an unfavorable factor for OS after relapse (5-year OS: 8% vs 37%). Adjusted model in multivariate analysis confirmed that presence of signs/symptoms was prognostically unfavorable. In order to improve the OS in symptomatic patients, their early identification-in the first two/three years after diagnosis- would be desirable. Perhaps, this could be obtained paying attention to “heuristically detected” subgroup of patients, not just describing general prognostic variables but discovering possible biology differences according to signs/symptoms.

EPN-02. FINAL RESULTS OF THE 2ND AIEOP PROTOCOL FOR INTRACRANIAL EPENDYMOMA (EPD) Maura Massimino1, Rosalba Miceli1, Felice Giangaspero2,3, Luna Boschetti1, Paolo Ferroli4, Paola Peretta5, Emilia Pecori1, Laura Valentini4, Veronica Biassoni1, Maria Luisa Garre6, Elisabetta Schiavello1, Iacopo Sardi7, Armando Cama6, Silvia Scoccianti8, Maurizio Mascarin9, Lorenzo Genitori7, Daniele Bertin5, Anna Mussano10, Elisabetta Viscardi11, Piergiorgio Modena12, GiuseppinaCalareso1, Salvina Barra13, Giovanni Scarzello14, LuciaQuaglietta15, Giuseppe Cinalli15, Angela Mastronuzzi16, Carlo Giussani17, Carlo Marras16, Rita Balter18, Patrizia Bertolini19, Ermanno Giombelli19, Francesca Buttarelli2, Manila Antonelli2, and Lorenza Gandola1; Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy; Universita Sapienza Roma, Roma, Italy; Neuromed Pozzilli, Pozzilli, Italy; Fond IRCCS Istituto Neurologico Carlo Besta, Milano, Italy; Ospedale Infantile Regina Margherita, Torino, Italy; Istituto Giannina Gaslini, Genova, Italy; Ospedale Pediatrico Meyer, Firenze, Italy; OspedaleCareggi,Firenze, Italy;CRO,Aviano, Italy;OspedaleS.Anna, Torino, Italy; Clinica di Oncoematologia Pediatrica, Padova, Italy; Genetica, Osp S. Anna, Como, Italy; Istituto dei Tumori, Genova, Italy; Istituto Oncologico del Veneto, Padova, Italy; Ospedale Pausillipon, Napoli, Italy; Ospedale Bambino Gesu, Roma, Italy; Ospedale S. Gerardo, Monza, Italy; Ospedale Borgo Roma, Verona, Italy; Ospedale, Parma, Italy This study stratified patients after surgical resection (complete 1⁄4 NED vs incomplete 1⁄4 ED) and centrally reviewed histology(gr.2 vs gr. 3). Gr2 tumors/NEDpts were focally irradiated with a 3D-conformal technique 1.8Gy/d up to 59.4 Gy, gr3/NED received also 4 VEC(Cyclo,VP16,VCR) after irradiation. EDpts received 1-4 VEC, second-look surgery whenever possible,59.4 Gy followed by 8 Gy boost into 2 fractions on still measurable residue. Children aged 1-3 yrs received the same treatment but for those gr2/NED who could receive only 6 VEC. Between January 2002/December 2014, 160 consecutive children, median age 4.9 years, entered the protocol; follow-up was a median 67 months. M/F was 100/60, infratentorial origin in 110(2 plus metastasis). After surgery, NEDpts were 110,grade 3 was assessed in 84. 100 resections were performed in 46/160 children with another 12 rendered NED after first excision,10 after 1-4 VEC,2 after radiation. Boost was applied to 24/40 still ED patients after surgery/ies and VEC obtaining PFS/OS of 58.1%/68.7% in this severe prognosis subgroup. For the whole series,5-year PFS/OS were 65.4%/81.1% with no toxic deaths. In univariable analysis, female gender, supratentorial origin, NED status before RT, grade 2, shunt absence were favourable for OS, in multivariable NED status and grade 2 were. For PFS, female gender, NED status before RT, grade 2 were significant in univariable, only grade in multivariable. In a multicentric collaboration this trial accrued the highest patient number so far published with comparable results to best monoinstitutional series. Radiation boost was feasible and efficacious in improving local control. Complete surgery, also through multiple excisions, still confirmed its prognostic strength as well as grade. Further biological parameter definition on this series will be the object of next coming studies. Neuro-Oncology 18:iii30–iii39, 2016. doi:10.1093/neuonc/now070.2 #The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Background This prospective study stratified patients by surgical resection (complete = NED vs incomplete = ED) and centrally reviewed histology (World Health Organization [WHO] grade II vs III). Methods WHO grade II/NED patients received focal radiotherapy (RT) up to 59.4 Gy with 1.8 Gy/day. Grade III/NED received 4 courses of VEC (vincristine, etoposide, cyclophosphamide) after RT. ED patients received 1-4 VEC courses, second-look surgery, and 59.4 Gy followed by an 8-Gy boost in 2 fractions on still measurable residue. NED children aged 1-3 years with grade II tumors could receive 6 VEC courses alone. Results From January 2002 to December 2014, one hundred sixty consecutive children entered the protocol (median age, 4.9 y; males, 100). Follow-up was a median of 67 months. An infratentorial origin was identified in 110 cases. After surgery, 110 patients were NED, and 84 had grade III disease. Multiple resections were performed in 46/160 children (28.8%). A boost was given to 24/40 ED patients achieving progression-free survival (PFS) and overall survival (OS) rates of 58.1% and 68.7%, respectively, in this poor prognosis subgroup. For the whole series, 5-year PFS and OS rates were 65.4% and 81.1%, with no toxic deaths. On multivariable analysis, NED status and grade II were favorable for OS, and for PFS grade II remained favorable. Conclusions In a multicenter collaboration, this trial accrued the highest number of patients published so far, and results are comparable to the best single-institution series. The RT boost, when feasible, seemed effective in improving prognosis. Even after multiple procedures, complete resection confirmed its prognostic strength, along with tumor grade. Biological parameters emerging in this series will be the object of future correlatives and reports.

This paper illustrates a control strategy for a submarine snorkel able to assure that the water surface profile can be tracked by the extremity of the device, called “fluctuating head”. The proposed solution is based on adaptive output regulation theory. More precisely, it is assumed that wave profile can be approximated as a linear combination of a number of harmonics of unknown amplitude, phase and frequency and we look for an internal model-based adaptive regulator able to enforce the top of the mast to track the reference profile. The effectiveness of the proposed adaptive scheme is shown through simulations.

A case of Schinzel-Giedion syndrome, a rare malformation syndrome, is described. In addition to the classic features of the syndrome, the patient had a malignant sacrococcygeal teratoma and agenesis of the corpus callosum. So far, this patient is the fifth case with a sacrococcygeal tumor and the eighth with anomalies of the corpus callosum. According to this occurrence of uncommon tumors, risk of malignancy could be a component of Schinzel-Giedion syndrome.

The management of children with cancer during the end-of-life (EOL) period is often difficult and requires skilled medical professionals. Patients with tumors of the central nervous system (CNS) with relapse or disease progression might have additional needs because of the presence of unique issues, such as neurological impairment and altered consciousness. Very few reports specifically concerning the EOL period in pediatric neuro-oncology are available.Among all patients followed at our center during the EOL, we retrospectively analyzed data from 39 children and adolescents with brain tumors, in order to point out on their peculiar needs.Patients were followed-up for a median time of 20.1 months. Eighty-two percent were receiving only palliative therapy before death. Almost half the patients (44%) died at home, while 56% died in a hospital. Palliative sedation with midazolam was performed in 58% of cases; morphine was administered in 51.6% of cases. No patient had uncontrolled pain.The EOL in children with advanced CNS cancer is a period of active medical care. Patients may develop complex neurological symptoms and often require long hospitalization. We organized a network-based collaboration among the reference pediatric oncology center, other pediatric hospitals and domiciliary care personnel, with the aim to ameliorate the quality of care during the EOL period. In our cohort, palliative sedation was widely used while no patients died with uncontrolled pain. A precise process of data collection and a better sharing of knowledge are necessary in order to improve the management of such patients.

In this paper, a servo system for a centrifugal fan complemented with an Inlet Guide Vane (IGV), is considered. An IGV-fan system, at constant fan speed, can be regarded as a single-input single-output dynamical system. The IGV-fan system is characterised by non-trivial non-linearities. For the servo design, a direct method, called Virtual Reference Direct Design, which makes use of I/O measurement only has been used. Such a method enables one to work out in a black-box fashion the approximate inverse of a non-linear system, and it provides satisfactory performances when used for the design of the approximate inverse of an IGV-fan system.

In this paper, the problem of stabilising the position and heading of a ship is considered. The problem is dealt with in the case of a single-thruster (under-actuated) vehicle, subject to external forces due to the wind and the current. The set of the admissible steady-state conditions is studied, and a control law which exactly linearizes the I/O behaviour of the ship is designed. The zero dynamics (which can be interpreted as the dynamics of the ship attitude) are locally stable about a subset of steady-state conditions.

In this paper, the problem of designing a servo system for Surface Effect Ship applications, based upon a centrifugal fan complemented with an Inlet Guide Vane (IGV), is considered. An IGV-fan system, at constant fan speed, can be regarded as a single-input (the opening of the intake valve) single-output (the delivered air flow) dynamical system, affected by a measurable disturbance (the pressure at the output). The IGV-fan system is characterised by non-trivial non-linearities. For the servo design, a back-box direct method which makes use of I/O measurement only has been used. Such a method provides satisfactory performances when used for the design of the approximate inverse of the IGV-fan system.

A well-known limit of air cushion catamarans is the so-called “cobblestone effect”, a resonance phenomenon due to the interaction between the ship body and the air cushion dynamics excited by the incoming waves. In this paper the problem of designing a ride control system for the attenuation of the wave-induced vertical accelerations of a surface effect ship (SES) is considered. It is shown that the damping of the two main resonant modes can be achieved by two independent control loops. Such a decoupled control scheme exploits the intrinsic orthogonality of the two oscillation phenomena, and provides better performances than classical control schemes based on two independent local control loops.

An autopilot for precise manoeuvring at low speed requires special attention to a number of factors including the effects of wind and current. The control system for track-keeping described here is based on the water-relative ship dynamics modelling and is characterised by the arbitrary tracking capability and the wind/current compensation within the LQG Optimal Control design.

Brainstem tumors (BSTs) are usually gliomas and are divided into diffuse BSTs (DBSTs) and focal BSTs (FBSTs). The aim of this study is to investigate the different outcomes of these two entities.Thirty-one patients with BSTs were admitted to our institution from 1995 to 2003. Patients with DBSTs were treated with locoregional radiotherapy (1.8 Gy/day for 54 Gy) and weekly vincristine for radiosensitization (1.5 mg/sm for six total doses). Patients with FBSTs underwent surgical resection. Chemotherapy and/or radiotherapy were considered in progression.Fourteen patients were diagnosed as having DBSTs. The responses to treatment were ten cases of partial response, three of stable disease, and one of progressive disease. General and/or neurological symptoms improved in more than 80% of patients. The median time from diagnosis to progression and to death were, nonetheless, 8 (range of 3-13) and 13 (range of 4-25) months, respectively, with a 2-year overall survival rate of 12.3% [standard error (SE) 11.2]. Seventeen patients were diagnosed as having FBSTs. Gross total removal was achieved in 4/17 cases, subtotal removal in 7/17, and partial removal in 6/17. There was one surgery-related death. Eight out of 17 patients had adjuvant chemo- and/or radiotherapy after progression: 6/8 are without neurological symptoms and 2/8 have died due to tumor progression. The 4-year overall and disease-free survival rates are 87.4 (SE 8.4) and 58.8% (SE 11.9), respectively, the extent of resection being the most important prognostic factor (p=0.012). DBSTs continue to carry a dismal prognosis, thus demanding new treatment modalities; FBSTs can be treated surgically and patients benefit from a better prognosis.

In this study the authors retrospectively evaluated the feasibility and effectiveness of prolonged oral etoposide therapy in children with recurrent ependymoma. Twelve ependymoma patients with documented recurrent or persistent disease were treated between May 1998 and October 2003. All patients were treated monthly with oral VP-16 administered at a dose of 50 mg/m2/d for 21 days, with a 7-day interval between cycles, for a planned minimum number of six cycles. Response (complete plus partial) after two cycles occurred in 5 of the 12 patients (41.6%). Response plus stable disease occurred in 10 of the 12 (83.3%), with a median duration of response or stable disease of 7 months (range 4-30). The median survival was 7 months; the 2-year progression-free survival was 16.7%. These results emphasize that oral etoposide is an attractive option for childhood recurrent ependymomas in terms of administration, tolerability, and neuroradiologic response.

In this article, the problem of modelling and simulating the 3-lobes stern seal of a Surface Effect Ship (S.E.S.) is considered. Recently it has been derived an algebraic model of the stern seal; unfortunately, the corresponding equation is an implicit, non-linear and stiff equation, which does not admit an explicit solution. On the other hand, the numerical solution of the equation turns out to be time-consuming and somewhat unreliable. In this article, we explore the possibility of replacing the stiff equation numerical simulator with a suitably trained neural network. The objective is to obtain a fast and reliable “black-box” model of the 3-lobes stem seal, suitable for an on-line use within the entire S.E.S. simulator. Several networks have been considered; among them, an innovative structured network revealed to provide the best performances in terms of approximation accuracy and parameters parsimony.

A well known limit of air cushion catamarans is the so called "cobblestone effect", a resonance phenomenon, which is due to the interaction between the ship body and the air cushion dynamics, excited by the incoming waves. The problem of designing a Ride Control System for the attenuation of the wave induced vertical accelerations of a Surface Effect Ship (SES) is considered. It is shown that the damping of two basic resonant modes can be achieved by two independent control loops. Such a decoupled control scheme exploits the intrinsic orthogonality of the two oscillation phenomena.

In CML, the presence of primary and acquired resistance to imatinib mesylate (IM) suggests the importance of developing new therapeutic agents that might be useful in case of suboptimal response to IM. In CML Bcr-Abl activates NF-k-B, which is involved in tumorigenesis. NF-k-B is activated by proteasomes, which also regulate the degradation of its inhibitor Ik-B. Proteasome blockers are thus optimal candidates for CML treatment. Several HIV protease inhibitors (PIs) and in particular saquinavir, at therapeutic concentrations, significantly inhibit human proteasome activities, NF-k-B activation and degradation of its inhibitor IkB. This supports a direct antitumor activity of PIs. The IM sensitive CML line K562 and the IM-resistant CML lines K562-R and KCL22-R have been exposed for 24, 48 and 72 hours to various concentrations of saquinavir alone or associated with imatinib 2μM. Viability was then evaluated by trypan blue exclusion and apoptosis by flow cytometry, using annexin V-FITC conjugates. Saquinavir inhibited proliferation and promoted apoptosis in cell lines in a dose and time related manner. Saquinavir IC50 after 72 hour culture was 43.9 μM in K562 and 6.0 and 9.6 μM in K562-R and KCL22-R, respectively. The addition of IM 2 μM caused a significant increase of the antiproliferative and pro-apoptotic effect of saquinavir. In the presence of IM, the saquinavir IC50 after 72 hours was 1.8 μM in K562 and 0.39 and 6.68 μM in K562-R and KCL22-R lines, respectively. | | CL | 1 μM | 5 μM | 10 μM | 20 μM | 30 μM | 40 μM | |:----------- | ---- | ---- | ---- | ----- | ----- | ----- | ----- | | CL =control | | K562 | 12.8 | 15.5 | 16.1 | 13.6 | 19.3 | 20.4 | 26.6 | | K562-R | 12.7 | 15.6 | 16.4 | 28.4 | 70.2 | 80.7 | 55.3 | | KCL22-R | 3.6 | 4.1 | 4.3 | 6.1 | 26.5 | 34.7 | 47.3 | Percentage of apoptotic cells in K562, K562-R and KCL22-R lines after 72 hour-exposure to different concentrations of saquinavir. The effect of saquinavir on the CFU-GM growth from peripheral blood (PB) of three CML patients was also investigated: one 15 year old male in chronic phase at diagnosis, one 45 year old female in chronic phase during interferon treatment, one 60 year old male in blastic phase. Saquinavir inhibited CFU-GM growth not only in chronic phase at diagnosis and during INF treatment, but also in IM-resistant blastic phase. | saquinavir concentrations | CML chronic phase at diagnosis | CML chronic phase in INF treatment | CML blastic phase | |:------------------------------------------------------------------------------------------------------------- | ------------------------------ | ---------------------------------- | ----------------- | | Percentages of inhibition of CFU-GM growth in comparison with control cultures, performed without saquinavir. | | 10 μM | 41% | 60% | 24% | | 20 μM | 82% | 60% | 71% | Saquinavir inhibits PB CFU-GM growth in CML patients In conclusion, saquinavir exerts a clear dose-related inhibitory and pro-apoptotic effect on Bcr-Abl positive cell lines. It acts on K562-R at concentrations lower than in the parental line and similar to those achievable in vivo and maintained in HIV patients for prolonged periods of time and usually well tolerated. This activity is further enhanced by the association of IM. The observation that saquinavir inhibits PB CFU-GM growth in CML patients even in blastic phase further supports the possibility of utilizing this compound in vivo in a combined therapeutic approach for CML.

The purpose of this paper is to compare by a simulation study a number of different recursive estimators for the tracking of timevarying parameters. They are obtained from the classical recursive leastsquares algorithm by introducing suitable forgetting factors to discount old information. In particular, two novel techniques for tuning the forgetting factor are proposed. They are generalizations of the so-called directional forgetting algorithm where the discount rate is evaluated on the basis of the current prediction error. Besides preventing the covariance matrix “blow-up” during periods of poor excitation, these new methods apparently provide better adaptivity to different parameters dynamics and high robustness with respect to the choice of the design parameters.