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The chances of patients with relapsing pediatric non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) being cured are limited. This retrospective single-institutional study examines the potential role of routine surveillance imaging for detecting recurrent tumor, and its impact on post-relapse survival.The analysis concerned 86 patientslt; 21 years old with relapsing NRSTS treated from 1985 to 2020. Clinical findings, treatment modalities and survival were analyzed, comparing patients whose relapse was first suspected from symptoms (symptomatic group) with those whose relapse was detected by radiological surveillance (imaging group).Tumor relapses were identified from clinical symptoms in 49 cases and on routine imaging in 37. Time to relapse was similar in the two groups. Routine imaging detected 6/32 local relapses and 31/48 distant relapses (and 79% of the cases of lung metastases). Overall survival (OS) at 5 years was 34.3% for the symptomatic group, and 24.0% for the imaging group (p-value 0.270). In patients with lung metastases at relapse, the 5-year OS was statistically better for the imaging group, that is, 25.8% versus 0% for the symptomatic group (p-value 0.044).This is the first study to explore the role of surveillance imaging in pediatric NRSTS. Judging from our findings, the value of routine scanning of primary sites seems limited, while radiological surveillance may help to detect lung metastases, improving survival for this patient category. The potentially negative effects of periodic radiological exams should be considered in deciding the optimal follow-up for patients off therapy.

Central nervous system (CNS) metastatic spread in neuroblastoma (NB) is rare and occurs more often at relapse/progression. We report on CNS involvement in high risk (HR) NB over 25 years. For this retrospective study, we reviewed the CNS imaging of all the patients treated at Bambino Gesù Children Hospital from 1 July 1996 to 30 June 2022. A total of 128 patients with HR NB were diagnosed over 26 years. Out of 128 patients, CNS metastatic spread occurred in 6 patients: 3 patients presented a metastatic spread at diagnosis, while in 3 patients, CNS was involved at relapse. Overall, the rate of occurrence of CNS spread is 4.7% with the same distribution at diagnosis and at relapse, namely 2.3%. Interestingly, CNS spread at diagnosis was observed only before 2012, whereas CNS was observed at relapse only after 2012, in the immunotherapy era. CNS metastases presented similar imaging features at diagnosis and at relapse, with a peculiar hemorrhagic aspect and mainly hemispheric localization in patients with bone skull involvement at the time of diagnosis. The outcome is dismal, and 3 out of 6 patients died for progressive disease.

Recurrence incidence for paediatric/adolescent high-grade glioma (HGG) exceeds 80%. Reirradiation (reRT) palliates symptoms and delays further progression. Strategies for reRT are scarce: we retrospectively analysed our series to develop rational future approaches.We re-evaluated MRI + RT plans of 21 relapsed HGG-patients, accrued 2010-2021, aged under 18 years. All underwent surgery and RT + chemotherapy at diagnosis. Pathologic/molecular re-evaluation allowed classification based on WHO 2021 criteria in 20/21 patients. Survival analyses and association with clinical parameters were performed.Relapse after 1st RT was local in 12 (7 marginal), 4 disseminated, 5 local + disseminated. Re-RT obtained 8 SD, 1 PR, 1PsPD, 1 mixed response, 10 PD; neurological signs/symptoms improved in 8. Local reRT was given to 12, followed again by 6 local (2 marginal) and 4 local + disseminated second relapses in 10/12 re-evaluated. The 4 with dissemination had 1 whole brain, 2 craniospinal irradiation (CSI), 1 spine reRT and further relapsed with dissemination and local + dissemination in 3/four assessed. Five local + disseminated tumours had 3 CSI, 1 spine reRT, further progressing locally (2), disseminated (1), n.a. (1). Three had a third RT; three were alive at 19.4, 29, 50.3 months after diagnosis. Median times to progression/survival after re-RT were 3.7 months (0.6-16.2 months)/6.9 months (0.6-17.9 months), improved for longer interval between 1st RT and re-RT (P = 0.017) and for non-PD after reRT (P 0.001). First marginal relapse showed potential association with dissemination after re-RT (P = 0.081).This is the biggest series of re-RT in paediatric HGG. Considering the dissemination observed at relapse, our results could prompt the investigation of different first RT fields in a randomized trial.

Each year approximately 35,000 children and adolescents are diagnosed with cancer in Europe. Five-year survival rates have improved and now reach 80% in most European countries, thanks to a combination of chemotherapy, radiotherapy, and surgery. To date, there are more than 44,000 Italians still living several years after being diagnosed with cancer in developmental age. The risk of premature morbidity and mortality for cancer survivors is well known and documented. Approximately 60% of survivors of cancer in childhood and adolescence have at least one chronic health condition in later life, and more than one in four develop severe or life-threatening disorders. Among the various long-term iatrogenic sequelae of cancer treatments, the most worrisome are second malignant neoplasms. We reported on our mono-institutional experiences of screening and treating secondary breast cancer, secondary thyroid cancer and secondary osteosarcoma. Recommendations on the surveillance needed for cancer survivors because of the risk of late effects of their disease or its treatment suggest that discussing the potential problems early on can be crucial to a patient’s future health. These considerations and our consolidated experience strengthen our conviction that survivors of cancer in childhood and adolescence who develop second malignant neoplasms should be treated at highly-specialized centers. Multidisciplinary care requires close communications and high levels of up-to-date professional expertise. This challenging area of health care is also changing rapidly because cancer survivorship is a work in progress, but we cannot wait for definitive conclusions on many aspects because this will take decades, especially for pediatric patients.

Diffuse midline gliomas (DMGs) originate in the thalamus, brainstem, cerebellum and spine. This entity includes tumors that infiltrate the pons, called diffuse intrinsic pontine gliomas (DIPGs), with a rapid onset and devastating neurological symptoms. Since surgical removal in DIPGs is not feasible, the purpose of this study was to profile circulating miRNA expression in DIPG patients in an effort to identify a non-invasive prognostic signature with clinical impact. Using a high-throughput platform, miRNA expression was profiled in serum samples collected at the time of MRI diagnosis and prior to radiation and/or systemic therapy from 47 patients enrolled in clinical studies, combining nimotuzumab and vinorelbine with concomitant radiation. With progression-free survival as the primary endpoint, a semi-supervised learning approach was used to identify a signature that was also tested taking overall survival as the clinical endpoint. A signature comprising 13 circulating miRNAs was identified in the training set (n = 23) as being able to stratify patients by risk of disease progression (log-rank p = 0.00014; HR = 7.99, 95% CI 2.38–26.87). When challenged in a separate validation set (n = 24), it confirmed its ability to predict progression (log-rank p = 0.00026; HR = 5.51, 95% CI 2.03–14.9). The value of our signature was also confirmed when overall survival was considered (log-rank p = 0.0021, HR = 4.12, 95% CI 1.57–10.8). We have identified and validated a prognostic marker based on the expression of 13 circulating miRNAs that can shed light on a patient’s risk of progression. This is the first demonstration of the usefulness of nucleic acids circulating in the blood as powerful, easy-to-assay molecular markers of disease status in DIPG. This study provides Class II evidence that a signature based on 13 circulating miRNAs is associated with the risk of disease progression.

BACKGROUND: The purposes of this trial were to evaluate the feasibility, response, PFS/OS of a randomized study comparing two different RT schedules for DIPG while administering the same systemic treatment. METHODS: Patients: 2-21 years-old with a not-pretreated radiologically verified DIPG (MRI blindly reviewed at diagnosis and every 12 weeks thereafter) and symptoms duration below 6 months. Biopsy was required if suggested by atypical imaging. Vinorelbine 20 mg/m2+nimotuzumab 150 mg/m2 were administered weekly for 12 weeks; thereafter every other week until tumor progression or for up to 2 years. Standard(ST) arm included focal RT at total dose of 54Gy (1.8Gy/day); for local progression re-irradiation was proposed at 19.8Gy, in case of dissemination craniospinal irradiation(CSI) at 36Gy was adopted. Experimental(SP) arm included three elective courses of RT at defined timepoints at 36Gy, 19.8Gy and 19.8Gy with possible reirradiation for relapse at 9 Gy. Incidences of local(L) and distant(D) progression were assessed in a competing risk setting. RESULTS: Aggregated preliminary results are given for 4 Italian centers. 54 pts were screened and 51 included, 27 in ST, 28 males, median age 7 years (range 3-17). Median time of observation was 17.9 months. Twelve patients needed a shunt, 10 during treatment; 20 were biopsied, in 18 cases according local protocols. 19/20 tumors had H3.3 K27 mutation. 41 relapsed, 28 locally, 13 with a component of dissemination. 36 died, one for tracheotomy bleeding. SP irradiation was feasible and never produced significant radionecrosis. Median EFS/OS were 7.3/12.9 months, respectively; EFS/OS at 1 year were 19.0%/57.3%, not differing between patients with local vs. disseminated relapses. Patients submitted to biopsies had more dissemination (P=0.04) and less local progression (P=0.077). CONCLUSIONS: Treatment was feasible and OS confirmed previous results obtained in a single center. Randomization results will be later reported.

A PENTEC review of childhood cancer survivors who received brain radiation therapy (RT) was performed to develop models that aid in developing dose constraints for RT-associated central nervous system (CNS) morbidities.A comprehensive literature search, through the PENTEC initiative, was performed to identify published data pertaining to 6 specific CNS toxicities in children treated with brain RT. Treatment and outcome data on survivors were extracted and used to generate normal tissue complication probability (NTCP) models.The search identified investigations pertaining to 2 of the 6 predefined CNS outcomes: neurocognition and brain necrosis. For neurocognition, models for 2 post-RT outcomes were developed to (1) calculate the risk for a below-average intelligence quotient (IQ) (IQ85) and (2) estimate the expected IQ value. The models suggest that there is a 5% risk of a subsequent IQ85 when 10%, 20%, 50%, or 100% of the brain is irradiated to 35.7, 29.1, 22.2, or 18.1 Gy, respectively (all at 2 Gy/fraction and without methotrexate). Methotrexate (MTX) increased the risk for an IQ85 similar to a generalized uniform brain dose of 5.9 Gy. The model for predicting expected IQ also includes the effect of dose, age, and MTX. Each of these factors has an independent, but probably cumulative effect on IQ. The necrosis model estimates a 5% risk of necrosis for children after 58.9 Gy or 59.9 Gy (2 Gy/fraction) to any part of the brain if delivered as primary RT or reirradiation, respectively.This PENTEC comprehensive review establishes objective relationships between patient age, RT dose, RT volume, and MTX to subsequent risks of neurocognitive injury and necrosis. A lack of consistent RT data and outcome reporting in the published literature hindered investigation of the other predefined CNS morbidity endpoints.

Background: Embryonal tumors represent a heterogeneous entity of brain tumors that need a multidisciplinary treatment including cranio-spinal irradiation (CSI), with a known impact on the acute toxicity. Proton therapy (PT) boasts a reduction in acute hematological toxicity. Methods: We retrospectively examined 20 pediatric patients affected by high-risk medulloblastoma and other rare embryonal brain tumors subjected to CSI with PT from September 2016 to April 2020. Before CSI, all patients received induction chemotherapy, and three patients additionally received two high-dose courses with thiotepa, followed by an autologous haemopoietic stem cell transplantation. We recorded the total white blood cell count, absolute neutrophil count, platelets, and hemoglobin levels for all patients during PT. Results: Leucocytes and neutrophils decreased directly after the beginning of treatment, reaching a complete recovery at the end of treatment. Hemoglobin values remained constant over the treatment course. The median platelet value decreased until reaching a plateau around halfway through therapy, followed by a slow increase. No cases of febrile neutropenia or severe infections were reported. No treatment discontinuation due to hematological toxicity was necessary. Conclusions: CSI with PT was proven to be safe in this setting of pediatric patients. Our study showed that despite all patients having undergone chemotherapy prior to irradiation, no serious hematological toxicity was reported at the end of the treatment with PT, and, therefore, no treatment was discontinued or delayed.

PURPOSE Diffusion kurtosis imaging (DKI) has not yet been tested for pediatric brain tumors. Estimating diffusion values from whole-tumor based (VOI) segmentations may improve diffusion measurement repeatability compared to conventional region-of-interest (ROI) approaches. Our purpose was to compare repeatability between ROI and VOI DKI-derived diffusion measurements and to assess VOI-based DKI accuracy in discriminating among pediatric posterior fossa tumors. MATERIALS AND METHODS We retrospectively analyzed 34 children (19 M, 15F, mean age 7.48 years) with posterior fossa tumors who underwent preoperative 3T MRI including DKI. For each patient, two neuroradiologists independently segmented the whole solid tumor (VOI), the area of maximum tumor diameter and a smallROI.Inter-observer variability was assessed with coefficient of variation (COV) and Bland-Altman plots. VOI-based DKI metrics accuracy in discriminating among tumor histology and for tumor grading were assessed with MANOVA and ROC analyses respectively. Correlation between grading accuracy and inter-observer variability was assessed with Spearman’s rho. RESULTS Tumor histology included medulloblastoma (15), pilocytic astrocytoma (14) and ependymoma (5). VOI-based measurements presented lower variability than ROI-based measurements across all DKI metrics. DKI-derived metrics could accurately discriminate between tumor subtypes (Pillai’s trace: p CONCLUSIONS DKI-derived metrics are useful for pediatric posterior fossa tumor discrimination and grading. VOI-based diffusion measurements present improved repeatability compared to ROI-based measurements and are significantly correlated to diagnostic accuracy.

To evaluate cystic dynamics in two pediatric low grade gliomas during proton beam therapy (PBT) by weekly MRI and in the follow up (FU) time. Early late toxicity was also reported. Both solid and cystic tumor’s components were drown in weekly MRI performed during proton radiation and in the FU phase. P1 case was a multiple partially resected 5 yo girl with hypothalamic pylocitic Astrocytoma no-responding after second line of chemotherapy, who acutely lost visual acuity due to cystic tumor’s progression. P2 case was a 13 yo boy with progressive mesencephalic pylocitic Astrocytoma previously treated with multi-agents chemotherapy and several surgeries. After cystic drainage both were treated with PBT at 54 Gy GCE. During proton therapy # 7 MRI for P1 and # 6 MRI for P2 patient were performed and didn’t shown cyst growth which required intervention; P1 developed two episodes of severe acute headache and both developed partial alopecia. In P1 patient both cystic and solid component progressively reduced (cyst/solid-1w +2/-15%, cyst/solid-2w -9/-22%, cyst/solid-3w -17/-28%, cyst/solid-4w -18/-38%, cyst/solid-5w -30/-43%, cyst/solid-6w -34/-44%, cyst/solid-1FU -43/-50%, cyst/solid-2FU -51/-63%). In P2 patient only cyst part progressively increased (cyst/solid-2w +7/-4%, cyst/solid-3w +36/-10%, cyst/solid-4w +58/-12%, cyst/solid-5w +73/-15%, cyst/solid-6w +90/-15%, cyst/solid-7w +94/-16%, cyst/solid-1FU +126/-37%, cyst/solid-2FU -18/-45%). P2 had transient cyst growth after PT with significant volume reduction on the second FU. After 10 months of median FU, no late side effects were noted however P1 improved visual acuity.

Purpose To assess the feasibility of radiation therapy treatment planning 4-dimensional computed tomography (4DCT) and deep-inspiration breath-hold (DIBH) CT to accurately contour the left anterior descending artery (LAD), a primary indicator of radiation-induced cardiac toxicity for patients undergoing radiation therapy. Methods and Materials Ten subjects were prospectively imaged with a cardiac-gated MRI protocol to determine cardiac motion effects, including the displacement of a region of interest comprising the LAD. A series of planar views were obtained and resampled to create a 3-dimensional (3D) volume. A 3D optical flow deformable image registration algorithm determined tissue displacement during the cardiac cycle. The measured motion was then used as a spatial boundary to characterize motion blurring of the radiologist-delineated LAD structure for a cohort of 10 consecutive patients enrolled prospectively on a breast study including 4DCT and DIBH scans. Coronary motion–induced blurring artifacts were quantified by applying an unsharp filter to accentuate the LAD structure despite the presence of motion blurring. The 4DCT maximum inhalation and exhalation respiratory phases were coregistered to determine the LAD displacement during tidal respiration, as visualized in 4DCT. Results The average 90th percentile heart motion for the region of interest was 0.7 ± 0.1 mm (left–right [LR]), 1.3 ± 0.6 mm (superior–inferior [SI]), and 0.6 ± 0.2 mm (anterior–posterior [AP]) in the cardiac-gated MRI cohort. The average relative increase in the number of voxels comprising the LAD contour was 69.4% ± 4.5% for the DIBH. The LAD volume overestimation had the dosimetric impact of decreasing the reported mean LAD dose by 23% ± 9% on average in the DIBH. During tidal respiration the average relative LAD contour increase was 69.3% ± 5.9% and 67.9% ± 4.6% for inhalation and exhalation respiratory phases, respectively. The average 90th percentile LAD motion was 4.8 ± 1.1 mm (LR), 0.9 ± 0.4 mm (SI), and 1.9 ± 0.6 mm (AP) for the 4DCT cohort, in the absence of cardiac gating. Conclusions An anisotropic margin of 2.7 mm (LR), 4.1 mm (SI), and 2.4 mm (AP) was quantitatively determined to account for motion blurring and patient setup error while placing minimum constraint on the plan optimization.

Introduction: Target volume definition is of critical relevance when re-irradiation is delivered and steep dose gradient irradiation techniques, such as proton therapy (PT), are employed. Aim of the study is to investigate the impact of 18F-DOPA on target volume contouring in recurrent glioblastoma (rGBM) patients (pts) undergoing re-irradiation with PT. MATERIAL AND METHODS: We investigated the differences in volume and relationship of magnetic resonance imaging (MRI)- vs. DOPA PET-derived gross tumor volumes (GTVs) of 14 rGBM pts re-irradiated with PT between January and November 2016. All pts had been previously treated with photon radiotherapy (60 Gy) with concomitant and adjuvant temozolomide. All the pts received morphological MRI with contrast enhancement medium administration and 18F-DOPA PET-CT study. We used the pathological distribution of 18F-DOPA in brain tissue to identify the so-called Biological Tumor Volume (BTV). Such areas were assessed using a tumor to normal brain ratio > 2. Moreover, any area of contrast enhancement on MRI was used to identify the MRI-based GTV (MRGTV). Definitive GTV included MRGTV plus BTV. Clinical target volume was generated by adding to GTV a 3-mm uniform margin manually corrected in proximity of anatomical barriers. CTV was expanded by 4 mm to create planning target volume. All pts received 36 GyRBE in 18 fractions. Mean values of differently delineated GTVs were compared each other by paired Student’s t-test; p < 0.05 was considered significant. To further compare MRGTV and BTV, the overlapping (MRGTV ^ BTV) and the composite (MRGTV U BTV) volumes were calculated, and a concordance index (CI) was defined as the ratio between the overlap and composite volumes. Results: MRGTV (mean 14.9 ± 14.5 cc) was larger than BTV (mean 10.9 ± 9.8 cc) although this difference was not statistically significant. The composite volume (mean 20.9 ± 14.7 cc) was significantly larger than each single volume (p < 0.006). The overlapping volume (mean 5.7 ± 3.3 cc) was quite small compared to each single volume and suggest that relevant part of MRIGTV is not covered by BTV as well as that relevant part of BTV is not covered by MRGTV. In line with such results we recorded also a low CI (mean 0.26 ± 0.2). The PT irradiation of PET-integrated target volumes provided a median progression-free survival (PFS) of 6 months, while the 6-month PFS rate was 57%; median survival after PT was 8.7 months, while 9-month survival rate was 60%. Conclusions: Target volume definition for rGBM undergoing PT re-irradiation may yield significantly differing results depending upon the imaging modality used for target contouring. Our data suggest that 18F-DOPA PET can detect relevant non-enhancing pathological areas outside the conventional MRGTV ultimately yielding to larger volumes to be irradiated. Influence on clinical outcomes deserves further evaluation.

INTRODUCTION: Proton therapy (PT) is a radiation therapy in increasing use for paediatric cerebral tumours, as in medulloblastoma. Although publications to date are relatively limited, they however include cases of potential development of radionecrosis. The aim of this study has been to compare our experience with data found in literature relating to the insurgence of premature radionecrosis, evaluating incidence, timing, appearance of clinical symptoms, risk factors and radiological characteristics. MATERIALS AND METHODS: We have retrospectively analysed 10 children with high risk medulloblastoma using protons on the cranio-spinal axis with a dose equal to 36 Gy RBE and with a successive higher dose in the posterior cranial fossa of 18 Gy RBE, at the PT Centre in Trento. All patients underwent PT, post-surgery on the primary tumour and intensive myeloablative chemotherapy: both are two potential risk factors in the appearance of premature radionecrosis. All the patients also underwent MRI on the brain and bone marrow, before and after proton therapy treatment, at an interval of 1 month at the end of PT and then every 3 months. RESULTS: In our clinical records in a median follow up of 4.9 months we did not encounter cases of radionecrosis according to the definition criteria as discussed or published in the consulted publications. CONCLUSIONS: The paediatric patients with high risk medulloblastoma undergoing treatment with proton therapy, the subjects of our study, presented a lower risk to premature radionecrosis in respect to the data present in current publications.

BACKGROUND: To report preliminary results of re-irradiation with proton therapy (PT) with or without chemotherapy (CHT) in difficult-to-treat recurrent glioblastoma (rGBM): patients (pts) were selected for PT because of the large tumor size or proximity to dose-limiting organs at risk that previously had received near-maximum dose tolerance during the first radiation course MATERIAL AND METHODS: Between January 2015 and January 2018, 34 pts with rGBM were re-irradiated with PT. All pts had been previously treated with Stupp regimen. Twenty-nine (85%) were re-irradiated at first relapse/progression, 5 at the second/third one. Nine pts (26%) were re-irradiated after partial tumor resection. Median (med) age and KPS at re-irradiation were 56 years and 90%, respectively. Med time between prior radiotherapy and PT was 13 months. Target definition was based on CT, MR, and 18F-DOPA PET imaging. Gross Tumor Volume (GTV) included any area of contrast enhancement after contrast medium administration plus any pathological PET uptake regions. Clinical Target Volume (CTV) was generated by adding to GTV a 3-mm margin. Med CTV volume was 47 cc (range, 13–153 cc). All pts received 36 GyRBE in 18 fractions. PT was delivered with or without chemotherapy as follows: eight (23.5%) pts (Group 1) also received concomitant TMZ (75 mg/m2/die, 7 days/week); 4 (12%) pts (Group 2) also received concomitant (as above) and adjuvant TMZ (150–200 mg/m2/die, 5 days/month); 9 (26.5%) pts (Group 3) received PT only; 13 (38%) pts (Group 4) received PT followed by CHT (different regimens/drugs). All pts were treated with active pencil beam scanning PT. Registered side effects were graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Treatment response was assessed according to Response Assessment in Neuro-Oncology criteria. Survival and progression-free survival after re-irradiation were calculated from initiation of PT until tumor progression or death (by any cause), using the Kaplan Meier method RESULTS: All pts completed the treatment without breaks. There were no grade 3 or higher acute toxicities. One pts developed TMZ-related grade 1 neutropenia. There were no grade 3 or higher late toxicities. During follow-up five pts (15%) developed radionecrosis (diagnosed at imaging) with mild symptoms controlled with steroids. The med progression-free survival (PFS) was 6.3 months, while 6-month PFS rate was 60%. The med PFS was 6.8, 4.3, 5.4, and 5.5 for Group 1-2-3-4, respectively. Med overall survival (OS) after PT was 10.7 months CONCLUSION: PT re-irradiation of difficult-to-treat rGBM showed to be feasible and safe even with concomitant and adjuvant chemotherapy administration. Despite the small number of patients of this series and the retrospective nature of the study PFS and OS rates are promising and deserve further evaluation in a larger pts sample to assess the most effective strategy

Proton Beam therapy (PBT) is known for determining a lower iexposure of normal tissues to the radiation, therefore leading to lower long-term neuro-cognitive impairment. The present study is aimed at evaluating whether PBT in pediatric patients with brain tumors may lower or counteract the negative neurocognitive outcomes usually associated with photon radiation (XRT). We considered not only general neurocognitive abilities, but also differentiated sub-cortical functions. Seven of 14 hospitalized oncologic patients aged 4-12 years (3medulloblastomas, 3 germ cell tumors, 1 pineoblastoma), treated with PBT after surgical resection and chemotherapy, completed neuropsychological tests assessing both general intelligence quotient(IQ) and sectoral cognitive functions (freedom from distractibility, processing speed, language skills, memory, visual perception, neuro-motor associations, attention, higher executive functions). Assessments were performed prior to surgical resection and one year after the end of the PBT. Non-parametric tests for paired samples (Wilcoxon test) were used to assess pre-to-post differences. IQ scores (total, verbal and performance) remained stable with a statistically nonsignificant and clinically non meaningful decline trend. Sectoral cognitive functions showed in contrast incremental changes over time, which reached significance only for visual accuracy(Z=-2.366; p=.018; pre:-3.39 ± 1.62; post:-1.53 ± 1.91)and visual speed(Z=-2.197; p=.028; pre:-2.19 ± 0.58; post:-1.53 ± 0.83).In sum, PBT may result in cognitive sparing that exceeds that of XRT protocols observed in the literature. Although preliminary, our results also suggest that after PBT, there may be recovery in sectoral cognitive, especially particularly visual functions. Additional long-term data with larger cohort of patients are needed to fully understand the neurocognitive impact of PBT in survivors of pediatric brain tumors.

Biologic activities of IL-16 have been well described (e.g., chemotaxis of CD4+ cells, CD25 upregulation, secretion of IL-1b, IL-4 and TNF-a secretion) but very few signaling events have been described. To gain a better understanding of how the biologic activities of IL-16 are regulated following receptor engagement (CD4) we have analyzed the activation state of numerous STAT proteins in primary human peripheral blood mononuclear cells (PBMCs) and the human monocytic cell line THP-1 following IL-16 stimulation. Of the four STAT proteins tested, only STAT6 was activated (phosphorylated) in a dose-dependant manner by IL-16. The activation of STAT6 was completely abolished when IL-16 was pre-incubated with soluble CD4 (the IL-16 cell surface receptor), demonstrating the need for CD4 engagement in STAT6 activation. These results are the first to demonstrate a link between IL-16 and STAT6 activation.

BACKGROUND: Thanks to their distinct physical properties proton therapy (PT) offers a superior dose distribution than photon radiation therapy. For brain and skull base (SB) tumors such dose sparing can be harnessed: a) in benign tumors, to achieve long-term better quality of life and reduced risk of neurocognitive deficits as well as radiation-related malignancies by delivering standard dose level; b) in malignant tumors or malignancies with local aggressiveness, to improve local control by safe delivery of tumor dose escalation. In the following we report an overview on our facility and the neuro-oncology program. METHODS/RESULTS: The Trento facility is built on over an area that will host the new Trento Hospital so that it will be a hospital-based PT center. As opposed to most centers using PT in the past, our facility is equipped with active beam delivery employing the spot scanning technique. A cyclotron provides a library of pencil beams of variable energy (70 - 226 MeV) and spot size (σ, 3 - 7 mm). Within the center, radiation therapy is offered in two treatment rooms. To allow for 360° rotation of the beamline these rooms are equipped with two gantries. In the treatment rooms, patients are placed on a robotic treatment table offering maximal variability and flexibility for patient positioning. The rooms are also equipped with devices enabling X-ray for treatment position verification. In a second step, the rooms will be equipped with cone-beam CT (room 1) and CT on-rails (room 2). Additionally there is one room equipped with horizontal beamline and equivalent beam scanning technology dedicated to quality assurance and preclinical research. For treatment planning imaging, the center is equipped with a dedicated CT and 1.5T MR. The staff is composed by professionals that experienced in leading particle centers in Villigen (CH), Heidelberg (GER), Boston (USA), Jacksonville (USA), Philadelphia (USA). Dedicated protocols for tumors of the brain and SB, for both adults and pediatric patients will be conducted based on the previous conducted trials on PT and potential expected benefit. As mentioned above, according to different clinical aims we are going to treat both benign and malignant tumors. The former group includes pituitary adenomas, schwannoma, benign meningioma, chondrosarcoma, craniopharyngioma, ependymoma, low-grade gliomas, medulloblastoma. In a second step, a PT radiosurgery program will be implemented for some of them. The latter group includes chordoma, high-grade gliomas, and atypical-malignant meningiomas. Regardless of the tumor type patients can be accepted also for re-irradiation. CONCLUSIONS: After a dedicated planning, construction and commissioning phase, patient treatment at Trento PT center is expected for summer 2014. Based on the already demonstrated as well as further potential clinical benefit neuro-oncology represents one of the most important field of interest.

Purpose:To report preliminary results of re-irradiation with proton therapy (PT) in large-volume recurrent glioblastoma (rGBM).Matherial/Methods:Between January and December 2015 ten patients (pts) with rGBM were re-irradiated with PT. All pts were previously treated with photon radiotherapy (60 Gy) with concomitant and adjuvant TMZ for 1–20 cycles (median, 7). Seven pts were re-irradiated at first relapse/progression. Four patients were re-irradiated after partial tumor resection. Median age and Karnofsky performance status at re-irradiation were 57 years (range, 41–68) and 80%, (range, 70–100), respectively. Median time between prior radiotherapy and PT was 9 months (range, 5–24). Target definition was based on CT, MR, and 18F-DOPA PET imaging. GTV included any area of contrast enhancement after contrast medium administration plus any pathological PET uptake regions. CTV was generated by adding to GTV a 3-mm uniform margin manually corrected in proximity of anatomical barriers. CTV was expanded by 4 mm to create PTV. Median PTV volume was 90 cc (range, 46–231). All pts received 36 GyRBE in 18 fractions. Four pts also received concomitant temozolomide (75 mg/m2/die, 7 days/week). All pts were treated with active beam scanning PT using 2–3 fields with single field optimization technique.Results:All pts completed the treatment without breaks. Registered acute side effects (according to Common Terminology Criteria for Adverse Events version 4.0 - CTCAE) include grade 1–2 skin erythema, alopecia, fatigue, conjunctivitis, concentration impairment, dysphasia, and headache. There were no grade 3 or higher toxicities. One patient developed grade 1 neutropenia. Five pts started PT under steroids (2–7 mg/daily); two of them reduced the dose during PT, while three kept the same steroids dose. None of remaining pts needed steroids therapy. Registered late side effects (according to CTCAE version 4.0) include grade 1–2 alopecia, fatigue, concentration impairment, and dysphasia. During follow-up two pts (20%) developed radionecrosis (diagnosed at imaging) with mild symptoms controlled with steroids. There were no grade 3 or higher toxicities. The median progression-free survival (PFS) was 6.4 months, while the 3-, 6- and 9-month PFS rates were 80%, 67% and 22%, respectively. Median overall survival (OS) after PT was not achieved, while the 6- and 12-month survival after PT rates were 100% and 60%, respectively.Conclusion:PT re-irradiation of large-volume rGBM showed to be feasible and safe even with concomitant chemotherapy administration. Despite the small number of patients and the retrospective nature of the study PFS and OS rates were promising and deserve further evaluation in a larger pts sample.