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Chordoma in pediatric patients is very rare. Proton therapy has become a gold standard in the treatment of these neoplasms, as high dose escalation can be achieved regarding the target while maximizing the sparing of the healthy tissues near the tumor. The aim of the work was to assess the evolution of morphological sequences during treatment using T1/T2-weighted magnetic resonance imaging (MRI) for the early response assessment of a classic chordoma of the skull base in a pediatric patient who had undergone surgical excision. Our results demonstrated a significant quantitative reduction in the residual nodule component adhered to the medullary bulb junction, with an almost complete recovery of normal anatomy at the end of the irradiation treatment. This was mainly shown in the T2-weighted MRI. On the other hand, the classic component of the lesion was predominantly present and located around the tooth of the axis. The occipital condyles were morphologically and dimensionally stable for the entire irradiation period. In conclusion, the application of this type of monitoring methodology, which is unusual during the administration of a proton treatment for chordoma, highlighted the unexpected early response of the disease. At the same time, it allowed the continuous assessment of the reliability of the treatment plan.

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.

Rosette-forming glioneuronal tumors (RGNTs) are rare, grade I, central nervous system (CNS) tumors typically localized to the fourth ventricle. We describe a 9-year-old girl with dizziness and occipital headache. A magnetic resonance imaging (MRI) revealed a large hypodense posterior fossa mass lesion in relation to the vermis, with cystic component. Surgical resection of the tumor was performed. A RGNT diagnosis was made at the histopathological examination. During follow-up, the patient experienced a first relapse, which was again surgically removed. Eight months after, MRI documented a second recurrence at the local level. She was a candidate for the proton beam therapy (PBT) program. Three years after the end of PBT, the patient had no evidence of disease recurrence. This report underlines that, although RGNTs are commonly associated with an indolent course, they may have the potential for aggressive behavior, suggesting the need for treatment in addition to surgery. Controversy exists in the literature regarding effective management of RGNTs. Chemotherapy and radiation are used as adjuvant therapy, but their efficacy management has not been adequately described in the literature. This is the first case report published in which PBT was proposed for adjuvant therapy in place of chemotherapy in RGNT relapse.

Brain tumors are the most common solid neoplasms of childhood. They are frequently reported in children with Neurofibromatosis type 1 (NF1). The most frequent central nervous system malignancies described in NF1 are optic pathway gliomas and brainstem gliomas. Medulloblastoma (MB) in NF1 patients is extremely rare, and to our knowledge, only 10 cases without molecular characterization are described in the literature to date. We report the case of a 14-year-old girl with NF1 that came to our attention for an incidental finding of a lesion arising from cerebellar vermis. The mass was completely resected, revealing a localized classic medulloblastoma (MB), subgroup 4. She was treated as a standard-risk MB with a dose-adapted personalized protocol. The treatment proved to be effective, with minor toxicity. Brain and spine MRI one year after diagnosis confirmed the complete remission of the disease. To our knowledge, this is the only case of MB reported in a patient with NF1 with molecular characterization by the methylation profile. The association between NF1 and MB, although uncommon, may not be an accidental occurrence.

Background Proton therapy has proven to be effective and safe in the treatment of radioresistant skull base tumors such as chordomas. Thanks to the peculiar physical properties of the proton beam, radiation energy is delivered in a narrow space called the Bragg peak and the surrounding normal tissues receive a minimal amount of the radiation dose. This is important to lower the risk of radiation-induced damage, especially in children. However, local adverse effects in proximity to the target volume may occur. In particular, the development of moyamoya syndrome (MMS) has been rarely reported in children receiving proton beam therapy for brain tumors. Case Description We report on a child who developed rapidly progressive MMS after proton beam therapy for a clivus chordoma. A combined indirect revascularization procedure by encephalo-duro-arterio-synangiosis and encephalo-myo-synangiosis was performed with good neuroradiologic and clinical outcome. Conclusions Regardless of the presence of known risk factors for MMS, strict neuroimaging surveillance is indicated in all patients treated with radiotherapy including those receiving proton beam therapy. We suggest that an early revascularization procedure should be considered in patients with worsening symptoms and/or sign of neuroradiologic progression of cerebral vasculopathy. This management of MMS could lower the risk of permanent neurologic deficits and improve patients' quality of life.

The purpose of this study was to compare the dose to heart, left anterior descending (LAD) artery and lung between proton and photon beam irradiation for left-sided early stage breast cancer.Ten women with early stage left-sided breast cancer were treated with breast conserving surgery and radiation. Whole breast radiation was delivered for actual treatment via a tangential technique with deep inspiration breath hold (DIBH) utilizing inverse planned intensity-modulated radiation therapy (IMRT). Each patient was replanned on an Institutional Review Board (IRB)-approved prospective study using en face proton beam radiation with both uniform scanning (US) and pencil beam scanning (PBS) techniques.Both PBS (0.011 Gy) and US (0.009 Gy) proton plans resulted in a significantly lower mean heart dose compared to IMRT (1.612 Gy) (p0.05 for PBS vs. IMRT and US vs. IMRT). The Dmean, Dmin, Dmax, and D0.2cm(3) of the LAD with either proton technique were significantly lower (p = 0.005) compared to IMRT. Both US and PBS reduced the mean dose to the lungs compared to IMRT. The coverage of the breast planning target volume was comparable between photon and proton plans.The dose to whole heart was relatively low in this study of patients treated under conditions of DIBH. However, proton beam radiation was associated with lower minimum, maximum, and dose to 0.2 cm(3) of the LAD, which is the critical structure for late radiation therapy effects, compared to even the most optimized photon beam plan with DIBH and IMRT.

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.

Chordoma is a slow-growing neoplasm arising from remnants of the embryonic notochord. Surgery is recognized as the gold standard approach, however gross total resection is rarely possible for this reason most patients undergo subtotal resection or biopsy followed by radiotherapy. Myasthenia gravis (MG) is neuromuscular autoimmune disorder .The feasibility and safety of radiotherapy and especially of proton therapy (PT) in patients affected by MG has never been adequately documented. We report the case of a patient with lumbar chordoma who was diagnosed of MG just at the beginning of PT.

Radiation therapy is a part of multidisciplinary management of several childhood cancers. Proton therapy is a new method of irradiation, which uses protons instead of photons. Proton radiation has been used safely and effectively for medulloblastoma, primitive neuro-ectodermal tumors, craniopharyngioma, ependymoma, germ cell intracranial tumors, low-grade glioma, retinoblastoma, rhabdomyosarcoma and other soft tissue sarcomas, Ewing’s sarcoma and other bone sarcomas. Moreover, other possible applications are emerging, in particular for lymphoma and neuroblastoma. Although both photon and proton techniques allow similar target volume coverage, the main advantage of proton radiation therapy is to sparing of intermediate-to-low-dose to healthy tissues. This characteristic could translate into clinical reduction of side effects, including a lower risk for secondary cancers. The following review presents the state of the art of proton therapy in the treatment of pediatric malignancies.

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.

The dosimetric impact of accurately delineating the left anterior descending artery (LAD) was investigated for routine treatment planning deep inspiration breath-hold (DIBH) CT where cardiac motion was not accounted for. The LAD was contoured in the routine DIBH CT images by an expert radiologist in a population of 10 patients with cancer of the left breast. The motion blurring of the LAD in the DIBH CT images was extracted from the contoured LAD to create a corrected LAD volume. This was used to compare the maximum and mean LAD dose over 3D conformal radiotherapy (3DCRT), uniform scattering (US) proton, and pencil beam scanning (PBS) proton plans. Using a corrected LAD volume reduced the maximum dose LAD DVH indicator by 2% (3DCRT), 4% (US), and 25% (PBS). A corrected LAD volume increased the mean dose LAD DVH indicator by 25% (3DCRT), 61% (US), and 35% (PBS). In terms of absolute dose the impact of contouring on LAD is higher for photon therapy due to the higher doses delivered using this modality. Overall, the results demonstrate that the LAD volume could potentially be the source of inconsistencies in correlation between dose and radiation-induced cardiac toxicity when uncompensated motion is present in the treatment planning images.

Recent technological advances in photon-RT have allowed an improvement in targeting accuracy, dose escalation, delivery of multiple large fractions (hypofractionated stereotactic radiation therapy HSRT) or single fraction stereotactic ablative radiation therapy (radiosur‐ gery SRS). Radiosurgery delivers a single large dose with very steep dose fall-off outside the lesion to very small volumes in order to be tumouricidal through DNA damage or ablative causing necrosis via a vascular endothelial damage [1]. Furthermore, it has been shown that molecular responses to radiation differ based on dose per fraction. More recently, HSRT in two to five sessions has been employed to deliver extremely hypofractionated regimens. Prelimi‐ nary data suggest that HSRT may represent an effective treatment associated with lower risk of radiation-related adverse effects in patients with perioptic or large benign tumours as compared with single fraction SRS, although potential benefits remain to be demonstrated.

To assess the visualisation of the left anterior descending (LAD) coronary artery on CT images used for breast radiation treatment planning.Delineation of the LAD artery was achieved for 25 breast patients by 1 radiologist and 1 radiation oncologist independently on two sets of images for each patient: one pre-operative CT scan using intravenous (IV) contrast media to determine the primary gross tumour volume (GTV) and one post-operative CT scan used for treatment planning. A Student's paired t-test was used to compare the number of CT slices in which the LAD was visible for each patient in the two series. Interpolations and extrapolations of the LAD volume were performed for the left-sided cases using a published heart atlas in order to report doses to the LAD structure.There was a non-significant difference between the results with and without IV contrast media (p=0.34 for the radiologist; p=0.90 for the radiation oncologist). The visible LAD artery corresponded to a 30% portion (range 12-47%) of the interpolated structure. The maximum dose to the left artery varied widely, from 2.7 to 41.7 Gy, in the group of patients with left breast tumours. The largest values (25 Gy) corresponded to those patients in whom the LAD artery distal extremity lay inside the breast fields.With the current planning CT protocol, only one-third of the LAD artery could be objectively visualised. Contrast-enhanced imaging used for GTV delineation before the breast surgery did not improve the visualisation of the artery.This study has revealed the lack of consistency that may be encountered when contouring heart vessels, thereby questioning the reliability of dose reporting.

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.