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Proton beam therapy (PBT) is an advanced type of radiotherapy that shows a dosimetric advantage over photon beam therapy and provides superior dose distribution. PBT may improve patient survival by improving the local disease control while reducing toxicity to normal organs, which may result in fewer treatment-related complications. During the last decade, technological progress has opened up new possibilities in the planning and conducting of PBT, so indications have gradually expanded to different cancers. However, many biological aspects of PBT are still unclear, and its role in clinical settings is controversial. Proton therapy is considered to be safe and effective for different types of pediatric cancers, and suitable in treatment of ocular melanomas, chordomas, and chondrosarcomas. Future research and more prospective clinical studies with long-term follow-up are required in order to clearly determine the benefits and proper indications for PBT.

Metàstasis; Pediatria; Radioteràpia Metástasis; Pediatría; Radioterapia Metastases; Paediatrics; Radiotherapy Purpose/objective About 20% of children with solid tumours (ST) present with distant metastases (DM). Evidence regarding the use of radical radiotherapy of these DM is sparse and open for personal interpretation. The aim of this survey was to review European protocols and to map current practice regarding the irradiation of DM across SIOPE-affiliated countries. Materials/methods Radiotherapy guidelines for metastatic sites (bone, brain, distant lymph nodes, lung and liver) in eight European protocols for rhabdomyosarcoma, non-rhabdomyosarcoma soft-tissue sarcoma, Ewing sarcoma, neuroblastoma and renal tumours were reviewed. SIOPE centres irradiating ≥50 children annually were invited to participate in an online survey. Results Radiotherapy to at least one metastatic site was recommended in all protocols, except for high-risk neuroblastoma. Per protocol, dose prescription varied per site, and information on delineation and treatment planning/delivery was generally missing. Between July and September 2019, 20/27 centres completed the survey. Around 14% of patients were deemed to have DM from ST at diagnosis, of which half were treated with curative intent. A clear cut-off for a maximum number of DM was not used in half of the centres. Regardless of the tumour type and site, conventional radiotherapy regimens were most commonly used to treat DM. When stereotactic radiotherapy was used, a wide range of fractionation regimens were applied. Conclusion Current radiotherapy guidelines for DM do not allow a consistent approach in a multicentre setting. Prospective (randomised) trials are needed to define the role of radical irradiation of DM from paediatric ST. Stichting Kinderen Kankervrij [project no. 343]. KiKa (Children Cancer Free) foundation, grant number 343 and title: Towards optimization of radiotherapy techniques for metastatic lesions in children stage IV disease. The funding source had no role in the study design, collection, analysis and interpretation of data, writing of this manuscript or the decision to submit the article for publication.

Purpose.The aim of the study was to assess health-related quality of life (HRQoL) and contributing factors among parents of children with solid tumors in Serbia.Methods.The cross-sectional study included 51 parents of children treated for different solid tumors at the Institute of Oncology and Radiology of Serbia. Parents filled out validated Serbian version of SF-36 questionnaire. Hierarchical multiple regression analysis was conducted to identify predictors of total score of SF-36.Results.Almost all parents (94.1%) were mothers and average age was 38.6 ± 6.7years. Majority of children had brain tumors (43.1%), followed by bone tumors (37.3%). The hierarchical regression analysis showed that socio-demographic characteristics explained 26% of the variance (p > 0.05) of the total score of SF-36. Addition of quality of life of children assessed by parents in the second model caused an increase of 21% in the variance explained (p p&thinsp

The Institute of Oncology and Radiology of Serbia in Belgrade is an institution in which the implementation of radiotherapy of children and adolescents started 35 years ago. To date, pediatric radiotherapy has been set up and has been following technological possibilities and progress, and a highly specialized multidisciplinary team has been established in the institution with a focus on pediatric oncology and radiotherapy. Purchase of equipment for three-dimensional conformal radiotherapy (3D-CRT) in 2006 enabled qualitative progress in the planning and implementation of pediatric radiotherapy. 60 to 80 patients aged 1 to 18 years are treated annually in our institution. For children aged up to 3 years, and in extremely rare cases older, radiotherapy is carried out in anesthesia, which is emphasized as a significant experience and quality of work of our institution. In the ten-year period from January 2007 to September 2016, 648 children were treated with radiotherapy. In the majority of children, 90.6%, radiotherapy was conducted using 3D conformal technique (3D-CRT) and in small number, 9.4% with conventional radiotherapy (2D-RT). The most frequent patients were children with central nervous system tumors 30.1%, leukemia 16.5%, bone tumors 15.4%, lymphoma 11.9%, soft tissue sarcoma 11.6%, neuroblastoma 6.5%, nephroblastoma 3.6%, retinoblastoma 1.7% and other rare tumors. Besides operative treatment, the majority of children were treated with chemotherapy and radiotherapy, 89.8%. Most of the children treated with radiotherapy were treated with chemotherapy in our institution, 45.8%. In a small number of children, radiotherapy was conducted as the only therapeutic approach, 10.2%. At the Institute for Oncology and Radiology of Serbia, as a central institution for pediatric radiotherapy, 3D-CRT has been fully adopted as a standard in the treatment of children and adolescents. In the past ten years, we have gained our own experiences which will be of great use to us with introduction of advanced techniques that we expect to gain by further purchase of machines and equipment for radiotherapy.

The purpose of this study was to present treatment results of childhood Ewing's sarcoma (ES) of the bone in Serbia and to analyze prognostic factors.We performed a detailed analysis on a series of 107 patients with ES of the bone treated at the Institute for Oncology and Radiology of Serbia between 2000 and 2014, using modern multimodal therapy.Median age at the time of diagnosis was 14 years, with 56.07% of the patients being ≤14 years. There was a male predominance (59.81%). The most common primary sites were pelvis (25.23%), femur (17.76%) and tibia (12.15%). Thirty-four patients (31.78%) had metastatic disease, 17 of which had isolated lung metastases, 9 bone metastases and 8 patients had both. Tumor size ≤ 8 cm had 38.32% and8 cm had 61.68% patients. Overall, 51.4% patients underwent surgery and radiotherapy as a local treatment modality after neoadjuvant chemotherapy. Radiotherapy alone was performed in 24 patients. The 5-year overall survival (OS) was 43.8%. For patients with localized disease, the 5-year OS was 56.4% and for patients with metastatic disease 17.6%. In patients with initially nonmetastatic disease, age under 14 years, with tumor size8 cm and a good response to the neoadjuvant chemotherapy, the OS correlated with better outcome.Modern multidisciplinary approach in treatment of childhood ES of the bone in accordance with the recommended pediatric protocols, gives good treatment results. Therapy should be performed in referral centers.

Objectives: Nasopharyngeal carcinoma is a rare malignancy in children. The aim of this study was to provide analysis of children with nasopharyngeal carcinoma treated in a single institution. Methods and materials: Between 1999 and 2016, fourteen pediatric patients with a diagnosis of undifferentiated nasopharyngeal carcinoma were treated in our institution, and the patients' clinical characteristics, treatment modality, outcome, and toxicity were analyzed. Results: The median age at diagnosis was 15,5 years. The gender ratio was 1:1. The majority of patients had regionally and/or locally advanced tumors and one had bone metastases at the time of diagnosis. All patients received chemotherapy before radiotherapy, with partial response in thirteen patients and complete response in one. Radiation dose to the primary tumor and involved cervical lymph nodes was 55-60 Gy, uninvolved cervical and supraclavicular regions received prophylactic radiation with dose of 45-50 Gy. Ten patients received adjuvant chemotherapy. Three-year progression-free rate and three-year overall survival (OS) rates were 75% and 73% respectively. Five-year progression-free rate was 65% and OS 63% respectively, and after ten years progression-free rate and OS remained the same. At the end of follow-up period, ten patients were alive, and four died. All of the patients that had distant metastases died. Most common late complications were skin fibrosis and xerostomia. Conclusions: Multimodal therapy of children with nasopharyngeal carcinoma is associated with long-term survival. It is expected that further advances in the management of these patients, with improved radiotherapy and chemotherapy, will reduce acute and late toxicity and improve quality of life of treated children.

The aim of this study was to evaluate characteristics of childhood glioblastoma multiforme, effectiveness of treatment modalities, and detect factors related to outcome. A detailed analysis was performed on a series of 15 patients treated between 2000 and 2013, based on their clinical, radiologic, pathologic, treatment, and follow-up data. Median survival time of children with glioblastoma was 13.5 months. One- and 2-year overall survival probabilities were 66.7 and 20 %, respectively. There were no significant differences in survival based on patients’ gender, age, disease presentation with or without epileptic seizures, signs/symptoms of increased intracranial pressure, or tumor location. The presence of neurological deficit initially, as well as prior to radiotherapy, which was quantified by neurologic function score (NFS), had an impact on overall survival. Children with NFS 0 lived longer compared to others (p = 0.001). Survival of children that underwent gross total resection was longer than that of children that underwent subtotal resection (p = 0.030). Mean survival time of children with gross total resection was 73.5 months, compared to 13 months in children with subtotal resection. There was no significant correlation between outcome and type of radiotherapy. In four patients with gigantocellular glioblastoma, we found no evidence of a better prognosis. Two long-term survivors were recorded. Both of them underwent gross total resection and were assigned a NFS 0. Gross total resection is essential for longer overall survival among pediatric patients with glioblastoma and offers a possibility for long-term survival. Severity of neurologic symptoms quantified by NFS can be considered as a potential predictor of outcome.

Intracranial germinomas (ICG) are uncommon brain neoplasms with extremely rare familial occurance. Since ICG invades hypothalamus and/or pituitary, the endocrine dysfunction is one of the common determinants of these tumors. We presented two brothers with the history of ICG. Patient 1 is a 25-year-old male who had been suffering from the weakness of the right half of his body at the age of 18. Cranial MRI revealed mass lesion in the left thalamus. He underwent neurosurgery, tumor was removed completely. Histopathological (HP) and immunohistochemical analyses verified the diagnosis of pure germinoma. He experienced complete remission of the tumor after a radiation therapy. At the age of 22 the diagnosis of isolated growth hormone deficiency (IGHD) was established and GH replacement was initiated. Patient 2 is a 20-year old boy who was presented with diabetes insipidus at the age of 12. MRI detected tumor in the third ventricle and pineal region. After the endoscopic tumor biopsy the HP diagnosis was pure germinoma. He received chemotherapy followed by radiotherapy, and treated with GH during childhood. At the age of 18 GH replacement was reintroduced. A six month follow-up during the next two years in both brothers demonstrated the IGF1 normalization with no MRI signs of tumor recurrence.To the best of our knowledge so far, only six reports have been published related to familial ICG. The presented two brothers are the first report of familial ICG case outside of Japan. They are treated successfully with GH therapy in adult period./pp.

Medulloblastoma has one of the highest rates of metastasis outside the central nervous system (CNS). Bone metastases are the most common lesions, although lymph node and visceral spread have also been reported.To present patients with bone metastasis in medulloblastoma and discuss their radiologic appearances and treatment approach.From 1993 to 2008, 82 patients diagnosed with medulloblastoma were treated at the Institute for Oncology and Radiology of Serbia. Three (3.6%) developed extraneural metastasis (ENM). In primary treatment, patients were treated with surgery, craniospinal radiotherapy with local boost to tumor bed, and adjuvant chemotherapy [lomustine (CCNU) and vincristine]. Of the three patients with ENM, all developed bone metastases at the time of relapse. Relapse occurred within 17 to 42 months of initial diagnosis. Patients received secondary chemotherapy and palliative radiotherapy to the affected bone in two cases.Among these three patients, case 1 had initially a solitary lytic lesion. Case 2 had diffuse blastic lesions and also bone marrow involvement. Case 3 had multiple mixed lytic-sclerotic lesions but later developed lymph node metastasis and metastases to both breasts, as well. All patients were without concurrent CNS involvement at the time of ENM. Unfortunately, after initial partial response, the three patients died at 24, 13, and 18 months after detection of metastases, respectively.With prolonged survival times in children with medulloblastoma, more emphasis should be placed on the possibility of systemic involvement. A greater understanding of the pathogenesis of the systemic metastases may be valuable in designing future, more aggressive multimodal therapy.

Primary spinal cord germinomas are an extremely rare group of tumors, most commonly reported as single cases in young Japanese adults. They usually present as intramedullary lesions located in the thoracic and thoracolumbar spine. The importance of preoperative diagnosis lies in the fact that by using radiotherapy and chemotherapy, even without surgery, a good cure rate can be achieved in patients with spinal cord germinoma. These tumors, however, demonstrate unspecific imaging characteristics, and only some secrete tumor markers. Therefore, a diagnosis of these lesions before biopsy or resection with pathohistologic examination can be difficult. We present a case of a 28-year-old white man with intramedullary spinal cord germinoma. The tumor was resected completely with electrophysiological monitoring, without a biopsy and frozen section analysis. Postoperative radiotherapy also was part of the treatment. The patient has had no relapse 4.5 years after diagnosis; however, significant neurologic deficits remain. Although not as frequent in white patients, germinoma should be considered as differential diagnosis in cases of young adult patients with intramedullary tumor in the thoracic or thoracolumbar spine. Therefore, spinal mass surgery should commence with a biopsy and intraoperative frozen section analysis. In this way, attempting a gross total resection becomes unnecessary. With an approach of intraoperative biopsy and frozen section analysis, a considerable amount of postoperative neurologic deficits can be reduced.

PURPOSE The aim of this study was: 1. to evaluate treatment results of combined therapy (surgery, postoperative craniospinal radiotherapy with or without chemotherapy) and 2. to assess factors affecting prognosis (extend of tumor removal, involvement of the brain stem, extent of disease, postoperative meningitis, shunt placement, age, sex and time interval from surgery to start of postoperative radiotherapy). PATIENTS AND METHODS During the period 1986-1996, 78 patients with medulloblastoma, aged 1-22 years (median 8.6 years), were treated with combined modality therapy and 72 of them were evaluable for the study endpoints. Entry criteria were histologically proven diagnosis, age under 22 years, and no history of previous malignant disease. The main characteristics of the group are shown in Table 1. Twenty-nine patients (37.2%) have total, 8 (10.3%) near total and 41 (52.5%) partial removal. Seventy-two of 78 patients were treated with curative intent and received postoperative craniospinal irradiation. Radiotherapy started 13-285 days after surgery (median 36 days). Only 13 patients started radiotherapy after 60 days following surgery. Adjuvant chemotherapy was applied in 63 (80.7%) patients. The majority of them (46; 73%) received chemotherapy with CCNU and Vincristine. The survival rates were calculated with the Kaplan-Meier method and the differences in survival were analyzed using the Wilcoxon test and log-rank test. RESULTS The follow-up period ranged from 1-12 years (median 3 years). Five-year overall survival (OS) was 51% and disease-free survival (DFS) 47% (Graph 1). During follow-up 32 relapses occurred. Patients having no brain stem infiltration had significantly better survival (p = 0.0023) (Graph 2). Patients with positive myelographic findings had significantly poorer survival compared to dose with negative myelographic findings (p = 0.0116). Significantly poorer survival was found in patients with meningitis developing in the postoperative period, with no patient living longer than two years (p = 0.0134) (Graph 3). By analysis of OS and DFS in relation to presence of the malignant cells in liquor, statistically significant difference, i.e. positive CSF cytology was not obtained, which was of statistical importance for survival (p = 0.8207). Neither shunt placement nor shunt type showed any impact on survival (p = 0.5307 and 0.7119, respectively). Children younger than three years had significantly poorer survival compared to those older than 16 years (p = 0.0473). Although there was a better survival rate in females than in males this was not statistically significant (p = 0.2386). The analysis results of treatment showed that significantly better survival occurred in patients in whom total or subtotal tumor removal was possible (p = 0.0022) (Graph 4). Patients who started radiotherapy within two months after surgery have better survival, but again this was not statistically significant, probably due to the small number of patients receiving delayed radiotherapy (p = 0.2231) (Graph 5). CONCLUSION Based on this factors standard and high risk group could be defined. Combined chemotherapy should to be investigated particularly for high risk subgroup. Future research should be done to define new therapeutic modalities (gene therapy, compounds active in tumor antiangiogenesis etc).

PURPOSE: The aim of our study is to evaluate results of treatment and to develop optimized treatment in children with Germinoma of Central nervous system (CNS). METHOD: Between 2001 and 2013., in Institute for Oncology and Radiology of Serbia we treated 9 patients with CNS Germinoma. The patients median age was 13 years (range 8 -18 yrs), and the male to female ratio was 8:1. A solitary tumor was found in pineal region (3 pts), in region ventriculi III and region supraselaris (2 pts), in one patient in region thalami, in one patient in region mesencephalon and 1 patient has leptomeningeal dissemination. Two patients had elevated B_HCG level in cerebrospinal fluid. After surgery (6 biopsy and 3 gross total resection) all patients received the boost to the primary tumor bed with additional prophylactic therapy to the craniospinal axis. Three patients (33,3 %) were treated with radiotherapy only and six pts (66,7%) were treated by using multimodal therapeutic approach including chemotherapy and radiotherapy. Two patients were treated according to SIOP GSCT trial - both achieved complete response (CR) after neoadjuvant chemotherapy. After irradiation patient with disseminated disease had also no residual tumor and afterwards he received 4 cycles of PEI regimen. One patient received 4 cycles of PEI regimen, also with complete response, followed by irradiation; one patient received only 2 cycles of SIOP GSCT regimen after irradiation (because of hematological toxicity); one patient received 1 cycle of PEI regimen, followed by irradiation and due to chematological toxicity, 3 cycles of Carboplatinum, Etoposid. RESULTS: All patients, treated either with radiotherapy or with radio and chemotherapy, remained disease free during the 20 to 146 months follow-up period (Me= 50 months). CONCLUSION: Results indicate that intracranial germinoma are highly radio and chemosensitive tumors. These excellent results suggest that ongoing trials are needed so to optimize treatment strategy in an effort to minimize late effects of therapy.

c t s fi p p b t s ifferent varieties of craniofacial defects occurred nd were recorded even in the art and culture of ncient civilizations. Some of them are very frequent n the general population; some are extremely rare. here are many environmental factors that have an dverse effect on craniofacial development: maternal iabetes, toxoplasmosis, rubella, cytomegalovirus, erpes simplex infections, smoking, alcohol abuse, edications such as steroids, contraceptives, etc. Facial bone malformations are usually accompanied ith cranial bone and brain malformations. Isolated alformation of the maxilla and mandible, known as yngnathia, is extremely rare. Only 24 cases of this isorder have been reported since 1936. Twenty ases involved fusion of the alveolar processes of the axilla and mandible; only 4 cases presented bony usion of the ascending ramus of mandible and the osterior part of the maxilla. Most of them were resented as an incomplete unilateral fusion, and only cases showed more extensive but still incomplete ntermaxillary bony fusion.

The aim of this study was: 1. to evaluate treatment results of combined therapy (surgery, postoperative craniospinal radiotherapy with or without chemotherapy) and 2. to assess factors affecting prognosis (extend of tumor removal, involvement of the brain stem, extent of disease, postoperative meningitis, shunt placement, age, sex and time interval from surgery to start of postoperative radiotherapy).During the period 1986-1996, 78 patients with medulloblastoma, aged 1-22 years (median 8.6 years), were treated with combined modality therapy and 72 of them were evaluable for the study endpoints. Entry criteria were histologically proven diagnosis, age under 22 years, and no history of previous malignant disease. The main characteristics of the group are shown in Table 1. Twenty-nine patients (37.2%) have total, 8 (10.3%) near total and 41 (52.5%) partial removal. Seventy-two of 78 patients were treated with curative intent and received postoperative craniospinal irradiation. Radiotherapy started 13-285 days after surgery (median 36 days). Only 13 patients started radiotherapy after 60 days following surgery. Adjuvant chemotherapy was applied in 63 (80.7%) patients. The majority of them (46; 73%) received chemotherapy with CCNU and Vincristine. The survival rates were calculated with the Kaplan-Meier method and the differences in survival were analyzed using the Wilcoxon test and log-rank test.The follow-up period ranged from 1-12 years (median 3 years). Five-year overall survival (OS) was 51% and disease-free survival (DFS) 47% (Graph 1). During follow-up 32 relapses occurred. Patients having no brain stem infiltration had significantly better survival (p = 0.0023) (Graph 2). Patients with positive myelographic findings had significantly poorer survival compared to dose with negative myelographic findings (p = 0.0116). Significantly poorer survival was found in patients with meningitis developing in the postoperative period, with no patient living longer than two years (p = 0.0134) (Graph 3). By analysis of OS and DFS in relation to presence of the malignant cells in liquor, statistically significant difference, i.e. positive CSF cytology was not obtained, which was of statistical importance for survival (p = 0.8207). Neither shunt placement nor shunt type showed any impact on survival (p = 0.5307 and 0.7119, respectively). Children younger than three years had significantly poorer survival compared to those older than 16 years (p = 0.0473). Although there was a better survival rate in females than in males this was not statistically significant (p = 0.2386). The analysis results of treatment showed that significantly better survival occurred in patients in whom total or subtotal tumor removal was possible (p = 0.0022) (Graph 4). Patients who started radiotherapy within two months after surgery have better survival, but again this was not statistically significant, probably due to the small number of patients receiving delayed radiotherapy (p = 0.2231) (Graph 5).Based on this factors standard and high risk group could be defined. Combined chemotherapy should to be investigated particularly for high risk subgroup. Future research should be done to define new therapeutic modalities (gene therapy, compounds active in tumor antiangiogenesis etc).