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Introduction Turoctocog alfa (NovoEight® ) is a B-domain-truncated recombinant factor VIII (FVIII) approved for patients with haemophilia A. Aim To investigate the long-term safety and efficacy of turoctocog alfa in routine clinical practice. Methods Guardian 5 was a prospective, multinational, non-interventional, post-authorisation safety study. Male previously treated patients (> 150 exposure days [EDs]) of any age with severe/moderately severe haemophilia A (FVIII ≤ 2%) and a negative inhibitor test prior to first dosing (independent of FVIII-inhibitor history) were included to receive prophylaxis or on-demand treatment. The primary endpoint was the proportion of patients developing FVIII inhibitors (≥.6 Bethesda Units [BU]) after baseline visit, measured as per routine practice of each study site during clinic visits. Secondary endpoints included haemostatic effect, annualised bleeding rate (ABR), and adverse reactions assessment. The study concluded when 50 patients reached 100 EDs/patient minimum. Results Seventy patients were screened and 68 exposed to turoctocog alfa; 63 (92.6%) were on prophylaxis and five received on-demand treatment. Six (8.8%) patients reported a history of positive inhibitors. During the study, patients were exposed to turoctocog alfa for a mean (standard deviation) of 131.9 (99.0) days/patient. Fifty-five of 58 patients who completed the study were tested for FVIII inhibitors; no positive tests were reported. Overall success rate of turoctocog alfa for treatment of bleeds was 87.3%. Among patients receiving prophylaxis, median (range) ABR was 1.97 (.0-25.5) bleeds/year; estimated ABR (negative binomial model) was 3.65 (95% confidence interval: 2.53-5.25). Conclusion Turoctocog alfa was safe and efficacious for haemophilia A treatment in routine clinical practice.

Purpose In Germany, Austria, and Switzerland, pretreatment radiotherapy quality control (RT-QC) for tumor bed boost (TB) in non-metastatic medulloblastoma (MB) was not mandatory but was recommended for patients enrolled in the SIOP PNET5 MB trial between 2014 and 2018. This individual case review (ICR) analysis aimed to evaluate types of deviations in the initial plan proposals and develop uniform review criteria for TB boost. Patients and methods A total of 78 patients were registered in this trial, of whom a subgroup of 65 patients were available for evaluation of the TB treatment plans. Dose uniformity was evaluated according to the definitions of the protocol. Additional RT-QC criteria for standardized review of target contours were elaborated and data evaluated accordingly. Results Of 65 initial TB plan proposals, 27 (41.5%) revealed deviations of target volume delineation. Deviations according to the dose uniformity criteria were present in 14 (21.5%) TB plans. In 25 (38.5%) cases a modification of the RT plan was recommended. Rejection of the TB plans was rather related to unacceptable target volume delineation than to insufficient dose uniformity. Conclusion In this analysis of pretreatment RT-QC, protocol deviations were present in a high proportion of initial TB plan proposals. These findings emphasize the importance of pretreatment RT-QC in clinical trials for MB. Based on these data, a proposal for RT-QC criteria for tumor bed boost in non-metastatic MB was developed.

The European Society for Paediatric Oncology (SIOPE) Radiation Oncology Working Group presents the QUARTET Project: a centralised quality assurance programme designed to standardise care and improve the quality of radiotherapy and imaging for inter-national clinical trials recruiting children and adolescents with cancer throughout Europe. QUARTET combines the paediatric radiation oncology expertise of SIOPE with the infra-structure and experience of the European Organisation for Research and Treatment of Cancer to deliver radiotherapy quality assurance programmes for large, prospective, international clinical trials. QUARTET-affiliated trials include children and adolescents with brain tu-mours, neuroblastoma, sarcomas including rhabdomyosarcoma, and renal tumours including Wilms' tumour. With nine prospective clinical trials and two retrospective studies within the active portfolio in March 2022, QUARTET will collect one of the largest repositories of paediatric radio-therapy and imaging data, support the clinical assessment of radiotherapy, and evaluate the role and benefit of radiotherapy quality assurance for this cohort of patients within the context of clinical trials. 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Purpose: We aimed to compare treatment results in and outside of a randomized trial and to confirm factors influencing outcome in a large retrospective cohort of nonmetastatic medulloblastoma treated in Austria, Switzerland and Germany. Methods and Materials: Patients with nonmetastatic medulloblastoma (n = 382) aged 4 to 21 years and primary neurosurgical resection between 2001 and 2011 were assessed. Between 2001 and 2006, 176 of these patients (46.1%) were included in the randomized HIT SIOP PNET 4 trial. From 2001 to 2011 an additional 206 patients were registered to the HIT 2000 study center and underwent the identical central review program. Three different radiation therapy protocols were applied. Genetically defined tumor entity (former molecular subgroup) was available for 157 patients. Results: Median follow-up time was 7.3 (range, 0.09-13.86) years. There was no difference between HIT SIOP PNET 4 trial patients and observational patients outside the randomized trial, with 7 years progression-free survival rates (PFS) of 79.5% ± 3.1% versus 78.7% ± 3.1% (P= .62). On univariate analysis, the time interval between surgery and irradiation (≤ 48 days vs ≥ 49 days) showed a strong trend to affect PFS (80.4% ± 2.2% vs 64.6% ± 9.1%;P= .052). Furthermore, histologically and genetically defined tumor entities and the extent of postoperative residual tumor influenced PFS. On multivariate analyses, a genetically defined tumor entity wingless-related integration site-activated vs non-wingless-related integration site/non-SHH, group 3 hazard ratio, 5.49;P= .014) and time interval between surgery and irradiation (hazard ratio, 2.2;P= .018) were confirmed as independent risk factors. Conclusions: Using a centralized review program and risk-stratified therapy for all patients registered to the study center, outcome was identical for patients with nonmetastatic medulloblastoma treated on and off the randomized HIT SIOP PNET 4 trial. The prognostic values of prolonged time to RT and genetically defined tumor entity were confirmed.

The purpose of this study was to investigate adherence to recommended adjuvant radiotherapy (aRT) in radical prostatectomy (RP) patients with adverse pathologic features and to analyse the outcome of patients who followed or denied this recommendation.We included 1140 consecutive RP patients (2006-2015) with non-organ confined (pT3) prostate cancer and either positive surgical margins (R1) and/or lymph node involvement (pN1) and non-detectable postoperative prostate-specific antigen who received multidisciplinary aRT recommendations. Patients were stratified into adherence versus non-adherence to recommendations. Additionally, subgroups within pathologic criteria (pT3R1N0, pT3R0N1, pT3R1N1) were analyzed. Kaplan-Meier, as well as multivariable Cox regression analyses were used to assess biochemical recurrence (BCR)-free survival, metastasis-free survival, cancer-specific survival, and overall survival.Overall, 508 (44.6%) patients were non-adherent. Of those, 273 (53.6%) did not receive any RT, and 235 (46.4%) received salvage RT. At 8 years, BCR-free survival was 57.7 versus 20.1%, metastasis-free survival was 76.5 versus 75.4%, cancer-specific survival was 91.7 versus 87.4%, and overall survival was 80.4 versus 75.8% in adherent versus non-adherent patients, respectively (P .001). In multivariable Cox regression predicting BCR, metastatic progression, cancer-specific mortality, and overall mortality, non-adherence to aRT recommendation represented an independent predictor (hazard ratio [HR], 3.8; 95% confidence interval [CI], 3.1-4.5; HR, 1.6; 95% CI, 1.2-2.2; HR, 2.8; 95% CI, 1.5-5.3; and HR, 1.8; 95% CI, 1.2-2.8, respectively).Only about 55% of patients followed our multidisciplinary recommendations. Adherent patients were significantly less likely to experience BCR, metastatic progression, cancer-specific mortality, and overall mortality. Thus, patients with high risk of recurrence may be advised about the possibility of improved oncologic outcomes in case of adherence to aRT recommendations.

Medulloblastoma (WHO grade 4) is the most common malignant brain tumor of childhood. Despite the high importance of radiotherapy for disease control, the mechanisms underlying response and resistance to radiotherapy are incompletely understood. Therefore, we assessed the radiosensitivity and DNA repair capacity of medulloblastoma cell lines in-vitro and of patient-derived xenograft (PDX) models ex-vivo. Cell survival after irradiation of seven medulloblastoma cell lines displaying different subgroups was assessed via colony formation assay (DAOY, UW228, UW473, SJMM4, ONS-76, HDMB-03, D283). The ONS-76 and the mouse SJMM4 cell line were the most radioresistant strains (surviving fraction after 6 Gy (SF6): 0.33 and 0.31, respectively), followed by UW473, UW 228 and DAOY cells (SF6 0.16-0.21). The non-WNT/non-SHH-activated cell lines HDMB-03 and D283 cells demonstrated profoundly higher cellular radiosensitivity (SF6

Este libro se escribió en la hora más oscura de Alemania, pero por primera vez arroja luz sobre la cuestión de la construcción de iglesias e ilumina todo el problema de la arquitectura en sí mismo. Rudolf Schwarz, el gran constructor de iglesias alemán, es uno de los pensadores más profundos de nuestro tiempo. Su libro, a pesar de su claridad, no es fácil de leer, pero quien se tome la molestia de estudiarlo con detenimiento obtendrá una visión real de los problemas discutidos

Purpose Several studies have demonstrated the negative impact of radiotherapy protocol deviations on tumor control in medulloblastoma. In the SIOP PNET5 MB trial, a pretreatment radiotherapy quality control (RT-QC) program was introduced. A first analysis for patients enrolled in Germany, Switzerland and Austria with focus on types of deviations in the initial plan proposals and review criteria for modern radiation technologies was performed. Methods and patients Sixty-nine craniospinal irradiation (CSI) plans were available for detailed analyses. RT-QC was performed according to protocol definitions on dose uniformity. Because of the lack of definitions for high-precision 3D conformal radiotherapy within the protocol, additional criteria for RT-QC on delineation and coverage of clinical target volume (CTV) and planning target volume (PTV) were defined and evaluated. Results Target volume (CTV/PTV) deviations occurred in 49.3% of initial CSI plan proposals (33.3% minor, 15.9% major). Dose uniformity deviations were less frequent (43.5%). Modification of the RT plan was recommended in 43.5% of CSI plans. Unacceptable RT plans were predominantly related to incorrect target delineation rather than dose uniformity. Unacceptable plans were negatively correlated to the number of enrolled patients per institution with a cutoff of 5 patients (p = 0.001). Conclusion This prospective pretreatment individual case review study revealed a high rate of deviations and emphasizes the strong need of pretreatment RT-QC in clinical trials for medulloblastoma. Furthermore, the experiences point out the necessity of new RT-QC criteria for high-precision CSI techniques.

Item does not contain fulltext Inhomogeneities in radiotherapy dose distributions covering the vertebrae in children can produce long-term spinal problems, including kyphosis, lordosis, scoliosis, and hypoplasia. In the published literature, many often interrelated variables have been reported to affect the extent of potential radiotherapy damage to the spine. Articles published in the 2D and 3D radiotherapy era instructed radiation oncologists to avoid dose inhomogeneity over growing vertebrae. However, in the present era of highly conformal radiotherapy, steep dose gradients over at-risk structures can be generated and thus less harm is caused to patients. In this report, paediatric radiation oncologists from leading centres in 11 European countries have produced recommendations on how to approach dose coverage for target volumes that are adjacent to vertebrae to minimise the risk of long-term spinal problems. Based on available information, it is advised that homogeneous vertebral radiotherapy doses should be delivered in children who have not yet finished the pubertal growth spurt. If dose fall-off within vertebrae cannot be avoided, acceptable dose gradients for different age groups are detailed here. Vertebral delineation should include all primary ossification centres and growth plates, and therefore include at least the vertebral body and arch. For partial spinal radiotherapy, the number of irradiated vertebrae should be restricted as much as achievable, particularly at the thoracic level in young children (

Ewing sarcoma is a rare tumor that requires complex multidisciplinary management. This report describes the general management and standard radiotherapy guidelines in both North America (Children's Oncology Group) and Europe (International Society of Pediatric Oncology). Standard treatment involves multiagent induction chemotherapy followed by local treatment with surgery, definitive radiation, or a combination of surgery and radiation followed by additional chemotherapy and consolidation local treatment to metastatic sites. The data supporting the role of chemotherapy, surgery, and radiation and specific radiation therapy guidelines are presented.

PURPOSE/OBJECTIVE(S) Patients with squamous cell carcinoma of the head and neck (HNSCC) under (chemo-)radiotherapy are at high risk of malnutrition. There are no studies investigating the influence of nutritional status on an altered side effect spectrum and only very few studies examining bioelectric impedance analysis (BIA) and its impact as a prognostic indicator in patients with HNSCC undergoing (chemo-)radiotherapy. Our prospective, randomized, and controlled HEADNUT-trial presented here aimed at preventing increasing malnutrition under radiotherapy or concurrent chemoradiotherapy through specialized and individualized nutritional counseling. Additionally, we investigated whether parameters from BIA were suitable indicators for (threatening) malnutrition and inspected their prognostic effect on (clinical) outcome. MATERIALS/METHODS Between October 2018 and October 2020, 61 patients were randomized into an intervention and control group. Questionnaires (MUST, NRS-2002, and Nutriscore), clinical examinations, laboratory analyses, and BIA were used to assess nutritional status for all patients at the beginning and end of therapy as well as every 2 weeks during therapy. The intervention consisted of an individualized nutritional counseling every 2 weeks during therapy. RESULTS Median baseline BMI for all participants was 23.8 (14.5-37.2) kg/m² and dropped to 22.9 (16.8-33) kg/m² after therapy (P < 0.001). In all patients, median baseline fat-free mass index (FFMI) was 18.1 (14-24.7) kg/m² and decreased to 17.8 (13.4-21.6) kg/m² till the end of therapy (P < 0.001). Compliant patients with a BMI < 22 kg/m² presented with less weight loss in the intervention group compared to the control (P = 0.015, CI: 0.33-2.95). At baseline, MUST was the only screening-test which showed both good sensitivity (86%) and specificity (88%) in detecting malnutrition. Median follow-up was 15 (1-26) months. 2-year overall survival rate was 70% in the control and 79% in the intervention group (log-rank P = 0.79). Pretherapeutic phase angle, posttherapeutic FFMI and albumin level were prognostic indicators for overall survival (log-rank P = 0.002, P = 0.008 and P = 0.016). CONCLUSION Malnutrition negatively impacts patients' outcome under (chemo-)radiotherapy. Baseline phase angle, posttherapeutic FFMI and albumin level are proposed as reliable indicators for overall survival.

Introduction The role of chemotherapy for patients with dedifferentiated chondrosarcoma (DDCS) is still under discussion. Here, we present the outcome in patients with DDCS treated with intensive chemotherapy from the EUROpean Bone Over 40 Sarcoma Study. Materials and methods The chemotherapy regimen included doxorubicin, ifosfamide and cisplatin. Postoperative methotrexate was added in case of poor histological response. Toxicity was graded based on the National Cancer Institute expanded common toxicity criteria, version 2.0, and survival was analysed using Kaplan-Meier curves, log-rank tests and univariate Cox regression models. Results Fifty-seven patients with DDCS (localised, 34 [60%]; metastatic, 23 [40%]) aged 42–65 years were included. Surgical complete remission (SCR) was achieved in 36 (63%) patients. The median overall survival (OS) was 24 months (95% confidence interval, 22–25), and the 5-year OS was 39%. Patients with extremity localisation had a 5-year OS of 49% compared with 29% in patients with a central tumour (P = 0.08). Patients with localised disease had a 5-year OS of 46%, whereas patients with metastatic disease had a 5-year OS of 29% (P = 0.12). Patients in SCR had a 5-year OS of 49%, whereas patients not in SCR had a 5-year OS of 23% (P = 0.004). Chemotherapy toxicity was considerable but manageable. There was no treatment-related death, and 39 (70%) patients received ≥6 cycles of the planned nine chemotherapy cycles. Conclusions Adding intensive chemotherapy to surgery for treatment of DDCS is feasible and shows favourable survival data compared with previous reports. With the limitations of data from a non-controlled trial, we conclude that chemotherapy could be considered in the management of patients aged >40 years.

BACKGROUND: Magnetic resonance imaging (MRI) of patients with medulloblastoma (MB) often shows persistent residual findings after primary treatment. Criteria for characterizing these lesions and consensus on further therapeutic approaches are not established. MATERIAL AND METHODS: Eighty-four patients ≥4 years with centrally reviewed residual lesions on MRI at the end of primary therapy with initial surgery between 2000 and 2018 were identified. Data were extracted from the German HIT-MED database. RESULTS: Median age at initial diagnosis was 9.3 (4.0-20.8) years. 91.7% were histologically classified as CMB, 7.1% as LC/AMB and 1.2% as DMB. The majority (65.5%) of the evaluated cohort was assigned to molecular subgroup 4, 24.1% to group 3, 6.8% to WNT, 3.4% to SHH. Median follow-up for survivors was 5.96 (1.41-16.67) years. Univariate analysis revealed that patients showing an overall partial response (PR) to primary therapy have a significantly lower risk of progression of residual lesions compared to patients with stable disease (SD) (5-year PFS [PR]: 62.5±7,0; 5-year PFS [SD]: 35.9±12.8; 5-year OS [PR]: 85.6±5.1; 5-year OS [SD]: 54.1±13.7; p=0.02 [PFS], p=0.04 [OS]). Additionally, patients with multiple residual lesions (M+ and R+) were at higher risk of progression (5-year PFS [R+ only]: 72.4±12.0, 5-year PFS [R+/M+]: 22.9±17.9; p=0.02 [PFS]). Further procedures after the end of primary therapy (additional resections, chemotherapy, radiotherapy) did not impact on PFS and OS. These results were confirmed by multivariate Cox regression. For molecular or histological type no significant effect was found, presumably due to small cohort. CONCLUSION: PFS in patients with residual lesions at the end of primary treatment depends on the overall response to primary therapy. Additional procedures do not seem to be superior compared to watch-and-wait strategies. Decisions regarding further therapies should be scrutinized on a case-by-case basis. Further identification of biomarkers is warranted.

INTRODUCTION: To date, a historical threshold of 1.5cm2 extent of resection (EOR) of the primary tumor is used for risk stratification in pediatric medulloblastoma (MB). METHODS: Data of n=348 patients with MB included into the German HIT-MED studies and registries from 2000-2017 were retrospectively analyzed. Kaplan-Meier statistics and Cox regressions were calculated to determine the influence of EOR, histological and molecular subtype, MYC/N-amplification and presence of metastases at first diagnosis on overall and progression-free survival (OS/PFS). ROC curves were calculated aiming at identifying a new EOR cut-off. RESULTS: Median age at diagnosis was 6.8 [0.1-20.5] years. After initial surgery, residual tumor (R) ≥1.5cm2 was present in 129/348 patients (37%). 57% presented with additional metastases. In most cases, classic histology was found (71%, DMB/MBEN: 20%, LC/AMB: 9%). Molecular subtype was nonWNT/nonSHH in 68% (Group 4: 37%, Group 3: 31%), WNT in 6% and SHH-activated types in 26% of evaluated cases (n=208). MYC/MYCN-amplification was present in 5 and 4%, respectively. 41/348 patients received additional surgery, resulting in 73% GTR (not reported: n=22). EOR had no significant impact on OS/PFS (GTR: 5y-OS/PFS 69.9±3.4/57.6±3.7%, STR: 5y-OS/PFS 71.4±4.1/56.2±4.5%, p=0.6/0.8; Cox: p=0.2/0.4; median follow-up 8.4 [0.1-18.0] years). ROC curves did not identify a significantly improved limit for outcome-relevant EOR cut-off. Analyses confirmed less favorable OS/PFS for patients with metastatic disease (p=0.04/p

Purpose/objective Patients with squamous cell carcinoma of the head and neck undergoing (chemo-)radiotherapy are at high risk of malnutrition. Nevertheless, there is still a lack of prospective, randomized trials investigating the influence of nutritional status on therapy-related toxicity and patients’ outcome. Materials and methods Between October 2018 and October 2020, 61 patients were randomized into an intervention and control group. Questionnaires (MUST, NRS-2002, and Nutriscore), clinical examinations, laboratory analyses, and bioelectrical impedance analysis (BIA) were used to assess nutritional status for all patients at the beginning and end of therapy as well as every 2 weeks during therapy. The intervention consisted of an individualized nutritional counseling every 2 weeks during therapy. Results Median baseline BMI for all participants was 23.8 (14.5–37.2) kg/m2 and dropped to 22.9 (16.8–33) kg/m2 after therapy (p Conclusions Malnutrition negatively impacts patients’ outcome under (chemo-)radiotherapy. Baseline phase angle, posttherapeutic FFMI and albumin level are proposed as reliable indicators for overall survival. This study was registered within the German Clinical Trials Register (DRKS00016862).

Objective Radiotherapy (RT) is an integral part of the interdisciplinary treatment of patients with high-risk neuroblastoma (NB). With the continuous improvements of outcome, the interest in local treatment strategies that reduce treatment-related side effects while achieving optimal oncological results is growing. Proton beam therapy (PBT) represents a promising alternative to conventional photon irradiation with regard to the reduction of treatment burden. Method Retrospective analysis of children with high or intermediate risk NB receiving PBT of the primary tumor site during first-line therapy between 2015 and 2020 was performed. Data from the prospective in-house registry Standard Protonentherapie WPE – Kinder- (KiProReg) with respect to tumor control and treatment toxicity were analyzed. Adverse events were classified according to CTCAE Version 4 (V4.0) before, during, and after PBT. Results In total, 44 patients (24 male, 20 female) with high (n = 39) or intermediate risk NB (n = 5) were included in the analysis. Median age was 3.4 years (range, 1.4–9.9 years). PBT doses ranged from 21.0 to 39.6 Gray (Gy) (median 36.0 Gy). Five patients received PBT to the MIBG-avid residual at the primary tumor site at time of PBT according to the NB-2004 protocol. In 39 patients radiation was given to the pre-operative tumor bed with or without an additional boost in case of residual tumor. After a median follow-up (FU) of 27.6 months, eight patients developed progression, either local recurrence (n = 1) or distant metastases (n = 7). Four patients died due to tumor progression. At three years, the estimated local control, distant metastatic free survival, progression free survival, and overall survival was 97.7, 84.1, 81.8, and 90.9%, respectively. During radiation, seven patients experienced higher-grade (CTCAE ≥ °3) hematologic toxicity. No other higher grade acute toxicity occurred. After PBT, one patient developed transient myelitis while receiving immunotherapy. No higher grade long-term toxicity was observed up to date. Conclusion PBT was a well tolerated and effective local treatment in children with high and intermediate risk NB. The role of RT in an intensive multidisciplinary treatment regimen remains to be studied in the future in order to better define timing, doses, target volumes, and general need for RT in a particularly sensitive cohort of patients.

(1) Background: The combination of the first-generation antiandrogens and radiotherapy (RT) has been studied extensively in the clinical setting of prostate cancer (PCa). Here, we evaluated the potential radiosensitizing effect of the second-generation antiandrogens abiraterone acetate, apalutamide and enzalutamide. (2) Methods: Cell proliferation and agarose-colony forming assay were used to measure the effect on survival. Double strand break repair efficiency was monitored using immunofluorescence staining of &gamma, H2AX/53BP1. (3) Results: We report retrospectively a minor benefit for PCa patients received first-generation androgen blockers and RT compared to patients treated with RT alone. Combining either of the second-generation antiandrogens and 2Gy suppressed cell growth and increased doubling time significantly more than 2Gy alone, in both hormone-responsive LNCaP and castration-resistant C4-2B cells. These findings were recapitulated in resistant sub-clones to (i) hormone ablation (LNCaP-abl), (ii) abiraterone acetate (LNCaP-abi), (iii) apalutamide (LNCaP-ARN509), (iv) enzalutamide (C4-2B-ENZA), and in castration-resistant 22-RV1 cells. This radiosensitization effect was not observable using the first-generation antiandrogen bicalutamide. Inhibition of DNA DSB repair was found to contribute to the radiosensitization effect of second-generation antiandrogens, as demonstrated by a significant increase in residual &gamma, H2AX and 53BP1 foci numbers at 24h post-IR. DSB repair inhibition was further demonstrated in 22 patient-derived tumor slice cultures treated with abiraterone acetate before ex-vivo irradiation with 2Gy. (4) Conclusion: Together, these data show that second-generation antiandrogens can enhance radiosensitivity in PCa through DSB repair inhibition, regardless of their hormonal status. Translated into clinical practice, our results may help to find additional strategies to improve the effectiveness of RT in localized PCa, paving the way for a clinical trial.

Contains fulltext : 219893.pdf (Publisher’s version ) (Closed access) BACKGROUND: Treatment of venous thromboembolism in children is based on data obtained in adults with little direct documentation of its efficacy and safety in children. The aim of our study was to compare the efficacy and safety of rivaroxaban versus standard anticoagulants in children with venous thromboembolism. METHODS: In a multicentre, parallel-group, open-label, randomised study, children (aged 0-17 years) attending 107 paediatric hospitals in 28 countries with documented acute venous thromboembolism who had started heparinisation were assigned (2:1) to bodyweight-adjusted rivaroxaban (tablets or suspension) in a 20-mg equivalent dose or standard anticoagulants (heparin or switched to vitamin K antagonist). Randomisation was stratified by age and venous thromboembolism site. The main treatment period was 3 months (1 month in children /=1 dose), were centrally assessed by investigators who were unaware of treatment assignment. Repeat imaging was obtained at the end of the main treatment period and compared with baseline imaging tests. This trial is registered with ClinicalTrials.gov, number NCT02234843 and has been completed. FINDINGS: From Nov 14, 2014, to Sept 28, 2018, 500 (96%) of the 520 children screened for eligibility were enrolled. After a median follow-up of 91 days (IQR 87-95) in children who had a study treatment period of 3 months (n=463) and 31 days (IQR 29-35) in children who had a study treatment period of 1 month (n=37), symptomatic recurrent venous thromboembolism occurred in four (1%) of 335 children receiving rivaroxaban and five (3%) of 165 receiving standard anticoagulants (hazard ratio [HR] 0.40, 95% CI 0.11-1.41). Repeat imaging showed an improved effect of rivaroxaban on thrombotic burden as compared with standard anticoagulants (p=0.012). Major or clinically relevant non-major bleeding in participants who received >/=1 dose occurred in ten (3%) of 329 children (all non-major) receiving rivaroxaban and in three (2%) of 162 children (two major and one non-major) receiving standard anticoagulants (HR 1.58, 95% CI 0.51-6.27). Absolute and relative efficacy and safety estimates of rivaroxaban versus standard anticoagulation estimates were similar to those in rivaroxaban studies in adults. There were no treatment-related deaths. INTERPRETATION: In children with acute venous thromboembolism, treatment with rivaroxaban resulted in a similarly low recurrence risk and reduced thrombotic burden without increased bleeding, as compared with standard anticoagulants. FUNDING: Bayer AG and Janssen Research & Development. 01 januari 2020

Combined high-dose-rate brachytherapy (HDR-BT) and external beam radiation therapy (EBRT) is a favorable treatment option in non-metastatic prostate cancer. However, reports on toxicity and outcome have mainly focused on younger patients. We aimed to determine toxicity and biochemical control rates after combined HDR-BT and EBRT in men ≥75 years. From 1999 to 2015, 134 patients aged ≥75 years (median 76 years; 75–82 years) were identified. Patients received 18 Gy of HDR-BT (9 Gy/fraction on days 1 and 8) with an iridium-192 source. After 1 week, supplemental EBRT with a target dose of 50.4 Gy was started (delivered in 1.8 Gy fractions). Median follow-up time was 25 months (0–127 months). No severe (grade 4) gastrointestinal (GIT) or genitourinary (GUT) toxicities were observed. In 76 patients (56.7%), 3D conformal radiation therapy (CRT) and in 34.3% intensity-modulated radiotherapy (IMRT) was applied. CRT-treated patients were at a 2.17-times higher risk (hazard ratio [HR]: 2.17, 95% confidence interval [CI]: 1.31–3.57, p = 0.002) of experiencing GUT. GIT risks could be reduced by 78% using IMRT (HR: 0.22, 95% CI: 0.07–0.75, p = 0.015). Patients with a higher T stage (T2c–3a/b) were less likely to experience GIT or GUT (HR: 0.49, 95% CI: 0.29–0.85, p = 0.011 and HR: 0.5, 95% CI: 0.3–0.81, p = 0.005, respectively). HDR-BT/EBRT is a well-tolerated treatment option for elderly men ≥75 years with a limited number of comorbidities and localized intermediate- or high-risk prostate cancer. IMRT should be favored since side effects were significantly reduced in IMRT-treated patients.

Kinder und Jugendliche mit schwerer Hamophilie leiden als typische Folge der Blutungen in Muskeln und Gelenken unter akuten und chronischen Schmerzen. Ebenso spielen interventionsbezogene Schmerzen eine erhebliche Rolle. Trotz ihrer hohen Pravalenz werden die Schmerzen in dieser Patientengruppe nicht immer ausreichend thematisiert oder gezielt analgetisch behandelt. Die Handlungsempfehlungen widmen sich der Frage, wie das Schmerzmanagement fur Kinder und Jugendliche mit Hamophilie verbessert werden kann und welche Besonderheiten bei ihnen in der Schmerztherapie zu beachten sind. Im Rahmen eines Expertentreffens wurde das Problem der Schmerzbehandlung bei Kindern und Jugendlichen (Alter 0 bis 18 Jahre) mit Hamophilie diskutiert. Anhand der verfugbaren Literatur und klinischen Erfahrung wurden Handlungsempfehlungen erarbeitet. Die schmerztherapeutische Versorgung von Kindern mit Hamophilie ist haufig insuffizient, sodass die Gefahr besteht, dass akute Schmerzen zu Chronifizierung und Traumatisierung fuhren. Sowohl das Alter der Patienten als auch die Grunderkrankung stellen besondere Anforderungen vor allem an die medikamentose Therapie. Konkrete Handlungsempfehlungen zur Verbesserung der Situation wurden erarbeitet.

To determine the impact of Gallium-68-labled prostate-specific membrane antigen positron-emission tomography/computed tomography ([68Ga]PSMA PET/CT) on radiotherapy planning for primary disease, biochemical cancer relapse, and advanced disease of prostate cancer. A total of 106 patients with prostate cancer scheduled for radiation therapy underwent 120 [68Ga]PSMA PET/CT scans prior to radiotherapy treatment. In 20 cases, patients underwent [68Ga]PSMA PET/CT for primary therapy (PT), 75 cases were referred for biochemical relapse after surgery (RL), and 25 cases were intended for palliative treatment of localized metastases (MD). We retrospectively compared the impact of [68Ga]PSMA PET/CT on lesion detection and treatment decision to CT alone. [68Ga]PSMA PET/CT revealed a total of 271 positive lesions, whereas CT detected 86 lesions (32%). Overall, the radiotherapy regime was changed in 55 of 120 cases (46%) based on the higher detection rate of [68Ga]PSMA PET/CT: in 15% of cases with PT, in 43% of cases with RL, and in 44% of cases with MD. [68Ga]PSMA PET/CT is superior to CT alone for lesion detection in prostate cancer, thereby significantly impacting on radiotherapy planning for primary disease, biochemical cancer relapse, and advanced disease of prostate cancer.

Background While the optimal use and timing of secondary therapy after radical prostatectomy (RP) remain controversial, there are limited data on patient-reported outcomes following multimodal therapy. Objective To assess the impact of additional radiation therapy (RT) and/or androgen deprivation therapy (ADT) on urinary continence, potency, and quality of life (QoL) after RP. Design, setting, and participants Among 13150 men who underwent RP from 1992 to 2013, 905 received RP + RT, 407 RP + ADT and 688 RP + RT + ADT. Outcome measurements and statistical analyses Urinary function, sexual function, and overall QoL were evaluated annually using self-administered validated questionnaires. Propensity score–matched and bootstrap analyses were performed, and the distributions for all functional outcomes were analyzed as a function of time after RP. Results and limitations Patients who received RP + RT had a 4% higher overall incontinence rate 3 yr after surgery, and 1% higher rate for severe incontinence (>3 pads/24h) compared to matched RP-only patients. ADT further increased the overall and severe incontinence rates by 4% and 3%, respectively, compared to matched RP + RT patients. RP + RT was associated with an 18% lower rate of potency compared to RP alone, while RP + RT + ADT was associated with a further 17% reduction compared to RP + RT. Additional RT reduced QoL by 10% and additional ADT by a further 12% compared to RP only and RP + RT, respectively. The timing of RT after RP had no influence on continence, but adjuvant compared to salvage RT was associated with significantly lower potency (37% vs 45%), but higher QoL (60% vs 56%). Limitations of our study include the observational study design and potential for selection bias in the treatments received. Conclusions Secondary RT and ADT after RP have an additive negative influence on urinary function, potency, and QoL. Patients with high-risk disease should be counseled before RP on the potential net impairment of functional outcomes due to multimodal treatment. Patient summary Men with high-risk disease choosing surgery upfront should be counseled on the potential need for additional radiation and or androgen deprivation, and the potential net impairment of functional outcomes arising from multimodal treatment.

PURPOSE To evaluate prognostic factors and impact of participation in a randomized trial in non-metastatic medulloblastoma. METHODS AND PATIENTS 382 patients with non-metastatic medulloblastoma aged 4–21 years with primary neurosurgical resections between 2001 and 2011 were enrolled into the HIT 2000 trial and centrally reviewed. Between 2001 and 2006, 176 of these patients participated in the randomized trial HIT-SIOP PNET 4. Three different radiotherapy protocols were applied. Molecular subgroup was available for 157 patients. RESULTS Median follow-up was 6.35 [0.09–13.86] years. The 5-year progression-free (PFS) and overall survival (OS) rates were 80.3 % ± 2.1 % and 86.5 % ± 1.8 %, respectively. On univariate analysis, there was no difference in PFS and OS according to radiotherapy protocols or in patients who participated in the HIT-SIOP PNET 4 trial or not, while histology, molecular subgroup and postoperative residual tumor influenced PFS significantly. Time interval between surgery and irradiation (≤48 days vs. ≥49 days) failed the significance level (p=0.052). On multivariate analyses, molecular subgroup (WNT activated vs. Group3 HR 5.49; p=0.014) and time interval between surgery and irradiation (HR 2.2; p=0.018) were confirmed as independent risk factors. CONCLUSION Using a centralized review system, multiprofessional and multiinstitutional collaboration as established for pediatric brain tumor patients in Germany, and risk-stratified therapy, outcome for non-metastatic medulloblastoma treated within HIT-SIOP PNET4 could be maintained outside the randomized trial. Prolonged time to radiotherapy negatively influenced survival.

BACKGROUND Impact of isolated spread into the cerebrospinal fluid (CSF) is still not investigated comprehensively for childhood medulloblastoma and the best therapeutic strategy is currently unclear. MATERIAL AND METHODS Sixty-six patients with isolated M1-MB registered to the HIT-MED-database from 2000–2018 were identified. CSF and MRI were centrally reviewed for all patients. Patients were stratified by age and either treated with upfront craniospinal irradiation (CSI) followed by maintenance chemotherapy (CT) or with postoperative CT and delayed CSI. RESULTS Forty-nine patients were non-infants ≥4 years and seventeen were infants CONCLUSION Isolated M1-MB is rare. Patients without contraindication for CSI appear to benefit from treatment by upfront CSI followed by maintenance CT, while cumulative CT-doses would be reduced compared to sandwich strategies.

The Austrian Haemophilia Registry collects epidemiological data on patients with haemophilia, on treatment modalities and potential side effects. The Registry covers more than 85% of the assumed total number of haemophilia patients in Austria. This report summarizes data on 753 patients: 84.3% (635) have haemophilia A and 15.7% (118) have haemophilia B. Patients' median age is 34 years (range: 1-93 years). Of the total cohort, 39.0% (294) patients have severe haemophilia, 11.3% (85) moderate haemophilia, and 49.4% (372) mild haemophilia. Of the patients with severe haemophilia, 38.4% (113) have been infected with hepatitis C virus (HCV) and 12.6% (37) are human immunodeficiency virus (HIV) positive. Overall, 10.6% (67) of patients with haemophilia A and 1.7% (2) of those with haemophilia B have had an inhibitor in their history. Among patients with severe haemophilia, 68.4% (201) receive prophylaxis and 28.6% (84) receive on-demand therapy. There are 65.0% (191) patients with severe haemophilia who are treated with recombinant products. In conclusion, most patients with severe haemophilia receive prophylactic treatment. HCV and HIV infections are still important issues in the Austrian haemophilia population.Das Österreichische Hämophilieregister sammelt epidemiologische Daten über Patienten mit Hämophilie, über die Behandlungsmodalitäten und über die möglichen Nebenwirkungen. Das Österreichische Hämophilie Register erfasst mehr als 85% der zu erwartenden Anzahl von Hämophilen in Österreich. Im Register sind 753 Patienten erfasst, von denen 84.3% (635) Hämophilie A und 15.7% (118) Hämophilie B haben. Das mediane Alter ist 34 Jahre (1–93). Es haben 39.0% (294) eine schwere, 11.3% (85) eine mittelschwere und 49.4% (372) eine leichte Hämophilie. Von den Patienten mit schwerer Hämophilie wurden 38.4% (113) mit HCV infiziert und 12.6% (37) sind HIV positiv. Insgesamt haben 10.6% (67) aller Patienten mit Hämophilie A und 1.7% (2) aller Patienten mit Hämophilie B einen Hemmkörper in ihrer Anamnese. Von den Patienten mit schwerer Hämophilie erhalten 68.4% (201) eine Prophylaxe und 28.6% (84) eine Bedarfsbehandlung. Von den Patienten mit schwerer Hämophilie erhalten 65.0% (191) ein rekombinantes Produkt. Zusammenfassend erhalten die meisten Patienten mit schwerer Hämophilie eine Prophylaxe. HCV und HIV Infektionen sind immer noch von großer Bedeutung für die österreichischen Hämophilie-Patienten.

Introduction: The EUROpean Bone Over 40 Sarcoma Study (EURO-B.O.S.S.) was the first prospective international study for patients 41-65 years old with high-grade bone sarcoma treated with an intensive chemotherapy regimen derived from protocols for younger patients with high-grade skeletal osteosarcoma. Methods: Chemotherapy based on doxorubicin, cisplatin, ifosfamide, and methotrexate was suggested, but patients treated with other regimens at the investigators’ choice were also eligible for the study. Results: The present report focuses on the subgroup of 218 patients with primary high-grade osteosarcoma. With a median follow-up of 47 months, the 5-year probability of overall survival (OS) was 66% in patients with localized disease and 22% in case of synchronous metastases. The 5-year OS in patients with localized disease was 29% in pelvic tumors, and 70% and 73% for extremity or craniofacial locations, respectively. In primary chemotherapy, tumor necrosis ≥90% was reported in 21% of the patients. There were no toxic deaths; however, hematological toxicity was considerable with 32% of patients experiencing 1 or more episodes of neutropenic fever. The incidence of nephrotoxicity and neurotoxicity (mainly peripheral) was 28% and 24%, respectively. After methotrexate, 23% of patients experienced delayed excretion, in 4 cases with nephrotoxicity. Conclusions: In patients over 40 years of age with primary high-grade osteosarcoma, an aggressive approach with chemotherapy and surgery can offer the probability of survival similar to that achieved in younger patients. Chemotherapy-related toxicity is significant and generally higher than that reported in younger cohorts of osteosarcoma patients treated with more intensive regimens.

To determine the impact of Gallium-68-labled prostate-specific membrane antigen positron-emission tomography/computed tomography ([A total of 106 patients with prostate cancer scheduled for radiation therapy underwent 120 [[[

To evaluate the outcome of holmium laser enucleation of the prostate (HoLEP) in the known presence of prostate cancer (PCa) and concomitant lower urinary tract symptoms (LUTS).We retrospectively identified 62 patients who underwent HoLEP for LUTS in the known presence of PCa at our center. Perioperative data were assessed including complications, functional outcomes, and quality of life (QoL). Giving respect to different disease characteristics, patients were stratified according to treatment strategy setting into palliative (I), radiation (II), and surveillance (III) groups and compared accordingly.Median follow-up (FU) of the entire study cohort was 27 months (range 2-65 mos). Medians of functional parameters (International Prostate Symptom Score): 18.5 vs 4.5, QoL: 4 vs 1, maximal flow rate: 9.0 vs 18.8 mL/s and residual urine: 100 vs 0 mL, all P0.05) improved significantly in all groups. Perioperative complications were low and without any statistically significant difference between the groups. Postoperatively, voiding was successful in 90.3% of all patients; at last FU, 17% had some degree of urinary incontinence. Treatment strategy groups showed comparable functional outcomes after HoLEP.In the presence of PCa and LUTS, HoLEP represents a feasible, safe, and effective treatment option for patients unfit or without indication for radical prostatectomy. This applies as well in a palliative situation of advanced, obstructive PCa as for patients with LUTS who are scheduled for radiation therapy or surveillance in presumably indolent disease.

Purpose To evaluate patient and tumor characteristics, treatment, and outcomes in a large cohort of unselected patients with second and subsequent recurrences of osteosarcoma. Patients and Methods Two hundred forty-nine consecutive patients who had originally received combined-modality therapy on neoadjuvant Cooperative Osteosarcoma Study Group protocols and went on to develop a total of 409 second and subsequent osteosarcoma recurrences were analyzed for patient-, tumor-, and treatment-related factors and outcomes. Results Five-year overall and event-free survival rates were 16% and 9% for 249 second, 14% and 0% for 93 third, 13% and 6% for 38 fourth, and 18% and 0% for 14 fifth recurrences, respectively. The proportion of recurrences confined to the lungs decreased and the proportion of those with chest wall involvement increased with increasing numbers of recurrences. The duration of relapse-free intervals and the number of lesions at recurrence correlated with outcomes. While only one of 205 patients with rerecurrence survived past 5 years without surgical remission, 5-year overall and event-free survival rates were 32% and 18% for 119 second, 26% and 0% for 45 third, 28% and 13% for 20 fourth, and 53% and 0% for five fifth recurrences, respectively, in which a renewed surgical remission was achieved. The use of chemotherapy correlated with longer survival in patients without surgical remissions. Conclusion To our knowledge, this is the first report of survival estimates derived from large cohorts of unselected patients with second and subsequent osteosarcoma recurrences. It confirms the overwhelming importance of surgical clearance. Prognostic indicators after rerecurrences resemble those known from first recurrence. The exact role of re-treatment with chemotherapy, particularly in the adjuvant situation, remains to be defined.

Recurrence rates of 20-40% after prostatectomy are described. This review will discuss curative treatment options for salvage after primary therapy. Relevant information was identified through searches of published studies, abstracts from scientific meetings, and review articles. Clinical experience in salvage therapy is limited. Conformal radiotherapy to the prostatic bed for PSA relapse and biopsy proven local recurrences after prostatectomy remains the only potentially curative therapy. It can provide durable biochemical control in a range from 17 to 78%. Salvage radiotherapy is well tolerated. Some prognostic factors exist which can help to select the right patient for this treatment. Patients have to be treated early for PSA relapse. Conformal radiotherapy to the prostatic bed for PSA relapse and biopsy proven local recurrences after prostatectomy is a good documented curative therapy. In a patient with a high probability of local recurrence early radiotherapy for PSA relapse is suggested.

To evaluate the accuracy of virtual simulation, which is less time-consuming than physical simulation, with the new laser system Dorado CT4 in 96 prostate cancer patients.Virtual simulation was based on a spiral scan with 8 mm reconstruction index and 8 mm slice thickness in 64 patients (group A), and 3 mm reconstruction index and 3 mm slice thickness in 32 patients (group B). Both groups were evaluated for impact on maximum difference (Deltamax) regarding the isocenters obtained from virtual simulation versus those obtained from physical simulation.In the entire cohort, mean differences were as follows: Deltamax 5.7 +/- 3.5 mm, Deltax (left/right) 2.8 +/- 2.9 mm, Deltay (anterior/posterior) 4.5 +/- 3.8 mm, and Deltaz (cranial/caudal) 2.1 +/- 2.2 mm. In group A, mean values were Deltamax 6.2 +/- 3.8 mm, Deltax 2.9 +/- 3.1 mm, Deltay 4.9 +/- 4.2 mm, and Deltaz 2.3 +/- 2.3 mm. In group B, mean values were Deltamax 4.8 +/- 2.8 mm, Deltax 2.7 +/- 2.7 mm, Deltay 3.7 +/- 2.7 mm, and Deltaz 1.7 +/- 2.0 mm. Time of radiotherapy (primary vs. salvage RT) and radiation regimen (external-beam radiotherapy [EBRT] vs. high-dose-rate brachytherapy [HDR-BT] plus EBRT) had no significant impact on Deltamax.Virtual simulation with the new laser system Dorado CT4 was very precise for both primary and salvage RT in the treatment of prostate cancer patients. High precision was achieved for both EBRT and HDR-BT plus EBRT. Virtual simulation should be performed with a planning CT with 3 mm reconstruction index and 3 mm slice thickness for high accuracy.

High-dose-rate brachytherapy (HDR-BT) with external-beam radiation therapy and radical prostatectomy (RP) are common treatment options for clinically localized prostate cancer. The aim was to describe risk factors for biochemical recurrence (BCR) and death, as well as BCR rates and overall survival (OS) rates in both treatment groups.Overall, 5,619 patients with localized prostate cancer underwent either RP (n = 5,200) or HDR-BT (n = 419) between 1999 and 2009. Median follow-up time was 72.4 months. Kaplan-Meier analyses and multivariable Cox regression analyses were performed for the overall cohort and for a propensity score-matched cohort to predict BCR and OS rates. Within the matched cohort, stratified analyses were repeated for HDR-BT alone (n = 206) and HDR-BT plus androgen deprivation therapy (ADT) (n = 213). Sensitivity analyses were performed to adjust for prostate-specific antigen rebound.The 5-year BCR-free survival rates were 82.1% vs. 80.3% (P0.01) for RP and HDR-BT, respectively. Corresponding 5-year OS rates were 97.1% vs. 92.4% (P0.01). In the propensity score-matched cohort, 5-year BCR-free survival rates were 80.3% vs. 77.1%; P = 0.06 and 5-year OS rates were 95.7% vs. 92.4%; P = 0.5. In multivariable models, the overall HDR-BT exerted no significant effect on BCR, and the same results were recorded in the matched cohort. In stratified analyses, HDR-BT alone vs. RP increased BCR risk (1.45; P0.01); conversely, HDR-BT plus ADT vs. RP decreased BCR risk (hazard ratio = 0.66; P = 0.02).First, RP offers equivalent oncological control without the need for concurrent hormone therapy and its morbidity. Second, patients who have RP avoid ADT (2%) and the need for salvage and adjuvant external-beam radiation therapy is low at 11% and 3%, respectively.

Objective: Recurrence rates of 40–60% after percutaneous radiotherapy or brachytherapy and 20–40% after prostatectomy are described. This review will discuss curative treatment options for salvage after primary therapy. Methods: Relevant information was identified through searches of published studies, abstracts from scientific meetings, and review articles. Results: Clinical experience in salvage therapy is limited. Salvage prostatectomy is an effective method to treat selected patients with recurrence after percutaneous radiotherapy. Cryoablation and brachytherapy are alternative methods. Conformal radiotherapy to the prostatic bed for PSA relapse and biopsy proven local recurrences after prostatectomy remains the only potentially curative therapy. It can provide durable biochemical control in a range from 17% to 78%. Salvage radiotherapy is well tolerated. Some prognostic factors exist which can help to select the right patient for this treatment. Patients have to be treated early for PSA relapse. Conclusions: Salvage prostatectomy for highly selected patients is an effective treatment with excellent long-term control. Complication rates were reduced in the last years. Conformal radiotherapy to the prostatic bed for PSA relapse and biopsy proven local recurrences after prostatectomy is a good documented curative therapy. In a patient with a high probability of local recurrence early radiotherapy for PSA relapse is suggested.