ABSTRACT Background Patients with alveolar rhabdomyosarcoma (ARMS) with regional lymph node involvement (N1) are defined as “very‐high‐risk rhabdomyosarcoma” in Europe. Different chemotherapy regimens were used in European study protocols. Methods Patients with FOXO1 fusion‐positive N1 ARMS registered in the CWS‐2002P study, the EpSSG RMS 2005 study, and SoTiSaR were retrospectively investigated. Patients received systemic treatment with chemotherapy (CHT) and local treatment of primary tumor (PT) and involved lymph nodes (LN) with radiotherapy (RT) and/or surgery. Kaplan–Meier estimators and Cox regression were used to examine event‐free survival (EFS) and overall survival (OS) according to prognostic factors and treatment. Results A total of 156 patients registered in RMS 2005 ( n = 99), CWS‐2002P ( n = 20), and SoTiSaR ( n = 37) between 2003 and 2020 were eligible for this analysis. Median age at diagnosis was 10.2 years [0.1–21.9]. Treatment comprised CHT with IVADo (ifosfamide, vincristine, actinomycin‐D, doxorubicin, n = 93; 60%), VAIA (vincristine, actinomycin‐D, ifosfamide, adriamycin/doxorubicin, n = 53; 34%) or other regimens ( n = 10; 6%); resection of the PT ( n = 89; 57%), LN sampling or dissection ( n = 92; 59%), and/or RT ( n = 139; 89%). Maintenance treatment (MT) was added in n = 99/135 (73%) patients who achieved complete remission. Five‐year EFS and OS of the cohort were 45% and 47%, respectively. Age and tumor size were independent prognostic factors for EFS. Local treatment applied to the LN with surgery, RT or both significantly improved EFS ( p = 0.02) and OS ( p = 0.04), with no difference between the modalities ( p = 0.7). Conclusions Patients with fusion‐positive N1 ARMS carry a poor prognosis. Adequate local treatment of LN improved survival.
Optimization of local therapies in synovial sarcoma (SS) considered unresectable at diagnosis is needed. We evaluated the effects of neoadjuvant versus adjuvant radiation versus surgery only on long-term outcomes.Patients with macroscopic SS tumors before chemotherapy (IRS-group-III) in the trials CWS-81, CWS-86, CWS-91, CWS-96, CWS-2002-P and SoTiSaR-registry were analyzed. Local therapies were scheduled after 3 neoadjuvant chemotherapy cycles.Median age of 145 patients was 14.5 years. 106 survivors had median follow-up of 7.0 years. Tumor site was 96 extremities, 19 head-neck, 16 shoulder/hip, 14 trunk. Tumors were < 3 cm in 16, 3-5 cm in 28, 5-10 cm in 55, > 10 cm in 34 patients. In a secondary resection during chemotherapy, R0-status was accomplished in 82, R1 in 30, R2 in 21 (12 missing). Radiotherapy was administered to 115 (R0 61, R1 29, R2 20, missing 5), thereof 57 before and 52 after tumor resection. 23 were treated with surgery only. For all patients, 5 year event-free (EFS) and overall survival (OS) was 68.9% ± 7.6 (95%CI) and 79.1% ± 6.9. To establish independent significance, tumor site, size, surgical results and sequencing of local therapies were analyzed in a Cox regression analysis. Variables associated with EFS and OS are site, size and sequencing of local therapies. Variables associated with local recurrence are site, surgical results and sequencing of local therapies. The only variable associated with suffering metastatic recurrence is tumor size.Differences in sequencing of local therapy procedures are independently associated with outcomes. Best local control is achieved when tumors are irradiated pre-operatively and undergo R0 or R1 resection thereafter.
Einleitung Protonentherapie ist ein wichtiger Bestandteil der Therapie von Kopf-Hals-Tumoren im Kindesalter. Durch die Nachbarschaft empfindlicher HNO-Organe sind Nebenwirkungen genau zu erfassen. Ziel der Studie war es, die Erfassung HNO-spezifischer Nebenwirkungen zu analysieren und eine Strategie zur Optimierung zu erarbeiten.
The accurate measurement of the beam range in the frame of quality assurance (QA) is a requirement for clinical use of a proton therapy machine. Conventionally used detectors mostly estimate the range by measuring the depth dose distribution of the protons. In this paper, we use pixel detectors designed for individual particle tracking in the high-radiation environment of the ATLAS experiment at LHC. The detector measures the deposited energy in the sensor for individual protons. Due to the limited dynamic energy range of the readout chip, several ways to measure the proton energy or range are examined. A staircase phantom is placed on the detector to perform an energy calibration relative to the NIST PSTAR stopping power database. In addition, track length measurements are performed using the detector aligned parallel with the beam axis to investigate the Linear Energy Transfer (LET) per pixel along the trajectory of individual protons. In this proof-of-principle study, we show that this radiation hardness detector can successfully be used to determine the initial proton energy for protons impinging on the sensor with an energy below 44 MeV after the range shifters. It becomes clear that an improvement of the energy resolution of the readout chip is required for clinical use.
Recommendations for primary treatment of pediatric CHG are well established, but comprehensive therapeutic strategies for subsequent progressive disease are needed. We evaluated salvage therapies applied within the German/Swiss SIOP-LGG-2004/LGG-register cohort. 446 patients with CHG among 2589 patients with low-grade glioma were registered between 2004 and 2015. Neurofibromatosis type 1: 209; histology: 159 pilocytic astrocytomas, 18 pilomyxoid astrocytomas, 27 other histologies and 242 radiological diagnosis. Resection (complete/subtotal/partial) was achieved in 115, biopsy in 89 patients. Only 131/446 patients remained observed without treatment for up to12.8 years. First non-surgical treatment was chemotherapy (ChT) for 268 (263 vincristine/carboplatin ±etoposide) and radiotherapy (RT) for 47. After primary treatment 136/315 patients progressed (median time 2.2 years), of whom 107 received second- (85ChT, 22RT), 54 third- (39ChT, 15RT), 15 fourth- (11ChT, 4RT) and 5 fifth-line therapy (2ChT, 3RT). Five-year overall survival (OS) of the complete cohort is 96.8%. Although 23/53 infants (age <1year) and 21/44 patients with dissemination needed 3-5 therapies, 5-year-OS for infants is still 83.7% and 84.9% for dissemination, respectively. While successive treatments mirrored the distribution of general options, the percentage of patients receiving RT increased up to 30-60% for fourth and fifth therapy. Multiple chemotherapies do not seem to hamper the effect of subsequent radiotherapy. Following vincristine/carboplatin ±etoposide second-line platinum-based ChT achieved 53.4% 2-year progression-free survival vs. 30.3% with vinblastine. Progression/relapse of pediatric CHG following first-line standard treatment still allows disease control for most patients with multiple treatment lines. Future studies should focus upon the effect on vision and integrate targeted treatment.
Sterilization is a major prerequisite for the utilization of nanoparticle colloids in biomedicine, a process well examined for particles derived from chemical synthesis although highly underexplored for electrostatically stabilized ligand-free gold nanoparticles (AuNPs). Hence, in this work, we comprehensively examined and compared the physicochemical characteristics of laser-generated ligand-free colloidal AuNPs exposed to steam sterilization and sterile filtration as a function of particle size and mass concentration and obtained physicochemical insight into particle growth processes. These particles exhibit long-term colloidal stability (up to 3 months) derived from electrostatic stabilization without using any ligands or surfactants. We show that particle growth attributed to cluster-based ripening occurs in smaller AuNPs (∼5 nm) following autoclaving, while larger particles (∼10 and ∼30 nm) remain stable. Sterile filtration, as an alternative effective sterilizing approach, has no substantial impact on the colloidal stability of AuNPs, regardless of particle size, although a mass loss of 5–10% is observed. Finally, we evaluated the impact of the sterilization procedures on potential particle functionality in proton therapy, using the formation of reactive oxygen species (ROS) as a readout. In particular, 5 nm AuNPs exhibit a significant loss in activity upon autoclaving, probably dedicated to specific surface area reduction and surface restructuring during particle growth. The filtered analog enhanced the ROS release by up to a factor of ∼2.0, at 30 ppm gold concentration. Our findings highlight the need for carefully adapting the sterilization procedure of ligand-free NPs to the desired biomedical application with special emphasis on particle size and concentration.
Abstract Background Local treatment of pelvic Ewing’s sarcoma may be challenging, and intergroup studies have focused on improving systemic treatments rather than prospectively evaluating aspects of local tumor control. The Euro-EWING99 trial provided a substantial number of patients with localized pelvic tumors treated with the same chemotherapy protocol. Because local control included surgical resection, radiation therapy, or a combination of both, we wanted to investigate local control and survival with respect to the local modality in this study cohort. Questions/purposes (1) Do patients with localized sacral tumors have a lower risk of local recurrence and higher survival compared with patients with localized tumors of the innominate bones? (2) Is the local treatment modality associated with local control and survival in patients with sacral and nonsacral tumors? (3) Which local tumor- and treatment-related factors, such as response to neoadjuvant chemotherapy, institution where the biopsy was performed, and surgical complications, are associated with local recurrence and patient survival in nonsacral tumors? (4) Which factors, such as persistent extraosseous tumor growth after chemotherapy or extent of bony resection, are independently associated with overall survival in patients with bone tumors undergoing surgical treatment? Methods Between 1998 and 2009, 1411 patients with previously untreated, histologically confirmed Ewing’s sarcoma were registered in the German Society for Pediatric Oncology and Hematology Ewing’s sarcoma database and treated in the Euro-EWING99 trial. In all, 24% (339 of 1411) of these patients presented with a pelvic primary sarcoma, 47% (159 of 339) of which had macroscopic metastases at diagnosis and were excluded from this analysis. The data from the remaining 180 patients were reviewed retrospectively, based on follow-up data as of July 2016. The median (range) follow-up was 54 months (5 to 191) for all patients and 84 months (11 to 191) for surviving patients. The study endpoints were overall survival, local recurrence and event-free survival probability, which were calculated with the Kaplan-Meier method and compared using the log-rank test. Hazard ratios (HRs) with their respective 95% CIs were estimated in a multivariate Cox regression model. Results Sacral tumors were associated with a reduced probability of local recurrence (12% [95% CI 1 to 22] versus 28% [95% CI 20 to 36] at 5 years, p = 0.032), a higher event-free survival probability (66% [95% CI 51 to 81] versus 50% [95% CI 41 to 58] at 5 years, p = 0.026) and a higher overall survival probability (72% [95% CI 57 to 87] versus 56% [95% CI 47 to 64] at 5 years, p = 0.025) compared with nonsacral tumors. With the numbers available, we found no differences between patients with sacral tumors who underwent definitive radiotherapy and those who underwent combined surgery and radiotherapy in terms of local recurrence (17% [95% CI 0 to 34] versus 0% [95% CI 0 to 20] at 5 years, p = 0.125) and overall survival probability (73% [95% CI 52 to 94] versus 78% [95% CI 56 to 99] at 5 years, p = 0.764). In nonsacral tumors, combined local treatment was associated with a lower local recurrence probability (14% [95% CI 5 to 23] versus 33% [95% CI 19 to 47] at 5 years, p = 0.015) and a higher overall survival probability (72% [95% CI 61 to 83] versus 47% [95% CI 33 to 62] at 5 years, p = 0.024) compared with surgery alone. Even in a subgroup of patients with wide surgical margins and a good histologic response to induction treatment, the combined local treatment was associated with a higher overall survival probability (87% [95% CI 74 to 100] versus 51% [95% CI 33 to 69] at 5 years, p = 0.009), compared with surgery alone. A poor histologic response to induction chemotherapy in nonsacral tumors (39% [95% CI 19 to 59] versus 64% [95% CI 52 to 76] at 5 years, p = 0.014) and the development of surgical complications after tumor resection (35% [95% CI 11 to 59] versus 68% [95% CI 58 to 78] at 5 years, p = 0.004) were associated with a lower overall survival probability in nonsacral tumors, while a tumor biopsy performed at the same institution where the tumor resection was performed was associated with lower local recurrence probability (14% [95% CI 4 to 24] versus 32% [95% CI 16 to 48] at 5 years, p = 0.035), respectively. In patients with bone tumors who underwent surgical treatment, we found that after controlling for tumor localization in the pelvis, tumor volume, and surgical margin status, patients who did not undergo complete (defined as a Type I/II resection for iliac bone tumors, a Type II/III resection for pubic bone and ischium tumors and a Type I/II/III resection for tumors involving the acetabulum, according to the Enneking classification) removal of the affected bone (HR 5.04 [95% CI 2.07 to 12.24]; p < 0.001), patients with a poor histologic response to induction chemotherapy (HR 3.72 [95% CI 1.51 to 9.21]; p = 0.004), and patients who did not receive additional radiotherapy (HR 4.34 [95% CI 1.71 to 11.05]; p = 0.002) had a higher risk of death. The analysis suggested that the same might be the case in patients with a persistent extraosseous tumor extension after induction chemotherapy (HR 4.61 [95% CI 1.03 to 20.67]; p = 0.046), although the wide CIs pointing at a possible sparse-data bias precluded any definitive conclusions. Conclusion Patients with sacral Ewing’s sarcoma appear to have a lower probability for local recurrence and a higher overall survival probability compared with patients with tumors of the innominate bones. Our results seem to support a recent recommendation of the Scandinavian Sarcoma Group to locally treat most sacral Ewing’s sarcomas with definitive radiotherapy. Combined surgical resection and radiotherapy appear to be associated with a higher overall survival probability in nonsacral tumors compared with surgery alone, even in patients with a wide resection and a good histologic response to neoadjuvant chemotherapy. Complete removal of the involved bone, as defined above, in patients with nonsacral tumors may be associated with a decreased likelihood of local recurrence and improved overall survival. Persistent extraosseous tumor growth after induction treatment in patients with nonsacral bone tumors undergoing surgical treatment might be an important indicator of poorer overall survival probability, but the possibility of sparse-data bias in our cohort means that this factor should first be validated in future studies. Level of Evidence Level III, therapeutic study.
