Search

Background: Dystocia is rare in horses, but is life-threatening for mares and foals. Therefore, veterinary research depends on up-to-date data to optimise equine dystocia management. In addition, knowledge of the prognosis of equine dystocia is necessary to advise animal owners. This retrospective study of equine dystocia aimed to enrich existing datasets with up-to-date information. For the first time, the focus was on the causes of dystocia that occurred alone or in combination. Over a period of 10 years, 72 cases of dystocia were analysed using a standardised, predetermined diagnosis code., Results: Of the 72 cases of dystocia, an isolated cause of dystocia was identified in 37 cases (51.4%) and 35 mares showed a combination of two or more causes (48.6%). Foetal causes were significantly more frequent origin of dystocia (66/69) than maternal causes (3/66) (P < 0.0001). Incorrect posture of the foetal forelimbs and head was the most common combination at 25.7%. The most common isolated cause of dystocia was incorrect posture of the foetal forelimbs (18.9%). A foetotomy was performed in 68% of cases. A caesarean section or an extraction was performed in 13.9% of the cases. Three mares died before any obstetric care was provided. Nine mares (12.5%) were not discharged alive. 73 foals were delivered of which 55 were already dead before veterinary treatment began. In relation to the total number of births in which the foetus was alive at the start of obstetric care, the foetal mortality rate was 61.1% and 88.9% by the time the mare was discharged., Conclusions: It has been demonstrated for the first time that multiple causes of dystocia in horses are almost as common as isolated causes of dystocia. Neonatal mortality remains high, indicating that the timely detection and treatment of dystocia has the highest priority., (© 2024. The Author(s).)

Background: Little is known about the resumption of sporting activities following megaprosthetic reconstruction of the distal femur and proximal tibia after resection of a bone sarcoma. Thus, the aims of our study were: (1) to assess the functional outcome; (2) to evaluate pre- and post-operatively performed sporting activities; and (3) to identify potential beneficial and limiting factors., Methods: Between 1993 and 2015, a total of 230 patients underwent distal femoral replacement (DFR), and 96 patients underwent proximal tibial replacement (PTR). The exclusion criteria were death, amputation, living overseas, and a congenital disability. Functional outcome and sporting activities were assessed using the Musculoskeletal Tumor Society Score (MSTS), Toronto Extremity Salvage Score (TESS), Forgotten Joint Score (FJS), subjective knee value (SKV), the Tegner activity score (TS), and the modified weighted activity score (WAS)., Results: There were 93 patients who had a median follow-up of 182 months (interquartile range (IQR) 130 to 260) after DFR with the following median scores: MSTS 18 (IQR 12 to 23), TESS 75% (IQR 60 to 84), FJS 25 (IQR 8 to 40), SKV 53% (IQR 40 to 70), TS 3 (IQR 3 to 4), and WAS 4 (IQR 0 to 8). There were 42 patients who had a median follow-up of 193 months (IQR 137 to 244) after PTR had the following median scores: MSTS 17 (IQR 15 to 22), TESS 78% (IQR 68 to 88), FJS 32 (IQR 20 to 46), SKV 60% (IQR 40 to 70), TS 3 (IQR 3 to 4), and WAS 4 (IQR 1 to 10). Postoperatively, 61% of DFR and 76% of PTR patients participated in at least one sporting activity., Conclusions: The functional outcome is overall good with a regular resumption of sporting activities. Patients' age at surgery and higher preoperative sporting levels were associated with better functional outcomes and higher postoperative sporting activity., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: Superior sulcus tumors are frequently treated with neoadjuvant chemoradiation therapy (nCRT) followed by surgery via a trimodal approach. The INKA study evaluated the replacement of photon irradiation by carbon ion radiation therapy (C12-RT) in this regimen., Methods and Materials: The prospective INKA study included patients with locally advanced non-small cell superior sulcus tumors (

Background & Aims: Inoperable hepatocellular carcinoma (HCC) can be treated by stereotactic body radiotherapy. However, carbon ion radiotherapy (CIRT) is more effective for sparing non-tumorous liver. High linear energy transfer could promote therapy efficacy. Japanese and Chinese studies on hypofractionated CIRT have yielded excellent results. Because of different radiobiological models and the different etiological spectrum of HCC, applicability of these results to European cohorts and centers remains questionable. The aim of this prospective study was to assess safety and efficacy and to determine the optimal dose of CIRT with active raster scanning based on the local effect model (LEM) I., Methods: CIRT was performed every other day in four fractions with relative biological effectiveness (RBE)-weighted fraction doses of 8.1-10.5 Gy (total doses 32.4-42.0 Gy [RBE]). Dose escalation was performed in five dose levels with at least three patients each. The primary endpoint was acute toxicity after 4 weeks., Results: Twenty patients received CIRT (median age 74.7 years, n = 16 with liver cirrhosis, Child-Pugh scores [CP] A5 [n = 10], A6 [n = 4], B8 [n = 1], and B9 [n = 1]). Median follow up was 23 months. No dose-limiting toxicities and no toxicities exceeding grade II occurred, except one grade III gamma-glutamyltransferase elevation 12 months after CIRT, synchronous to out-of-field hepatic progression. During 12 months after CIRT, no CP elevation occurred. The highest dose level could be applied safely. No local recurrence developed during follow up. The objective response rate was 80%. Median overall survival was 30.8 months (1/2/3 years: 75%/64%/22%). Median progression-free survival was 20.9 months (1/2/3 years: 59%/43%/43%). Intrahepatic progression outside of the CIRT target volume was the most frequent pattern of progression., Conclusions: CIRT of HCC yields excellent local control without dose-limiting toxicity., Impact and Implications: To date, safety and efficacy of carbon ion radiotherapy for hepatocellular carcinoma have only been evaluated prospectively in Japanese and Chinese studies. The optimal dose and fractionation when using the local effect model for radiotherapy planning are unknown. The results are of particular interest for European and American particle therapy centers, but also of relevance for all specialists involved in the treatment and care of patients with hepatocellular carcinoma, as we present the first prospective data on carbon ion radiotherapy in hepatocellular carcinoma outside of Asia. The excellent local control should encourage further use of carbon ion radiotherapy for hepatocellular carcinoma and design of randomized controlled trials., Clinical Trials Registration: The study is registered at ClinicalTrials.gov (NCT01167374)., Competing Interests: PH and JL are funded by the Physician-Scientist Program of Heidelberg University, Faculty of Medicine. PH received fees for an advisory board from NovoCure GmbH. FW received speaker fees from AstraZeneca and Merck Sharp & Dohme. JD received grants from Accuray International Sàrl, Merck Serono GmbH, CRI – The Clinical Research Institute GmbH, View Ray Inc., Accuray Incorporated, RaySearch Laboratories AB, Vision RT limited, Astellas Pharma GmbH, Astra Zeneca GmbH, Solution Akademie GmbH, Ergomed PLC Surrey Research Park, Siemens Healthcare GmbH, Quintiles GmbH, NovoCure, Pharmaceutical Research Associates GmbH, Boehringer Ingelheim Pharma GmbH Co, PTW-Freiburg Dr Pychlau GmbH, Nanobiotix A.A. and IntraOP Medical outside the submitted work. JHR received speaker fees and travel reimbursement from ViewRay Inc., travel reimbursement from IntraOP Medical and Elekta Instrument AB, and a grant from IntraOP Medical outside the submitted work. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2024 The Authors.)

Dystocia typically presents a life-threatening condition for both the mare and the foal. This prospective long-term study aimed to ascertain whether mares with prior pregnancy disorders or a history of dystocia were at a higher risk of experiencing subsequent dystocia in comparison to those without such medical antecedents. To achieve this goal, the authors analysed 207 parturitions and 164 mares over a 10-year period. Of these, 57 were associated with pregnancy disorders or prior dystocia (Group 1), while 150 parturitions followed uneventful pregnancies in mares that had not yet experienced dystocia (Group 2). Mares in Group 1 were significantly more likely to develop dystocia than those in Group 2 (p = .0180; odds ratio = 2.98). Foetal causes of dystocia were more prevalent than maternal causes (p < .0389). Maternal mortality stood at 0.5%, and neonatal mortality reached 1.9%. The results demonstrate that mares are at significantly higher risk of developing dystocia after experiencing pregnancy disorders or parturition complications during previous pregnancies, emphasizing the need for systematic birth monitoring., (© 2024 The Authors. Reproduction in Domestic Animals published by Wiley-VCH GmbH.)

Background: The current study aims to evaluate the occurrence of temporal lobe reactions and identify possible risk factors for patients who underwent particle therapy of the skull base., Methods: 244 patients treated for skull base chordoma ( n = 144) or chondrosarcoma ( n = 100) at the Heidelberg Ion Beam Therapy Center (HIT) using a raster scan technique, were analyzed. Follow-up MRI-scans were matched with the initial planning images. Radiogenic reactions were contoured and analyzed based on volume and dose of treatment., Results: 51 patients with chordoma (35.4%) and 30 patients (30%) with chondrosarcoma experienced at least one temporal lobe reaction within the follow-up period (median 49 months for chondrosarcoma, 62 months for chordoma). Age, irradiated volume, and dose values were significant risk factors for the development of temporal lobe reactions with the highest significance for the value of DMax-7 being defined as the dose maximum in the temporal lobe minus the 7cc with the highest dose ( p = 0.000000000019; OR 1.087)., Conclusion: Temporal lobe reactions are a common side effect after particle therapy of the skull base. We were able to develop a multivariate model, which predicted radiation reactions with a specificity of 99% and a sensitivity of 52.2%.

Purpose: The aim of this matched-pair cohort study was to evaluate the potential of intensity-modulated proton therapy (IMPT) for sparring of the pelvic bone marrow and thus reduction of hematotoxicity compared to intensity-modulated photon radiotherapy (IMRT) in the setting of postoperative irradiation of gynaecological malignancies. Secondary endpoint was the assessment of predictive parameters for the occurrence of sacral insufficiency fractures (SIF) when applying IMPT. Materials and Methods: Two cohorts were analyzed consisting of 25 patients each. Patients were treated with IMPT compared with IMRT and had uterine cervical (n = 8) or endometrial cancer (n = 17). Dose prescription, patient age, and diagnosis were matched. Dosimetric parameters delivered to the whole pelvic skeleton and subsites (ilium, lumbosacral, sacral, and lower pelvis) and hematological toxicity were evaluated. MRI follow-up for evaluation of SIF was only available for the IMPT group. Results: In the IMPT group, integral dose to the pelvic skeleton was significantly lower (23.4GyRBE vs 34.3Gy; p  < 0.001), the average V 5Gy , V 10Gy , and V 20Gy were reduced by 40%, 41%, and 28%, respectively, compared to the IMRT group ( p  < 0.001). In particular, for subsites ilium and lower pelvis, the low dose volume was significantly lower. Hematotoxicity was significantly more common in the IMRT group (80% vs 32%; p  = 0009), especially hematotoxicity ≥ CTCAE II (36% vs 8%; p  = 0.037). No patient in the IMPT group experienced hematotoxicity > CTCAE II. In the IMPT cohort, 32% of patients experienced SIF. Overall SIF occurred more frequently with a total dose of 50.4 GyRBE (37.5%) compared to 45 GyRBE (22%). No significant predictive dose parameters regarding SIF could be detected aside from a trend regarding V50Gy to the lumbosacral subsite. Conclusion: Low-dose exposure to the pelvic skeleton and thus hematotoxicity can be significantly reduced by using IMPT compared to a matched photon cohort. Sacral insufficiency fracture rates appear similar to reported rates for IMRT in the literature., Competing Interests: Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: JHR reports honoraria from ViewRay Inc. and Pfizer Inc. as well as research grants from IntraOP Medical and Varian Medical Systems. LK reports grants from Ruprecht-Karls Universität Heidelberg, during the conduct of the study, personal fees from Accuray Inc., and Novocure GmbH outside the submitted work. KH reports grants for trial support from Roche Pharma, German Cancer Aid outside the submitted work, support for attending meetings and/or travel from the German Lymphoma Alliance (GLA) and leadership/fiduciary role in the Radiation Oncology working group of the GLA. JD received grants or has contracts with Viewray Inc, CRI – The Clinical Research Institute GmbH, Accuray International Sari, RaySearch Laboratories AB, Vision RT Limited, Merck Serono GmbH, Astellas Pharma GmbH, Astra Zeneca GmbH, Siemens Healthcare GmbH, Solution Akademie GmbH, Ergomed PLC Surrey Research Park, Quintiles GmbH, Pharmaceutical Research Associates GmbH, Boehringer Ingelheim Pharma GmbH & CoKG, PTW-Freiburg Dr Pychlau GmbH, Nanobiotix S.A. and Accuray Incorporated outside the submitted work. All other authors declare that they have nothing to disclose.

Dystocia represents a life-threatening condition for mare and foal. Morbidity and mortality rates due to a difficult birth, as well as the influence on fertility of the mare were analyzed, based on a review of publications. This was aggravated by the fact that no standardized diagnostic code was used and that most publications do not clearly describe how extensively the examinations were performed beforehand. Retentio secundinarum is the most common complication caused by dystocia. Other complications are injuries to the soft birth canal and the colon. These occur more frequently after surgical obstetrics than following assisted vaginal deliveries. Performing a fetotomy increases the risk of injury to the birth canal. After a caesarean section, the risk for retained placenta increases significantly. In order to evaluate the possibility of medical progress over time, mortality rates of mare and foal were investigated and divided in surgical and conservative obstetrics within the period of 1970-1990 and 1991-2021. The average maternal mortality rate following caesarean section amounted to 18% in the time period between 1970 and 1990 and 14% between the years from 1991-2021. After fetotomy, the two determined mortality rates amounted to 29% and 10% for the time between 1970 and 1990. In the period 1991-2021, the rate varies between 4% and 44% with an average mortality rate of 14%. Following controlled vaginal delivery, the average mortality rate is 9%. Literary sources were however only available for the current time period and range between 6% and 29%. The morbidity and mortality rate of foals is very high. Following caesarean section on average 53% of foals are dead on delivery, with a range of 13-79% in case reports from the years 1991-2021. The number of dead foals in the context of conservative obstetrics is of a similar scale. Postnatal foal diseases are largely due to intrapartum hypoxia during dystocia and obstetric injury. In consequence of a difficult delivery, mares experience reduced fertility. In numerous cases this however may be compensated by pausing from further breeding in the same year. The number of cases evaluated in this context however remains too small to advocate any recommendations for breeding following incidents of dystocia., Competing Interests: Die Autoren bestätigen, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Purpose: Helium ions offer intermediate physical and biological properties to the clinically used protons and carbon ions. This work presents the commissioning of the first clinical treatment planning system (TPS) for helium ion therapy with active beam delivery to prepare the first patients' treatment at the Heidelberg Ion-Beam Therapy Center (HIT)., Methods and Materials: Through collaboration between RaySearch Laboratories and HIT, absorbed and relative biological effectiveness (RBE)-weighted calculation methods were integrated for helium ion beam therapy with raster-scanned delivery in the TPS RayStation. At HIT, a modified microdosimetric kinetic biological model was chosen as reference biological model. TPS absorbed dose predictions were compared against measurements with several devices, using phantoms of different complexities, from homogeneous to heterogeneous anthropomorphic phantoms. RBE and RBE-weighted dose predictions of the TPS were verified against calculations with an independent RBE-weighted dose engine. The patient-specific quality assurance of the first treatment at HIT using helium ion beam with raster-scanned delivery is presented considering standard patient-specific measurements in a water phantom and 2 independent dose calculations with a Monte Carlo or an analytical-based engine., Results: TPS predictions were consistent with dosimetric measurements and independent dose engines computations for absorbed and RBE-weighted doses. The mean difference between dose measurements to the TPS calculation was 0.2% for spread-out Bragg peaks in water. Verification of the first patient treatment TPS predictions against independent engines for both absorbed and RBE-weighted doses presents differences within 2% in the target and with a maximum deviation of 3.5% in the investigated critical regions of interest., Conclusions: Helium ion beam therapy has been successfully commissioned and introduced into clinical use. Through comprehensive validation of the absorbed and RBE-weighted dose predictions of the RayStation TPS, the first clinical TPS for helium ion therapy using raster-scanned delivery was employed to plan the first helium patient treatment at HIT., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: The APROVE study is a prospective one-arm phase-2 study investigating the safety and treatment tolerability of postoperative proton beam therapy in women with uterine cervical or endometrial cancer. In this analysis, we report the primary study endpoint of safety and treatment tolerability as well as toxicity rates and progression-free survival (PFS)., Methods and Materials: 25 patients were treated with postoperative proton beam therapy with a total dose of 45 to 50.4 Gy (RBE) in 5 to 6 × 1.8 Gy (RBE) fractions weekly using active raster-scanning intensity modulated proton beam therapy (IMPT). Sequential or simultaneous platinum-based chemotherapy was administered if indicated. The primary endpoint was defined as the lack of any acute ≥grade 3 gastrointestinal (GI) or urogenital (GU) toxicity according to the Common Terminology Criteria for Adverse Events v 4.0 or premature treatment abortion. Secondary endpoints were clinical symptoms and toxicity, quality of life, and PFS., Results: All patients completed IMPT according to the protocol, with a median treatment duration of 43 days (range, 33 to 51 days). No patient developed gastrointestinal or genitourinary toxicity ≥grade 3, and the treatment tolerability rate was 100%. Therefore, the null hypothesis H0: Tolerability Rate ≤80% could be rejected in favor of the alternative hypothesis H1: Tolerability rate >80% using an exact binomial test with a one-sided significance level of α = 10% (one-sided P value P = .0059). The median follow-up time after the end of IMPT was 25.1 months (range, 20.2 to 50.3 months). 18 of 25 (75%) patients completed the study follow-up of 24 months. 7 patients had progressive disease. Kaplan-Meier-estimated mean PFS was 39.9 months (95% confidence interval: 33.37 to 46.5 months)., Conclusions: Postoperative IMPT is a safe treatment option for cervical and endometrial cancer patients, with only low-grade acute and late toxicities. Larger randomized trials are necessary to further assess the potential of IMPT and improve patient selection., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Distal humeral replacement (DHR) is a limb-salvage option for the endoprosthetic reconstruction of bone defects following the resection of a primary bone sarcoma. As primary bone sarcomas are only occasionally located around the distal humerus, there is a paucity of information regarding postoperative function, and patients' resumption of sporting activities. With advances in diagnostics and in surgical and oncological treatment leading to an increased patient life expectancy and higher quality of life, patients' functional outcome and return to sports activities are of increasing interest. Between 1997 and 2021, a total of 24 patients underwent DHR with a single-design modular implant at a tertiary sarcoma center. A total of 14 patients who died of their disease were excluded, leaving a study cohort of 10 patients, with a median age of 30 years on the day of surgery (IQR 20-37). At the last follow-up, after a median of 230 months (IQR 165-262), the median MSTS was 19 (IQR 13-24), the median TESS was 79 (IQR 66-87), the median SEV was 38% (IQR 24-53), the median TS was 6 (IQR 4-7), and the median WAS was 3 (IQR 1-8). Among the variables of gender, surgery on the dominant extremity, intraoperative nerve resection, extra-articular tumor resection, chemotherapy, radiotherapy, and revision surgeries, none were associated with a better/lower functional outcome score or return to sports activities. However, a higher level of sports performance prior to diagnosis (WAS > 10) was associated with a higher level of sports performance postoperatively ( p = 0.044)., Competing Interests: G.G. certifies that he holds a patent for the silver coating of a metallic prosthesis, and receives payments from Implantcast GmbH (Buxtehude, Germany). C.T. and N.D. certify that they have received travel expenses from Implantcast GmbH (Buxtehude, Germany). All other authors declare that they have no competing interest.

Background and Purpose: Studies have shown large variations in stopping-power ratio (SPR) prediction from computed tomography (CT) across European proton centres. To standardise this process, a step-by-step guide on specifying a Hounsfield look-up table (HLUT) is presented here., Materials and Methods: The HLUT specification process is divided into six steps: Phantom setup, CT acquisition, CT number extraction, SPR determination, HLUT specification, and HLUT validation. Appropriate CT phantoms have a head- and body-sized part, with tissue-equivalent inserts in regard to X-ray and proton interactions. CT numbers are extracted from a region-of-interest covering the inner 70% of each insert in-plane and several axial CT slices in scan direction. For optimal HLUT specification, the SPR of phantom inserts is measured in a proton beam and the SPR of tabulated human tissues is computed stoichiometrically at 100 MeV. Including both phantom inserts and tabulated human tissues increases HLUT stability. Piecewise linear regressions are performed between CT numbers and SPRs for four tissue groups (lung, adipose, soft tissue, and bone) and then connected with straight lines. Finally, a thorough but simple validation is performed., Results: The best practices and individual challenges are explained comprehensively for each step. A well-defined strategy for specifying the connection points between the individual line segments of the HLUT is presented. The guide was tested exemplarily on three CT scanners from different vendors, proving its feasibility., Conclusion: The presented step-by-step guide for CT-based HLUT specification with recommendations and examples can contribute to reduce inter-centre variations in SPR prediction., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

In horses, birth is classified as dystocia when the process of parturition threatens to inflict damage onto the mare or the foal, when assistance is required to complete the process of parturition, or when there are temporal deviations in the physiological duration of the first and/or second parturition stages. In this, the duration of the second stage is an important indicator in identifying dystocia, as this phase is easily discernible by the mare's behavior. Equine dystocia is classified as an emergency with life-threatening consequences for mare and foal. A large degree of variation has been found in the reported incidence of dystocia. Stud farm surveys reported dystocia in 2-13% of all births, regardless of breed. Fetal malpositioning of the limbs and neck during parturition is described as the most common cause of dystocia in horses. The species-specific length of limbs and neck is considered to be the reason for this finding., Competing Interests: Die Autoren bestätigen, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Background: This study aimed to compare the results of irradiation with protons versus irradiation with carbon ions in a raster scan technique in patients with skull base chordomas and to identify risk factors that may compromise treatment results., Methods: A total of 147 patients (85 men, 62 women) were irradiated with carbon ions (111 patients) or protons (36 patients) with a median dose of 66 Gy (RBE (Relative biological effectiveness); carbon ions) in 4 weeks or 74 Gy (RBE; protons) in 7 weeks at the Heidelberg Ion Beam Therapy Center (HIT) in Heidelberg, Germany. The median follow-up time was 49.3 months. All patients had gross residual disease at the beginning of RT. Compression of the brainstem was present in 38%, contact without compression in 18%, and no contact but less than 3 mm distance in 16%. Local control and overall survival were evaluated using the Kaplan-Meier Method based on scheduled treatment (protons vs. carbon ions) and compared via the log rank test. Subgroup analyses were performed to identify possible prognostic factors., Results: During the follow-up, 41 patients (27.9%) developed a local recurrence. The median follow-up time was 49.3 months (95% CI: 40.8-53.8; reverse Kaplan-Meier median follow-up time 56.3 months, 95% CI: 51.9-60.7). No significant differences between protons and carbon ions were observed regarding LC, OS, or overall toxicity. The 1‑year, 3‑year, and 5‑year LC rates were 97%, 80%, and 61% (protons) and 96%, 80%, and 65% (carbon ions), respectively. The corresponding OS rates were 100%, 92%, and 92% (protons) and 99%, 91%, and 83% (carbon ions). No significant prognostic factors for LC or OS could be determined regarding the whole cohort; however, a significantly improved LC could be observed if the tumor was > 3 mm distant from the brainstem in patients presenting in a primary situation., Conclusion: Outcomes of proton and carbon ion treatment of skull base chordomas seem similar regarding tumor control, survival, and toxicity. Close proximity to the brainstem might be a negative prognostic factor, at least in patients presenting in a primary situation., (© 2022. The Author(s).)

Introduction: The APROVE-trial investigated the tolerability of postoperative proton beam therapy in women with cervical or endometrial cancer. The present analysis evaluated the secondary endpoints of health-related quality of life (HRQOL) and patient-reported symptoms., Methods: 25 patients were included in this prospective phase-II-trial and treated with postoperative radiotherapy using protons alone or in combination with chemotherapy. To attain general and gynecologic-specific HRQOL measures, the EORTC-QLQ-C30 questionnaires combined with -QLQ-CX24 for cervical and -QLQ-EN24 for endometrial cancer were assessed at baseline, at the end of RT and up to 2 years after radiotherapy. The results were compared to an age-matched norm reference population. Symptoms were assessed using Common Terminology Criteria for Adverse Events (CTCAE) and institutional patient-reported symptoms grading., Results: Scores regarding global health status were markedly impaired at baseline (mean: 58.0 ± 20.1) compared to reference population data, but significantly (p = 0.036) improved and evened out to comparable norm values 2 years after proton therapy (mean: 69.9 ± 19.3). Treatment caused acute and long-term worsening of pain (p = 0.048) and gastrointestinal symptoms (p = 0.016) for women with endometrial cancer, but no higher-grade CTCAE ≥ 3° toxicity was observed. Dosimetric evaluation of rectum, sigmoid, large and small bowel showed no correlation with the reported gastrointestinal symptoms. After 2 years, fatigue had significantly improved (p = 0.030), whereas patients with cervical cancer experienced more often lymphedema (p = 0.017). Scores for endometrial cancer pertaining to sexual activity (p = 0.048) and body image (p = 0.022) had improved post treatment; in the latter this effect persisted after 2 years., Conclusion: Proton beam therapy in the adjuvant setting was well tolerated with only low-grade side effects concerning gastrointestinal symptoms, lymphedema and pain. Overall quality of life was impaired at baseline, but patients were able to recover to values comparable to norm population 2 years after proton therapy. Larger studies are needed to confirm whether the benefit of proton therapy translates into a clinical effect. Sexual dysfunction remains an important issue., Trial Registration: The trial was registered at https://clinicaltrials.gov (ClinicalTrials.gov Identifier: NCT03184350, 09th June 2017)., (© 2023. The Author(s).)

Background: Improved patient and limb survival rates have led to an increased interest in the functional outcome and return to sports of patients undergoing megaprosthetic reconstruction in musculoskeletal oncology. This study evaluates the functional outcome and postoperatively performed level of sports in patients undergoing proximal humeral replacement (PHR) following resection of a primary bone sarcoma and identifies potential beneficial and limiting factors., Patients and Methods: Between 2007 and 2020, a total of 606 patients underwent resection of a primary bone sarcoma and reconstruction with a single-design modular implant. For 112 (18%) patients, the location of the tumour was the proximal humerus. Exclusion criteria were death (n = 65), patients living overseas (n = 8), and subsequent amputation (n = 1), leaving 38 patients for evaluation, of whom 32 were available for the study (13 women, median age 42 years). Clinical data regarding oncological and surgical treatment as well as subsequent complications were obtained from the patients' electronic medical records. Functional outcome was determined using the Musculoskeletal Tumor Society Score (MSTS) and Toronto Extremity Salvage Score (TESS) as well as the Subjective Shoulder Value (SSV). Return to sports was assessed using the Tegner Activity Score (TS) and the modified Weighted Activity Score (WAS)., Results: At the last follow-up after a median of 30 months (IQR 22-58), median MSTS was 18 (IQR 12-24), median TESS was 80% (IQR 69-87), median SSV was 35% (IQR 10-58), median TS was 5 (IQR 4-6) and median WAS was 5 (IQR 0-10). Preservation of the axillary nerve, a reverse shoulder reconstruction and a WAS of > 10 prior to surgery were associated with better functional outcome and return to sports activity scores., Conclusion: Following PHR, good to excellent functional outcomes are possible, and patients regularly return to participate in sports activities-most commonly in low-impact types of sports, but some individuals are even able to participate in high-impact sports activities., Level of Evidence: IV., (© 2022. The Author(s).)

Purpose: To report dosimetric characteristics and early clinical outcomes in patients with pelvic Ewing sarcoma undergoing particle therapy., Methods: Patients ≥ 18 years old with pelvic Ewing sarcoma treated in adjuvant or definitive settings were considered for this retrospective analysis. Proton therapy was carried out with 45-60 Gy (RBE) (1.5-2 Gy (RBE) per fraction) and carbon ion therapy for recurrent disease with 51 Gy (RBE) (3 Gy (RBE) per fraction). Local control (LC), disease control (DC) and overall survival (OS) were calculated using the Kaplan-Meier method., Results: For our sample, 21 patients were available, 18 of whom were treated for primary, 3 for locally recurrent and 16 for inoperable disease. The median CTV and PTV were 1215 cm 3 and 1630 cm 3 . Median Dmean values for the PTV, bladder and rectum and median V40 Gy for the bowel for patients undergoing proton therapy were 56 Gy (RBE), 0.6 Gy (RBE), 9 Gy (RBE) and 15 cm 3 , respectively. At the end of particle therapy, G 1-2 skin reactions ( n = 16/21) and fatigue ( n = 9/21) were the main reported symptoms. After a median follow-up of 21 months, the 2-year LC, DC and OS were 76%, 56% and 86%, respectively., Conclusions: Particle therapy in adult pelvic Ewing sarcoma is feasible and provides excellent dosimetric results. First clinical outcomes are promising; however, further long-term follow-up is needed.

Purpose: Surface-guided radiation therapy (SGRT) has been investigated intensively to ensure correct patient positioning during a radiation therapy course. Although the implementation is well defined for photon-beam facilities, only a few analyses have been published for ion-beam therapy centers. To investigate the accuracy, reliability, and efficiency of SGRT used in ion-beam treatments against the conventional skin marks, a retrospective study of a unique SGRT installation in an ion gantry treatment room was conducted, where the environment is quite different to conventional radiation therapy., Methods and Materials: There were 32 patients, divided into 3 cohorts-pelvis, limb, and chest/spine tumors-and treated with ion-beams. Two patient positioning workflows based on 300 fractions were compared: workflow with skin marks and workflow with SGRT. Position verification was followed by planar kilo voltage imaging. After image matching, 6 degrees of freedom corrections were recorded to assess interfraction positioning errors. In addition, the time required for patient positioning, image matching, and the number of repeated kilo voltage imaging also were gathered., Results: SGRT decreased the translational magnitude shifts significantly ( P < .05) by 0.5 ± 1.4 mm for pelvis and 1.9 ± 0.5 mm for limb, whereas for chest/spine, it increased by 0.7 ± 0.3 mm. Rotational corrections were predominantly lowered with SGRT for all cohorts with significant differences in pitch for pelvis ( P  = .002) and chest/spine ( P  = .009). The patient positioning time decreased by 18%, 9%, and 15% for pelvis, limb, and chest/spine, respectively, compared with skin marks. By using SGRT, 53% of all studied patients had faster positioning time, and 87.5% had faster matching time. Repositioning and consequent reimaging decreased from about 7% to 2% with a statistically significant difference of .042., Conclusions: The quality of patient positioning before ion-beam treatments has been optimized by using SGRT without additional imaging dose. SGRT clearly reduced inefficiencies in the patient positioning workflow., (© 2022 The Author(s).)

Purpose: Experimental assessment of inter-centre variation and absolute accuracy of stopping-power-ratio (SPR) prediction within 17 particle therapy centres of the European Particle Therapy Network., Material and Methods: A head and body phantom with seventeen tissue-equivalent materials were scanned consecutively at the participating centres using their individual clinical CT scan protocol and translated into SPR with their in-house CT-number-to-SPR conversion. Inter-centre variation and absolute accuracy in SPR prediction were quantified for three tissue groups: lung, soft tissues and bones. The integral effect on range prediction for typical clinical beams traversing different tissues was determined for representative beam paths for the treatment of primary brain tumours as well as lung and prostate cancer., Results: An inter-centre variation in SPR prediction (2σ) of 8.7%, 6.3% and 1.5% relative to water was determined for bone, lung and soft-tissue surrogates in the head setup, respectively. Slightly smaller variations were observed in the body phantom (6.2%, 3.1%, 1.3%). This translated into inter-centre variation of integral range prediction (2σ) of 2.9%, 2.6% and 1.3% for typical beam paths of prostate-, lung- and primary brain-tumour treatments, respectively. The absolute error in range exceeded 2% in every fourth participating centre. The consideration of beam hardening and the execution of an independent HLUT validation had a positive effect, on average., Conclusion: The large inter-centre variations in SPR and range prediction justify the currently clinically used margins accounting for range uncertainty, which are of the same magnitude as the inter-centre variation. This study underlines the necessity of higher standardisation in CT-number-to-SPR conversion., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: Ion beam radiotherapy offers enhances dose conformity to the tumor volume while better sparing healthy tissue compared to conventional photon radiotherapy. However, the increased dose gradient also makes it more sensitive to uncertainties. While the most important uncertainty source is the patient itself, the beam delivery is also subject to uncertainties. Most of the proton therapy centers used cyclotrons, which deliver typically a stable beam over time, allowing a continuous extraction of the beam. Carbon-ion beam radiotherapy (CIRT) in contrast uses synchrotrons and requires a larger and energy-dependent extrapolation of the nozzle-measured positions to obtain the lateral beam positions in the isocenter, since the nozzle-to-isocenter distance is larger than for cyclotrons. Hence, the control of lateral pencil beam positions at isocenter in CIRT is more sensitive to uncertainties than in proton radiotherapy. Therefore, an independent monitoring of the actual lateral positions close to the isocenter would be very valuable and provide additional information. However, techniques capable to do so are scarce, and they are limited in precision, accuracy and effectivity., Methods: The detection of secondary ions (charged nuclear fragments) has previously been exploited for the Bragg peak position of C-ion beams. In our previous work, we investigated for the first time the feasibility of lateral position monitoring of pencil beams in CIRT. However, the reported precision and accuracy were not sufficient for a potential implementation into clinical practice. In this work, it is shown how the performance of the method is improved to the point of clinical relevance. To minimize the observed uncertainties, a mini-tracker based on hybrid silicon pixel detectors was repositioned downstream of an anthropomorphic head phantom. However, the secondary-ion fluence rate in the mini-tracker rises up to 1.5 × 10 5 ions/s/cm 2 , causing strong pile-up of secondary-ion signals. To solve this problem, we performed hardware changes, optimized the detector settings, adjusted the setup geometry and developed new algorithms to resolve ambiguities in the track reconstruction. The performance of the method was studied on two treatment plans delivered with a realistic dose of 3 Gy (RBE) and averaged dose rate of 0.27 Gy/s at the Heidelberg Ion-Beam Therapy Center (HIT) in Germany. The measured lateral positions were compared to reference beam positions obtained either from the beam nozzle or from a multi-wire proportional chamber positioned at the room isocenter., Results: The presented method is capable to simultaneously monitor both lateral pencil beam coordinates over the entire tumor volume during the treatment delivery, using only a 2-cm 2 mini-tracker. The effectivity (defined as the fraction of analyzed pencil beams) was 100%. The reached precision of (0.6 to 1.5) mm and accuracy of (0.5 to 1.2) mm are in line with the clinically accepted uncertainty for QA measurements of the lateral pencil beam positions., Conclusions: It was demonstrated that the performance of the method for a non-invasive lateral position monitoring of pencil beams is sufficient for a potential clinical implementation. The next step is to evaluate the method clinically in a group of patients in a future observational clinical study., (© 2021 American Association of Physicists in Medicine.)

Background and Purpose: Proton therapy may be promising for treating non-small-cell lung cancer due to lower doses to the lung and heart, as compared to photon therapy. A reported challenge is degradation, i.e. , a smoothing of the depth-dose distribution due to heterogeneous lung tissue. For pencil beams, this causes a distal falloff widening and a peak-to-plateau ratio decrease, not considered in clinical treatment planning systems., Materials and Methods: We present a degradation model implemented into an analytical dose calculation, fully integrated into a treatment planning workflow. Degradation effects were investigated on target dose, distal dose falloffs, and mean lung dose for ten patient cases with varying anatomical characteristics., Results: For patients with pronounced range straggling (in our study large tumors, or lesions close to the mediastinum), degradation effects were restricted to a maximum decrease in target coverage ( D 95 of the planning target volume) of 1.4%. The median broadening of the distal 80-20% dose falloffs was 0.5 mm at the maximum. For small target volumes deep inside lung tissue, however, the target underdose increased considerably by up to 26%. The mean lung dose was not negatively affected by degradation in any of the investigated cases., Conclusion: For most cases, dose degradation due to heterogeneous lung tissue did not yield critical organ at risk overdosing or overall target underdosing. However, for small and deep-seated tumors which can only be reached by penetrating lung tissue, we have seen substantial local underdose, which deserves further investigation, also considering other prevalent sources of uncertainty., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 The Authors.)

The dose conformation and the sparing of neighboring critical healthy structures are improved in carbon-ion beam radiotherapy in comparison to conventional photon radiotherapy. Inter and intrafractional plan adaptation strategies may preclude the quality assurance (QA) of the actually applied treatment plan before the treatment starts. Therefore, independent measurements of the positions of scanned pencil 12 C ion beams are of interest in order to monitor the beam application during the treatment and the beam in the isocenter. In this work, secondary ions outgoing from a patient-like phantom are exploited for the assessment of the lateral pencil beam position in a clinic-like 12 C treatment fraction. The experiment was performed at the Heidelberg Ion-Beam Therapy Center (HIT) in Germany. A carbon-ion treatment plan was used to treat a 100 cm 3 tumor volume in the center of an Alderson head phantom. Two silicon pixel detectors based on the Timepix3 technology developed at CERN were operated in synchronization to detect and to track outgoing secondary ions. We established an analysis of the measured secondary ion track distribution which enabled us to follow the beam scanning movement of the carbon-ion pencil beam by assessing the lateral position of the single beam spots. The precision of the developed method was found to range from 0.84 mm to 2.59 mm. For beam energies greater than 197.58 MeV/n, the mean of absolute distances of the measured lateral pencil beam positions with respect to the pencil beam positions measured by the beam application system (averaged over each energy layer) were smaller than 2 mm. We conclude that the presented method has shown capabilities of monitoring the lateral pencil beam positions by means of secondary ions with precision and sensitivity of clinical interest.

Background: Ionizing radiation was shown to be able to influence the function of cardiac implantable electronic devices (CIED's) leading to malfunctions with potentially severe consequences. Those effects presumably correlate with beam energy and neutron production. Thus, particle facilities are commonly cautious to treat patients with CIED's with particles, but substantial evidence is lacking. Methods and Materials: In total 31 patients were investigated, who have been treated at the Heidelberg Ion-Beam Therapy Center (HIT) from September 2012 to February 2019 with protons and carbon ions in active-scanning technique. All CIED's were checked after every single irradiation by the department of cardiology. The minimum distance between the CIED and the planning target volume (PTV), the 10% isodose and the single beam in Beam's Eye View (BEV) was analyzed for 12 patients. Results: In total, 31 patients received 32 courses of radiotherapy (RT). Twenty-two received treatment with carbon ion beam and ten with proton beam. The cumulative number of fractions was 582, the cumulative number of documented controls after RT was 504 (87%). Three patients had an implantable cardioverter-defibrillator (ICD) and 28 patients had a pacemaker at the time of treatment. Seven patients had a heart rate of ≤30/min. The majority of patients (69%) were treated for tumors of the head and neck. The median minimum distance between CIED and PTV, 10% isodose and the single beam on BEV was 13.4, 11.6, and 8.3 cm, respectively. There were no registered events associated with the treatment in this evaluation. Conclusion: Treatment of CIED-patients with protons and carbon ions applied with active raster scanning technique was safe without any incidents in our single center experience. Monitoring after almost every fraction provided systematic and extensive data. Further investigations are necessary in order to form reliable guidelines, which should consider different modes of beam application, as active scanning supposedly provides a greater level of safety from malfunctions for patients with CIED undergoing particle irradiation.

Background: Commissioning of treatment planning systems (TPS) and beam delivery for scanned light ion beams is an important quality assurance task. This requires measurement of large sets of high quality dosimetric data in anthropomorphic phantoms to benchmark the TPS and dose delivery under realistic conditions., Method: A novel measurement setup is described, which allows for an efficient collection of a large set of accurate dose data in complex phantom geometries. This setup allows dose measurements based on a set of 24 small volume ionization chambers calibrated in dose to water and mounted in a holder, which can be freely positioned in a water phantom with various phantoms mounted in front of the water tank. The phantoms can be scanned in a CT and a CT-based treatment planning can be performed for a direct benchmark of the dose calculation algorithm in various situations., Results: The system has been used for acceptance testing in scanned light ion beam therapy at Heidelberg Ion Beam Therapy Center for scanned proton and carbon ion beams. It demonstrated to be useful to collect large amounts of high quality data for comparison with the TPS calculation using various phantom geometries., Conclusion: The setup is an efficient tool for commissioning and verification of treatment planning systems. It is especially suited for dynamic beam delivery, as many data points can be obtained during a single plan delivery, but can be adapted also for other dynamic therapies, like rotational IMRT.

Background: The current study compares the results of irradiation with protons and irradiation with carbon ions via a raster scan technique in patients with G1 and G2 skull base chondrosarcomas., Methods: Between 2009 and 2014, a total of 101 patients (40 men and 61 women) with a median age of 44 years (range, 19-77 years) were irradiated with carbon ions (79 patients) or protons (22 patients) via a raster scan technique at the Heidelberg Ion Beam Therapy Center. The median total dose was 60 Gy (relative biological effectiveness [RBE]) at 3 Gy per fraction for carbon ions and 70 Gy (RBE) at 2 Gy per fraction for protons. The median boost planning target volume was 38 cm 3 (range, 8-133 cm 3 ). Overall survival (OS) and local control (LC) were evaluated with the Kaplan-Meier method., Results: The median follow-up period was 40 months (range, 0.8-78.1 months). At the start of the irradiation, all patients had residual macroscopic tumors. Five patients (5%) developed a local recurrence during the follow-up. The 1-, 2-, and 4-year LC rates were 100%, 100%, and 100%, respectively, for protons and 98.6%, 97.2%, and 90.5%, respectively, for carbon ions. The OS rates during the same periods of time were 100%, 100%, and 100%, respectively, for protons and 100%, 98.5%, and 92.9%, respectively, for carbon ions. An age ≤ 44 years was associated with a trend for a better outcome. No toxicity worse than Common Toxicity Criteria grade 3 was observed after treatment., Conclusions: No significant difference between carbon ions and protons in the therapy of skull base chondrosarcoma could be detected in these initial retrospective results. Cancer 2018;124:2036-44. © 2018 American Cancer Society., (© 2018 American Cancer Society.)

Background and Purpose: Stopping-power ratios (SPRs) are used in particle therapy to calculate particle range in patients. The heuristic CT-to-SPR conversion (Hounsfield Look-Up-Table, HLUT), needed for treatment planning, depends on CT-scan and reconstruction parameters as well as the specific HLUT definition. To assess inter-centre differences in these parameters, we performed a survey-based qualitative evaluation, as a first step towards better standardisation of CT-based SPR derivation., Materials and Methods: A questionnaire was sent to twelve particle therapy centres (ten from Europe and two from USA). It asked for details on CT scanners, image acquisition and reconstruction, definition of the HLUT, body-region specific HLUT selection, investigations of beam-hardening and experimental validations of the HLUT. Technological improvements were rated regarding their potential to improve SPR accuracy., Results: Scan parameters and HLUT definition varied widely. Either the stoichiometric method (eight centres) or a tissue-substitute-only HLUT definition (three centres) was used. One centre combined both methods. The number of HLUT line segments varied widely between two and eleven. Nine centres had investigated influence of beam-hardening, often including patient-size dependence. Ten centres had validated their HLUT experimentally, with very different validation schemes. Most centres deemed dual-energy CT promising for improving SPR accuracy., Conclusions: Large inter-centre variability was found in implementation of CT scans, image reconstruction and especially in specification of the CT-to-SPR conversion. A future standardisation would reduce time-intensive institution-specific efforts and variations in treatment quality. Due to the interdependency of multiple parameters, no conclusion can be drawn on the derived SPR accuracy and its inter-centre variability., (© 2018 The Authors.)

Purpose: We report on the development of the open-source cross-platform radiation treatment planning toolkit matRad and its comparison against validated treatment planning systems. The toolkit enables three-dimensional intensity-modulated radiation therapy treatment planning for photons, scanned protons and scanned carbon ions., Methods: matRad is entirely written in Matlab and is freely available online. It re-implements well-established algorithms employing a modular and sequential software design to model the entire treatment planning workflow. It comprises core functionalities to import DICOM data, to calculate and optimize dose as well as a graphical user interface for visualization. matRad dose calculation algorithms (for carbon ions this also includes the computation of the relative biological effect) are compared against dose calculation results originating from clinically approved treatment planning systems., Results: We observe three-dimensional γ-analysis pass rates ≥ 99.67% for all three radiation modalities utilizing a distance to agreement of 2 mm and a dose difference criterion of 2%. The computational efficiency of matRad is evaluated in a treatment planning study considering three different treatment scenarios for every radiation modality. For photons, we measure total run times of 145 s-1260 s for dose calculation and fluence optimization combined considering 4-72 beam orientations and 2608-13597 beamlets. For charged particles, we measure total run times of 63 s-993 s for dose calculation and fluence optimization combined considering 9963-45574 pencil beams. Using a CT and dose grid resolution of 0.3 cm 3 requires a memory consumption of 1.59 GB-9.07 GB and 0.29 GB-17.94 GB for photons and charged particles, respectively., Conclusion: The dosimetric accuracy, computational performance and open-source character of matRad encourages a future application of matRad for both educational and research purposes., (© 2017 The Authors. Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.)

Purpose: The purpose of this study was to compare safety and feasibility of proton therapy with that of carbon ion therapy in hypofractionated raster-scanned irradiation of the prostate, in a prospective randomized phase 2 trial., Methods and Materials: In this trial, 92 patients with localized prostate cancer were enrolled. Patients were randomized to receive either proton therapy (arm A) or carbon ion therapy (arm B) and treated with a total dose of 66 Gy(relative biological effectiveness [RBE]) administered in 20 fractions (single dose of 3.3 Gy[RBE]). Patients were stratified by the use of antihormone therapy. Primary endpoint was the combined assessment of safety and feasibility. Secondary endpoints were specific toxicities, prostate-specific antigen progression-free survival (PFS), overall survival (OS), and quality of life (QoL)., Results: Ninety-one patients completed therapy and have had a median follow-up of 22.3 months. Among acute genitourinary toxicities, grade 1 cystitis rates were 34.1% (39.1% in A; 28.9% in B) and 17.6% grade 2 (21.7% in A; 13.3% in B). Seven patients (8%) required urinary catheterization during treatment due to urinary retention, 5 of whom were in arm A. Regarding acute gastrointestinal toxicities, 2 patients treated with protons developed grade 3 rectal fistulas. Grade 1 radiation proctitis occurred in 12.1% (13.0% in A; 11.1% in B) and grade 2 in 5.5% (8.7% in A; 2.2% in B). No statistically significant differences in toxicity profiles between arms were found. Reduced QoL was evident mainly in fatigue, pain, and urinary symptoms during therapy and 6 weeks thereafter. All European Organization for Research and Treatment of Cancer QLQ-C30 and -PR25 scores improved during follow-up., Conclusions: Hypofractionated irradiation using either carbon ions or protons results in comparable acute toxicities and QoL parameters. We found that hypofractionated particle irradiation is feasible and may be safe. Due to the occurrence of gel in the rectal wall and the consecutive occurrence of 2 rectal fistulas, we stopped using the insertion of spacer gel. Longer follow-up is necessary for evaluation of PFS and OS. (Ion Prostate Irradiation (IPI); NCT01641185; ClinicalTrials.gov.)., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: The purpose of this work was to evaluate the results of high-dose radiation treatment using carbon ion therapy, alone or combined with intensity-modulated radiation treatment (IMRT), in patients with sacral chordoma., Materials and Methods: Between 2009 and 2012, 56 patients with sacral chordoma were treated in our center. The tumor was located above S3 in 33 patients and in S3 or below in 23 patients. In all, 41 patients received radiation therapy for the primary tumor, while 15 patients were treated for the recurrent tumor. Toxicity was measured using NCI CTCAE v.4.03. Local control (LC) and overall survival (OS) were evaluated with the Kaplan-Meier method., Results: A total of 23 patients were irradiated with carbon ions in combination with photon IMRT, while 33 received carbon ion therapy only. Forty-three patients had a macroscopic tumor at treatment start with a median tumor size (GTV) of 244 ml (range 5-1188 ml). The median total dose was 66 Gy (range 60-74 Gy; RBE). After a median follow-up time of 25 months, the 2- and 3-year local control probability was 76 % and 53 %, respectively. The overall survival rate was 100 %. Treatment for primary tumor and male patients resulted in significant better local control. No higher toxicity occurred within the follow-up time., Conclusion: High-dose photon/carbon ion beam radiation therapy is safe and, especially for primary sacral chordomas, highly effective. A randomized trial is required to evaluate the role of primary definitive hypofractionated particle therapy compared with surgery with or without adjuvant radiotherapy.

Motor symptoms in Parkinson's disease (PD) are usually assessed with semi-quantitative tests such as the Unified PD Rating Scale (UPDRS) which are limited by subjectivity, categorical design, and low sensitivity. Particularly bradykinesia as assessed e.g. with speeded index finger tapping exhibits low validity measures. This exploratory study set out to (i) assess whether force transducer-based objective and quantitative analysis of motor coordination in index finger tapping is able to distinguish between PD patients and controls, and (ii) assess longitudinal changes. Sixteen early-stage and 17 mid-stage PD patients as well as 18 controls were included in the cross-sectional part of the study; thirteen, 16 and 16 individuals of the respective groups agreed in a reassessment 12 months later. Frequency, force, rhythmicity, regularity and laterality of speeded and metronome paced tapping were recorded by digitomotography using a quantitative motor system ("Q-Motor"). Analysis of cross-sectional data revealed most consistent differences between PD patients and controls in variability of tap performance across modalities assessed. Among PD patients, variability of taps and the ability to keep a given rhythm were associated with UPDRS motor and finger tapping scores. After 12 months, laterality parameters were reduced but no other parameters changed significantly. This data suggests that digitomotography provides quantitative and objective measures capable to differentiate PD from non-PD in a small cohort, however, the value of the assessment to track PD progression has to be further evaluated in larger cohorts of patients.

Background: Locally recurrent rectal cancer remains a dreaded event because curative resection is unlikely to be performed in a large number of cases. Carbon ion radiotherapy offers physical and biologic advantages. A high precise local dose deposition and sparing of normal tissue is possible. This work summarizes our experience on feasibility and early toxicity of carbon ion radiotherapy in previously irradiated and operated patients., Methods: Between 2010 and 2013, a total of 19 patients with a median age of 62 years (range 14-76 years) received carbon ion irradiation to treat locally recurrent rectal cancer at the Heidelberg Ion Beam Therapy Center (HIT). All patients had a history of surgery and pelvic radiotherapy of at least 50.4 Gy. Median dose was 36 Gy [relative biologic efficacy (RBE)] [range 36-51 Gy(RBE)], and median planning target volume was 456 ml (range 75-1,597 ml). Some patients were treated in the recruiting phase I/II of the PANDORA study (NCT01528683)., Results: Median follow-up was 7.8 months. Four patients were diagnosed with local relapse after carbon ion radiotherapy, and three patients developed distant metastases. Estimated mean local progression-free survival was 20.6 months by the Kaplan-Meier estimator. Two patients had preexisting rectovaginal fistula, and another patient had a preexisting presacral localized abscess formation in which the local relapse took place. No grade III or higher toxicities were observed., Conclusions: Our first experiences in a pretreated patient group with a dismal prognosis are encouraging, and therapy-related side effects are mild. Longer follow-up is required to determine possible late effects and long-term disease control.

Background: The current study was conducted to evaluate the long-term results of irradiation with carbon ions in a raster scanning technique in patients with skull base chordomas., Methods: Between 1998 and 2008, a total of 155 patients (76 men and 79 women) with a median age of 48 years (range, 15 years-85 years) were irradiated with carbon ions using a raster scan technique. The irradiation was performed at the Society for Heavy Ion Research in Darmstadt, Germany. The median total dose was 60 gray (relative biological effectiveness) at 3 gray (relative biological effectiveness) per fraction. The median boost planning target volume was 70 mL (range, 2 mL-294 mL). Local control (LC) and overall survival (OS) were evaluated using the Kaplan-Meier method, whereas long-term toxicity was evaluated via questionnaires., Results: The median follow-up was 72 months (range, 12 months-165 months). All patients had residual macroscopic tumors at the initiation of radiotherapy. The authors observed 55 local recurrences during follow-up, as well as systemic disease progression in 4 patients. The resulting 3-year, 5-year, and 10-year LC rates were 82%, 72%, and 54%, respectively, whereas the 3-year, 5-year, and 10-year OS rates were 95%, 85%, and 75%, respectively. Age <48 years and a boost volume >75 mL were associated with a significantly improved LC and OS. Primary treatment resulted in a significantly better OS probability. No higher late toxicity could be detected after carbon ion treatment., Conclusions: Carbon ion therapy appears to be a safe and effective treatment for patients with skull base chordoma, resulting in high LC and OS rates., (© 2014 American Cancer Society.)

Monte Carlo (MC) simulations of beam interaction and transport in matter are increasingly considered as essential tools to support several aspects of radiation therapy. Despite the vast application of MC to photon therapy and scattered proton therapy, clinical experience in scanned ion beam therapy is still scarce. This is especially the case for ions heavier than protons, which pose additional issues like nuclear fragmentation and varying biological effectiveness. In this work, we present the evaluation of a dedicated framework which has been developed at the Heidelberg Ion Beam Therapy Center to provide automated FLUKA MC simulations of clinical patient treatments with scanned proton and carbon ion beams. Investigations on the number of transported primaries and the dimension of the geometry and scoring grids have been performed for a representative class of patient cases in order to provide recommendations on the simulation settings, showing that recommendations derived from the experience in proton therapy cannot be directly translated to the case of carbon ion beams. The MC results with the optimized settings have been compared to the calculations of the analytical treatment planning system (TPS), showing that regardless of the consistency of the two systems (in terms of beam model in water and range calculation in different materials) relevant differences can be found in dosimetric quantities and range, especially in the case of heterogeneous and deep seated treatment sites depending on the ion beam species and energies, homogeneity of the traversed tissue and size of the treated volume. The analysis of typical TPS speed-up approximations highlighted effects which deserve accurate treatment, in contrast to adequate beam model simplifications for scanned ion beam therapy. In terms of biological dose calculations, the investigation of the mixed field components in realistic anatomical situations confirmed the findings of previous groups so far reported only in homogenous water targets. This work can thus be useful to other centers commencing clinical experience in scanned ion beam therapy.

Purpose: To evaluate the safety and efficacy of reirradiation with carbon ions in patients with relapse of skull base chordoma and chondrosarcoma., Patients and Methods: Reirradiation with carbon ions was performed on 25 patients with locally recurrent skull base chordoma (n = 20) or chondrosarcoma (n = 5). The median time between the last radiation exposure and the reirradiation with carbon ions was 7 years. In the past, 23 patients had been irradiated once, two patients twice. Reirradiation was delivered using the active raster scanning method. The total median dose was 51.0 GyE carbon ions in a weekly regimen of five to six fractions of 3 GyE. Local progression-free survival (LPFS) was evaluated using the Kaplan-Meier method; toxicity was evaluated using the NCI Common Terminology Criteria for Adverse Events (CTCAE v.4.03)., Results: The treatment could be finished in all patients without interruption. In 80% of patients, symptom control was achieved after therapy. The 2-year-LPFS probability was 79.3%. A PTV volume of < 100 ml or a total dose of > 51 GyE was associated with a superior local control rate. The therapy was associated with low acute toxicity. One patient developed grade 2 mucositis during therapy. Furthermore, 12% of patients had tympanic effusion with mild hypacusis (grade 2), while 20% developed an asymptomatic temporal lobe reaction after treatment (grade 1). Only one patient showed a grade 3 osteoradionecrosis., Conclusion: Reirradiation with carbon ions is a safe and effective method in patients with relapsed chordoma and chondrosarcoma of the skull base.

Background: The current study was performed to evaluate the safety and effectiveness of irradiation with carbon ions using raster scanning as well as prognostic factors in patients with skull base chondrosarcomas., Methods: Between 1998 and 2008, 79 patients with chondrosarcoma of the skull base were treated using carbon ions in raster scanning. The applied median total dose was 60 gray equivalent (GyE) at 3 GyE per fraction. Local control and overall survival (OS) were evaluated using the Kaplan-Meier method. Long-term toxicity was quantitatively assessed using questionnaires., Results: The median follow-up after irradiation was 91 months (range, 3 months-175 months). Within the follow-up, 10 patients developed local disease recurrence. The 3-year, 5-year, and 10-year local control rates were 95.9%, 88%, and 88%, respectively; the corresponding OS rates were 96.1%, 96.1%, and 78.9%, respectively. With a median follow-up of 110 months after first diagnosis, the corresponding 3-year, 5-year, and 10-year OS rates were 97.5%, 97.5%, and 91.5%, respectively. Age ≤ 45 years and boost volume ≤ 55 mL were associated with significantly better local control rates. We observed a clinically relevant improvement in cranial nerve deficits 7 to 10 years after treatment (range, 45.5%-53.3%) compared with the baseline (73.4%). During follow-up, none of the patients in the current study developed a secondary malignancy., Conclusions: Carbon ion therapy is a safe and effective treatment in patients with chondrosarcoma of the skull base. For further evaluation, a prospective randomized phase 3 trial comparing protons versus carbon ions has been recruiting patients with low-grade and intermediate-grade chondrosarcoma of the skull base since 2009., (© 2014 American Cancer Society.)

Purpose: Estimation of the actual delivered 4-dimensional (4D) dose in treatments of patients with mobile hepatocellular cancer with scanned carbon ion beam therapy., Methods and Materials: Six patients were treated with 4 fractions to a total relative biological effectiveness (RBE)-weighted dose of 40 Gy (RBE) using a single field. Respiratory motion was addressed by dedicated margins and abdominal compression (5 patients) or gating (1 patient). 4D treatment dose reconstructions based on the treatment records and the measured motion monitoring data were performed for the single-fraction dose and a total of 17 fractions. To assess the impact of uncertainties in the temporal correlation between motion trajectory and beam delivery sequence, 3 dose distributions for varying temporal correlation were calculated per fraction. For 3 patients, the total treatment dose was formed from the fractional distributions using all possible combinations. Clinical target volume (CTV) coverage was analyzed using the volumes receiving at least 95% (V95) and 107% (V107) of the planned doses., Results: 4D dose reconstruction based on daily measured data is possible in a clinical setting. V95 and V107 values for the single fractions ranged between 72% and 100%, and 0% and 32%, respectively. The estimated total treatment dose to the CTV exhibited improved and more robust dose coverage (mean V95 > 87%, SD < 3%) and overdose (mean V107 < 4%, SD < 3%) with respect to the single-fraction dose for all analyzed patients., Conclusions: A considerable impact of interplay effects on the single-fraction CTV dose was found for most of the analyzed patients. However, due to the fractionated treatment, dose heterogeneities were substantially reduced for the total treatment dose. 4D treatment dose reconstruction for scanned ion beam therapy is technically feasible and may evolve into a valuable tool for dose assessment., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Treatment of surgically unresectable recurrence in the head and neck region remains a therapeutic problem with the only curative option being a second course of radiation with a tumouricidal dose. We report initial toxicity and efficacy of charged particle therapy in this situation., Methods: Treatment-related side-effects of patients treated with charged particle beams for recurrent tumours of the head and neck were prospectively collected and patient data was retrospectively analysed with regard to toxicity and efficacy of the treatment according to CTCAE v. 4.03 and RECIST., Results: Treatment was tolerated well without any severe acute toxicity. In non-chordoma/chondrosarcoma patients, overall response rate was 53.3% at 8 weeks post RT. 4/5 chordoma/chondrosarcoma patients showed no signs of further tumour progression., Conclusion: Initial experience of re-irradiation with scanned particle beams in recurrent tumours of the head and neck seems feasible and encouraging. Further follow-up is needed to investigate potential late effects., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background and Purpose: To investigate toxicity and efficacy in high-risk malignant salivary gland tumors (MSGT) of the head and neck. Local control in R2-resected adenoid cystic carcinoma was already improved with a combination of IMRT and carbon ion boost at only mild side-effects, hence this treatment was also offered to patients with MSGT and microscopic residual disease (R1) or perineural spread (Pn+)., Methods: From November 2009, all patients with MSGT treated with carbon ion therapy were evaluated. Acute side effects were scored according to CTCAE v.4.03. Tumor response was assessed according to RECIST where applicable., Results: 103 patients were treated from 11/2009 to 03/2011, median follow-up is 6 months. 60 pts received treatment following R2 resections or as definitive radiation, 43 patients received adjuvant radiation for R1 and/or Pn+. 16 patients received carbon ion treatment for re-irradiation. Median total dose was 73.2 GyE (23.9 GyE carbon ions + 49,9 Gy IMRT) for primary treatment and 44.9 GyE carbon ions for re-irradiation. All treatments were completed as planned and generally well tolerated with no > CTC°III toxicity. Rates of CTC°III toxicity (mucositis and dysphagia) were 8.7% with side-effects almost completely resolved at first follow-up.47 patients showed good treatment responses (CR/PR) according to RECIST., Conclusion: Acute toxicity remains low in IMRT with carbon ion boost also in R1-resected patients and patients undergoing re-irradiation. R2-resected patients showed high rates of treatment response, though follow-up is too short to assess long-term disease control.

Purpose: To evaluate feasibility and toxicity of carbon ion therapy for treatment of sinonasal malignancies. First site of treatment failure in malignant tumours of the paranasal sinuses and nasal cavity is mostly in-field, local control hence calls for dose escalation which has so far been hampered by accompanying acute and late toxicity. Raster-scanned carbon ion therapy offers the advantage of sharp dose gradients promising increased dose application without increase of side-effects., Methods: Twenty-nine patients with various sinonasal malignancies were treated from 11/2009 to 08/2010. Accompanying toxicity was evaluated according to CTCAE v.4.0. Tumor response was assessed according to RECIST., Results: Seventeen patients received treatment as definitive RT, 9 for local relapse, 2 for re-irradiation. All patients had T4 tumours (median CTV1 129.5 cc, CTV2 395.8 cc), mostly originating from the maxillary sinus. Median dose was 73 GyE mostly in mixed beam technique as IMRT plus carbon ion boost. Median follow-up was 5.1 months [range: 2.4-10.1 months]. There were 7 cases with grade 3 toxicity (mucositis, dysphagia) but no other higher grade acute reactions; 6 patients developed grade 2 conjunctivits, no case of early visual impairment. Apart from alterations of taste, all symptoms had resolved at 8 weeks post RT. Overall radiological response rate was 50% (CR and PR)., Conclusion: Carbon ion therapy is feasible; despite high doses, acute reactions were not increased and generally resolved within 8 weeks post radiotherapy. Treatment response is encouraging though follow-up is too short to estimate control rates or evaluate potential late effects. Controlled trials are warranted.

Ameloblastic carcinomas are rare odontogenic tumors. Treatment usually consists of surgical resection and sometimes adjuvant radiation. We report the case of a 71 year-old male patient undergoing carbon ion therapy for extensive local relapse of ameloblastic carcinoma. Treatment outcome was favourable with a complete remission at 6 weeks post completion of radiotherapy while RT-treatment itself was tolerated well with only mild side effects. High dose radiation hence is a potential alternative for patients unfit or unwilling to undergo extensive surgery or in cases when only a subtotal resection is planned or the resection is mutilating.

Unlabelled: The Heidelberg Ion Therapy Center (HIT) started clinical operation in November 2009. In this report we present the first 80 patients treated with proton and carbon ion radiotherapy and describe patient selection, treatment planning and daily treatment for different indications., Patients and Methods: Between November 15, 2009 and April 15, 2010, 80 patients were treated at the Heidelberg Ion Therapy Center (HIT) with carbon ion and proton radiotherapy. Main treated indications consisted of skull base chordoma (n = 9) and chondrosarcoma (n = 18), malignant salivary gland tumors (n=29), chordomas of the sacrum (n = 5), low grade glioma (n=3), primary and recurrent malignant astrocytoma and glioblastoma (n=7) and well as osteosarcoma (n = 3). Of these patients, four pediatric patients aged under 18 years were treated., Results: All patients were treated using the intensity-modulated rasterscanning technique. Seventy six patients were treated with carbon ions (95%), and four patients were treated with protons. In all patients x-ray imaging was performed prior to each fraction. Treatment concepts were based on the initial experiences with carbon ion therapy at the Gesellschaft für Schwerionenforschung (GSI) including carbon-only treatments and carbon-boost treatments with photon-IMRT. The average time per fraction in the treatment room per patient was 29 minutes; for irradiation only, the mean time including all patients was 16 minutes. Position verification was performed prior to every treatment fraction with orthogonal x-ray imaging., Conclusion: Particle therapy could be included successfully into the clinical routine at the Department of Radiation Oncology in Heidelberg. Numerous clinical trials will subsequently be initiated to precisely define the role of proton and carbon ion radiotherapy in radiation oncology.

We describe a method to irradiate arbitrarily shaped target volumes with simultaneously optimized multiple fields of fast carbon ions, explicitly taking into account sparing of organs at risk. The method was developed with realistic technical boundary conditions in mind, so that irradiations can be executed with devices like the GSI raster scanner or its successors at the upcoming dedicated ion-beam radiotherapy facilities. By virtue of the local effect model (LEM) biological effects are fully taken into account. Several minimization algorithms were investigated, and plain gradient search was found to be more effective than methods based on conjugate gradients or Newton's root finding algorithm. Two sets of cell survival experiments for the experimental verification of patient-like treatment plans were performed. Chinese hamster cells were used for quasi two-dimensional biological dosimetry. The plans combine a very good target conformation with an excellent sparing of organs-at-risk which was verified by the measurements. The results are compared to predictions of the local effect model in its original formulation and a modified version taking additional effects of clustered DNA damage into account. The new method is implemented in GSI's TRiP98 treatment planning system. It has already been applied clinically for planning and irradiating selected patients within the GSI pilot project.

Seventeen community hospitals within the 16 division of the Sisters of Mercy Health Corporation cooperatively participated in a medication allergy audit program. Initial and follow-up audits were conducted at each hospital to determine whether allergy information for penicillin- or aspirin-sensitive patients was appropriately communicated to the pharmacist. A total of 483 patient records were reviewed during each audit which corresponded to 12% of each hospital's average patient census. In the initial audit, the overall acceptance rate for the combined hospitals was 62.3%. Following the first audit, each hospital undertook corrective follow-up measures in an attempt to improve its results. In the second audit, the overall acceptance rate improved significantly to 78.9%. It is concluded that this auditing process followed by corrective follow-up measures was an effective mechanism for improving the communication of patient allergy information and is a means to quality assurance. Future audits will be necessary to determine whether the beneficial effects produced will be sustained or improved.