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Background Intensity-modulated helical tomotherapy (HT) is a promising technique in preparation for bone marrow transplantation. Nevertheless, radiation-sensitive organs can be substantially compromised due to suboptimal delivery techniques of total body irradiation (TBI). To reduce the potential burden of radiation toxicity to organs at risk (OAR), high-quality coverage and homogeneity are essential. We investigated dosimetric data from kidney, lung and thorax, liver, and spleen in relation to peripheral blood kinetics. To further advance intensity-modulated total body irradiation (TBI), the potential for dose reduction to lung and kidney was considered in the analysis. Patients and methods 46 patients undergoing TBI were included in this analysis, partially divided into dose groups (2, 4, 8, and 12 Gy). HT was performed using a rotating gantry to ensuring optimal reduction of radiation to the lungs and kidneys and to provide optimal coverage of other OAR. Common dosimetric parameters, such as D05, D95, and D50, were calculated and analysed. Leukocytes, neutrophils, platelets, creatinine, GFR, haemoglobin, overall survival, and graft-versus-host disease were related to the dosimetric evaluation using statistical tests. Results The mean D95 of the lung is 48.23%, less than half the prescribed and unreduced dose. The D95 of the chest is almost twice as high at 84.95%. Overall liver coverage values ranged from 96.79% for D95 to 107% for D05. The average dose sparing of all patients analysed resulted in an average D95 of 68.64% in the right kidney and 69.31% in the left kidney. Average D95 in the spleen was 94.28% and D05 was 107.05%. Homogeneity indexes ranged from 1.12 for liver to 2.28 for lung. The additional significance analyses conducted on these blood kinetics showed a significant difference between the 2 Gray group and the other three groups for leukocyte counts. Further statistical comparisons of the dose groups showed no significant differences. However, there were significant changes in the dose of OAR prescribed with dose sparing (e.g., lung vs. rib and kidney). Conclusion Using intensity-modulated helical tomotherapy to deliver TBI is a feasible method in preparation for haematopoietic stem cell transplantation. Significant dose sparing in radiosensitive organs such as the lungs and kidneys is achievable with good overall quality of coverage. Peripheral blood kinetics support the positive impact of HT and its advantages strongly encourage its implementation within clinical routine.

Background Radiotherapy (RT) of ependymoma in children is an important part of the interdisciplinary treatment concept. However, feasibility and dose concepts are still under investigation, particularly in very young children. The aim of this study was to evaluate the standard dose and volume of proton therapy (PT) in children with ependymoma. Methods In this analysis, 105 patients with localized, intracranial ependymoma under the age of 18 years treated with PT between 2013 and 2018 were included. Patient characteristics, treatment, outcome, and follow-up data were analyzed using descriptive statistics, Kaplan-Meier, and Cox regression analysis. Results The median age of patients at PT was 2.8 years (0.9-17.0 years). The molecular subgroup analysis was performed in a subset of 50 patients (37 EP-PFA, 2 EP-PFB, 7 EP-RELA, 2 EP-YAP, 2 NEC [not elsewhere classified]). The median total dose was 59.4 Gy (54.0-62.0 Gy). The median follow-up time was 1.9 years. The estimated 3-year overall survival (OS), local control (LC), and progression-free survival (PFS) rates were 93.7%, 74.1%, and 55.6%, respectively. Within univariable analysis, female gender and lower dose had a positive impact on OS, whereas age ≥4 years had a negative impact on OS and PT given after progression had a negative impact on PFS. In the multivariable analysis, multiple tumor surgeries were associated with lower PFS. New ≥3° late toxicities occurred in 11 patients. Conclusion For children with localized ependymoma, PT was effective and well tolerable. Multiple surgeries showed a negative impact on PFS.

Background: Neoadjuvant radiotherapy (naRT) in addition to neoadjuvant chemotherapy (naCT) has been used for locally advanced, inoperable breast cancer or to allow breast conserving surgery (BCS). Retrospective analyses suggest that naRT + naCT might result in an improvement in pathological complete response (pCR rate and disease-free survival). pCR is a surrogate parameter for improved event-free and overall survival (OS) and allows for the adaption of the post-neoadjuvant therapy regimens. However, it is not clear whether pCR achieved with the addition of naRT has the same prognostic value. Patients and methods: We performed a retrospective re-analysis of 356 patients (cT1-cT4/cN0-N+) treated with naRT and naCT with a long-term follow-up. Patients underwent naRT on the breast and regional lymph nodes combined with a boost to the primary tumor. Chemotherapy with different agents was given either sequentially or concomitantly to naRT. We used the Cox proportional hazard regression model to estimate the effect of pCR in our cohort in different subgroups as well as chemotherapy protocols. Clinical response markers correlating with OS were also analyzed. Results: For patients with median follow-ups of 20 years, 10 years, 15 years, 20 years, and 25 years, OS rates were 69.7%, 60.6%, 53.1%, and 45.1%, respectively. pCR was achieved in 31.1% of patients and associated with a significant improvement in OS (HR = 0.58; CI-95%: 0.41–0.80; p = 0.001). The prognostic impact of pCR was evident across breast cancer subtypes and chemotherapy regimens. Multivariate analysis showed that age, clinical tumor and nodal stage, chemotherapy, and pCR were prognostic for OS. Conclusion: NaCT and naRT prior to surgical resection achieve good long-term survival in high-risk breast cancer. pCR after naRT maintains its prognostic value in breast cancer subtypes and across different subgroups. pCR driven by naRT and naCT independently influences long-term survival.

Background: Vascular surgery of the inguinal area can be complicated by persistent lymphatic fistulas. Rapid and effective treatment is essential to prevent infection, sepsis, bleeding, and possible leg amputation. Current data on irradiation of lymphatic fistulas lacks recommendation on the appropriate individual and total dose, the time of irradiation, and the target volume. Presumably, a dose of 0.3-0.5 to 1-12 Gy should be sufficient for the purpose. Currently, radiotherapy is a “can” recommendation, with a level 4 low evidence and a grade C recommendation, according to the DEGRO S2 guidelines. As part of a pilot study, we analyzed the impact and limitations of low-dose radiation therapy in the treatment of inguinal lymphatic fistulas.Patients and Methods: As part of an internal quality control project, patients with lymphatic fistulas irradiated in the groin area after vascular surgery for arterial occlusive disease (AOD) III-IV, repair of pseudo aneurysm or lymph node dissection due to melanoma were selected, and an exploratory analysis on retrospectively collected data performed.Results: Twelve patients (10 males and 2 females) aged 62.83 + 12.14 years underwent open vascular reconstruction for stage II (n= 2), III (n=1), and IV (n=7) arterial occlusive disease (AOD), lymph node dissection for melanoma (n=1) or repair of a pseudoaneurysm (n=1). Surgical vascular access was obtained through the groin and was associated with a persistent lymphatic fistula, secreting more than 50 ml/day. Patients were irradiated five times a week up to a maximum of 10 fractions for the duration of the radiation period. Fraction of 0.4 Gy were applied in the first 7 cases, while 5 patients were treated with a de-escalating dose of 0.3 Gy. There was a resolution of the lymphatic fistula in every patient without higher grade complications.Conclusion: Low-dose irradiation of the groin is a treatment option for persistent lymphatic fistula after inguinal vascular surgery.

Aims Proton beam therapy (PBT) has increasingly been applied for the treatment of young children when radiotherapy is needed. The treatment requires intensive multimodality care and is logistically demanding. In this analysis, we evaluated our experiences in treating infants with tumours of the central nervous system with PBT. Materials and methods Children younger than 2 years of age treated with PBT for central nervous system tumours enrolled in the prospective registry study KiProReg were retrospectively analysed. Information on patient characteristics, treatment, toxicities and outcome were evaluated. Adverse events were classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE V4.0) before, during and after PBT. Results Between September 2013 and June 2018, 51 infants were eligible. The median age was 19 months (range 11–23 months) at the time of PBT. Tumour entities were ependymoma (51.0%), atypical teratoid rhabdoid tumour (39.0%), high-grade glioma (6.0%), pineoblastoma (2.0%) and medulloblastoma (2.0%). The prescribed median total dose was 54.0 Gy (range 45.0–59.4 Gy). Most received local radiotherapy. In four patients, craniospinal irradiation followed by a boost to the local tumour bed was applied. The median follow-up time was 42.0 months (range 7.3–86.2 months). The estimated 3-year local control, progression-free survival and overall survival rates for all patients were 62.7, 47.1 and 76.5%, respectively. During radiotherapy, 24 events of higher-grade (CTCAE ≥ °III) toxicities were reported. Interruption of radiotherapy for more than 2 days was due to infection (n = 3) or shunt complication (n = 2). Unexpected hospitalisation during radiotherapy affected 12 patients. Late adverse events attributable to radiotherapy included endocrinopathy (CTCAE °II; 7.8%), new onset of hearing loss (CTCAE °III; 5.8%) and visual impairment (CTCAE °IV; 1.9%). Transient radiation-induced imaging changes occurred in five patients (9.8%). Conclusions Our study indicates that PBT is feasible for very young children with central nervous system tumours, at least in the short term. However, it requires challenging interdisciplinary medical care and high logistical effort. For evaluation of late effects, longer follow-up and evaluation of neurocognitive outcome are desirable. More data have to be gathered to further define the role of radiotherapy in infants over time.

Background/Aims: Due to its favorable dose distribution and targeting of the region at highest risk of recurrence due to direct visualization of tumor bed, intraoperative electron radiation therapy (IOERT) is used as part of a breast-conserving treatment approach. The aim of this study was to analyze tumor control and survival, as well as the toxicity profile, and cosmetic outcomes in patients irradiated with an IOERT boost for breast cancer. Materials and Methods: 139 Patients treated at our institution between January 2010 and January 2015 with a single boost dose of 10 Gy to the tumor bed during breast-conserving surgery followed by whole-breast irradiation were retrospectively analyzed. Results: 139 patients were included in this analysis. The median age was 54 years (range 28–83 years). The preferred surgical strategy was segmental resection with sentinel lymphonodectomy (66.5%) or axillary dissection (23.1%). Regarding adjuvant radiotherapy, the vast majority received 5 × 1.8 Gy to 50.4 Gy. At a median follow-up of 33.6 months, recurrence-free and overall survival were 95.5% and 94.9%, respectively. No patient developed an in-field recurrence. Seven patients (5.0%) died during the follow-up period, including two patients due to disease recurrence (non-in-field). High-grade (CTCAE > 2) perioperative adverse events attributable to IOERT included wound healing disorder (N = 1) and hematoma (N = 1). High-grade late adverse events (LENT-SOMA grade III) were reported only in one patient with fat necrosis. Low-grade late adverse events (LENT-SOMA grade I-II) included pain (18.0%), edema (10.5%), fibrosis (21%), telangiectasia (4.5%) and pigmentation change (23.0%). The mean breast retraction assessment score was 1.66 (0–6). Both patients and specialists rated the cosmetic result “excellent/good” in 84.8% and 87.9%, respectively. Conclusion: Our study reports favorable data on the cosmetic outcome as well as the acute and early long-term tolerability for patients treated with an IOERT boost. Our oncologic control rates are comparable to the previous literature. However, prospective investigations on the role of IOERT in comparison to other boost procedures would be desirable.

Neoadjuvant chemotherapy enables close monitoring of tumor response in patients with breast cancer. Being able to assess tumor response during treatment provides an opportunity to evaluate new therapeutic strategies. Thus, for triple-negative breast tumors, it was demonstrated that additional immunotherapy could improve prognosis compared with chemotherapy alone. Furthermore, adjuvant therapy can be escalated or de-escalated correspondingly. The CREATE-X trial randomly assigned HER2-negative patients with residual tumor after neoadjuvant therapy to either observation or capecitabine. In HER2-negative patients with positive BRCA testing, the OlympiA study randomly assigned patients to either observation or olaparib. HER2-positive patients without pathologic remission were randomly assigned to trastuzumab or trastuzumab–emtansine within the KATHERINE study. These studies were all able to show an improvement in oncologic outcome associated with the escalation of therapy in patients presenting with residual tumor after neoadjuvant treatment. On the other hand, this individualization of therapy may also offer the possibility to de-escalate treatment, and thereby reduce morbidity. Among WSG-ADAPT HER2+/HR-, HER2-positive patients achieved comparable results without chemotherapy after complete remission following neoadjuvant treatment. In summary, the concept of post-neoadjuvant therapy constitutes a great opportunity for individualized cancer treatment, potentially improving outcome. In this review, the most important trials of post-neoadjuvant therapy are compiled and discussed.

Stage III non-small cell lung cancer (NSCLC) represents a highly heterogeneous disease and treatment burden. Advances in imaging modality show promising results for radiotherapy planning. In this multicentric study, we evaluated the impact of PET/CT-based radiotherapy planning on the prognosis of patients with stage III NSCLC.A retrospective observational cohort study (ARO 2017-01/NCT03055715) was conducted by the young DEGRO trial group of the German Society for Radiation Oncology (DEGRO) with the primary objective to assess the effect of tumour volume change during chemoradiotherapy and the secondary objective to assess the effect of treatment planning on survival. Three hundred forty-seven patients with stage III NSCLC treated at 21 university centers between January 2010 and December 2013 were enrolled in this trial. Patients received primary curative chemoradiotherapy with an intended dose of 50 Gy (hypofractionated) or 60 Gy (normofractionated). To assess the effect of radiotherapy planning modality on overall survival, we used multivariate frailty models. Models were adjusted for gross tumor volume at the initiation of therapy, age, sex, simultaneous chemotherapy, lung comorbidities, RT dose and tumor grade. By considering the random effect, we can account for heterogeneity in survival and considered covariates within the model in relation to the study side.Patients were predominantly male (n = 269, 78.4%) with mainly adenocarcinoma (56.4%) and an average of 67.2 years. Adaptation of radiotherapy with consecutive reduction of irradiation volume showed no significant disadvantage for patient survival (HR = 1.21, 95% CI 0.89-1.64). The use of PET/CT co-registration in radiation planning tended to result in better oncologic outcomes, although no significant association could be shown (HR = 0.8, 95% CI 0.56-1.16). Centers with a consistent planning strategy performed better than those without a preferred planning method (0.62, 95% CI 0.41-0.94).A consistent planning strategy has positive effects on overall survival. The use of PET/CT-based adaptive radiotherapy planning shows a similar survival prospect with the prospective of lower treatment volumes. In future research, toxicities need to be analysed in order to assess such reasoning.

Aim: Evaluation of pain reduction using orthovolt or cobalt-based radiation treatment for painful heel spurs and determination of long-term response as well as prognostic parameters.Methods: We identified a total of 102 consecutive patients treated for a total of 117 symptomatic heel spurs. 59 patients were treated with cobalt radiation, 31 patients with orthovolt therapy and 12 patients with both radiation systems. Pain reduction was scored using the modified Rowe-Score prior therapy, at the end of each treatment series as well as after 6 weeks and at the time of data collection. Long-term outcome was evaluated in patients with a follow-up period of longer than three years. Results: Before radiation therapy, 61 patients (60.4%) had a score of 0, significant strong pain. At the time of completion of radiation treatment, 3 patients (2.7%) were pain free (score of 30), whereas 8 patients (7.9%) had still severe pain (score 0). 6 weeks after radiation therapy, 33 patients (32.7%) were pain-free and 8 patients (7.9%) had severe pain (score 0), while at the time data of collection, 74 patients (73%) were free of pain and 1 patient (1%) had strong pain (score 0). Duration of pain before the start of radiation treatment was a significant prognostic factor (p=0.012) for response to treatment. Hier noch etwas über die Nebenwirkungen schreiben? Darauf gehen wir in der Conclusion ja ein.Conclusion: Radiotherapy of painful heel spurs is a highly effective therapy with little side effects providing long-term therapeutic response. The only significant prognostic parameter for response to treatment is the duration of pre-radiation therapy pain. Early integration of radiation therapy in the treatment seems to result in superior pain reduction.

Purpose The standard of care of childhood parameningeal rhabdomyosarcoma (pRMS) is chemotherapy and local radiation therapy. Protons are increasingly being used to decrease late effects. The aim of the present study is to analyze the pattern of relapse and the correlation with dosimetric factors in pRMS treated with proton therapy. Methods and Materials This retrospective evaluation includes children treated in our institution for pRMS. Information on demographics, treatment, tumor characteristics, and toxicities and outcome was prospectively collected within the in-house registry. For patients presenting with local relapse, a fusion of the dosimetry with magnetic resonance imaging displaying site and geometry of recurrence was performed. Results Median follow-up time was 2.9 years (0.5-4.7). Forty-six patients were identified in our institution between July 2013 and November 2017. Main characteristics of patients were as follows: 56.5% male, median age 5.1 years (1.3-17.5), 39.1% alveolar histology, 26.1%, 52.2%, 8.7%, and 13% patients with subgroup risk classification D, E/F/G, H, or metastatic, respectively, median total prescribed dose 55.8 Gy (50.4-56.4). Estimated 2-year local control, metastasis-free survival, event-free survival, and overall survival were 83.8%, 87.8%, 76.9%, and 88.9%, respectively. No acute or late local toxicity exceeding grade 3 was observed. Risk-group was identified as prognostic factor for metastasis-free survival in univariate analysis but not in multivariate analysis (trend: P = .09). In this cohort, dosimetric factors did not correlate with outcome. Isolated local failure happened in 5 of the 11 relapses. Local relapses were matched with dosimetry for 6 patients: 4 of them occurred in the high dose volume and 2 in the intermediate or low dose volume. Conclusions Proton therapy was effective and well feasible even in a critical cohort. Still, local relapse within the target volume of the radiation therapy remains an important issue in pRMS and new treatment strategies are needed.

Purpose Neuroblastoma (NB) is the most common extracranial solid malignancy during childhood. Despite a multimodal treatment approach, the prognosis of patients with metastatic NB is not satisfactory. Although radiotherapy (RT) has become an integral part of treatment of the primary tumor, the role of RT in osteomedullary lesions is not well defined. A retrospective analysis was conducted to evaluate the impact of RT for metastatic sites in children with high-risk NB. Methods All patients with stage 4 NB from the prospective, multicenter NB trials NB97 and NB2004 who received RT to metastatic sites during frontline treatment were included in this retrospective analysis. Results A total of 18 children were irradiated with a median dose of 36 Gray (Gy; range 20–45 Gy) to one or more (range 1–3) osteomedullary metastases with or without concomitant RT to the primary tumor site. The median follow-up time was 149 months (range 55–220) in survivors. At 5 years, local relapse-free survival (LRFS) at irradiated metastatic sites and metastases-free survival (MFS) at distant, non-irradiated site rates were 51.4 and 39.9%, respectively. The estimated overall survival (OS) rate at 5 years was 49.4%. No high-grade acute or late toxicity and no secondary malignancy was reported. Conclusion RT to metastases is feasible for patients with stage 4 NB. However, an impact of RT to residual metastatic sites on outcome was not found. Studies with larger cohorts or prospective trials would be desirable in order to elucidate the role of RT for metastases.

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

Background Repetitive transcranial magnetic stimulation (rTMS) is able to modify cortical excitability. Rat rTMS studies revealed a modulation of inhibitory systems, in particular that of the parvalbumin-expressing (PV+) interneurons, when using intermittent theta-burst stimulation (iTBS). Objective The potential disinhibitory action of iTBS raises the questions of how neocortical circuits stabilize excitatory-inhibitory balance within a physiological range. Neuropeptide Y (NPY) appears to be one candidate. Methods Analysis of cortical expression of PV, NPY and vesicular glutamate transporter type 1 (vGluT1) by immunohistochemical means at the level of cell counts, mean neuropil expression and single cell pre-/postsynaptic expression, with and without intraventricular NPY-injection. Results Our results show that iTBS not only reduced the number of neurons with high-PV expression in a dose-dependent fashion, but also increased the cortical expression of NPY, discussed to reduce glutamatergic transmission, and this was further associated with a reduced vGluT1 expression, an indicator of glutamateric presynaptic activity. Interneurons showing a low-PV expression exhibit less presynaptic vGluT1 expression compared to those with a high-PV expression. Intraventricular application of NPY prior to iTBS prevented the iTBS-induced reduction in the number of high-PV neurons, the reduction in tissue vGluT1 level and that presynaptic to high-PV cells. Conclusions We conclude that NPY, possibly via a global but also slow homeostatic control of glutamatergic transmission, modulates the strength and direction of the iTBS effects, likely preventing pathological imbalance of excitatory and inhibitory cortical activity but still allowing enough disinhibition beneficial for plastic changes as during learning.

Cancer is a disease of the genome caused by oncogene activation and tumor suppressor gene inhibition. Deep sequencing studies including large consortia such as TCGA and ICGC identified numerous tumor‐specific mutations not only in protein‐coding sequences but also in non‐coding sequences. Although 98% of the genome is not translated into proteins, most studies have neglected the information hidden in this “dark matter” of the genome. Malignancy‐driving mutations can occur in all genetic elements outside the coding region, namely in enhancer, silencer, insulator, and promoter as well as in 5′‐UTR and 3′‐UTR. Intron or splice site mutations can alter the splicing pattern. Moreover, cancer genomes contain mutations within non‐coding RNA, such as microRNA, lncRNA, and lincRNA. A synonymous mutation changes the coding region in the DNA and RNA but not the protein sequence. Importantly, oncogenes such as TERT or miR‐21 as well as tumor suppressor genes such as TP53/p53,APC,BRCA1, or RB1 can be affected by these alterations. In summary, coding‐independent mutations can affect gene regulation from transcription, splicing, mRNA stability to translation, and hence, this largely neglected area needs functional studies to elucidate the mechanisms underlying tumorigenesis. This review will focus on the important role and novel mechanisms of these non‐coding or allegedly silent mutations in tumorigenesis.

Korrespondenz zu 10.1016/j.ijrobp.2019.08.005