How to improve initial diagnostic accuracy of kidney tumours in childhood?-A non-invasive approach.

Non-invasive differentiation of paediatric kidney tumours is particularly important in the SIOP-RTSG protocols, which recommend pre-operative chemotherapy without histological confirmation. The identification of clinical and tumour-related parameters may enhance diagnostic accuracy. Age, metastases, and tumour volume (TV) were retrospectively analysed in 3306 patients enrolled in SIOP/GPOH 9, 93-01, and 2001 including Wilms tumour (WT), congenital mesoblastic nephroma (CMN), clear cell sarcoma (CCSK), malignant rhabdoid tumour of the kidney (MRTK), and renal cell carcinoma (RCC). WT was diagnosed in 2927 (88.5%) patients followed by CMN 138 (4.2%), CCSK 126 (3.8%), MRTK 58 (1.8%) and RCC 57 (1.7%). CMN, the most common localized tumour (71.6%) in patients younger than 3 months of age, was diagnosed earliest and RCC the latest (median age [months]: 0 and 154, respectively) both associated with significantly smaller TV (median TV [mL]: 67.2 and 45.0, respectively). RCC occurred in >14% of patients older than 120 months or older than 84 months with TV <100 mL. Receiver operating characteristic analyses discriminated WT from CMN, RCC and MRTK regarding age (AUC = 0.976, 0.929 and 0.791) and TV (AUC = 0.768, 0.813 and 0.622). MRTK had the highest risk of metastasis (37.9%) despite young age, whereas the risk of metastasis increased significantly with age in WT. Age and TV at diagnosis can differentiate WT from CMN and RCC. MRTK must be considered for metastatic tumours at young age. Identification of CCSK without histology remains challenging. Combined with MRI-characteristics, including diffusion-weighted imaging, and radiomics and liquid biopsies in the future, our approach allows optimization of biopsy recommendations and prevention of misdiagnosis-based neoadjuvant treatment.

ArthroRad trial: randomized multicenter single-blinded trial on the effect of low-dose radiotherapy for painful osteoarthritis-final results after 12-month follow-up.

OBJECTIVE: Updated report about the randomized comparison of the effect of radiotherapy on painful osteoarthritis (OA) applying a standard dose vs. a very low dose regime after a follow-up of 1 year. PATIENTS AND METHODS: Patients presenting with OA of the hand/finger and knee joints were included. After randomization (every joint region was randomized separately) the following protocols were applied: (a) standard arm: total dose 3.0 Gy, single fractions of 0.5 Gy twice a week; (b) experimental arm: total dose 0.3 Gy, single fractions of 0.05 Gy twice a week. The dosage was blinded for the patients. For evaluation the scores after 1­year visual analog scale (VAS), Knee Injury and Osteoarthritis Outcome Score-Short Form (KOOS-PS), Short Form Score for the Assessment and Quantification of Chronic Rheumatic Affections of the Hands (SF-SACRAH) and 12-item Short-Form Health Survey (SF-12) were used (for further details: see [1]). RESULTS: The standard dose was applied to 77 hands and 33 knees, the experimental dose was given to 81 hands and 30 knees. After 12 months, the data of 128 hands and 45 knees were available for evaluation. Even after this long time, we observed a favorable response of pain to radiotherapy in both trial arms; however, there were no reasonable statistically significant differences between both arms concerning pain, functional, and quality of life scores. Side effects did not occur. The only prognostic factor was the pain level before radiotherapy. CONCLUSIONS: We found a favorable pain relief and a limited response in the functional and quality of life scores in both treatment arms. The possible effect of low doses such as 0.3 Gy on pain is widely unknown.

Impact of Time to Surgery on Outcome in Wilms Tumor Treated with Preoperative Chemotherapy.

(1) Background: Wilms tumor (WT) treated preoperatively is cured in over 90% of cases. However, how long preoperative chemotherapy can be given is unknown. (2) Methods: 2561/3030 patients with WT (age < 18 years) treated between 1989 and 2022 according to SIOP-9/GPOH, SIOP-93-01/GPOH, and SIOP-2001/GPOH are retrospectively analyzed to assess the risk of time to surgery (TTS) for relapse-free survival (RFS) and overall survival (OS). (3) Results: TTS was calculated for all surgeries, with the mean being 39 days (38.5 ± 12.5) for unilateral tumors (UWT) and 70 days (69.9 ± 32.7) for bilateral disease (BWT). Relapse occurred in 347 patients, of which 63 (2.5%) were local, 199 (7.8%) were metastatic, and 85 (3.3%) were combined. Moreover, 184 patients (7.2%) died, 152 (5.9%) due to tumor progression. In UWT, recurrences and mortality are independent of TTS. For BWT without metastases at diagnosis, the incidence of recurrence is less than 18% up to 120 days and increases to 29% after 120 days, and to 60% after 150 days. The risk of relapse (Hazard Ratio) adjusted for age, local stage, and histological risk group increases to 2.87 after 120 days (CI 1.19-7.95, p = 0.022) and to 4.62 after 150 days (CI 1.17-18.26, p = 0.029). In metastatic BWT, no influence of TTS is detected. (4) Conclusions: The length of preoperative chemotherapy has no negative impact on RFS or OS in UWT. In BWT without metastatic disease, surgery should be performed before day 120, as the risk of recurrence increases significantly thereafter.

Harmonica consensus, controversies, and future directions in radiotherapy for pediatric Wilms tumors.

Radiotherapy (RT) is essential for multimodality treatment of pediatric renal tumors, particularly in higher-risk and metastatic disease. Despite decades of use, particularly for Wilms tumor, there remain controversies regarding RT indications, timing, dose, and targets. To align global management, we address these issues in this international HARMONIsation and CollAboration (HARMONICA) project. There are multiple knowledge gaps and opportunities for future research including: (1) utilization of advanced RT technologies, including intensity-modulated RT, proton beam therapy, combined with image-guided RT to reduce target volumes; (2) impact of molecular biomarkers including loss of heterozygosity at 1p, 16q, and 1q gain on RT indications; (3) mitigation of reproductive toxicity following RT; (4) promotion of RT late effects research; and (5) support to overcome challenges in RT utilization in low- and middle-income countries where 90% of the world's children reside. Here, we outline current status and future directions for RT in pediatric renal tumors.

Outcomes of patients with Wilms' tumour stage III due to positive resection margins only: An analysis of patients treated on the SIOP-WT-2001 protocol in the UK-CCLG and GPOH studies.

Stage III Wilms' tumour (WT) represents a heterogeneous group which includes different criteria, but all stage III patients are treated according to the same study regiment. The aim of the study was to retrospectively analyse outcomes in patients with stage III due to positive resection margins (RM) only, sub-grouped in RM with viable (RM-v) and nonviable (RM-nv) tumour. Patients were treated pre- and postoperatively according to the SIOP-WT-2001 protocol in the UK-CCLG and GPOH WT trials and studies (2001-2020). There were 197 patients, including 134 with localised, abdominal stage III and 63 with overall stage IV, but abdominal stage III. Stage III due to RM-v had 126 patients, and due to RM-nv 71 patients. The overall 5-year local-relapse-free survival (RFS), event-free (EFS) and overall survival (OS) estimates for all patients with abdominal stage III RM were 95.7% (±SE1.5%), 85.1 (±SE2.6%) and 90.3% (±SE2.2%), respectively. Patients with stage III RM-nv had significantly better RFS and EFS than patients with RM-v (P = .027 and P = .003, respectively). A multivariate analysis showed that RM-v remained a significant factor for EFS when adjusted for age, presence of metastasis at diagnosis, histological risk group and overall stage in Cox regression analysis (P = .006). Patients with stage III due to RM-nv only exhibited no local recurrence and have a significantly better RFS and EFS than patients with RM-v. The results suggest that exclusion of RM-nv as a stage III criterion in the UMBRELLA staging system and consequent treatment reduction is warranted.

Surgical Factors Influencing Local Relapse and Outcome in the Treatment of Unilateral Nephroblastoma.

OBJECTIVE: This study aims to identify factors associated with the occurrence of local relapse (LR) after treatment for unilateral nephroblastoma. BACKGROUND: Despite the fact that LR is rare (~5%) its adverse impact on the need for relapse treatment and outcome (40%-80% overall survival) cannot be neglected. Identifying the causative factors may improve initial treatment to achieve better local control. METHODS: Altogether 2386 patients with unilateral nephroblastoma prospectively enrolled over a period of 32 years (1989-2020) by the German Society for Pediatric Oncology and Hematology (SIOP-9/GPOH, SIOP-93-01/GPOH and SIOP-2001/GPOH) were retrospectively analyzed. Hazard ratios (HR) of LR were calculated for sex, age, size, local staging, histology, type of removal, rupture, lymph node (LN) removal using univariate and multivariate Cox models. RESULTS: Age >48 months, tumor volume >500 mL, histology and LN extent of removal were identified as significant risk factors for LR [HR: 1.68, P =0.018, confidence interval (CI): 1.09-2.58; HR: 1.84, P =0.015, CI: 1.13-3.00; HR: 3.19, P <0.001, CI: 2.03-5.00; HR: 2.26, P =0.002, CI: 1.36-3.576]. LR occur significantly more often in Stage I and II, even if no LN are removed. The risk of metastases is significantly increased after local recurrence (HR: 11.5, P <0.001, CI: 7.11-18.60). LR is associated with a subsequent 18.79-fold increased risk of death (HR: 18.79, P <0.001, CI: 2.07-5.28). CONCLUSIONS: Several factors are responsible for the occurrence of LR. Surgical ones, like LN sampling allow further reduction of LR and consequently a better outcome of patients with unilateral nephroblastoma.

Vena Cava Thrombus in Patients with Wilms Tumor.

(1) Background: Vena cava thrombus (VCT) is rare in Wilms tumor (WT) (4−10%). The aim of this study is to identify factors for an outcome to improve treatment for better survival. (2) Methods: 148/3015 patients with WT (aged < 18 years) and VCT, prospectively enrolled over a period of 32 years (1989−2020) by the German Society for Pediatric Oncology and Hematology (SIOP-9/GPOH, SIOP-93-01/GPOH and SIOP-2001/GPOH), are retrospectively analyzed to describe clinical features, response to preoperative chemotherapy (PC) (142 patients) and surgical interventions and to evaluate risk factors for overall survival (OS). (3) Results: 14 VCT regressed completely with PC and another 12 in parts. The thrombus was completely removed in 111 (85.4%), incompletely in 16 (12.3%), and not removed in 3 (2.3%). The type of removal is unknown in four patients. Patients without VCT have a significantly (p < 0.001) better OS (97.8%) than those with VCT (90.1%). OS after complete resection is (89.9%), after incomplete (93.8%) and with no resection (100%). Patients with anaplasia or stage IV without complete remission (CR) after PC had a significantly worse OS compared to the remaining patients with VCT (77.1% vs. 94.4%; p = 0.002). (4) Conclusions: As a result of our study, two risk factors for poor outcomes in WT patients with VCT emerge: diffuse anaplasia and metastatic disease, especially those with non-CR after PC.

Comparison of Breast Cancer Radiotherapy Techniques Regarding Secondary Cancer Risk and Normal Tissue Complication Probability - Modelling and Measurements Using a 3D-Printed Phantom.

Background: Radiotherapy after breast-conserving therapy is a standard postoperative treatment of breast cancer, which can be carried out with a variety of irradiation techniques. The treatment planning must take into consideration detrimental effects on the neighbouring organs at risk-the lung, the heart, and the contralateral breast, which can include both short- and long-term effects represented by the normal tissue complication probability and secondary cancer risk. Patients and Methods: In this planning study, we investigate intensity-modulated (IMRT) and three-dimensional conformal (3D-CRT) radiotherapy techniques including sequential or simultaneously integrated boosts as well as interstitial multicatheter brachytherapy boost techniques of 38 patients with breast-conserving surgery retrospectively. We furthermore develop a 3D-printed breast phantom add-on to allow for catheter placement and to measure the out-of-field dose using thermoluminescent dosimeters placed inside an anthropomorphic phantom. Finally, we estimate normal tissue complication probabilities using the Lyman-Kutcher-Burman model and secondary cancer risks using the linear non-threshold model (out-of-field) and the model by Schneider et al. (in-field). Results: The results depend on the combination of primary whole-breast irradiation and boost technique. The normal tissue complication probabilities for various endpoints are of the following order: 1%-2% (symptomatic pneumonitis, ipsilateral lung), 2%-3% (symptomatic pneumonitis, whole lung), and 1%-2% (radiation pneumonitis grade ≥ 2, whole lung). The additional relative risk of ischemic heart disease ranges from +25% to +35%. In-field secondary cancer risk of the ipsilateral lung in left-sided treatment is around 50 per 10,000 person-years for 20 years after exposure at age 55. Out-of-field estimation of secondary cancer risk results in approximately 5 per 10,000 person-years each for the contralateral lung and breast. Conclusions: In general, 3D-CRT shows the best risk reduction in contrast to IMRT. Regarding the boost concepts, brachytherapy is the most effective method in order to minimise normal tissue complication probability and secondary cancer risk compared to teletherapy boost concepts. Hence, the 3D-CRT technique in combination with an interstitial multicatheter brachytherapy boost is most suitable in terms of risk avoidance for treating breast cancer with techniques including boost concepts.

Infants and Newborns with Atypical Teratoid Rhabdoid Tumors (ATRT) and Extracranial Malignant Rhabdoid Tumors (eMRT) in the EU-RHAB Registry: A Unique and Challenging Population.

Introduction: Malignant rhabdoid tumors (MRT) predominantly affect infants and young children. Patients below six months of age represent a particularly therapeutically challenging group. Toxicity to developing organ sites limits intensity of treatment. Information on prognostic factors, genetics, toxicity of treatment and long-term outcomes is sparse. Methods: Clinical, genetic, and treatment data of 100 patients (aged below 6 months at diagnosis) from 13 European countries were analyzed (2005-2020). Tumors and matching blood samples were examined for SMARCB1 mutations using FISH, MLPA and Sanger sequencing. DNA methylation subgroups (ATRT-TYR, ATRT-SHH, and ATRT-MYC) were determined using 450 k / 850 k-profiling. Results: A total of 45 patients presented with ATRT, 29 with extracranial, extrarenal (eMRT) and 9 with renal rhabdoid tumors (RTK). Seventeen patients demonstrated synchronous tumors (SYN). Metastases (M+) were present in 27% (26/97) at diagnosis. A germline mutation (GLM) was detected in 55% (47/86). DNA methylation subgrouping was available in 50% (31 / 62) with ATRT or SYN; for eMRT, methylation-based subgrouping was not performed. The 5-year overall (OS) and event free survival (EFS) rates were 23.5 ± 4.6% and 19 ± 4.1%, respectively. Male sex (11 ± 5% vs. 35.8 ± 7.4%), M+ stage (6.1 ± 5.4% vs. 36.2 ± 7.4%), presence of SYN (7.1 ± 6.9% vs. 26.6 ± 5.3%) and GLM (7.7 ± 4.2% vs. 45.7 ± 8.6%) were significant prognostic factors for 5-year OS. Molecular subgrouping and survival analyses confirm a previously described survival advantage for ATRT-TYR. In an adjusted multivariate model, clinical factors that favorably influence the prognosis were female sex, localized stage, absence of a GLM and maintenance therapy. Conclusions: In this cohort of homogenously treated infants with MRT, significant predictors of outcome were sex, M-stage, GLM and maintenance therapy. We confirm the need to stratify which patient groups benefit from multimodal treatment, and which need novel therapeutic strategies. Biomarker-driven tailored trials may be a key option.

Current and Emerging Therapeutic Approaches for Extracranial Malignant Rhabdoid Tumors.

Extracranial malignant rhabdoid tumors (extracranial MRT) are rare, highly aggressive malignancies affecting mainly infants and children younger than 3 years. Common anatomic sites comprise the kidneys (RTK - rhabdoid tumor of kidney) and other soft tissues (eMRT - extracranial, extrarenal malignant rhabdoid tumor). The genetic origin of these diseases is linked to biallelic pathogenic variants in the genes SMARCB1, or rarely SMARCA4, encoding subunits of the SWI/SNF chromatin-remodeling complex. Even if extracranial MRT seem to be quite homogeneous, recent epigenome analyses reveal a certain degree of epigenetic heterogeneity. Use of intensified therapies has modestly improved survival for extracranial MRT. Patients at standard risk profit from conventional therapies; most high-risk patients still experience a dismal course and often therapy resistance. Discoveries of clinical and molecular hallmarks and the exploration of experimental therapeutic approaches open exciting perspectives for clinical and molecularly stratified experimental treatment approaches. To ultimately improve the outcome of patients with extracranial MRTs, they need to be characterized and stratified clinically and molecularly. High-risk patients need novel therapeutic approaches including selective experimental agents in phase I/II clinical trials.

ArthroRad trial: multicentric prospective and randomized single-blinded trial on the effect of low-dose radiotherapy for painful osteoarthritis depending on the dose-results after 3 months' follow-up.

PURPOSE: Randomized comparison of the effect of radiotherapy on painful osteoarthritis (OA) applying a standard-dose vs. a very-low-dose regime PATIENTS AND METHODS: Patients with OA of the hand and knee joints were included. Further inclusion criteria: symptoms for more than 3 months, favorable general health status, age above 40 years. Patients with prior local radiotherapy, trauma, rheumatoid arthritis, or vascular diseases were excluded. After randomization (every joint was randomized separately), the following protocols were applied: standard arm: total dose 3.0 Gy, single fractions of 0.5 Gy twice weekly; experimental arm: total dose 0.3 Gy, single fractions of 0.05 Gy twice weekly. The dosage was not known to the patients. The patients were examined 3 and 12 months after radiotherapy. Scores like VAS (visual analogue scale), KOOS-SF (the knee injugy and osteoarthritis outcome score), SF-SACRAH (short form score for the assessment and quantification of chronic rheumatic affections of the hands), and SF-12 (short form 12) were used. RESULTS: A total of 64 knees and 172 hands were randomized. 3.0 Gy was applied to 87 hands and 34 knees, 0.3 Gy was given to 85 hands and 30 knees. After 3 months, we observed good pain relief after 3 Gy and after 0.3 Gy, there was no statistically significant difference. Side effects were not recorded. The trial was closed prematurely due to slow recruitment. CONCLUSION: We found favorable pain relief and a limited response in the functional and quality of life scores in both arms. The effect of low doses such as 0.3 Gy on pain is widely unknown. Further trials are necessary to compare a conventional dose to placebo and to further explore the effect of low doses on inflammatory disorders.

Feasibility and clinical usefulness of modelling glioblastoma migration in adjuvant radiotherapy.

Glioblastoma (GBM) is one of the most common primary brain tumours in adults, with a dismal prognosis despite aggressive multimodality treatment by a combination of surgery and adjuvant radiochemotherapy. A detailed knowledge of the spreading of glioma cells in the brain might allow for more targeted escalated radiotherapy, aiming to reduce locoregional relapse. Recent years have seen the development of a large variety of mathematical modelling approaches to predict glioma migration. The aim of this study is hence to evaluate the clinical applicability of a detailed micro- and meso-scale mathematical model in radiotherapy. First and foremost, a clinical workflow is established, in which the tumour is automatically segmented as input data and then followed in time mathematically based on the diffusion tensor imaging data. The influence of several free model parameters is individually evaluated, then the full model is retrospectively validated for a collective of 3 GBM patients treated at our institution by varying the most important model parameters to achieve optimum agreement with the tumour development during follow-up. Agreement of the model predictions with the real tumour growth as defined by manual contouring based on the follow-up MRI images is analyzed using the dice coefficient. The tumour evolution over 103-212 days follow-up could be predicted by the model with a dice coefficient better than 60% for all three patients. In all cases, the final tumour volume was overestimated by the model by a factor between 1.05 and 1.47. To evaluate the quality of the agreement between the model predictions and the ground truth, we must keep in mind that our gold standard relies on a single observer's (CB) manually-delineated tumour contours. We therefore decided to add a short validation of the stability and reliability of these contours by an inter-observer analysis including three other experienced radiation oncologists from our department. In total, a dice coefficient between 63% and 89% is achieved between the four different observers. Compared with this value, the model predictions (62-66%) perform reasonably well, given the fact that these tumour volumes were created based on the pre-operative segmentation and DTI.

Correction: Welter et al. Characteristics of Nephroblastoma/Nephroblastomatosis in Children with a Clinically Reported Underlying Malformation or Cancer Predisposition Syndrome. Cancers 2021, 13, 5016.

In the original article [...].

Characteristics of Nephroblastoma/Nephroblastomatosis in Children with a Clinically Reported Underlying Malformation or Cancer Predisposition Syndrome.

(1) Background: about 10% of Wilms Tumor (WT) patients have a malformation or cancer predisposition syndrome (CPS) with causative germline genetic or epigenetic variants. Knowledge on CPS is essential for genetic counselling. (2) Methods: this retrospective analysis focused on 2927 consecutive patients with WTs registered between 1989 and 2017 in the SIOP/GPOH studies. (3) Results: Genitourinary malformations (GU, N = 66, 2.3%), Beckwith-Wiedemann spectrum (BWS, N = 32, 1.1%), isolated hemihypertrophy (IHH, N = 29, 1.0%), Denys-Drash syndrome (DDS, N = 24, 0.8%) and WAGR syndrome (N = 20, 0.7%) were reported most frequently. Compared to others, these patients were younger at WT diagnosis (median age 24.5 months vs. 39.0 months), had smaller tumors (349.4 mL vs. 487.5 mL), less often metastasis (8.2% vs. 18%), but more often nephroblastomatosis (12.9% vs. 1.9%). WT with IHH was associated with blastemal WT and DDS with stromal subtype. Bilateral WTs were common in WAGR (30%), DDS (29%) and BWS (31%). Chemotherapy induced reduction in tumor volume was poor in DDS (0.4% increase) and favorable in BWS (86.9% reduction). The event-free survival (EFS) of patients with BWS was significantly (p = 0.002) worse than in others. (4) Conclusions: CPS should be considered in WTs with specific clinical features resulting in referral to a geneticist. Their outcome was not always favorable.

Chemoradiotherapy-induced increase in Th17 cell frequency in cervical cancer patients is associated with therapy resistance and early relapse.

Cervical cancer therapy is still a major clinical challenge, as patients substantially differ in their response to standard treatments, including chemoradiotherapy (CRT). During cervical carcinogenesis, T-helper (Th)-17 cells accumulate in the peripheral blood and tumor tissues of cancer patients and are associated with poor prognosis. In this prospective study, we find increased Th17 frequencies in the blood of patients after chemoradiotherapy and a post-therapeutic ratio of Th17/CD4+ T cells > 8% was associated with early recurrence. Furthermore, Th17 cells promote resistance of cervical cancer cells toward CRT, which was dependent on the AKT signaling pathway. Consistently, patients with high Th17 frequencies in pretherapeutic biopsies exhibit lower response to primary CRT. This work reveals a key role of Th17 cells in CRT resistance and elevated Th17 frequencies in the blood after CRT correspond with early recurrence. Our results may help to explain individual treatment responses of cervical cancer patients and suggest evaluation of Th17 cells as a novel predictive biomarker for chemoradiotherapy responses and as a potential target for immunotherapy in cervical cancer.

Inter-clinician delineation variation for a new highly-conformal flank target volume in children with renal tumors: A SIOP-Renal Tumor Study Group international multicenter exercise.

BACKGROUND AND PURPOSE: Recently, the SIOP-RTSG developed a highly-conformal flank target volume definition for children with renal tumors. The aims of this study were to evaluate the inter-clinician delineation variation of this new target volume definition in an international multicenter setting and to explore the necessity of quality assurance. MATERIALS AND METHODS: Six pediatric renal cancer cases were transferred to ten radiation oncologists from seven European countries ('participants'). These participants delineated the pre- and postoperative Gross Tumor Volume (GTVpre/post), and Clinical Target Volume (CTV) during two test phases (case 1-2 and 3-4), followed by guideline refinement and a quality assurance phase (case 5-6). Reference target volumes (TVref) were established by three experienced radiation oncologists. The Dice Similarity Coefficient between the reference and participants (DSCref/part) was calculated per case. Delineations of case 5-6 were graded by four independent reviewers as 'per protocol' (0-4 mm), 'minor deviation' (5-9 mm) or 'major deviation' (≥10 mm) from the delineation guideline using 18 standardized criteria. Also, a major deviation resulting in underestimation of the CTVref was regarded as an unacceptable variation. RESULTS: A total of 57/60 delineation sets were completed. The median DSCref/part for the CTV was 0.55 without improvement after sequential cases (case 3-4 vs. case 5-6: p = 0.15). For case 5-6, a major deviation was found for 5/18, 12/17, 18/18 and 4/9 collected delineations of the GTVpre, GTVpost, CTV-T and CTV-N, respectively. An unacceptable variation from the CTVref was found for 7/9 participants for case 5 and 6/9 participants for case 6. CONCLUSION: This international multicenter delineation exercise demonstrates that the new consensus for highly-conformal postoperative flank target volume delineation leads to geometrical variation among participants. Moreover, standardized review showed an unacceptable delineation variation in the majority of the participants. These findings strongly suggest the need for additional training and centralized pre-treatment review when this target volume delineation approach is implemented on a larger scale.

Optimizing Adjuvant Stereotactic Radiotherapy of Motor-Eloquent Brain Metastases: Sparing the nTMS-Defined Motor Cortex and the Hippocampus.

Brain metastases can effectively be treated with surgical resection and adjuvant stereotactic radiotherapy (SRT). Navigated transcranial magnetic stimulation (nTMS) has been used to non-invasively map the motor cortex prior to surgery of motor eloquent brain lesions. To date, few studies have reported the integration of such motor maps into radiotherapy planning. The hippocampus has been identified as an additional critical structure of radiation-induced deficits. The aim of this study is to assess the feasibility of selective dose reduction to both the nTMS-based motor cortex and the hippocampi in SRT of motor-eloquent brain metastases. Patients with motor-eloquent brain metastases undergoing surgical resection and adjuvant SRT between 07/2014 and 12/2018 were retrospectively analyzed. The radiotherapy treatment plans were retrieved from the treatment planning system ("original" plan). For each case, two intensity-modulated treatment plans were created: the "motor" plan aimed to reduce the dose to the motor cortex, the "motor & hipp" plan additionally reduce the dose to the hippocampus. The optimized plans were compared with the "original" plan regarding plan quality, planning target volume (PTV) coverage, and sparing of organs at risk (OAR). 69 plans were analyzed, all of which were clinically acceptable with no significant differences for PTV coverage. All OAR were protected according to standard protocols. Sparing of the nTMS motor map was feasible: mean dose 9.66 ± 5.97 Gy (original) to 6.32 ± 3.60 Gy (motor) and 6.49 ± 3.78 Gy (motor & hipp), p<0.001. In the "motor & hipp" plan, dose to the ipsilateral hippocampi could be significantly reduced (max 1.78 ± 1.44 Gy vs 2.49 ± 1.87 Gy in "original", p = 0.003; mean 1.01 ± 0.92 Gy vs. 1.32 ± 1.07 Gy in "original", p = 0.007). The study confirms the results from previous studies that inclusion of nTMS motor information into radiotherapy treatment planning is possible with a relatively straightforward workflow and can achieve reduced doses to the nTMS-defined motor area without compromising PTV coverage. Furthermore, we demonstrate the feasibility of selective dose reduction to the hippocampus at the same time. The clinical significance of these optimized plans yet remains to be determined. However, with no apparent disadvantages these optimized plans call for further and broader exploration.

Outcome of Stage IV Completely Necrotic Wilms Tumour and Local Stage III Treated According to the SIOP 2001 Protocol.

OBJECTIVE: Wilms tumour (WT) patients with a localised completely necrotic nephroblastoma after preoperative chemotherapy are a favourable outcome group. Since the introduction of the SIOP 2001 protocol, the SIOP- Renal Tumour Study Group (SIOP-RTSG) has omitted radiotherapy for such patients with low-risk, local stage III in an attempt to reduce treatment burden. However, for metastatic patients with local stage III, completely necrotic WT, the recommendations led to ambiguous use. The purpose of this descriptive study is to demonstrate the outcomes of patients with metastatic, completely necrotic and local stage III WT in relation to the application of radiotherapy or not. METHODS AND MATERIALS: all metastatic patients with local stage III, completely necrotic WT after 6 weeks of preoperative chemotherapy who were registered in the SIOP 2001 study were included in this analysis. The pattern of recurrence according to the usage of radiation treatment and 5 year event-free survival (EFS) and overall survival (OS) was analysed. RESULTS: seven hundred and three metastatic WT patients were registered in the SIOP 2001 database. Of them, 47 patients had a completely necrotic, local stage III WT: 45 lung metastases (11 combined localisations), 1 liver/peritoneal, and 1 tumour thrombus in the renal vein and the inferior vena cava with bilateral pulmonary arterial embolism. Abdominal radiotherapy was administered in 29 patients (62%; 29 flank/abdominal irradiation and 9 combined with lung irradiation). Eighteen patients did not receive radiotherapy. Median follow-up was 6.6 years (range 1-151 months). Two of the 47 patients (4%) developed disease recurrence in the lung (one combined with abdominal relapse) and eventually died of the disease. Both patients had received abdominal radiotherapy, one of them combined with lung irradiation. Five-year EFS and OS were 95% and 95%, respectively. CONCLUSIONS: the outcome of patients with stage IV, local stage III, completely necrotic Wilms tumours is excellent. Our results suggest that abdominal irradiation in this patient category may not be of added value in first-line treatment, consistent with the current recommendation in the SIOP-RTSG 2016 UMBRELLA protocol.