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Purpose: Extracranial malignant rhabdoid tumors (eMRT) are a challenging entity. Despite the use of multimodal treatment approaches, therapy failure occurs in 55% to 67% of these. Molecular markers for identification of patients at increased risk for relapse or refractory (R/R) disease are not available. Clinical characteristics may only insufficiently predict the individual course of disease., Experimental Design: Using the EU-RHAB database, we analyzed a cohort of 121 patients with eMRT clinically. For 81 patients, molecular and clinical data were available, which were further complemented with publicly available DNA molecular data from 92 eMRTs. We aimed to delineate molecular risk factors by dissecting the DNA methylome of these tumors. Moreover, we establish clinical characteristics and treatment details of R/R disease in a subcohort of 80 patients., Results: Using consensus hierarchical clustering, we identified three distinct subgroups, one of which (eMRT standard risk) was associated with significantly improved survival, irrespective of germline status and/or localization. At the transcriptome level, this subgroup was characterized by an overexpression of genes involved in muscle development. A relevant proportion of patients developed distant relapses or progressions; the median time to the event was 4 months, underlining the need for early identification and risk stratification of R/R disease. The overall survival was significantly decreased in patients with progressive disease when compared with relapse cases, and reaching complete remission during salvage therapy provided a survival benefit., Conclusions: Our analysis of eMRT in this comprehensive cohort provides novel insights into the patterns of relapse and integrates molecular and clinical risk factors to guide clinical decision-making., (©2024 American Association for Cancer Research.)

Objectives: Pregnancies in women with Fontan circulation are on the rise, and they are known to imply high maternal and fetal complication rates. The altered hemodynamic profile of univentricular circulation affects placental development and function. This study describes placental sonomorphologic appearance and Doppler examinations and correlates these to histopathologic findings and pregnancy outcomes in women with Fontan circulation. Methods: A single-center retrospective analysis of pregnancies in women with Fontan circulation was conducted between 2018 and 2023. Maternal characteristics and obstetric and neonatal outcomes were recorded. Serial ultrasound examinations including placental sonomorphologic appearance and Doppler studies were assessed. Macroscopic and histopathologic findings of the placentas were reviewed. Results: Six live births from six women with Fontan physiology were available for analysis. Prematurity occurred in 83% (5/6 cases) and fetal growth restriction and bleeding events in 66% (4/6 cases) each. All but one placenta showed similar sonomorphologic abnormalities starting during the late second trimester, such as thickened globular shape, inhomogeneous echotexture, and hypoechoic lakes, resulting in a jelly-like appearance. Uteroplacental blood flow indices were within normal range in all women. The corresponding histopathologic findings were non-specific and consisted of intervillous and subchorionic fibrin deposition, villous atrophy, hypoplasia, or fibrosis. Conclusions: Obstetric and perinatal complication rates in pregnancies of women with Fontan circulation are high. Thus, predictors are urgently needed. Our results suggest that serial ultrasound examinations with increased awareness of the placental appearance and its development, linked to the Doppler sonographic results of the uteroplacental and fetomaternal circulation, may be suitable for the early identification of cases prone to complications.

Objective: This study aimed to identify parameters that allow the estimation of tumor-infiltrated lymph nodes (LN) after pretreatment for unilateral Wilms tumor (WT)., Summary Background Data: Complete tumor resection with removal of regional LN is always necessary. Positive LNs require local irradiation influencing benefits in case of NSS in long-term follow-up. Clinical and tumor-related data available at the time of surgery in combination with intraoperative findings (IAF) were used to estimate the LN status during surgery., Methods: Altogether, 2115 patients with unilateral WT were prospectively enrolled in SIOP-93-01 / GPOH and SIOP-2001 / GPOH over a period of 30 years (1993-2023). LN infiltration by tumor was calculated for age, sex, metastases at diagnosis, tumor volume (TV), TV shrinkage, and intraoperative findings (IAF) using logistic regression models., Results: Age ≥48 months (P<0.001, OR 2.17, CI 1.57 - 3.00), TV at diagnosis ≥300 (P<0.001, OR 3.72, CI 2.37 - 5.85), metastasis at diagnosis (P<0.001, OR 6.21, CI 4.47 - 8.62) and IAF (>1: P<0.001, OR 3.54, CI 2.13 - 5.88) correlated with positive LNs. TV shrinkage was not predictive of positive LN. Three flow charts were developed based on age, TV at diagnosis, metastasis, and IAF. These flowcharts defined risks between 0% and 41.5% for LN infiltration by tumor., Conclusions: The combination of age, TV at diagnosis, and metastasis with IAF allows the estimation of the frequency of positive LNs, which may help surgeons deciding about NSS., Competing Interests: Conflicts of Interest and Sources of Funding: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

GCTs are developmental tumors and are likely to reflect ontogenetic and teratogenetic determinants. The objective of this study was to identify syndromes with or without congenital anomalies and non-syndromic defects as potential risk factors. Patients with extracranial GCTs (eGCTs) registered in MAKEI 96/MAHO 98 between 1996 and 2017 were included. According to Teilum's holistic concept, malignant and benign teratomas were registered. We used a case-control study design with Orphanet as a reference group for syndromic defects and the Mainz birth registry (EUROCAT) for congenital anomalies at birth. Co-occurring genetic syndromes and/or congenital anomalies were assessed accordingly. Odds ratios and 95% confidence intervals were calculated and p -values for Fisher's exact test with Bonferroni correction if needed. A strong association was confirmed for Swyer (OR 338.6, 95% CI 43.7-2623.6) and Currarino syndrome (OR 34.2, 95% CI 13.2-88.6). We additionally found 16 isolated cases of eGCT with a wide range of syndromes. However, these were not found to be significantly associated following Bonferroni correction. Most of these cases pertained to girls. Regarding non-syndromic defects, no association with eGCTs could be identified. In our study, we confirmed a strong association for Swyer and Currarino syndromes with additional congenital anomalies.

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., (© 2024 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: Treatment of Epstein-Barr virus(EBV)-positive nasopharyngeal carcinoma (NPC) with cisplatin/5-fluorouracil (5-FU) induction chemotherapy, followed by radiochemotherapy and subsequent interferon‑β, has yielded high survival rates in children, adolescents, and young adults. A previous study has shown that reduction of radiation dose from 59.4 to 54.0 Gy appears to be safe in patients with complete response (CR) to induction chemotherapy. As immune checkpoint-inhibitors have shown activity in NPC, we hypothesize that the addition of nivolumab to standard induction chemotherapy would increase the rate of complete tumor responses, thus allowing for a reduced radiation dose in a greater proportion of patients., Methods: This is a prospective multicenter phase 2 clinical trial including pediatric and adult patients with their first diagnosis of EBV-positive NPC, scheduled to receive nivolumab in addition to standard induction chemotherapy. In cases of non-response to induction therapy (stable or progressive disease), and in patients with initial distant metastasis, treatment with nivolumab will be continued during radiochemotherapy. Primary endpoint is tumor response on magnetic resonance imaging (MRI) and positron emission tomography (PET) after three cycles of induction chemotherapy. Secondary endpoints are event-free (EFS) and overall survival (OS), safety, and correlation of tumor response with programmed cell death ligand 1 (PD-L1) expression., Discussion: As cure rates in localized EBV-positive NPC today are high with standard multimodal treatment, the focus increasingly shifts toward prevention of late effects, the burden of which is exceptionally high, mainly due to intense radiotherapy. Furthermore, survival in patients with metastatic disease and resistant to conventional chemotherapy remains poor. Primary objective of this study is to investigate whether the addition of nivolumab to standard induction chemotherapy in children and adults with EBV-positive NPC is able to increase the rate of complete responses, thus enabling a reduction in radiation dose in more patients, but also offer patients with high risk of treatment failure the chance to benefit from the addition of nivolumab., Trial Registration: EudraCT (European Union Drug Regulating Authorities Clinical Trials Database) No. 2021-006477-32., (© 2024. The Author(s).)

Introduction: Wilms tumor (WT) is the most common childhood kidney cancer. It is a rapid growing embryonal tumor in young children and can be diagnosed with and without tumor related symptoms., Methods: We retrospectively analyzed the route to diagnosis of WT treated prospectively according to the SIOP 93-01/GPOH and 2001/GPOH in Germany between 1993 and 2022. Four routes were defined: diagnosis due to tumor-related symptoms, incidental diagnosis during another disease, diagnosis by preventive examinations, and diagnosis within a surveillance program. For these groups we compared clinical and tumor characteristics and outcome., Results: Of 2549 patients with WT 1822 (71.5%) were diagnosed by tumor-related symptoms, 472 (18.5%) incidentally, 213 (8.4%) by preventive medical examinations, and 42 (1.6%) by surveillance. Age, general health status, tumor volume, and local and overall stage varied significantly between these groups. The youngest patients were those diagnosed by preventive medical examination (mean: 1.70 years). These patients also showed the best general health status. Tumor volume at diagnosis (549 mL) and after preoperative chemotherapy (255 mL) was significantly higher for children with tumor-related symptoms. The highest percentage of local stage I (78.6%) and the lowest percentage of metastatic disease (4.8%) was found in the surveillance group. The outcome of patients was not significantly different, with up to 19.0% relapses in the surveillance group and 3.0% deaths in the group with tumor-related symptoms., Conclusion: The route to diagnosis of WT correlates with age, general health status, tumor volume, and stage distribution, but does not impact the outcome of patients. Nonetheless, diagnosis without tumor related symptoms results in lower treatment burden and thus improved quality of life., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Paediatric appendiceal neuroendocrine tumours (appNET) are very rare tumours, mostly detected incidentally by histopathological evaluation after appendectomy. Treatment recommendations are based on adult data considering high-risk NET as defined by European Neuroendocrine Tumour Society (ENETS) guidelines for completion right-sided hemicolectomy (RHC). Recent data suggest that less aggressive therapy may be justified., Procedure: Analysis of children and adolescents with appNET prospectively registered with the German Malignant Endocrine Tumour (MET) studies between 1997 and 2022., Results: By December 2022, 662 patients (64.7% females, 35.3% male) had been reported. Median age was 13.3 years [4.5-17.9], median duration of follow-up 2.2 years [0-10.9]. No distant metastases were reported. Tumour size was <1 cm in 63.5%, 1-2 cm in 33.2%, and >2 cm in 3.2% of patients. WHO grade 1 and 2 tumours were diagnosed in 76.9% and 23.1% of patients, respectively. Lymphovascular invasion and lymph node metastases were associated with tumour size ≥1.5 cm. 27.0% of patients presented with high-risk NET according to ENETS criteria. Of those, only 55.9% underwent secondary oncological right hemicolectomy. Neither distant metastases, nor recurrences or disease-related deaths occurred in patients with appendectomy only as well as in patients with completion RHC. Overall and event-free survival were both 100%., Conclusions: Internationally harmonized consensus recommendations on treatment of children and adolescents with appendiceal NET are urgently needed to avoid completion RHC in high-risk patients., 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., (© 2024 Published by Elsevier Ltd.)

Background: Outcome of primary metastatic rhabdomyosarcoma (RMS) is poor. Certain risk factors as fusion status, Oberlin score, and local treatment of primary tumor are known to influence prognosis., Procedure: Patients with metastatic RMS were treated according to Cooperative Weichteilsarkom Studiengruppe (CWS) guidance with chemotherapy (CHT), radiotherapy (RT) excluding total lung irradiation (TLI), complete resection of the primary tumor, and metastasectomy if possible. Kaplan-Meier estimators and Cox proportional hazard models were used to examine event-free survival (EFS) and overall survival (OS) involving also landmark analyses., Results: In the European Soft Tissue Sarcoma Registry SoTiSaR (2009-2018), 211 patients were analyzed. Many patients had fusion-positive alveolar RMS (n = 83; 39%). Median age was 9.4 years [0.1-19.7 years]. Treatment primarily consisted of CHT with CEVAIE (carboplatin, epirubicine, vincristine, actinomycin-D, ifosfamide, etoposide: 86%, other regimens: 14%), RT (71%), resection of primary tumor (37%), metastasectomy (19%), and lymph node sampling/dissection (21%). Maintenance treatment (MT) (oral trofosfamide, idarubicin, etoposide) was added in 74% of patients. Oberlin factors, fusion status, and MT were predictive for EFS and OS. MT with O-TIE was not improving outcome when adjusting for the immortal time bias. Local treatment of the primary tumor and radical irradiation (except TLI) improved EFS, not OS, when adjusting for the Oberlin score. Patients with fusion-negative alveolar RMS (n = 9) had an excellent outcome with a 5-year EFS and OS of 100%, compared to patients with embryonal RMS (49%/62%), PAX7- (22%/47%) and PAX3/FOXO1-positive ARMS (10/13%), respectively (p < .001)., Conclusions: Prognosis of metastatic RMS primarily depends on fusion status and Oberlin score. Fusion status needs to be considered in future trials to optimize treatment outcome. The role of radical irradiation needs further investigation., (© 2023 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Background: Parameningeal location of rhabdomyosarcoma (PM RMS) is known to be an unfavorable prognostic factor. Scarce data are available on radiotherapy (RT) concepts with regard to outcome., Methods: Treatment and outcome of 395 children with PM RMS registered within two Cooperative Weichteilsarkom Studiengruppe (CWS) trials and one registry (1995-2021) were evaluated., Results: Patients were IRS group II (n = 15) and III (n = 380) and received systemic treatment according to the enrolled protocols: I2VA (n = 172), VAIA/CEVAIE (n = 223). Delayed resection was performed in 88/395 (22%) patients, and RT was additionally given in 79/88 (90%) resected patients. RT was the predominant local treatment in 355/395 (90%) patients: hyperfractionated accelerated photon (HART; n = 77), conventionally fractionated photon (n = 91) or proton beam (n = 126), brachytherapy (n = 4), heavy ions (n = 1), not available (n = 56). In the subgroup of RT as only local treatment (n = 278), no intracranial tumor extension and complete remission at end of treatment were significant positive prognostic factors. No significant difference on tumor outcome was seen between different radiotherapy concepts. Long-term toxicity with mostly endocrinological and visual deficiencies was reported in 161/279 (58%) surviving patients with a lower trend after proton beam RT (48%) when compared to HART or conventionally fractionated photon RT (71% and 72%, respectively). Ten-year event-free and overall survival in the overall group were 62% (±5, 95% confidence interval [CI]) and 67% (±5, 95% CI); in the RT-only group 67% (±6, 95% CI) and 71% (±6, 95% CI), respectively., Conclusion: CWS data confirm the recent RT concept in PM RMS. Long-term sequelae as endocrinological and visual deficiencies need to be addressed., (© 2023 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Wilms tumors (WTs) are histologically diverse childhood cancers with variable contributions of blastema, stroma, and epithelia. A variety of cancer genes operate in WTs, including the tripartite-motif-containing-28 gene (TRIM28). Case reports and small case series suggest that TRIM28 mutations are associated with epithelial morphology and WT predisposition. Here, we systematically investigated the prevalence of TRIM28 inactivation and predisposing mutations in a cohort of 126 WTs with >2/3 epithelial cells, spanning 20 years of biobanking in the German SIOP93-01/GPOH and SIOP2001/GPOH studies. Overall, 44.4% (56/126) cases exhibited loss of TRIM28 by immunohistochemical staining. Of these, 48 could be further analyzed molecularly, revealing TRIM28 sequence variants in each case - either homozygous (~2/3) or heterozygous with epigenetic silencing of the second allele (~1/3). The majority (80%) of the mutations resulted in premature stops and frameshifts. In addition, we detected missense mutations and small deletions predicted to destabilize the protein through interference with folding of key structural elements such as the zinc-binding clusters of the RING, B-box-2, and PHD domains or the central coiled-coil region. TRIM28-mutant tumors otherwise lacked WT-typical IGF2 alterations or driver events, except for rare TP53 progression events that occurred with expected frequency. Expression profiling identified TRIM28-mutant tumors as a homogeneous subset of epithelial WTs that mostly present with stage I disease. There was a high prevalence of perilobar nephrogenic rests, putative precursor lesions, that carried the same biallelic TRIM28 alterations in 7/7 cases tested. Importantly, 46% of the TRIM28 mutations were present in blood cells or normal kidney tissue, suggesting germline events or somatic mosaicism, partly supported by family history. Given the high prevalence of predisposing variants in TRIM28-driven WT, we suggest that immunohistochemical testing of TRIM28 be integrated into diagnostic practice as the management of WT in predisposed children differs from that with sporadic tumors. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland., (© 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)

Purpose: To investigate the genetic cause, clinical characteristics, and potential therapeutic targets of infantile corneal myofibromatosis., Design: Case series with genetic and functional in vitro analyses., Participants: Four individuals from 2 unrelated families with clinical signs of corneal myofibromatosis were investigated., Methods: Exome-based panel sequencing for platelet-derived growth factor receptor beta gene ( PDGFRB ) and notch homolog protein 3 gene ( NOTCH3 ) was performed in the respective index patients. One clinically affected member of each family was tested for the pathogenic variant detected in the respective index by Sanger sequencing. Immunohistochemical staining on excised corneal tissue was conducted. Functional analysis of the individual PDGFRB variants was performed in vitro by luciferase reporter assays on transfected porcine aortic endothelial cells using tyrosine kinase inhibitors. Protein expression analysis of mutated PDGFRB was analyzed by Western blot., Main Outcome Measures: Sequencing data, immunohistochemical stainings, functional analysis of PDGFRB variants, and protein expression analysis., Results: We identified 2 novel, heterozygous gain-of-function variants in PDGFRB in 4 individuals from 2 unrelated families with corneal myofibromatosis. Immunohistochemistry demonstrated positivity for alpha-smooth muscle actin and β-catenin, a low proliferation rate in Ki-67 (< 5%), marginal positivity for Desmin, and negative staining for Caldesmon and CD34. In all patients, recurrence of disease occurred after corneal surgery. When transfected in cultured cells, the PDGFRB variants conferred a constitutive activity to the receptor in the absence of its ligand and were sensitive to the tyrosine kinase inhibitor imatinib. The variants can both be classified as likely pathogenic regarding the American College of Medical Genetics and Genomics classification criteria., Conclusions: We describe 4 cases of corneal myofibromatosis caused by novel PDGFRB variants with autosomal dominant transmission. Imatinib sensitivity in vitro suggests perspectives for targeted therapy preventing recurrences in the future., Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (© 2023 by the American Academy of Ophthalmology.)

Solid pseudopapillary neoplasms (SPNs) are the most common entity among pediatric pancreatic tumors. Still, these are rare tumors with an annual incidence of 0.1-0.2/1,000,000, and little is known about their optimal treatment. This analysis aimed to increase knowledge about the occurrence and treatment strategies of SPN in childhood. Data regarding diagnostics, treatment, and outcome of children aged 0-18 years with SPN recorded in the German Registry for Rare Pediatric Tumors (STEP) were analyzed. Thirty-eight patients were identified with a median age of 14.5 years at diagnosis (range: 8-18) and a female preponderance (81.6%). The most frequent location of the tumor was the pancreatic tail. In histopathological and immunohistochemical examination, pseudopapillary, solid, and cystic lesions as well as expression of beta-catenin, progesterone receptors, and cyclin D1 were the most common findings. All patients underwent surgical resection. Most patients underwent open resection, predominantly tail resection for tumors in the tail region and pylorus-preserving pancreaticoduodenectomy for tumors in the head region. The main postoperative sequela was exogenous pancreatic insufficiency (23.7%), especially with SPN in the pancreatic head. No recurrence occurred during follow-up, although two patients underwent resection with microscopic residue., Conclusion: SPN of the pancreas in childhood are low-grade malignancies with usually favorable treatment outcomes. However, therapy can lead to relevant long-term sequelae. To prevent recurrence, complete surgical resection is recommended, sparing as much healthy pancreatic tissue as possible. Interdisciplinary collaboration between specialists is essential to optimize treatment. Molecular genetic analysis of these tumors could improve understanding of their genesis., What Is Known: • Solid pseudopapillary neoplasms (SPNs) of the pancreas are very rare tumors in childhood. • Little is known about tumorigenesis, and there are no specific guidelines for treatment and follow-up in pediatric patients., What Is New: • Characteristics, treatment, and outcome were comprehensively assessed in a large cohort of pediatric patients with SPN. • We propose recommendations for diagnosis, treatment, and follow-up of children with SPN, based on our analysis and considering published experience., (© 2023. The Author(s).)

Pediatric spindle cell tumors are rare and often difficult to diagnose due to a similar morphology and a non-specific immunohistochemical profile. Genetic characterization of these lesions has been constantly improving, which has led to the identification of new subgroups that were partly included in the WHO classification. Receptor tyrosine kinase fusions play a special role in these tumors and their verification has diagnostic relevance and can be an option for target-oriented therapies. In the case of pediatric spindle cell tumors, genetic fusions form especially with NTRK1‑3, ALK, RET, and ROS1. Overall, pediatric tumors with receptor tyrosine kinase fusions are predominantly low-grade tumors, which are often subdivided into the group of intermediate-malign tumors., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Background: The outcome of children with refractory or relapsed soft tissue sarcoma (STS) is extremely poor. Whereas larger clinical trials evaluated specific treatment modalities, real-life data on individual multimodal therapeutic strategies, given alone or in combination, are scarce., Patients and Methods: We retrospectively analyzed the clinical course of 18 pediatric patients with progression of or relapsed STS treated between 2008 and 2018 in our institution., Results: A total of 18 patients (median age 12.4 years) suffered from progression or relapse of alveolar (n=7), embryonal (n=5), undifferentiated (n=2) rhabdomyosarcoma or desmoplastic small round cell tumor (n=4). 14 patents had an initial stage IV disease. All but one patient died. Median survival was 12.5 months. Shortest survival was seen in patients with systemic progression of the disease, longest in patients with local relapse. Patients with an Oberlin score<2 at the time of relapse had a significant longer time of survival than those with a score≥2. No significant advantage of a specific therapeutic modality was observed., Discussion: We critically analyzed the clinical course in the real-life setting, in which various treatment options were applied to an individual patient according to the best of available data. We observed that some patients died within a short period of time despite multiple treatment modalities, which underlines the need for better prognostic parameters., Conclusion: In addition to well characterized clinical factors such as local or systemic relapse, the Oberlin score could be helpful in counselling patients and their families for choosing the best strategy of care., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Langerhans cell Histiocytosis is a rare neoplastic disease, which occurs mainly in children and adolescents. The disease may affect any organ, and therefore, the clinical symptoms vary widely. Some patients have a spontaneous remission of the disease, whereas others experience a rapid and potentially lethal clinical course. The therapeutic approach depends on the extent of the disease, and reaches from a watch-and-wait strategy to chemotherapy with the standard drugs vinblastine and prednisone. The identification of mutations in the MAPK-pathway resulted in growing interest in targeted therapy using compounds such as the BRAF inhibitors. Chronic relapses and permanent sequelae are important problems of LCH and are the focus of current research., Competing Interests: Die Autorinnen und Autoren geben an, dass kein Interessenkonfliktbesteht., (Thieme. All rights reserved.)

Peripheral neuroblastic tumors represent the fourth-largest group of malignant tumors in childhood. The majority of these tumors are neuroblastomas, which can be classified into undifferentiated, poorly differentiated, and differentiating subtypes. In addition, peripheral neuroblastic tumors include ganglioneuroblastoma, a composite tumor composed of Schwannian cell stroma and neuroblasts as well as benign ganglioneuroma. In this overview, histopathological diagnostic criteria and grading systems, as well as common molecular alterations that are of prognostic and therapeutic significance, are discussed., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Study Question: In children affected by rhabdoid tumors (RT), are there clinical, therapeutic, and/or (epi-)genetic differences between those conceived following ART compared to those conceived without ART?, Summary Answer: We detected a significantly elevated female predominance, and a lower median age at diagnosis, of children with RT conceived following ART (RT&#95;ART) as compared to other children with RT., What Is Known Already: Anecdotal evidence suggests an association of ART with RT., Study Design, Size, Duration: This was a multi-institutional retrospective survey. Children with RT conceived by ART were identified in our EU-RHAB database (n = 11/311 children diagnosed between January 2010 and January 2018) and outside the EU-RHAB database (n = 3) from nine different countries. A population-representative German EU-RHAB control cohort of children with RTs conceived without ART (n = 211) (EU-RHAB control cohort) during the same time period was used as a control cohort for clinical, therapeutic, and survival analyses. The median follow-up time was 11.5 months (range 0-120 months) for children with RT&#95;ART and 18.5 months (range 0-153 months) for the EU-RHAB control cohort., Participants/materials, Setting, Methods: We analyzed 14 children with RT&#95;ART diagnosed from January 2010 to January 2018. We examined tumors and matching blood samples for SMARCB1 mutations and copy number alterations using FISH, multiplex ligation-dependent probe amplification, and DNA sequencing. DNA methylation profiling of tumor and/or blood samples was performed using DNA methylation arrays and compared to respective control cohorts of similar age (n = 53 tumors of children with RT conceived without ART, and n = 38 blood samples of children with no tumor born small for gestational age)., Main Results and the Role of Chance: The median age at diagnosis of 14 individuals with RT&#95;ART was 9 months (range 0-66 months), significantly lower than the median age of patients with RT (n = 211) in the EU-RHAB control cohort (16 months (range 0-253), P = 0.03). A significant female predominance was observed in the RT&#95;ART cohort (M:F ratio: 2:12 versus 116:95 in EU-RHAB control cohort, P = 0.004). Eight of 14 RT&#95;ART patients were diagnosed with atypical teratoid rhabdoid tumor, three with extracranial, extrarenal malignant rhabdoid tumor, one with rhabdoid tumor of the kidney and two with synchronous tumors. The location of primary tumors did not differ significantly in the EU-RHAB control cohort (P = 0.27). Six of 14 RT&#95;ART patients presented with metastases at diagnosis. Metastatic stage was not significantly different from that within the EU-RHAB control cohort (6/14 vs 88/211, P = 1). The incidence of pathogenic germline variants was five of the 12 tested RT&#95;ART patients and, thus, not significantly different from the EU-RHAB control cohort (5/12 versus 36/183 tested, P = 0.35). The 5-year overall survival (OS) and event free survival (EFS) rates of RT&#95;ART patients were 42.9 ± 13.2% and 21.4 ± 11%, respectively, and thus comparable to the EU-RHAB control cohort (OS 41.1 ± 3.5% and EFS 32.1 ± 3.3). We did not find other clinical, therapeutic, outcome factors distinguishing patients with RT&#95;ART from children with RTs conceived without ART (EU-RHAB control cohort). DNA methylation analyses of 10 tumors (atypical teratoid RT = 6, extracranial, extrarenal malignant RT = 4) and six blood samples from RT&#95;ART patients showed neither evidence of a general DNA methylation difference nor underlying imprinting defects, respectively, when compared to a control group (n = 53 RT samples of patients without ART, P = 0.51, n = 38 blood samples of patients born small for gestational age, P = 0.1205)., Limitations, Reasons for Caution: RTs are very rare malignancies and our results are based on a small number of children with RT&#95;ART., Wider Implications of the Findings: This cohort of patients with RT&#95;ART demonstrated a marked female predominance, and a rather low median age at diagnosis even for RTs. Other clinical, treatment, outcome, and molecular factors did not differ from those conceived without ART (EU-RHAB control cohort) or reported in other series, and there was no evidence for imprinting defects. Long-term survival is achievable even in cases with pathogenic germline variants, metastatic disease at diagnosis, or relapse. The female preponderance among RT&#95;ART patients is not yet understood and needs to be evaluated, ideally in larger international series., Study Funding/competing Interest(s): M.C.F. is supported by the 'Deutsche Kinderkrebsstiftung' DKS 2020.10, by the 'Deutsche Forschungsgemeinschaft' DFG FR 1516/4-1 and by the Deutsche Krebshilfe 70113981. R.S. received grant support by Deutsche Krebshilfe 70114040 and for infrastructure by the KinderKrebsInitiative Buchholz/Holm-Seppensen. P.D.J. is supported by the Else-Kroener-Fresenius Stiftung and receives a Max-Eder scholarship from the Deutsche Krebshilfe. M.H. is supported by DFG (HA 3060/8-1) and IZKF Münster (Ha3/017/20). BB is supported by the 'Deutsche Kinderkrebsstiftung' DKS 2020.05. We declare no competing interests., Trial Registration Number: N/A., (© The Author(s) 2023. 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Primary vaginal malignancies are rare, comprising only 2% of all female genital tract malignancies in adults and 4.5% in children. As part of its mission to improve the quality of care for women with gynecological cancers across Europe, the European Society of Gynaecological Oncology (ESGO) jointly with the European Society for Radiotherapy & Oncology (ESTRO) and the European Society of Pediatric Oncology (SIOPe) developed evidence-based guidelines in order to improve the management of patients with vaginal cancer within a multidisciplinary setting. ESTRO/ESGO/SIOPe nominated practicing clinicians who are involved in the management of vaginal cancer patients and have demonstrated leadership through their expertise in clinical care and research, their national and international engagement and profile as well as dedication to the topics addressed to serve on the expert panel (13 experts across Europe comprising the international development group). To ensure that the statements were evidence based, the current literature was reviewed and critically appraised. In the case of absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the international development group. Prior to publication, the guidelines were reviewed by 112 independent international practitionners in cancer care delivery and patient representatives and their comments and input were incorporated and addressed accordingly. These guidelines cover comprehensively the diagnostic pathways as well as the surgical, radiotherapeutical and systemic management and follow-up of adult patients (including those with rare histological subtypes) and pediatric patients (vaginal rhabdomyosarcoma and germ cell tumours) with vaginal tumours., 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 Elsevier B.V., IGCS and ESGO. Published by Elsevier B.V. All rights reserved.)

Objectives: Bronchial carcinoid tumors (BC) are exceptionally rare in childhood, with an incidence of <0.2/1,000,000 per year. Typical low-grade BCs are distinguished from atypical, intermediate-grade BCs. Little is known about BCs in pediatric patients and management guidelines are missing. In this study, we explored characteristics and outcome of pediatric patients with BC prospectively registered with the Malignant Endocrine Tumor studies., Material and Methods: We performed a retrospective multicenter study in children, adolescents, and young adults (aged 0-20 years) with BC reported to the German MET registry between January 1997 and December 2022. Data were last updated on 28 of February 2023., Results: Thirty-two patients were diagnosed at a median age of 15.0 years (range, 9.8-19.2). Atypical BCs (23.3%) were less frequent than typical, but more common than in adulthood. Lymph node metastases were present in 14.3% of cases (atypical BC: 28.6%, typical BC: 10.5%), distant metastases in one (3.1%) patient with atypical BC. 92.6% of patients were in complete remission after surgical resection (median follow-up: 2.7 years). The patient with metastatic spread and one patient with atypical BC and multiple recurrences were on treatment at last follow-up. 5-year event-free survival of typical BC was 100% and 83.3% in atypical BC., Conclusions: Completely resected localized BCs in pediatric patients have a favorable outcome also with lung tissue sparing surgery. Atypical BC with risk of metastatic spread and recurrence occurred more frequently compared to adults. Interdisciplinary management and collaborative efforts are needed to improve our understanding and the management of pediatric BC., 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 Elsevier B.V. All rights reserved.)

Background: Locally advanced tumors account for approximately 50% of children and adolescents with adrenocortical carcinoma (ACC), and of these, up to 50% relapse. We explored the five-item microscopic score and the pS-GRAS score for guiding management., Methods: Data from children and adolescents with COG stage II and III ACC registered in the MET studies were included. The five-item and pS-GRAS score were retrospectively calculated., Results: By December 2021, 55 patients with stage II and III (stage II n = 18, stage III n = 37) had been reported. Median age was 4.3 years [0.1-17.8], median duration of follow-up 6.0 years [0-16.7]. 3-year event-free survival (EFS) rate was 76.5% and 49.8% ( p = 0.088), respectively. In stage II tumors, neither the five-item score ( p = 0.872) nor pS-GRAS grouping ( p = 0.218) had any effect as prognostic factors. In stage III patients, EFS was impaired in tumors with unfavorable histology according to the five-item score (100% vs. 30.8%, p = 0.018). No difference was observed for pS-GRAS groups ( p = 0.798)., Conclusions: In patients with COG stage III, but not stage II, the five-item score affected EFS. Further studies are needed to identify patients at risk in COG stage II.

Background: The hTERT promoter mutation represents a common and early event in hepatocarcinogenesis, but its linkage to the morphological status of the underlying liver tissue is poorly understood. We analyzed the connection between the histopathological changes in tumor-bearing liver tissue and the occurrence of the hTERT promoter mutation in hepatocellular carcinoma (HCC), correlated with clinical data., Methods: The study cohort comprised 160 histologically confirmed HCC in patients with or without cirrhosis that were investigated for the hTERT promoter mutation. We evaluated the frequency of the hTERT promoter mutation in patients with HCC with or without cirrhosis and correlated it with potential clinical and histopathological drivers. In particular, we examined tumor-bearing noncirrhotic liver tissue regarding inflammation; the modified histological activity index (mHAI), fibrosis, and steatosis; and its correlation with the frequency of the hTERT promoter mutation in HCC. We evaluated overall survival with multivariate Cox regression. Furthermore, we compared hTERT antibody immunohistochemistry and molecular hTERT promoter mutation analysis of both HCC and background liver tissue., Results: The hTERT promoter mutation was especially related to HCC in cirrhotic compared with noncirrhotic liver ( p < 0.001) and independently of cirrhosis in patients ≥ 60 years ( p = 0.005). Furthermore, the hTERT promoter mutation was associated with cirrhosis caused by alcohol toxicity and hepatitis C virus infection. In noncirrhotic liver tissue, the frequency of hTERT -promoter-mutated HCC increased with the degree of inflammation and fibrosis. Nevertheless, 25% of the hTERT -promoter-mutated HCC developed in normal liver tissue without HCC risk factors. Multivariate Cox regression analysis did not reveal an influence of the hTERT promoter mutation in HCC on overall survival at 3, 5, and 16 years. Immunohistochemical analysis with the hTERT antibodies LS-B95 and 2D8 in hTERT -promoter-mutated HCC and hTERT -wildtype HCC showed a mildly stronger immunoreaction compared with the tumor-bearing liver tissue (LS-B95: p < 0.01, 2D8: p < 0.01)., Conclusions: Our study reveals a connection between pathological changes in tumor-bearing liver tissue and the hTERT promoter mutation in most HCC, even in noncirrhotic liver tissue. Immunohistochemical hTERT antibodies do not discriminate between hTERT -promoter-mutated and wildtype HCC., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2023 Anne Kristin Fischer et al.)

Primary vaginal malignancies are rare, comprising only 2% of all female genital tract malignancies in adults and 4.5% in children. As part of its mission to improve the quality of care for women with gynecological cancers across Europe, the European Society of Gynaecological Oncology (ESGO) jointly with the European Society for Radiotherapy & Oncology (ESTRO) and the European Society of Pediatric Oncology (SIOPe) developed evidence-based guidelines in order to improve the management of patients with vaginal cancer within a multidisciplinary setting.ESTRO/ESGO/SIOPe nominated practicing clinicians who are involved in the management of vaginal cancer patients and have demonstrated leadership through their expertise in clinical care and research, their national and international engagement and profile as well as dedication to the topics addressed to serve on the expert panel (13 experts across Europe comprising the international development group). To ensure that the statements were evidence based, the current literature was reviewed and critically appraised.In the case of absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the international development group. Prior to publication, the guidelines were reviewed by 112 independent international practitionners in cancer care delivery and patient representatives and their comments and input were incorporated and addressed accordingly.These guidelines cover comprehensively the diagnostic pathways as well as the surgical, radiotherapeutical and systemic management and follow-up of adult patients (including those with rare histological subtypes) and pediatric patients (vaginal rhabdomyosarcoma and germ cell tumours) with vaginal tumours., Competing Interests: Competing interests: CC has reported advisory boards for GSK and MSD; SL has reported advisory boards for GSK, MSD, Novartis and AstraZeneca;MPS has reported grants and personal fees for workshops from Elekta AB; CF has reported advisory board for Roche, Tesaro, GSK, MDS/AZ, Clovis., (© IGCS and ESGO 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

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., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Outcome of relapsed disease of localized rhabdomyosarcoma remains poor. An individual treatment approach considering the initial systemic treatment and risk group was included in the Cooperative Weichteilsarkom Studiengruppe (CWS) Guidance., Methods: Second-line chemotherapy (sCHT) ACCTTIVE based on anthracyclines (adriamycin, carboplatin, cyclophosphamide, topotecan, vincristine, etoposide) was recommended for patients with initial low- (LR), standard- (SR), and high-risk (HR) group after initial treatment without anthracyclines. TECC (topotecan, etoposide, carboplatin, cyclophosphamide) was recommended after initial anthracycline-based regimen in the very high-risk (VHR) group. Data of patients with relapse (n = 68) registered in the European Soft Tissue Sarcoma Registry SoTiSaR (2009-2018) were retrospectively analyzed., Results: Patients of initial LR (n = 2), SR (n = 16), HR (n = 41), and VHR (n = 9) group relapsed. sCHT consisted of ACCTTIVE (n = 36), TECC (n = 12), or other (n = 15). Resection was performed in 40/68 (59%) patients and/or radiotherapy in 47/68 (69%). Initial risk stratification, pattern/time to relapse, and achievement of second complete remission were significant prognostic factors. Microscopically incomplete resection with additional radiotherapy was not inferior to microscopically complete resection (p = .17). The 5-year event-free survival (EFS) and overall survival (OS) were 26% (±12%) and 31% (±14%). The 5-year OS of patients with relapse of SR, HR, and VHR groups was 80% (±21%), 20% (±16%), and 13% (±23%, p = .008), respectively., Conclusion: Adapted systemic treatment of relapsed disease considering the initial risk group and initial treatment is reasonable. New treatment options are needed for patients of initial HR and VHR groups., (© 2023 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Background: In certain rare undifferentiated small round cell sarcomas new specific molecular CIC-DUX4/other partner, BCOR-CCNB3/other partner, YWHAE fusions, or BCOR-ITD (internal tandem duplication) were identified. These new "CIC fused" (CIC-fused/ATXN1::NUTM1) and "BCOR rearranged" (BCOR fused/ITD/ YWHAE) soft tissue sarcomas (STS) are not well described., Methods: Multi-institutional European retrospective analysis of young patients (0-24 years) with CIC-fused and BCOR rearranged STS., Results: Overall, out of the 60 patients selected, the fusion status was CIC-fused (n = 29), ATXN1::NUTM1 (n = 2), BCOR::CCNB3 (n = 18), BCOR-ITD (n = 7), and YWHAE (n = 3), MAML::BCOR STS (n = 1). The main primaries were abdomen-pelvic (n = 23) and limbs (n = 18). Median age was 14 years (0.9-23.8) and 0.9 (0.1-19.1) for CIC-fused and BCOR-rearranged groups, respectively (n = 29; p < 0.001). IRS stages were I (n = 3), II (n = 7), III (n = 35), and IV (n = 15). Overall, 42 patients had large tumors (>5 cm) but only six had lymph node involvement. Patients received mainly chemotherapy (n = 57), local surgery (n = 50), and/or radiotherapy (n = 34). After a median follow-up of 47.1 months (range, 3.4-230), 33 (52%) patients had an event and 23 patients died. Three-year event-free survivals were 44.0% (95% CI 28.7-67.5) and 41.2% (95% CI 25.4-67.0) for CIC and BCOR groups (p = 0.97), respectively. Three-year overall survivals were 46.3% (95% CI 29.6-72.4) and 67.1% (95% CI 50.4-89.3; p = 0.24), respectively., Conclusions: Pediatric patients often present with large tumors and metastatic disease, especially CIC sarcomas. Overall outcome is dismal. New treatment options are needed., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Liver tumors are rare in children with histologic heterogeneity that makes diagnosis challenging. Systematic histopathological review, performed as part of collaborative therapeutic protocols, identified relevant histologic subtypes that are important to distinguish. The Children's Hepatic tumors International Collaboration (CHIC) was established to study pediatric liver tumors on a global scale and led to establishment of a provisional consensus classification for use in international clinical trials. The current study is the validation of this initial classification and first large-scale application by international expert reviewers., Procedure: The CHIC initiative includes data from 1605 children treated on eight multicenter hepatoblastoma (HB) trials. Review of 605 available tumors was performed by seven expert pathologists from three consortia (US, EU, Japan). Cases with discordant diagnoses were collectively reviewed to reach a final consensus diagnosis., Results: Of 599 cases with sufficient material for review, 570 (95.2%) were classified as HB by all consortia, and 29 (4.8%) as non-HB, which included "hepatocellular neoplasm, NOS" and malignant rhabdoid tumors. 453 of 570 HBs were classified as epithelial by final consensus. Some patterns (i.e., small cell undifferentiated, macrotrabecular, cholangioblastic) were selectively identified by reviewers from different consortia. All consortia identified a similar number of mixed epithelial-mesenchymal HB., Conclusions: This study represents the first large-scale application and validation of the pediatric malignant hepatocellular tumors consensus classification. It is a valuable resource to train future generations of investigators on accurate diagnosis of these rare tumors and provides a framework for further international collaborative studies and refinement of the current classification of pediatric liver tumors., (© 2023 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Background: Patients treated with preoperative chemotherapy with stage I intermediate-risk Wilms tumor (IR-WT) represent the largest group of patients with Wilms tumor (WT), and they have excellent outcomes., Methods: The authors performed a retrospective analysis of patients with stage I epithelial (ET-WT) or stromal type WT (ST-WT) treated pre- and postoperatively according to the International Society of Paediatric Oncology-WT-2001 protocol in the UK Children's Cancer and Leukaemia Group and Gesellschaft für Pädiatrische Onkologie und Hämatologie groups' participation in the relevant WT trials and studies (2001-2020)., Results: There were 880 patients with stage I IR-WT, including 124 with ET-WT, 156 with ST-WT, and 600 with other IR-WT (oIR-WT). Patients with stage I ET-WT or ST-WT were significantly younger than patients with oIR-WT, represented a large proportion of stage I WTs in their groups, and tumors showed poor histologic response to preoperative chemotherapy. The 5-year event-free survival (EFS) estimates for patients with stage I ET-WT (96.8% ± 1.8 SE) or ST-WT (96.8% ± 1.6 SE) were significantly better than for patients with oIR-WT (90.3% ± 1.3 SE) (p = .014 and p = .009, respectively). A multivariate analysis showed that histologic type (ET-WT or ST-WT) remained a significant factor for EFS when adjusted for age and gender (p = .032 and p = .022, respectively). In both groups, relapses occurred in 3.2% of patients, and the overall survival was 99.2%., Conclusions: The results suggest that stage I ET-WT or ST-WT could be regarded as low-risk WT, for which omission of postoperative chemotherapy should be considered., Plain Language Summary: Patients with pretreated intermediate-risk Wilms tumor (WT) represent the largest group of patients with WT. This study reports the outcomes of patients with stage I epithelial type (ET-WT) or stromal type WT (ST-WT). These patients were significantly younger and had a larger proportion of stage I cases than patients with other intermediate-risk WT (oIR-WT). The event-free survival for patients with stage I ET-WT and ST-WT was significantly better than for patients with oIR-WT. Rare relapses were curable resulting in 99.2% overall survival., (© 2023 American Cancer Society.)

Background and Aims: Nuclear protein of the testis ( NUT ) carcinoma (NC) is a rare and highly aggressive tumor mainly occurring in adolescents and young adults, defined by the presence of a somatic NUTM1 rearrangement. The aim is to establish internationally harmonized consensus recommendations for the diagnosis and treatment of adolescents and young adults with NC in the framework of the European Reference Network for Paediatric Oncology., Methods: The European Cooperative Study Group for Pediatric Rare Tumors developed recommendations according to the Consensus Conference Standard Operating procedure methodology and reviewed by external "experts." No evidence of level I to II exists. Recommendations were developed based on published prospective (level III), but more frequently retrospective series (level IV), case reports (level V), and personal expertise (level V). In addition, "strength" of recommendations were categorized by grading (grade A to E)., Results: Histology is mandatory for the diagnosis of NC, including immunolabeling with anti-NUT antibodies and molecular biology ( NUTM1 rearrangement) (level V; grade A). Treatment of NC usually combines aggressive approaches in multimodal regimens. Chemotherapy should be considered as first-line treatment (neoadjuvant vincristine-adriamycin-ifosfamide/cisplatin-adriamycin-ifsofamide or vincristine-doxorubicin-cyclophosphamide/ifosfamide-etoposide) for unresectable or metastatic tumor (ie, 3 courses), rapidly followed by local treatment (level IV; grade B). Referral to a specialized surgical oncology center is highly recommended (level V; grade A). In localized NC, a complete microscopic surgical resection should be attempted whenever and as soon as possible, followed by primary irradiation (60 to 70 Gy) and involved lymph nodes area (level IV; grade B). For head and neck tumors, a systematic neck dissection might be considered, even if N0 (level V; grade C). Adjuvant postirradiation chemotherapy is recommended, for a total of 9 to 12 courses (level IV; grade B). For first-line resected tumors, concomitant adjuvant chemotherapy to radiotherapy may be discussed (level IV; grade B). Targeted therapies and immunotherapeutic regimens should be delivered in the setting of prospective trials (level V; grade B)., Conclusions: This project leads to a consensus strategy based on international experience with this very rare disease., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Soft tissue sarcomas (STS) may arise as a consequence of germline variants in cancer predisposition genes (CPGs). We believe that elucidating germline sarcoma predisposition is critical for understanding disease biology and therapeutic requirements. Participation in surveillance programs may allow for early tumor detection, early initiation of therapy and, ultimately, better outcomes. Among children, adolescents, and adults diagnosed with soft-tissue sarcomas and examined as part of published germline sequencing studies, pathogenic/likely pathogenic (P/LP) variants in CPGs were reported in 7-33% of patients. P/LP germline variants were detected most frequently in TP53, NF1 and BRCA1/2. In this review, we describe reported associations between soft tissue sarcomas and germline variants in CPGs, with mentioning of locally aggressive and benign soft tissue tumors that have important associations with cancer predisposition syndromes. We also discuss recommendations for diagnostic germline genetic testing. Testing for sarcoma-predisposing germline variants should be considered as part of the routine clinical workup and care of any child, adolescent, or adult diagnosed with STS and take into account consequences for the whole family., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Purpose: Optimization of local therapies in synovial sarcoma (SS) considered unresectable at diagnosis is needed. We evaluated the effects of neoadjuvant versus adjuvant radiation versus surgery only on long-term outcomes., Methods: Patients with macroscopic SS tumors before chemotherapy (IRS-group-III) in the trials CWS-81, CWS-86, CWS-91, CWS-96, CWS-2002-P and SoTiSaR-registry were analyzed. Local therapies were scheduled after 3 neoadjuvant chemotherapy cycles., Results: Median age of 145 patients was 14.5 years. 106 survivors had median follow-up of 7.0 years. Tumor site was 96 extremities, 19 head-neck, 16 shoulder/hip, 14 trunk. Tumors were < 3 cm in 16, 3-5 cm in 28, 5-10 cm in 55, > 10 cm in 34 patients. In a secondary resection during chemotherapy, R0-status was accomplished in 82, R1 in 30, R2 in 21 (12 missing). Radiotherapy was administered to 115 (R0 61, R1 29, R2 20, missing 5), thereof 57 before and 52 after tumor resection. 23 were treated with surgery only. For all patients, 5 year event-free (EFS) and overall survival (OS) was 68.9% ± 7.6 (95%CI) and 79.1% ± 6.9. To establish independent significance, tumor site, size, surgical results and sequencing of local therapies were analyzed in a Cox regression analysis. Variables associated with EFS and OS are site, size and sequencing of local therapies. Variables associated with local recurrence are site, surgical results and sequencing of local therapies. The only variable associated with suffering metastatic recurrence is tumor size., Conclusion: Differences in sequencing of local therapy procedures are independently associated with outcomes. Best local control is achieved when tumors are irradiated pre-operatively and undergo R0 or R1 resection thereafter., (© 2022. The Author(s).)

Background: Margin status following surgery in children, adolescents, and young adults with soft tissue sarcomas is controversial and has been defined differently by various specialties, with definitions changing over time and by cooperative group. The International Soft Tissue Sarcoma Consortium (INSTRuCT) is a collaboration of the Children's Oncology Group (COG) Soft Tissue Sarcoma Committee, European pediatric Soft Tissue sarcoma Study Group (EpSSG), and the European Cooperative Weichteilsarkom Studiengruppe (CWS) devoted to improving patient outcomes by pooling and mining cooperative group clinical trial data., Methods: The INSTRuCT non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) working group aimed to develop international harmonized recommendations regarding surgical margin assessment and definitions in children and adolescents with soft tissue tumors., Results and Conclusion: This review addresses accepted principles and areas of controversy, including the perspectives of surgeons, pathologists, radiation oncologists, and pediatric oncologists, to develop a framework for building common guidelines for future research., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

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., (© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

(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.

Small cell undifferentiated (SCU) histology and alpha-fetoprotein (AFP) levels below 100 ng/mL have been reported as poor prognostic factors in hepatoblastoma (HB); subsequent studies reported SMARCB1 mutations in some SCU HBs confirming the diagnosis of rhabdoid tumor. The Children's Hepatic tumors International Collaboration (CHIC) database was queried for patients with HB who had AFP levels less than 100 ng/mL at diagnosis or were historically diagnosed as SCU HBs. Seventy-three of 1605 patients in the CHIC database were originally identified as SCU HB, HB with SCU component, or HB with low AFP levels. Upon retrospective review, they were re-classified as rhabdoid tumors ( n = 11), HB with SCU component ( n = 41), and HB with low AFP ( n = 14). Seven were excluded for erroneously low AFP levels. Overall survival was 0% for patients with rhabdoid tumors, 76% for patients with HB with SCU component, and 64% for patients with HB with AFP less than 100 ng/mL. Patients with HB with SCU component or low AFP should be assessed for SMARCB1 mutations and, if confirmed, treated as rhabdoid tumors. When rhabdoid tumors are excluded, the presence of SCU component and low AFP at diagnosis were not associated with poor prognosis in patients diagnosed with HB.

Background: Adrenocortical tumors (ACTs) encompassing the adrenocortical adenoma (ACA), carcinoma (ACC), and tumors of undetermined malignant potential (ACx) are rare endocrine neoplasms with a poor prognosis. We report on pediatric ACT patients registered with the Malignant Endocrine Tumor studies and explore the EXPeRT recommendations for management. Patients: Data from the ACT patients (<18 years) were analyzed. For the risk prediction, the patients were retrospectively assigned to the COG stages and the five-item score. Results: By December 2021, 161 patients with ACT (ACA n = 51, ACx n = 19, and ACC n = 91) had been reported (the median age at the diagnosis was 4.3 years with a range of 0.1−17.8), with lymph node and distant metastases in 10.7% and 18.9% of the patients with ACC/ACx. The mean follow-up was 4.5 years (with a range of 0−16.7). The three-year overall (OS) and event-free survival (EFS) rates were 65.5% and 50.6%. In the univariate analyses, the OS was impaired for patients aged ≥ 4 years (p = 0.001) with the initial biopsy (p = 0.016), tumor spillage (p = 0.028), incomplete tumor resection (p < 0.001), unfavorable histology (p = 0.047), and COG stages III/IV (p = 0.002). Multivariate analysis revealed COG stages III/IV and an unfavorable five-item score as independent negative prognostic factors for the EFS and OS. Conclusions: Age defines the clinical presentation and prognosis in pediatric ACTs. The outcome is best predicted by the COG stage and five-item score.

Background: The survival of patients with localized embryonal rhabdomyosarcoma (RMS) completely resected at diagnosis is greater than 90%. Most patients have paratesticular, uterine, or vaginal RMS, limiting specific analyses of RMS localized in other anatomic regions. This international study was conducted to define the outcome for completely resected embryonal RMS at sites other than paratesticular, uterine, or vaginal primary sites., Methods: A total of 113 patients aged 0-18 years were identified who were enrolled from January 1995 to December 2016 in Children's Oncology Group (COG) (64 patients) and European protocols (49). Genitourinary nonbladder and prostate RMS were excluded. The recommended chemotherapy was vincristine and actinomycin-D (VA) for 24 weeks or ifosfamide plus VA in the European protocols and VA for 48 weeks or VA plus cyclophosphamide in the COG protocols., Results: The most common primary sites were nonparameningeal head and neck (40.7%), other (23.9%), and extremities (20.4%). In the COG studies, 42% of patients received VA and 58% VA plus cyclophosphamide. In Europe, 53% received VA and 47% ifosfamide plus VA. With a median follow-up of 97.5 months, the 5-year progression-free and overall survival was 80.0% (71.2%-86.4%) and 92.5% (85.6%-96.2%), respectively, without significant differences between chemotherapy regimens. Tumor size (< or >5 cm) significantly influenced overall survival: 96.2% (88.6%-98.8%) vs. 80.6% (59.5%-91.4%), respectively (p = .01)., Conclusions: Survival of patients with nonalveolar RMS completely resected at diagnosis is excellent among tumors arising from nonparatesticular, uterine, and vaginal sites, and patients may be treated successfully with low-intensity chemotherapy. To reduce the burden of treatment, VA for 24 weeks may be considered in children with tumors <5 cm., (© 2022 American Cancer Society.)

Background: CWS/RMS-96 was an international multicenter trial with randomization between two therapy arms of the standard four-drug therapy (vincristine, ifosfamide, adriamycin, dactinomycin [VAIA]) versus an intensified six-drug regimen (carboplatin, epirubicin, vincristine, dactinomycin, ifosfamide, and etoposide [CEVAIE]) for high-risk rhabdomyosarcoma (RMS), extraskeletal Ewing sarcoma (EES), and undifferentiated sarcoma (UDS) in children, adolescents, and young adults aiming to improve their survival. Intensified chemotherapy with CEVAIE did not improve outcome., Methods: Patients younger than 21 years with a previously untreated localized HR-RMS, EES, and UDS were enrolled from Cooperative Weichteilsarkom Studiengruppe (CWS) centers in Germany, Austria, Poland, Switzerland, and from Italian Soft Tissue Sarcoma Committee (STSC) centers. Randomization (1:1) to receive either 9 × 21 days cycles of VAIA or CEVAIE was performed separately in CWS and STSC. Hyperfractionated accelerated radiotherapy (32-44.8 Gy) was added at week 9-12 according to histology and response to chemotherapy. A secondary microscopically complete nonmutilating resection was performed if possible. Primary endpoints were response to chemotherapy, event-free (EFS) and overall survival (OS)., Results: Five hundred fifty-seven patients (HR-RMS: n = 416, EES and UDS: n = 141) underwent randomization: VAIA (n = 273) or CEVAIE (n = 284). Radiotherapy was given to 70% of patients in both groups. A secondary resection was performed in 47% and 48% patients, respectively. The 5-year EFS and OS for the VAIA and CEVAIE treatment arms were 59.8% and 60.8% (p = .89), and 74.2% and 68.3% (p = .16), respectively. No differences in response, toxicity, or second malignancies emerged in the two groups., Conclusion: The use of an intensified regimen failed to show a significant improvement in tumor response and outcome of patients with localized HR-RMS, EES, and UDS., (© 2022 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Rhabdomyosarcomas (RMSs) are the most common soft tissue sarcomas in children/adolescents less than 18 years of age with an annual incidence of 1-2/million. Inter/intra-tumour heterogeneity raise challenges in clinical, pathological and biological research studies. Risk stratification in European and North American clinical trials previously relied on clinico-pathological features, but now, incorporates PAX3/7-FOXO1-fusion gene status in the place of alveolar histology. International working groups propose a coordinated approach through the INternational Soft Tissue SaRcoma ConsorTium to evaluate the specific genetic abnormalities and generate and integrate molecular and clinical data related to patients with RMS across different trial settings. We review relevant data and present a consensus view on what molecular features should be assessed. In particular, we recommend the assessment of the MYOD1-LR122R mutation for risk escalation, as it has been associated with poor outcomes in spindle/sclerosing RMS and rare RMS with classic embryonal histopathology. The prospective analyses of rare fusion genes beyond PAX3/7-FOXO1 will generate new data linked to outcomes and assessment of TP53 mutations and CDK4 amplification may confirm their prognostic value. Pathogenic/likely pathogenic germline variants in TP53 and other cancer predisposition genes should also be assessed. DNA/RNA profiling of tumours at diagnosis/relapse and serial analyses of plasma samples is recommended where possible to validate potential molecular biomarkers, identify new biomarkers and assess how liquid biopsy analyses can have the greatest benefit. Together with the development of new molecularly-derived therapeutic strategies that we review, a synchronised international approach is expected to enhance progress towards improved treatment assignment, management and outcomes for patients with RMS., Competing Interests: Conflict of interest statement 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 article., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Resistance to conventional chemotherapy remains a huge challenge in the clinical management of hepatoblastoma, the most common liver tumor in childhood. By integrating the gene expression data of hepatoblastoma patients into the perturbation prediction tool Connectivity Map, we identified the clinical widely used anthelmintic mebendazole as a drug to circumvent chemoresistance in permanent and patient-derived xenograft cell lines that are resistant to cisplatin, the therapeutic backbone of hepatoblastoma treatment. Viability assays clearly indicated a potent reduction of tumor cell growth upon mebendazole treatment in a dose-dependent manner. The combination of mebendazole and cisplatin revealed a strong synergistic effect, which was comparable to the one seen with cisplatin and doxorubicin, the current treatment for high-risk hepatoblastoma patients. Moreover, mebendazole treatment resulted in reduced colony and tumor spheroid formation capabilities, cell cycle arrest, and induction of apoptosis of hepatoblastoma cells. Mechanistically, mebendazole causes blockage of microtubule formation and transcriptional downregulation of genes encoding the unwindosome, which are highly expressed in chemoresistant tumors. Most importantly, mebendazole significantly reduced tumor growth in a subcutaneous xenograft transplantation mouse model without side effects. In conclusion, our results strongly support the clinical use of mebendazole in the treatment of chemoresistant hepatoblastoma and highlight the potential theranostic value of unwindosome-associated genes.

(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.

Recently, immunotherapeutic approaches have become a feasible option for a subset of pediatric cancer patients. Low MHC class I expression hampers the use of immunotherapies relying on antigen presentation. A well-established stemness score (mRNAsi) was determined using the bulk transcriptomes of 1134 pediatric small round blue cell tumors. Interestingly, MHC class I gene expression (HLA-A/-B/-C) was correlated negatively with mRNAsi throughout all diagnostic entities: neuroblastomas (NB) (n = 88, r = −0.41, p < 0.001), the Ewing’s sarcoma family of tumors (ESFT) (n = 117, r = −0.46, p < 0.001), rhabdomyosarcomas (RMS) (n = 158, r = −0.5, p < 0.001), Wilms tumors (WT) (n = 224, r = −0.39, p < 0.001), and central nervous system-primitive neuroectodermal tumors CNS-PNET (r = −0.49, p < 0.001), with the exception of medulloblastoma (MB) (n = 76, r = −0.24, p = 0.06). The negative correlation of MHC class I and mRNAsi was independent of clinical features in NB, RMS, and WT. In NB and WT, increased MHC class I was correlated negatively with tumor stage. RMS patients with a high expression of MHC class I and abundant CD8 T cells showed a prolonged overall survival (n = 148, p = 0.004). Possibly, low MHC class I expression and stemness in pediatric tumors are remnants of prenatal tumorigenesis from multipotent precursor cells. Further studies are needed to assess the usefulness of stemness and MHC class I as predictive markers.

In children and adolescents, neuroblastoma (NBL), pheochromocytoma (PCC), and adrenocortical tumors (ACT) can arise from the adrenal gland. It may be difficult to distinguish between these three entities including associated extra-adrenal tumors (paraganglioma, PGL). Precise discrimination, however, is of crucial importance for management. Biopsy in ACT or PCC is potentially harmful and should be avoided whenever possible. We herein report data on 10 children and adolescents with ACT and five with PCC/PGL, previously mistaken as NBL. Two patients with adrenocortical carcinoma died due to disease progression. Two (2/9, missing data in one patient) patients with a final diagnosis of ACT clearly presented with obvious clinical signs and symptoms of steroid hormone excess, while seven patients did not. Blood analyses indicated increased levels of steroid hormones in one additional patient; however, urinary steroid metabolome analysis was not performed in any patient. Two (2/10) patients underwent tumor biopsy, and in two others tumor rupture occurred intraoperatively. In 6/10 patients, ACT diagnosis was only established by a reference pediatric pathology laboratory. Four (4/5) patients with a final diagnosis of PCC/PGL presented with clinical signs and symptoms of catecholamine excess. Urine tests indicated possible catecholamine excess in two patients, while no testing was carried out in three patients. Measurements of plasma metanephrines were not performed in any patient. None of the five patients with PCC/PGL received adrenergic blockers before surgery. In four patients, PCC/PGL diagnosis was established by a local pathologist, and in one patient diagnosis was revised to PGL by a pediatric reference pathologist. Genetic testing, performed in three out of five patients with PCC/PGL, indicated pathogenic variants of PCC/PGL susceptibility genes. The differential diagnosis of adrenal neoplasias and associated extra-adrenal tumors in children and adolescents may be challenging, necessitating interdisciplinary and multidisciplinary efforts. In ambiguous and/or hormonally inactive cases through comprehensive biochemical testing, microscopical complete tumor resection by an experienced surgeon is vital to preventing poor outcome in children and adolescents with ACT and/or PCC/PGL. Finally, specimens need to be assessed by an experienced pediatric pathologist to establish diagnosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kuhlen, Pamporaki, Kunstreich, Wudy, Hartmann, Peitzsch, Vokuhl, Seitz, Kreissl, Simon, Hero, Frühwald, Vorwerk and Redlich.)

Background: Spindle cell rhabdomyosarcoma (RMS) is a rare variant of RMS accounting for up to 10% of cases in infants. In older children and adults, spindle cell RMS is associated with MYOD1 mutations and a poor prognosis. In infants, it is associated with recurring fusions involving NCOA2 and VGLL2. Reports in the literature suggest a favorable prognosis for this subset, however, little is known about treatment and outcome data of infants with spindle cell RMS., Methods: Characteristics, treatment, and outcome of an international cohort of 40 patients aged ≤ 12 months with spindle cell RMS treated from 1997 to 2018 were evaluated., Results: Localized disease (LD) was diagnosed in 39 patients. The median age at diagnosis was 2.5 months (range 0-12 months). Expert pathologic review confirmed the diagnosis of spindle cell RMS in all patients. Among 26 tumors that had molecular evaluation, 13 had rearrangements of NCOA and/or VGLL. Multimodal treatment of infants with LD included conventional (age adjusted) chemotherapy (n = 37), resection (n = 31) and radiotherapy (RT) (n = 5, brachytherapy in 3). Complete remission was achieved in 37/39 patients. Progressive disease occurred in two infants, relapsed disease in three. Microscopically complete surgical resection was associated with five-year event-free survival (EFS) and overall survival (OS) of 100%. Two patients with tumors ≤ 5 cm were treated with microscopically complete resection only and were alive 1 and 4.2 years after diagnosis. The 5-year EFS and OS for infants with LD were 86% (±11; CI 95%) and 91% (±9; CI 95%), respectively. One patient had metastatic disease (NCOA fusion positive) with primary tumor in head and neck and brain metastases. This patient died despite chemotherapy and delayed resection of the primary tumor due to respiratory failure secondary to cytomegalovirus infection 1.2 years after diagnosis., Conclusion: Infants with spindle cell RMS have an excellent prognosis. Multimodal treatment including microscopically complete resection of the tumor is strongly recommended., Competing Interests: Conflict of interest statement The authors declare no conflict of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)