Consensus classification of pediatric hepatocellular tumors: A report from the Children's Hepatic tumors International Collaboration (CHIC).

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.

Telomerase activation by genomic rearrangements in high-risk neuroblastoma.

Neuroblastoma is a malignant paediatric tumour of the sympathetic nervous system. Roughly half of these tumours regress spontaneously or are cured by limited therapy. By contrast, high-risk neuroblastomas have an unfavourable clinical course despite intensive multimodal treatment, and their molecular basis has remained largely elusive. Here we have performed whole-genome sequencing of 56 neuroblastomas (high-risk, n = 39; low-risk, n = 17) and discovered recurrent genomic rearrangements affecting a chromosomal region at 5p15.33 proximal of the telomerase reverse transcriptase gene (TERT). These rearrangements occurred only in high-risk neuroblastomas (12/39, 31%) in a mutually exclusive fashion with MYCN amplifications and ATRX mutations, which are known genetic events in this tumour type. In an extended case series (n = 217), TERT rearrangements defined a subgroup of high-risk tumours with particularly poor outcome. Despite a large structural diversity of these rearrangements, they all induced massive transcriptional upregulation of TERT. In the remaining high-risk tumours, TERT expression was also elevated in MYCN-amplified tumours, whereas alternative lengthening of telomeres was present in neuroblastomas without TERT or MYCN alterations, suggesting that telomere lengthening represents a central mechanism defining this subtype. The 5p15.33 rearrangements juxtapose the TERT coding sequence to strong enhancer elements, resulting in massive chromatin remodelling and DNA methylation of the affected region. Supporting a functional role of TERT, neuroblastoma cell lines bearing rearrangements or amplified MYCN exhibited both upregulated TERT expression and enzymatic telomerase activity. In summary, our findings show that remodelling of the genomic context abrogates transcriptional silencing of TERT in high-risk neuroblastoma and places telomerase activation in the centre of transformation in a large fraction of these tumours.

Undifferentiated sarcoma of the liver: Multicenter international experience of the Cooperative Soft-Tissue Sarcoma Group and Polish Paediatric Solid Tumor Group.

BACKGROUND: Undifferentiated embryonal sarcomas of the liver (UESL) are extremely rare and continue to pose a diagnostic and therapeutic challenge. The aim of the study was to present a multicenter experience of the German CWS and Polish PPSTG groups in the treatment of UESL in children. PROCEDURE: Twenty-five patients were treated according to the CWS-96, CWS-2002, and CYVADIC protocols. Distant metastases were observed in four cases (16%). In four cases, an initial disease presentation mimicked other entities. A pure cystic appearance of liver mass led to misdiagnosis of hydatid cyst in three cases. In one case, laparotomy was performed due to the signs of appendicitis, and bleeding from ruptured liver tumor was found. All these patients were finally diagnosed as UESL. RESULTS: Thirteen patients received preoperative chemotherapy. Partial response was observed in 10 cases. Tumor resection was performed in 20 patients (primary resections, 12; delayed resections-, 8). In five patients, the primary tumor never became operable. The macroscopically complete resection rate was 95% (19/20). Postoperative chemotherapy was given to 20 children. Local radiotherapy was used in three children. After a median follow-up time of 136 months, 17 patients (68%) were alive with no evidence of disease. All children with unresectable tumor and three out of four patients with distant metastases died. The five-year overall survival (OS) rate was 72%. CONCLUSIONS: In summary, a complete tumor excision plays the central role in the treatment of UESL. A cystic presentation of the liver lesion on imaging does not exclude the diagnosis of malignant tumor.

Treatment and outcome of the patients with rhabdomyosarcoma of the biliary tree: Experience of the Cooperative Weichteilsarkom Studiengruppe (CWS).

BACKGROUND: Biliary rhabdomyosarcoma (RMS) is the most common biliary tumor in children. The management of affected patients contains unique challenges because of the rarity of this tumor entity and its critical location at the porta hepatis, which can make achievement of a radical resection very difficult. METHODS: In a retrospective chart analysis we analysed children suffering from biliary RMS who were registered in three different CWS trials (CWS-96, CWS-2002P, and SoTiSaR registry). RESULTS: Seventeen patients (12 female, 5 male) with a median age of 4.3 years were assessed. The median follow-up was 42.2 months (10.7-202.5). The 5-year overall (OS) and event free survival (EFS) rates were 58% (45-71) and 47% (34-50), respectively. Patients > 10 years of age and those with alveolar histology had the worst prognosis (OS 0%). Patients with botryoid histology had an excellent survival (OS 100%) compared to those with non-botryoid histology (OS 38%, 22-54, p = 0.047). Microscopic complete tumor resection was achieved in almost all patients who received initial tumor biopsy followed by chemotherapy and delayed surgery. CONCLUSION: Positive predictive factors for survival of children with biliary RMS are age ≤ 10 years and botryoid tumor histology. Primary surgery with intention of tumor resection should be avoided.

IL-6 trans-signaling is essential for the development of hepatocellular carcinoma in mice.

Hepatocellular carcinoma (HCC) is one of the most frequent tumors worldwide with rising incidence. The inflammatory cytokine, interleukin-6 (IL-6), is a critical mediator of HCC development. It can signal through two distinct pathways: the IL-6 classic and the IL-6 trans-signaling pathway. Whereas IL-6 classic signaling is important for innate and acquired immunity, IL-6 trans-signaling has been linked to accelerated liver regeneration and several chronic inflammatory pathologies. However, its implication in liver tumorigenesis has not been addressed yet. Here, we show that IL-6 trans-signaling, but not IL-6 classic signaling, is essential to promote hepatocellular carcinogenesis by two mechanisms: First, it prevents DNA-damage-induced hepatocyte apoptosis through suppression of p53 and enhances ß-catenin activation and tumor proliferation. Second, IL-6 trans-signaling directly induces endothelial cell proliferation to promote tumor angiogenesis. Consequently, soluble gp130 fused to Fc transgenic mice lacking IL-6 trans-signaling are largely protected from tumor formation in a diethylnitrosamine/3,3',5,5'-tetrachloro-1,4-bis(pyridyloxy)benzene model of HCC. CONCLUSION: IL-6 trans-signaling, and not IL-6 classic signaling, is mandatory for development of hepatocellular carcinogenesis. Therefore, specific inhibition of IL-6 trans-signaling, rather than total inhibition of IL-6 signaling, is sufficient to blunt tumor initiation and impair tumor progression without compromising IL-6 classic signaling-driven protective immune responses. (Hepatology 2017;65:89-103).

ETV6-NTRK3 in congenital mesoblastic nephroma: A report of the SIOP/GPOH nephroblastoma study.

BACKGROUND: Congenital mesoblastic nephroma (MN) is a rare pediatric renal tumor representing approximately 5% of all pediatric renal tumors. Three different types of MN are distinguished histologically: classical, cellular, and mixed. A frequent genetic alteration is the translocation t(12;15) resulting in a fusion of the ETV6 gene on 12p13 and the NTRK3 gene on 15p15 that occurs almost exclusively in cellular MN. The aim of this study was to determine translocation status of a large cohort of MN with respect to tumor subtype and outcome. PROCEDURE: In total, clinical data from 111 patients were available. Sixty-seven tumors were classical MN (51%), 29 cellular MN (31%), and 15 were mixed MN (18%). From these 111 cases, 79 were analyzed by FISH and RT-PCR. RESULTS: All classical and mixed MN were translocation negative. Seventeen out of 29 (58%) cellular MN harbored the ETV6-NTRK3 translocation. Five-year relapse-free survival (RFS) and overall survival (OS) were 93.2% and 96.8% for the complete cohort. All seven relapses occurred in translocation negative tumors. Five-year RFS was significantly inferior for cellular and mixed MN compared to classic MN (89%, 80%, and 98%), whereas 5-year OS was similar (93%, 96%, and 98%). Within the group of cellular MN, patients having translocation-positive tumors had a significantly superior RFS (5-year RFS: 100% vs. 73%). CONCLUSION: The majority of cellular MNs harbor the ETV6-NTKR3 gene fusion, whereas all classic- and mixed-type MNs were translocation negative. Within the cellular subgroup, patients having translocation-positive tumors had a significantly superior RFS.

High-dose treatment for malignant rhabdoid tumor of the kidney: No evidence for improved survival-The Gesellschaft für Pädiatrische Onkologie und Hämatologie (GPOH) experience.

BACKGROUND: Malignant rhabdoid tumor of the kidney (MRTK) is the most aggressive childhood renal tumor with overall survival (OS) rates ranging from 22% to 42%. Whether high-dose chemotherapy with autologous stem-cell transplantation (HDSCT) in an intensive first-line treatment offers additional benefit is an ongoing discussion. METHODS: A retrospective analysis of all 58 patients with MRTK from Austria, Switzerland, and Germany treated in the framework of consecutive, prospective renal/rhabdoid tumor studies SIOP9/GPO, SIOP93-01/GPOH (where SIOP is International Society of Pediatric Oncology and GPOH is German Society of Pediatric Oncology and Hematology), SIOP2001/GPOH, and European Rhabdoid Tumor Registry from 1991 to 2014. RESULTS: Median age at diagnosis was 11 months. Fifty percent of patients had metastases or multifocal disease at diagnosis (Stage IV). Local stage distribution was as follows: not done/I/II/III-1/6/11/40. Fifteen (26%) patients underwent upfront surgery. Thirty-seven (64%) patients achieved a complete remission, 17 (29%) relapsed, 34 (59%) died of disease progression, and two (3%) died of treatment-related complication. Mean time to the first event was 3.5 months. Two-year EFS/OS (where EFS is event-free survival) for the whole group was 37 ± 6%/38 ± 6%. Metastases/multifocal disease, younger age, and local stage III were associated with significantly inferior survival. Eleven (19%) patients underwent HDSCT (carboplatin + thiotepa, n = 6; carboplatin + etoposide + melphalan, n = 4; others, n = 1); 2-year OS in this group was 60 ± 15% compared to 34 ± 8% in the non-HDSCT group (P = 0.064). However, the time needed from radiologic to histologic diagnosis, stem-cell harvest, and HDSCT must also be taken into account to avoid selection bias by excluding the highest risk group with early progression (<90 days). Thus, 2-year EFS only for patients without progression until day 90 was 60 ± 16% consolidated by HDSCT compared to 62 ± 11% without (P = 0.8). CONCLUSION: Our retrospective analysis suggests comparable outcomes for patients with and without HDSCT, if adjusted for early disease progression.

Systemic therapy of aggressive fibromatosis in children and adolescents: Report of the Cooperative Weichteilsarkom Studiengruppe (CWS).

BACKGROUND: Treatment algorithms for patients with aggressive fibromatosis (AF) are challenging. There are limited data available about the use of systemic therapy (ST) in pediatric patients with AF. METHODS: Patient-, tumor-, and treatment-related factors of 90 children and adolescents with AF treated on multiple prospective trials of the Cooperative Weichteilsarkom Studiengruppe (1981-2015) were analyzed with focus on response and outcome of ST. RESULTS: Median age was 9.48 years (0.02-18.05). Primary resection was performed in 54 patients and ST was administered in 29 of 54 patients because of disease progression or relapse. In 35 patients, ST was the initial treatment modality. A secondary resection was performed in 21 of 35 patients after ST. A total of 64 patients received ST, mainly methotrexate and vinblastine (40%) with a median duration of 380 days. The most frequent radiological response to ST was stable disease at 3 months (39%) and partial response at 6 months (53%). Radiotherapy was administered to 15 of 90 patients. One patient remained on observation only. The 5-year overall survival was 100% and the 5-year event-free survival (EFS) was 44%. Patients who had a primary resection showed a 5-year EFS of 35% versus 59% in patients who had received primary ST (P = 0.08). Functional deficiencies as long-term sequelae following resection occurred in 11 patients. At a median follow-up of 5.05 years (0.25-14.88), complete remission was achieved in 51 patients and partial remission in 28 patients. CONCLUSIONS: ST seems appropriate if a primary complete resection is not feasible and at relapse/progression after resection.

Risk-stratified staging in paediatric hepatoblastoma: a unified analysis from the Children's Hepatic tumors International Collaboration.

BACKGROUND: Comparative assessment of treatment results in paediatric hepatoblastoma trials has been hampered by small patient numbers and the use of multiple disparate staging systems by the four major trial groups. To address this challenge, we formed a global coalition, the Children's Hepatic tumors International Collaboration (CHIC), with the aim of creating a common approach to staging and risk stratification in this rare cancer. METHODS: The CHIC steering committee-consisting of leadership from the four major cooperative trial groups (the International Childhood Liver Tumours Strategy Group, Children's Oncology Group, the German Society for Paediatric Oncology and Haematology, and the Japanese Study Group for Paediatric Liver Tumours)-created a shared international database that includes comprehensive data from 1605 children treated in eight multicentre hepatoblastoma trials over 25 years. Diagnostic factors found to be most prognostic on initial analysis were PRETreatment EXTent of disease (PRETEXT) group; age younger than 3 years, 3-7 years, and 8 years or older; α fetoprotein (AFP) concentration of 100 ng/mL or lower and 101-1000 ng/mL; and the PRETEXT annotation factors metastatic disease (M), macrovascular involvement of all hepatic veins (V) or portal bifurcation (P), contiguous extrahepatic tumour (E), multifocal tumour (F), and spontaneous rupture (R). We defined five clinically relevant backbone groups on the basis of established prognostic factors: PRETEXT I/II, PRETEXT III, PRETEXT IV, metastatic disease, and AFP concentration of 100 ng/mL or lower at diagnosis. We then carried the additional factors into a hierarchical backwards elimination multivariable analysis and used the results to create a new international staging system. RESULTS: Within each backbone group, we identified constellations of factors that were most predictive of outcome in that group. The robustness of candidate models was then interrogated using the bootstrapping procedure. Using the clinically established PRETEXT groups I, II, III, and IV as our stems, we created risk stratification trees based on 5 year event-free survival and clinical applicability. We defined and adopted four risk groups: very low, low, intermediate, and high. INTERPRETATION: We have created a unified global approach to risk stratification in children with hepatoblastoma on the basis of rigorous statistical interrogation of what is, to the best of our knowledge, the largest dataset ever assembled for this rare paediatric tumour. This achievement provides the structural framework for further collaboration and prospective international cooperative study, such as the Paediatric Hepatic International Tumour Trial (PHITT). FUNDING: European Network for Cancer Research in Children and Adolescents, funded through the Framework Program 7 of the European Commission (grant number 261474); Children's Oncology Group CureSearch grant contributed by the Hepatoblastoma Foundation; Practical Research for Innovative Cancer Control and Project Promoting Clinical Trials for Development of New Drugs and Medical Devices, Japan Agency for Medical Research; and Swiss Cancer Research grant.

Childhood cancer predisposition syndromes-A concise review and recommendations by the Cancer Predisposition Working Group of the Society for Pediatric Oncology and Hematology.

Heritable predisposition is an important cause of cancer in children and adolescents. Although a large number of cancer predisposition genes and their associated syndromes and malignancies have already been described, it appears likely that there are more pediatric cancer patients in whom heritable cancer predisposition syndromes have yet to be recognized. In a consensus meeting in the beginning of 2016, we convened experts in Human Genetics and Pediatric Hematology/Oncology to review the available data, to categorize the large amount of information, and to develop recommendations regarding when a cancer predisposition syndrome should be suspected in a young oncology patient. This review summarizes the current knowledge of cancer predisposition syndromes in pediatric oncology and provides essential information on clinical situations in which a childhood cancer predisposition syndrome should be suspected.

The impact of local control in the treatment of type II/III pleuropulmonary blastoma. Experience of the Cooperative Weichteilsarkom Studiengruppe (CWS).

BACKGROUND AND OBJECTIVES: This study aims at examining the potential survival benefits of primary versus secondary surgery in the management of children diagnosed with pleuropulmonary blastoma (PPB) type II/III. PATIENTS AND METHODS: Disease characteristics, treatment, and survival of 29 children with localized PPB type II/III, treated in six prospective Cooperative Weichteilsarkom Studiengruppe (CWS) trials, were reviewed retrospectively. RESULTS: Five year event free survival (EFS) and overall survival (OS) of children treated according to CWS protocols was 72%. Patients with tumors ≤10 cm had a 5 year OS of 91% versus 57% in patients with tumors >10 cm (P = 0.025). Five year OS of patients with macroscopically incomplete upfront resections was 44% as opposed to 68% in patients with delayed/secondary microscopically or macroscopically complete resection after an initial biopsy (P = 0.476). Ten patients died of disease, one patient died of second malignancy. Tumor size and complete tumor resection at any time were significant prognostic factors (P = 0.025/0.003) for EFS. EFS for microscopically complete, microscopically incomplete, and macroscopically incomplete resection at any time was 91%, 90%, and 25%, respectively (P = 0.01). CONCLUSIONS: Primary or secondary microscopically/macroscopically complete tumor resections in combination with chemotherapy correlates with long term survival in children with PPB. J. Surg. Oncol. 2017;115:164-172. © 2017 Wiley Periodicals, Inc.

The prognostic impact of SYT-SSX fusion type and histological grade in pediatric patients with synovial sarcoma treated according to the CWS (Cooperative Weichteilsarkom Studie) trials.

BACKGROUND: The aim of our analysis was the evaluation of the prognostic impact of SYT-SSX fusion status and histological grading in synovial sarcoma (SS) of children and adolescents in the context of the consistent multimodal treatment strategy of the CWS (Cooperative Weichteilsarkom Studie; Cooperative Soft Tissue Sarcoma Study Group) and in comparison with other risk factors. PROCEDURE: Between 1986 and 2006, out of 243 patients with SS, tumor samples from 84 patients with localized disease were available for RT-PCR analysis. Outcome depending on fusion status in the context with known clinical risk factors was analyzed. RESULTS: No prognostic significance was shown for SYT-SSX fusion status and for histological grade. Highest significance of negative prognostic impact was found for large tumor size in uni- and multivariate analysis (P < 0.01). Furthermore, male gender was shown to be an adverse prognostic factor in multivariate analysis (P = 0.01). CONCLUSIONS: Based on our results, neither histological grading nor SYT-SSX fusion status seems to be suitable for outcome prediction and risk stratification in localized SS treated according to the CWS. This is in contrast to several other publications concerning more heterogeneous age groups including children and adults, and this indicates that prognostic factors should not be interpreted apart from the particular study population and the therapeutic context.

Mutually exclusive BCOR internal tandem duplications and YWHAE-NUTM2 fusions in clear cell sarcoma of kidney: not the full story.

Internal tandem duplication within the BCOR gene sequence that encodes the PUFD domain, important in the formation of the non-canonical or variant polycomb repressor complex 1 (v-PRC1), was very recently described in 100% of 20 clear cell sarcomas of kidney (CCSKs). None of those 20 cases bore the YWHAE-NUTM2 transcript, previously described by us in CCSK, and which constitutes the only other recurrent genetic aberration observed in CCSK, prompting consideration that these mutations might be mutually exclusive in CCSK. We analysed a cohort of 159 CCSKs and can now not only confirm that there is indeed mutual exclusivity of these BCOR and YWHAE mutations, but also show that a substantial proportion (in this series 11.8%) of CCSKs bear neither mutation when tested by these assays, raising the possibility of distinct aetiologies for subsets of CCSK. Clinical differences observed between the subsets support this notion. As CCSK may show poor chemo-responsiveness, and current treatment protocols mandate the use of doxorubicin with its associated side-effects, advances in understanding the disease biology with a view to more targeted and personalized treatment is a pressing need.

2017 GPOH Guidelines for Diagnosis and Treatment of Patients with Neuroblastic Tumors.

The clinical course of neuroblastoma is more heterogeneous than any other malignant disease. Most low-risk patients experience regression after limited or even no chemotherapy. However, more than half of high-risk patients die from disease despite intensive multimodal treatment. Precise patient characterization at diagnosis is key for risk-adapted treatment. The guidelines presented here incorporate results from national and international clinical trials to produce recommendations for diagnosing and treating neuroblastoma patients in German hospitals outside of clinical trials.

Pediatric NUT-midline carcinoma: Therapeutic success employing a sarcoma based multimodal approach.

A subset of poorly differentiated squamous cell carcinomas, NUT midline carcinomas (NMC) are characterized by a translocation t(15;19)(q13;p13) [ 1 ]. The prognosis is generally dismal [ 2 ] and therapeutic success has been limited to exceptional cases [ 3 ]. We present two cases of pediatric NMC from two different institutions treated according to a multimodal sarcoma approach involving surgery, chemotherapy, and focal radiotherapy. One patient has remained in complete continuous remission for over 6 years, while the other is in CR in early follow-up off therapy. Our proposed multimodal strategy apparently meets the aggressive biologic nature of NMC and should be considered for further evaluation in this context potentially in the setting of a clinical trial.

Small cell undifferentiated (SCUD) hepatoblastomas: All malignant rhabdoid tumors?

Small cell undifferentiated (SCUD) hepatoblastoma is a rare variant of hepatoblastoma with poor outcome and loss of INI1 expression, sharing this with malignant rhabdoid tumors (MRT). We studied all tumors from the files of the Kiel Pediatric Tumor Registry (KTR) with the initial diagnosis of SCUD and MRT. After re-review, we performed immunistochemistry, fluorescence in situ hybridization, and multiplex ligation dependent probe amplification for loss of expression and deletion of INI1/SMARCB1 in 23 tumors. Morphologically, 12 of the tumors had a small cell morphology, 9 showed the typical picture of MRT, and 2 were composed of both small cells and rhabdoid cells. All but 1 of the 23 tumors showed loss of INI1 protein expression by immunohistochemistry. Nineteen of the INI1 negative tumors were analyzed by FISH technique and all showed a deletion of the INI1/SMARCB1 gene (17 homozygous deletions, 2 heterozygous deletions). We investigated 14 of these cases by multiplex ligation dependent probe amplification and verified the deletions in all cases. In conclusion, we postulate that SCUD hepatoblastoma is not a hepatoblastoma but represents a malignant rhabdoid tumor of the liver. © 2016 Wiley Periodicals, Inc.

The clinical phenotype of YWHAE-NUTM2B/E positive pediatric clear cell sarcoma of the kidney.

Clear cell sarcoma of the kidney (CCSK) although uncommon, is the second most frequent renal malignancy of childhood. Until now, the sole recurrent genetic aberration identified in CCSKs is t(10;17)(q22;p13), which gives rise to a fusion transcript of YWHAE and NUTM2B/E. So far, the clinical relevance of this fusion transcript is unknown. The aim of this descriptive study was to determine the clinical phenotype of t(10;17)(q22;p13) positive CCSKs. Snap-frozen tissues, formalin-fixed paraffin-embedded tissues or RNA previously extracted from CCSK samples throughout European, North-American and Japanese study groups were screened by RT-PCR for the YWHAE-NUTM2B/E transcript. Clinical characteristics, tumor characteristics, and outcome of patients with and without the fusion transcript were studied. The cohort comprised 51 previously published cases to which were added 139 internationally collected CCSK samples. RNA from 57 of these additionally collected cases was of sufficient quality to be successfully screened for the YWHAE-NUTM2B/E transcript. In total, seven of the 108 cases harbored the fusion transcript. Patients with tumors containing the fusion transcript were relatively young (median age 10 months), had associated low median tumor volumes and stage I disease was not observed in these patients. Two of seven patients relapsed and one of seven patients died of disease. Ranges of values were not overtly different between patients with and without the fusion transcript; however, the number of fusion transcript positive cases turned out to be too small to permit reliable statistical analysis. The current study did not identify an explicit clinical phenotype of CCSK cases harboring the YWHAE-NUTM2B/E fusion transcript.

Outcome, Treatment, and Treatment Failures in Patients Suffering Localized Embryonal Paratesticular Rhabdomyosarcoma: Results From the "Cooperative Weichteilsarkom Studiengruppe" Trials CWS-86, -91, -96, and -2002P.

OBJECTIVE: To evaluate outcome in respect to local treatment strategies in 4 prospective CWS trials in patients with paratesticular rhabdomyosarcoma (PTRMS). SUMMARY BACKGROUND DATA: PTRMS patients have a high number of surgical treatment failures. Retroperitoneal lymph node (LN) involvement is common in patients more than 10 years, and the optimal treatment is unknown. METHODS: A total of 173 patients with diagnosis of PTRMS were enrolled. Of these, 26 were excluded and 147 patients were finally analyzed. All patients were treated according to the Cooperative Soft Tissue Sarcoma (CWS) trial protocols. RESULTS: The 5-year overall survival was 95.5%, and the 5-year event-free survival (EFS) was 89.8%. Positive predictive factors for EFS were age younger than 10 years and tumor size less than 5 cm. Surgical treatment failures were observed in 34 of 135 patients undergoing primary resection. Primary inguinal/iliacal LN sampling was carried out in 15 of 147 patients with no impact on the EFS (87.5%; P = 0.666). Secondary retroperitoneal LN dissection was done in 32 of 147 patients, of which only 8 patients had viable tumor and a worse outcome (EFS: 50%; P = 0.01). Loco-regional, combined, and metastatic relapses were observed in 13 of 147 patients. CONCLUSIONS: The outcome of PTRMS patients is excellent and is hardly improvable. Positive predictors for outcome are age younger than 10 years and tumor size less than 5 cm. Primary LN sampling seems to have no impact on the EFS and should not be recommended. Inadequate surgery can be avoided by treatment in specialized centers. Secondary retroperitoneal LN dissection revealed a high number of unnecessary procedures, but patients with positive LN had a poor prognosis and require additional local therapy.

Omission of doxorubicin from the treatment of stage II-III, intermediate-risk Wilms' tumour (SIOP WT 2001): an open-label, non-inferiority, randomised controlled trial.

BACKGROUND: Before this study started, the standard postoperative chemotherapy regimen for stage II-III Wilms' tumour pretreated with chemotherapy was to include doxorubicin. However, avoidance of doxorubicin-related cardiotoxicity effects is important to improve long-term outcomes for childhood cancers that have excellent prognosis. We aimed to assess whether doxorubicin can be omitted safely from chemotherapy for stage II-III, histological intermediate-risk Wilms' tumour when a newly defined high-risk blastemal subtype was excluded from randomisation. METHODS: For this international, multicentre, open-label, non-inferiority, phase 3, randomised SIOP WT 2001 trial, we recruited children aged 6 months to 18 years at the time of diagnosis of a primary renal tumour from 251 hospitals in 26 countries who had received 4 weeks of preoperative chemotherapy with vincristine and actinomycin D. Children with stage II-III intermediate-risk Wilms' tumours assessed after delayed nephrectomy were randomly assigned (1:1) by a minimisation technique to receive vincristine 1·5 mg/m(2) at weeks 1-8, 11, 12, 14, 15, 17, 18, 20, 21, 23, 24, 26, and 27, plus actinomycin D 45 µg/kg every 3 weeks from week 2, either with five doses of doxorubicin 50 mg/m(2) given every 6 weeks from week 2 (standard treatment) or without doxorubicin (experimental treatment). The primary endpoint was non-inferiority of event-free survival at 2 years, analysed by intention to treat and a margin of 10%. Assessment of safety and adverse events included systematic monitoring of hepatic toxicity and cardiotoxicity. This trial is registered with EudraCT, number 2007-004591-39, and is closed to new participants. FINDINGS: Between Nov 1, 2001, and Dec 16, 2009, we recruited 583 patients, 341 with stage II and 242 with stage III tumours, and randomly assigned 291 children to treatment including doxorubicin, and 292 children to treatment excluding doxorubicin. Median follow-up was 60·8 months (IQR 40·8-79·8). 2 year event-free survival was 92·6% (95% CI 89·6-95·7) for treatment including doxorubicin and 88·2% (84·5-92·1) for treatment excluding doxorubicin, a difference of 4·4% (95% CI 0·4-9·3) that did not exceed the predefined 10% margin. 5 year overall survival was 96·5% (94·3-98·8) for treatment including doxorubicin and 95·8% (93·3-98·4) for treatment excluding doxorubicin. Four children died from a treatment-related toxic effect; one (<1%) of 291 receiving treatment including doxorubicin died of sepsis, three (1%) of 292 receiving treatment excluding doxorubicin died of varicella, metabolic seizure, and sepsis during treatment for relapse. 17 patients (3%) had hepatic veno-occlusive disease. Cardiotoxic effects were reported in 15 (5%) of 291 children receiving treatment including doxorubicin. 12 children receiving treatment including doxorubicin, and ten children receiving treatment excluding doxorubicin, died, with the remaining deaths from tumour recurrence. INTERPRETATION: Doxorubicin does not need to be included in treatment of stage II-III intermediate risk Wilms' tumour when the histological response to preoperative chemotherapy is incorporated into the risk stratification. FUNDING: See Acknowledgments for funders.

Improvements in the Treatment of Patients Suffering from Bladder-Prostate Rhabdomyosarcoma: A Report from the CWS-2002P Trial.

PURPOSE: Modern treatment concepts for bladder/prostate rhabdomyosarcoma (BPRMS) are designed to improve survival, to reduce therapy intensity, and to increase bladder preservation rates. Nevertheless, treatment is not optimal. The purpose of this study was to analyze BPRMS patients treated within the CWS-2002P trial regarding outcome, treatment modalities, complications, and to compare the data with the precursor trial CWS-96. METHODS: Fifty children with localized embryonal BPRMS were analyzed. Eight patients were excluded. Patients received neoadjuvant chemotherapy. At week 9, reassessment using MRI scan was performed. Depending on tumor size, age, and response, local therapy consisting of radiotherapy and/or surgery was initiated. After local therapy, systemic therapy was continued. RESULTS: Patients' median age was 35.6 months. Median follow-up was 59 months. The 5-year OS was 84.5 % and the 5-year ES 79.9 %. Ten patients underwent combined radiochemotherapy and tumor resection (5-year ES: 87.5 %). Six patients were treated solely with radiochemotherapy (5-year ES: 60 %). Twenty-six patients received preoperative chemotherapy followed by tumor resection (ES: 80.8). One patient was treated with chemotherapy only and survived. The bladder preservation rate was 80.9 %. CONCLUSIONS: The outcome within the CWS-2002P trial regarding OS and ES seemed to be better than in the precursor trial CWS-96 due to a reduction of protocol violations, but there was no statistical significant difference possibly due to low numbers. Radiotherapy was used less frequently, and the bladder preservation rate was slightly higher. Novel concepts will be required in the future to improve bladder preservation rates.