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TW2003, the third Italian prospective study on Wilms tumor, aimed to improve survival in patients with stage III-IV tumors, de-escalate therapy for stage I-II nonanaplastic tumors, refine the risk stratification of therapy, and develop a national infrastructure for biobanking and central pathology review.TW2003 recruited children 18 years old or younger with primary intrarenal tumors. Local physicians chose nephrectomy with or without preoperative chemotherapy as the initial treatment based on the risk of unsafe and/or incomplete immediate surgery. The main drivers for adjuvant therapy were tumor stage and diffuse anaplasia. A new risk stratification schema was investigated, incorporating patient age, reason for stage III designation and completeness of lung nodule response in stage IV disease.We report on 453 patients with unilateral Wilms tumor. Preoperative chemotherapy was administered to 42% of patients. The 5-year event-free survival and overall survival rates were 89.1% (95% CI 83.6-94.9) and 97.0% (93.7-100) for stage I; 85.1% (79.6-91.1) and 94.0% (90.1-98.1) for stage II (160); 82.7% (75.3-90.8) and 90.9% (85.0-97.1) for stage III (101); and 72.1% (61.9-84.0) and 82.5% (73.1-93.1) for stage IV (69), respectively. On multivariable analysis only anaplasia was significant for event-free survival (HR 2.68, 95% CI 1.48-4.86, p=0.001; bias corrected c-index 0.580) and overall survival (HR 5.29, 95% CI 2.52-11.12, p0.001; bias corrected c-index 0.697).The survival rates achieved and the proposed risk stratification schema provide a basis for future comparisons of Wilms tumor treatment burden and patient outcome.

// Annalisa Astolfi 1, 2 , Fraia Melchionda 2 , Daniela Perotti 3 , Maura Fois 2 , Valentina Indio 1 , Milena Urbini 1, 2 , Chiara Giusy Genovese 1 , Paola Collini 4 , Nunzio Salfi 5 , Marilina Nantron 6 , Paolo D’Angelo 7 , Filippo Spreafico 8 , Andrea Pession 2 1 “Giorgio Prodi” Cancer Research Center, University of Bologna, Bologna, Italy 2 Pediatric Hematology and Oncology Unit, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy 3 Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy 4 Soft Tissue and Bone Pathology, Histopathology, and Pediatric Pathology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy 5 Pathology Unit, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy 6 Department of Pediatric Hematology and Oncology, Istituto G. Gaslini, Genova, Italy 7 Pediatric Hematology and Oncology Unit, A.R.N.A.S. Civico, Di Cristina and Benfratelli Hospital, Palermo, Italy 8 Pediatric Oncology Unit, Department of Hematology and Pediatric Onco-Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy Correspondence to: Fraia Melchionda, e-mail: fraia.melchionda@aosp.bo.it Keywords: CCSK, whole transcriptome sequencing, BCOR Received: August 10, 2015 Accepted: September 28, 2015 Published: October 22, 2015 ABSTRACT Purpose: Clear cell sarcoma of the kidney (CCSK) is a rare pediatric renal tumor that is frequently difficult to distinguish among other childhood renal tumors due to its histological heterogeneity. This work evaluates genetic abnormalities carried by a series of CCSK samples by whole transcriptome sequencing (WTS), to identify molecular biomarkers that could improve the diagnostic process. Methods: WTS was performed on tumor RNA from 8 patients with CCSK. Bioinformatic analysis, with implementation of a pipeline for detection of intragenic rearrangements, was executed. Sanger sequencing and gene expression were evaluated to validate BCOR internal tandem duplication (ITD). Results: WTS did not identify any shared SNVs, Ins/Del or fusion event. Conversely, analysis of intragenic rearrangements enabled the detection of a breakpoint within BCOR transcript recurrent in all samples. Three different in-frame ITD in exon15 of BCOR, were detected. The presence of the ITD was confirmed on tumor DNA and cDNA, and resulted in overexpression of BCOR. Conclusion: WTS coupled with specific bioinformatic analysis is able to detect rare genetic events, as intragenic rearrangements. ITD in the last exon of BCOR is recurrent in all CCSK samples analyzed, representing a valuable molecular marker to improve diagnosis of this rare childhood renal tumor.

Background Children with Wilms’ tumor (WT) aged under 24 months (infants) have a better prognosis than older patients. Our aim was to study the epidemiology of this age group, with focus on the modality of diagnosis, tumor size, and association with malformations/syndromes, seeking to understand if any of these factors might be related to prognosis. Patients and methods Infants diagnosed with WT between 2003 and February 2010 were evaluated. A query form was used to collect data on the modality of WT diagnosis (symptomatic or incidental), tumor volume, maximum diameter, site, and stage. Results Data were collected for 117 of 124 WT infants registered. Twenty-four cases had an incidental diagnosis (ID) of renal mass, usually arising from an abdominal ultrasound performed for other reasons, and 93 had been diagnosed based on clinical signs/symptoms. The incidental cohort displayed unifocal disease, mean tumor diameter 5.52 cm, mean tumor volume 84.30 ml, and 14 patients showed associated malformations. Symptomatic patients had mean maximum tumor diameter of 10.18 cm, mean tumor volume of 451.18 ml, and six had associated malformations. Conclusions Our study showed that 20% of the infants had an ID of WT; they had a relatively smaller nonmetastatic tumor and a higher rate of malformations than infants of the symptomatically diagnosed group, but we did not detect any difference in age at diagnosis between the two groups. Conversely, we found a significant difference in the 5-year event-free survival rate (P = 0.018) between infants under 1 year (96%), more frequently associated with congenital malformations, and infants 1–2 years (80%).

Despite the excellent survival rate of Wilms tumor (WT) patients, only approximately one-half of children who suffer tumor recurrence reach second durable remission. This underlines the need for novel markers to optimize initial treatment. We investigated 77 tumors using Illumina 370CNV-QUAD genotyping BeadChip arrays and compared their genomic profiles to detect copy number (CN) abnormalities and allelic ratio anomalies associated with the following clinicopathological variables: relapse (yes vs. no), age at diagnosis (≤24 months vs. >24 months), and disease stage (low stage, I and II, vs. high stage, III and IV). We found that CN gains at chromosome region 1q21.1-q31.3 were significantly associated with relapse. Additional genetic events, including allelic imbalances at chromosome arms 1p, 1q, 3p, 3q, and 14q were also found to occur at higher frequency in relapsing tumors. Interestingly, allelic imbalances at 1p and 14q also showed a borderline association with higher tumor stages. No genetic events were found to be associated with age at diagnosis. This is the first genome wide analysis with single nucleotide polymorphism (SNP) arrays specifically investigating the role of genetic anomalies in predicting WT relapse on cases prospectively enrolled in the same clinical trial. Our study, besides confirming the role of 1q gains, identified a number of additional candidate genetic markers, warranting further molecular investigations. © 2012 Wiley Periodicals, Inc.

BACKGROUND Intracranial immature teratomas (IT) are very rare germ cell tumors (GCT). The value of chemotherapy in their treatment has not been defined. METHODS A child was referred to our hospital for consultation regarding the need for adjuvant treatment after being operated upon twice (at the age of 7 months and 11 months) for a large supratentorial intracerebral mass. The patient was staged and the tumor specimens reviewed. Histology was that of an IT with no other type of malignant GCT. RESULTS Considering the age, lack of any sign of residual tumor by computed tomography and magnetic resonance imaging, absence of tumor cells in the spinal fluid or elevation of tumor markers, and based on the reported poor response of such tumors to chemotherapy, a policy of “wait and see” was adopted. One month later, the child presented with a rapidly growing intracranial mass invading the cranial bones on the left side. Chemotherapy consisting of 4 cycles of carboplatin, etoposide, and bleomycin followed by another 4 cycles of ifosfamide, vincristine, and dactinomycin alternating with carboplatin and etoposide, achieved complete remission, and 24 months after discontinuation of treatment, the patient continued free of disease. CONCLUSIONS This report indicates that chemotherapy may be effective therapy for intracranial IT. In our patient, chemotherapy modified the natural aggressive behavior of this disease and achieved a persistent, complete remission. Given the minimal information available in the literature concerning the response of IT to chemotherapy, this case addresses the issue of whether chemotherapy alone is adequate to treat intracranial germ cell tumors. Cancer 1996;77:977-82.

Neuroblastoma, a tumor of post-ganglionic sympathetic neurons, may be associated with a variety of genetic defects and congenital malformations (1). We report a case of neuroblastoma (NB) stage IV-S (2) in an infant with bilateral microphthalmia and other ocular malformations.