Paolo D'Angelo

Disseminated Neuroblastoma in Children Older Than One Year at Diagnosis: Comparable Results With Three Consecutive High-Dose Protocols Adopted by the Italian Co-Operative Group for Neuroblastoma

PURPOSE To compare the outcomes associated with modifications in three consecutive protocols employed by the Italian Co-Operative Group for Neuroblastoma (ICGNB) in disseminated neuroblastoma. PATIENTS AND METHODS Between January 1985 and November 1997, a total of 359 children aged 1 to 15 years with newly diagnosed stage 4 neuroblastoma were enrolled in three consecutive protocols. Compared with ICGNB-85, the ICGNB-89 protocol contained two more chemotherapy cycles, and some drugs were given at greater doses, whereas in the ICGNB-92 protocol, the induction phase included a chelating agent, and individual cycles contained four drugs instead of two. RESULTS A total of 330 of 359 evaluable children were included in this analysis; 106 children were treated with ICGNB-85, 65 children were treated with ICGNB-89, and 159 children were treated with ICGNB-92 protocols. Radical resection of primary tumor was carried out in 59.4%, 50.8%, and 57.9% of the patients, respectively. Major tumor response after induction therapy was achieved in 66.7%, 69.2%, and 68.6% of the patients, respectively. A total of 218 of 232 patients received consolidation therapy consisting of conventional chemotherapy in 65 patients and of high-dose chemotherapy in 153 patients. Disease recurrence or progression occurred in 82.1%, 69.2%, and 74.8% of the patients, respectively. Therapy-related deaths occurred in 1.9%, 12.3%, and 6.9% of the patients, respectively. Five-year overall survival (OS) for the three studies was 26%, 23%, and 28%, and event-free survival (EFS) was 19%, 17%, and 17%, respectively. CONCLUSION The therapeutic modifications adopted in the ICGNB-89 and ICGNB-92 protocols were not associated with a significant improvement in response rate or in the 5-year OS and EFS as compared with the ICGNB-85 protocol. Attempts at intensifying chemotherapy were associated with greater toxicity.

Improved Survival of Children With Neuroblastoma Between 1979 and 2005: A Report of the Italian Neuroblastoma Registry

PURPOSE To describe treatment, clinical course, and survival of a cohort of Italian patients with neuroblastoma. PATIENTS AND METHODS The study includes data from 2,216 children (age 0 to 14 years) diagnosed between 1979 and 2005. Overall survival (OS) was analyzed by clinical and biologic features at presentation and periods of diagnosis: 1979 to 1984, 1985 to 1991, 1992 to 1998, and 1999 to 2005. The relative risk of second malignant neoplasm (SMN) was assessed by the standardized incidence ratio (SIR), with the Italian population selected as referent. RESULTS Yearly patient accrual increased over time from 58 to 102. Patients age 0 to 17 months represented 45.6% of the total population, and their incidence increased over time from 36.5% to 48.5%. The incidence of stage 1 patients increased over time from 5.8% to 23.2%. A total of 898 patients (40.5%) developed disease progression or relapse, 19 patients developed SMN, and two patients developed myelodysplasia. The cumulative risk of SMN at 20 years was 7.1%, for an SIR of 8.4 (95% CI, 5.1 to 13.2). A total of 858 patients (39%) died (779 of disease, 71 of toxicity, six of SMN, and two of tumor-unrelated surgical complications). Ten-year OS was 55.3% (95% CI, 53.0% to 57.6%) and increased over time from 34.9% to 65.0%; it was significantly better for females and patients age 0 to 17 months at diagnosis, with extra-abdominal primary, and stage 1 and 2 disease. OS improved significantly over time in stage 1 and 3 patients. In patients with stage 4 disease, the improvement occurred between the first and second time cohorts (6.7% v 23.5%), but not afterward. CONCLUSION The outcome of children with neuroblastoma has progressively improved. Long-term survivors bear a significant risk of SMN.

Soft-tissue sarcomas in children and adolescents with neurofibromatosis type 1

Patients affected by neurofibromatosis type 1 (NF1) are at higher risk of developing soft‐tissue sarcomas (STS) than the general population. The clinical findings and outcome in 43 children and adolescents with NF1 treated for STS in the Italian protocols between 1988 and 2004 are reported.

Pancreatic tumors in children and adolescents: the Italian TREP project experience.

Malignant pancreatic tumors are exceedingly rare in pediatric age and their clinical features and treatment usually go unappreciated by most pediatric oncologists and surgeons.

Teratoma with a malignant somatic component in pediatric patients: The Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) experience

Teratoma with a malignant somatic component (TMSC) is rare but described in adults, whereas information on pediatric presentation is sparse.

Whole transcriptome sequencing identifies BCOR internal tandem duplication as a common feature of clear cell sarcoma of the kidney

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.

Genomic profiling by whole-genome single nucleotide polymorphism arrays in Wilms tumor and association with relapse

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.

Loss of Heterozygosity Analysis at Different Chromosome Regions in Wilms Tumor Confirms 1p Allelic Loss as a Marker of Worse Prognosis: A Study from the Italian Association of Pediatric Hematology and Oncology

PURPOSE The specific aims of the AIEOP-TW-2003 protocol included prospectively investigating a possible association of tumor loss of heterozygosity with outcomes in children treated for Wilms tumor. MATERIALS AND METHODS We analyzed 125 unilateral favorable histology Wilms tumors registered between 2003 and 2008 in the Italian cooperative protocol for microsatellite markers mapped to chromosomes 1p, 7p, 11q, 16q and 22q. RESULTS The 3-year disease-free survival and overall survival probabilities were 0.87 (95% CI 0.81-0.93) and 0.98 (95% CI 0.96-1.0), respectively. Loss of heterozygosity at 1p was significantly associated with a worse disease-free survival (probability 0.67 for patients with and 0.92 for those without 1p loss of heterozygosity, p = 0.0009), as confirmed also by multivariate analysis adjusting for tumor stage and patient age at diagnosis. There was no difference in disease-free survival probability among children with loss of heterozygosity in the other chromosomal regions tested. The worse outlook for children older than 2 years at diagnosis did not seem to be influenced by the loss of heterozygosity patterns considered. CONCLUSIONS Chromosome 1p loss of heterozygosity seems to be a risk factor for nonanaplastic Wilms tumor, possibly regardless of other clinical factors. Our findings were uninformative regarding loss of heterozygosity in the other chromosomal regions tested.

Prognostic value of ferritin, neuron-specific enolase, lactate dehydrogenase, and urinary and plasmatic catecholamine metabolites in children with neuroblastoma.

Different plasma and urinary parameters have been tested as valuable prognostic markers for children with neuroblastoma (NB), but conclusive results from multivariate analyses are still lacking. Samples collected at diagnosis from 505 patients diagnosed in Italy between June 1994 and November 2010 were analyzed at the Italian reference laboratory according to standard methodologies. Patient clinical data were retrieved from the Italian NB Registry. For statistical analysis, patients were grouped according to stage, age, MYCN status, and outcome. Cumulative survival was calculated by the Kaplan–Meier procedure using the first quartile of the marker distribution as a cut-off value to stratify the patients. Multivariate analysis was performed by the Cox regression model by considering only the significant variables. When the entire cohort of patients was considered, none of the different parameters had an independent prognostic value. However, in patients with localized disease without MYCN amplification the significant positive associations between urinary and plasmatic vanillylmandelic acid (VMA)/homovanillic acid (HVA) ratio and a better prognosis remained significant (P < 0.05 and P < 0.01, respectively), as well as, the positive association between high lactate dehydrogenase (LDH) values and a worse prognosis (P < 0.001). Moreover, in stage 4 patients without MYCN amplification, neuron-specific enolase levels above 200 ng/mL and LDH levels above 2500 IU/mL maintained their significant association with a worse outcome (P = 0.01 and P = 0.0001, respectively). In conclusion, LDH had an independent prognostic value in patients of all stages without MYCN amplification. Moreover, the urinary and plasmatic VMA/HVA ratio was an independent predictor of prognosis in patients with localized disease without MYCN amplification. Since LDH and catecholamine metabolites are measured in all patients at diagnosis, these findings may be helpful for an easy, cost-effective, patient risk stratification.

Mature and immature teratoma: A report from the second Italian pediatric study.

Teratomas demonstrate a benign clinical behavior, however they may recur with malignant components or as teratoma, and in a small group of patients prognosis could be fatal. After the first Italian study, we collected cases of teratoma, alongside the protocol for malignant germ cell tumors.