No abstract

Genome-wide expression profiles can partition large tumor cohorts into subgroups that are enriched for specific genetic alterations. This approach may assist ultimately in the selection of patients for future clinical trials of molecular targeted therapies.

Soft tissue undifferentiated round cell sarcoma (URCS) occurring in infants is a heterogeneous group of tumors, often lacking known genetic abnormalities. Based on a t(10;17;14) karyotype in a pelvic URCS of a 4-month-old boy showing similar breakpoints with clear cell sarcoma of kidney (CCSK), we have investigated the possibility of shared genetic abnormalities in CCSK and soft tissue URCS. Most CCSK are characterized by BCOR exon 16 internal tandem duplications (ITD), while a smaller subset shows YWHAE-NUTM2B/E fusions. Due to overlapping clinicopathologic features, we have also investigated these genetic alterations in the so-called primitive myxoid mesenchymal tumor of infancy (PMMTI). Among the 22 infantile URCS and 7 PMMTI selected, RNA sequencing (RNAseq) was performed in 5 and 2 cases, with frozen tissue, respectively. The remaining cases with archival material were tested for YWHAE-NUTM2B/E by FISH or RT-PCR, and BCOR ITD by PCR. A control group of 4 CCSK, 14 URCS in older children or adults without known gene fusion, and 20 other sarcomas with similar histomorphology or age at presentation were also tested. A YWHAE-NUTM2B fusion was confirmed in the index case by FISH and RT-PCR, while lacking BCOR ITD. An identical YWHAE-NUTM2B fusion was found in another URCS case of a 5-month-old girl from the back. The remaining cases and control group lacked YWHAE gene rearrangements; instead, consistent BCOR ITD, similar to CCSK, were found in 15/29 (52%) infantile sarcoma cases (9/22 infantile URCS and 6/7 PMMTI). In the control cohort, BCOR ITD was found only in 3 CCSK but not in the other sarcomas. Histologically, URCS with both genotypes and PMMTI shared significant histologic overlap, with uniform small blue round cells with fine chromatin and indistinct nucleoli. A prominent capillary network similar to CCSK, rosette structures and varying degree of myxoid change were occasionally seen. BCOR ITD positive tumors occurred preferentially in the somatic soft tissue of trunk, abdomen and head and neck, sparing the extremities. RNAseq showed high BCOR mRNA levels in BCOR ITD-positive cases, compared to other URCSs. In summary, we report recurrent BCOR exon 16 ITD and YWHAE-NUTM2B fusions in half of infantile soft tissue URCS and most PMMTI, but not in other pediatric sarcomas. These findings suggest a significant overlap between infantile URCS and CCSK, such as age at presentation, histologic features and genetic signature; thus raising the possibility of a soft tissue counterpart to CCSK.

Central and rapid molecular analysis of frozen medulloblastomas collected from multiple institutions is feasible. ERBB2 expression and clinical risk factors together constitute a highly accurate disease risk stratification tool.

Forty-one percent of surviving patients and 50% of all patients were treated successfully with chemotherapy only without irradiation. Chemotherapy-only regimens for CNS GCT, although encouraging, should continue to be used only in the setting of formal clinical trials.

PURPOSE SJMB03 (ClinicalTrials.gov identifier: NCT00085202 ) was a phase III risk-adapted trial that aimed to determine the frequency and clinical significance of biological variants and genetic alterations in medulloblastoma. PATIENTS AND METHODS Patients 3-21 years old were stratified into average-risk and high-risk treatment groups based on metastatic status and extent of resection. Medulloblastomas were molecularly classified into subgroups (Wingless [WNT], Sonic Hedgehog [SHH], group 3, and group 4) and subtypes based on DNA methylation profiles and overlaid with gene mutations from next-generation sequencing. Coprimary study end points were (1) to assess the relationship between ERBB2 protein expression in tumors and progression-free survival (PFS), and (2) to estimate the frequency of mutations associated with WNT and SHH tumors. Clinical and molecular risk factors were evaluated, and the most robust were used to model new risk-classification categories. RESULTS Three hundred thirty eligible patients with medulloblastoma were enrolled. Five-year PFS was 83.2% (95% CI, 78.4 to 88.2) for average-risk patients (n = 227) and 58.7% (95% CI, 49.8 to 69.1) for high-risk patients (n = 103). No association was found between ERBB2 status and PFS in the overall cohort ( P = .74) or when patients were stratified by clinical risk ( P = .71). Mutations in CTNNB1 (96%), DDX3X (37%), and SMARCA4 (24%) were most common in WNT tumors and PTCH1 (38%), TP53 (21%), and DDX3X (19%) in SHH tumors. Methylome profiling classified 53 WNT (17.4%), 48 SHH (15.7%), 65 group 3 (21.3%), and 139 group 4 (45.6%) tumors. A comprehensive clinicomolecular risk factor analysis identified three low-risk groups (WNT, low-risk SHH, and low-risk combined groups 3 and 4) with excellent (5-year PFS > 90%) and two very high-risk groups (high-risk SHH and high-risk combined groups 3 and 4) with poor survival (5-year PFS < 60%). CONCLUSION These results establish a new risk stratification for future medulloblastoma trials.

Weekly vinblastine seems to be a reasonable alternative to radiation for pediatric patients with LGG who have experienced treatment failure with first-line chemotherapy. The 5-year progression-free survival observed in this phase II trial is comparable to results observed with first-line chemotherapy in chemotherapy-naive patients. The role of single-agent vinblastine and other vinca alkaloid in the management of pediatric LGGs deserves further investigation.

Cisplatin in higher doses have been used routinely in the treatment of childhood tumours including neuroblastoma and germ cell tumors. Amifostine, a broad-spectrum cytoprotector of normal tissues, has been approved by U.S. Food and Drug Administration for use in patients receiving cisplatin. Such administration of amifostine has been reported to reduce cisplatin-related toxicities in some studies, but not all. The authors report a case of severe toxicity with cisplatin in a girl with epithelial cell carcinoma of the ovary despite the use of amifostine.