Case report: value of gene expression profiling in the diagnosis of atypical neuroblastoma

BACKGROUND: Nephroblastoma and neuroblastoma belong to the most common abdominal malignancies in childhood. Similarities in the initial presentation may provide difficulties in distinguishing between these two entities, especially if unusual variations to prevalent patterns of disease manifestation occur. Because of the risk of tumor rupture, European protocols do not require biopsy for diagnosis, which leads to misdiagnosis in some cases. CASE PRESENTATION: We report on a 4½-year-old girl with a renal tumor displaying radiological and laboratory characteristics supporting the diagnosis of nephroblastoma. Imaging studies showed tumor extension into the inferior vena cava and bilateral lung metastases while urine catecholamines and MIBG-scintigraphy were negative. Preoperative chemotherapy with vincristine, actinomycine D and adriamycin according to the SIOP2001/GPOH protocol for the treatment of nephroblastoma was initiated and followed by surgical tumor resection. Histopathology revealed an undifferentiated tumor with expression of neuronal markers, suggestive of neuroblastoma. MYCN amplification could not be detected. DNA-microarray analysis was performed using Affymetrix genechip human genome U133 plus 2.0 and artificial neural network analysis. Results were confirmed by multiplex RT-PCR. RESULTS: Principal component analysis using 84 genes showed that the patient sample was clearly clustering with neuroblastoma tumors. This was confirmed by hierarchical clustering of the multiplex RT-PCR data. The patient underwent treatment for high-risk neuroblastoma comprising chemotherapy including cisplatin, etoposide, vindesine, dacarbacine, ifosfamide, vincristine, adriamycine and autologous stem cell transplantation followed by maintenance therapy with 13-cis retinoic acid (GPOH NB2004 High Risk Trial Protocol) and is in complete long-term remission. CONCLUSION: The use of gene expression profiling in an individual patient strongly contributed to clarification in a diagnostic dilemma which finally led to a change of diagnosis from nephroblastoma to neuroblastoma. This case underlines the importance of gene-expression profiling in the correct diagnosis of childhood neoplasms with atypical presentation to ensure that adequate treatment regimens can be applied

Phase I/II Study of the WEE1 Inhibitor Adavosertib (AZD1775) in Combination with Carboplatin in Children with Advanced Malignancies: Arm C of the AcSé-ESMART Trial

International audienceAbstract Purpose: AcSé-ESMART Arm C aimed to define the recommended dose and activity of the WEE1 inhibitor adavosertib in combination with carboplatin in children and young adults with molecularly enriched recurrent/refractory malignancies. Patients and Methods: Adavosertib was administered orally, twice every day on Days 1 to 3 and carboplatin intravenously on Day 1 of a 21-day cycle, starting at 100 mg/m2/dose and AUC 5, respectively. Patients were enriched for molecular alterations in cell cycle and/or homologous recombination (HR). Results: Twenty patients (median age: 14.0 years; range: 3.4–23.5) were included; 18 received 69 treatment cycles. Dose-limiting toxicities were prolonged grade 4 neutropenia and grade 3/4 thrombocytopenia requiring transfusions, leading to two de-escalations to adavosertib 75 mg/m2/dose and carboplatin AUC 4; no recommended phase II dose was defined. Main treatment-related toxicities were hematologic and gastrointestinal. Adavosertib exposure in children was equivalent to that in adults; both doses achieved the cell kill target. Overall response rate was 11% (95% confidence interval, 0.0–25.6) with partial responses in 2 patients with neuroblastoma. One patient with medulloblastoma experienced unconfirmed partial response and 5 patients had stable disease beyond four cycles. Seven of these eight patients with clinical benefit had alterations in HR, replication stress, and/or RAS pathway genes with or without TP53 alterations, whereas TP53 pathway alterations alone (8/10) or no relevant alterations (2/10) were present in the 10 patients without benefit. Conclusions: Adavosertib–carboplatin combination exhibited significant hematologic toxicity. Activity signals and identified potential biomarkers suggest further studies with less hematotoxic DNA-damaging therapy in molecularly enriched pediatric cancers

The European MAPPYACTS Trial: Precision Medicine Program in Pediatric and Adolescent Patients with Recurrent Malignancies

International audienceMAPPYACTS (NCT02613962) is an international prospective precision medicine trial aiming to define tumor molecular profiles in pediatric patients with recurrent/refractory malignancies in order to suggest the most adapted salvage treatment. From February 2016 to July 2020, 787 patients were included in France, Italy, Ireland, and Spain. At least one genetic alteration leading to a targeted treatment suggestion was identified in 436 patients (69%) with successful sequencing; 10% of these alterations were considered ``ready for routine use.'' Of 356 patients with follow-up beyond 12 months, 107 (30%) received one or more matched targeted therapies-56% of them within early clinical trials-mainly in the AcSe-ESMART platform trial (NCT02813135). Overall, matched treatment resulted in a 17% objective response rate, and of those patients with ready for routine use alterations, it was 38%. In patients with extracerebral tumors, 76% of actionable alterations detected in tumor tissue were also identified in circulating cell-free DNA (cfDNA)