Jennifer Reichek

Genomic and clinical analysis of amplification of the 13q31 chromosomal region in alveolar rhabdomyosarcoma: a report from the Children's Oncology Group

Purpose: This study determined the molecular characteristics and clinical significance of amplification of the 13q31 chromosomal region in alveolar rhabdomyosarcoma (ARMS), an aggressive pediatric cancer with frequent PAX3-FOXO1 and PAX7-FOXO1 gene fusions. Experimental Design: The 13q31 amplicon was localized in an initial panel of ARMS cases using oligonucleotide arrays. A fluorescence in situ hybridization assay for this localized region was designed, and applied to more ARMS cases to determine the frequency and distribution of amplification. Quantitative reverse transcription-PCR assays were applied to measure gene expression. The clinical significance of copy number and expression was determined with Kaplan–Meier and Cox proportional hazard models. Results: We localized the 13q31 amplicon to a 0.15 Mb region containing the MIR17HG gene encoding the polycistronic microRNA cluster, miR-17–92. This amplicon is present in 23% of ARMS cases with a marked preference for PAX7-FOXO1-positive cases. In tumors with 13q31 amplification, there is significantly increased expression of 5 of 6 microRNAs within the miR-17–92 cluster (miR-17, miR-19a, miR-19b, miR-20a, and miR-92a). In addition, a subset of nonamplified tumors with copy number-independent overexpression of all 6 microRNAs was identified. In clinical analyses, there was a significantly worse outcome associated with increased expression of the 5 microRNAs described above in 13q31-amplified cases when compared to nonamplified cases. There was also an improved outcome in 13q31-amplified cases with lower expression of these microRNAs. Conclusions: 13q31 amplification and expression of the miR-17–92 cluster provide novel markers for identifying good and poor prognostic subsets of PAX7-FOXO1-positive ARMS. Clin Cancer Res; 17(6); 1463–73. ©2011 AACR.

What is New in Rhabdomyosarcoma Management in Children

Optimal management of rhabdomyosarcoma requires establishing the correct pathologic diagnosis, histologic sub-type, primary site, extent of disease (Stage), and extent of resection (Group). Based on these features, cooperative groups in North America and Europe have defined risk-adapted treatments that include surgery, chemotherapy, and usually radiotherapy. This article focuses on recent findings that can impact or have already impacted rhabdomyosarcoma treatment guidelines and highlights controversies that should be addressed in order to improve outcome for children with rhabdomyosarcoma.Rhabdomyosarcoma is currently sub-classified in children based on histology into the favorable embryonal/botryoid/spindle cell types and the unfavorable alveolar form. Risk group assignment depends in part on histologic sub-type. Alveolar rhabdomyosarcoma is sometimes associated with chromosomal translocations, which impact clinical behavior. An important ongoing debate is whether molecular diagnostic tools to identify chromosomal translocations and/or define gene expression profiles should be used to sub-classify rhabdomyosarcoma rather than histology. Clinical trials continue to evaluate retrospective as well as prospective cohorts in order to carefully determine the impact of histology versus biologic features on outcome in the context of specific therapeutic regimens.Most rhabdomyosarcoma recurrences involve the primary site or adjacent region. Cooperative groups continue to investigate new approaches to local control in order to reduce local recurrences and sequelae associated with local therapy. Delaying primary resection until after chemotherapy has started appears to increase the number of tumors that can be completely resected with acceptable morbidity in some primary sites. Radiation dose reductions following delayed primary resection have been investigated. Although outcomes appear similar to the conventional approach of full-dose radiotherapy without delayed primary resection, long-term effects of the two approaches have not been rigorously compared. Early evidence suggests that newer methods of delivering radiotherapy, including intensity-modulated radiotherapy (IMRT), proton beam radiotherapy, and brachytherapy maintain efficacy but may reduce long-term sequelae compared with 3-dimensional conformal radiotherapy.Chemotherapy regimens defined by the cooperative groups vary by risk group. The most commonly used regimens include vincristine and dactinomycin in combination with an alkylating agent, either cyclophosphamide or ifosfamide. In order to improve outcomes, recent clinical trials have introduced new chemotherapeutic agents (e.g. topotecan, carboplatin, or epirubicin) into the treatment regimens. However, outcomes have not been significantly impacted. Novel chemotherapy administration schedules have been tested in patients with metastatic rhabdomyosarcoma, including interval compressed dosing or maintenance therapy, and may be promising. Molecularly targeted agents are currently under investigation in combination with chemotherapy for patients with recurrent or metastatic rhabdomyosarcoma. It is hoped that these novel agents will benefit all patients with rhabdomyosarcoma in the future.

Gemcitabine with or without docetaxel and resection for recurrent osteosarcoma: the experience at Children's Memorial Hospital.

It remains unclear how to optimally incorporate gemcitabine and docetaxel into the management of patients with recurrent osteosarcoma. We describe 4 pediatric patients with recurrent osteosarcoma who were treated with gemcitabine±docetaxel and resection. One patient had a partial response and 2 had stable disease. Two patients subsequently underwent surgical resections. Median duration of response was 8 months and was longer for patients who underwent resection. One patient remains disease-free 57 months from recurrence. Our limited series provides additional support for the use of gemcitabine±docetaxel for recurrent osteosarcoma and suggests benefit of concurrent local control measures if possible.

Clinical research participation among adolescent and young adults at an NCI-designated Comprehensive Cancer Center and affiliated pediatric hospital

PurposeMinimal clinical trial participation among adolescents and young adults (AYAs) with cancer limits scientific progress and ultimately their clinical care and outcomes. These analyses examine the current state of AYA clinical research participation at a Midwestern comprehensive cancer center and affiliated pediatric hospital to advise program development and increase availability of trials and AYA participation. Enrollment is examined across all diagnoses, the entire AYA age spectrum (15–39), and both cancer therapeutic and supportive care protocols.Methodshis study was a retrospective review of electronic medical records via existing databases and registries for all AYAs. Data were collected for AYAs seen by an oncologist at the adult outpatient cancer center or at the pediatric hospital between the years 2010 and 2014. Descriptive statistics and logistic regression analyses were conducted to characterize this sample.ResultsIn the pediatric setting, 42.3% of AYAs were enrolled in a study compared to 11.2% in the adult setting. Regression analyses in the pediatric setting revealed that AYAs with private insurance or Caucasian race were more likely to participate. Within the adult setting, ethnicity, race, insurance, and diagnosis were associated with study participation; 54.8% of study enrollments were for cancer therapeutic and 43.4% for supportive care studies.ConclusionsThese results are comparable to previously published data and support the need for new local and national AYA initiatives to increase the availability of and enrollment in therapeutic clinical trials. The same is true for supportive care studies which play a crucial role in improving quality of life.

Longitudinal Characterization of Herpes Simplex Virus (HSV) Isolates Acquired From Different Sites in an Immune-Compromised Child: A New HSV Thymidine Kinase Mutation Associated With Resistance

BACKGROUND Herpes simplex virus resistance to acyclovir is well described in immune-compromised patients. Management of prolonged infection and recurrences in such patients may be problematic. METHODS A patient with neuroblastoma developed likely primary herpes gingivostomatitis shortly after starting a course of chemotherapy, with spread to the eye during treatment with acyclovir. Viral isolates were serially obtained from separate sites after treatment was begun and tested for susceptibility to acyclovir and foscarnet by plaque reduction and plating efficiency assays. The thymidine kinase and DNA polymerase genes from each isolate were sequenced. RESULTS Initial isolates from a throat swab, an oral lesion, and conjunctiva were resistant to acyclovir within 13 days of treatment. Subsequent isolates while on foscarnet were initially acyclovir-susceptible, but reactivation of an acyclovir-resistant isolate was subsequently documented while on acyclovir suppression. Genotypic analysis identified a previously unreported UL23 mutation in some resistant isolates. None of the amino acid changes identified in UL30 were associated with resistance. CONCLUSIONS Phenotypic and genotypic antiviral resistance of herpes simplex isolates may vary from different compartments and over time in individual immune-compromised hosts, highlighting the importance of obtaining cultures from all sites. Phenotypic resistance testing should be considered for isolates obtained from at-risk patients not responding to first-line therapy. Empiric combination treatment with multiple antivirals could be considered in some situations.

Late Effects in Pediatric High-risk Neuroblastoma Survivors after Intensive Induction Chemotherapy Followed by Myeloablative Consolidation Chemotherapy and Triple Autologous Stem Cell Transplants

Multimodal treatment in high-risk neuroblastoma has modestly improved survival; limited data exist on the late effects from these regimens. We report the sequelae of treatment incorporating 3 consecutive cycles of high-dose therapy and autologous stem cell transplants (ASCTs) without the use of total body irradiation (TBI). We reviewed the medical records of 61 patients treated on or following the Chicago Pilot 2 protocol between 1991 and 2008. Of the 25 patients who are alive (41%), 19 had near complete data to report. Specific treatment modalities and therapy-related side effects were collected. Fourteen of these 19 patients (74%) received 3 cycles of high-dose therapy with ASCT; follow-up occurred over a median of 13.9 years (range, 5.8 to 18.8 y). The majority of late effects were endocrine-related, including growth failure, hypothyroidism, and hypogonadism. Patients also developed secondary neoplasms and skeletal deformities. The most frequent sequela was hearing loss, seen in 17/19 patients. We found a high prevalence of various late effects in survivors of high-risk neuroblastoma using a non–TBI-based regimen including 3 cycles of high-dose therapy with ASCTs. As current treatment regimens recommend tandem ASCT without TBI, it is imperative that we understand and monitor for the sequelae from these modalities.

Treatment of neuroblastoma in congenital central hypoventilation syndrome with a PHOX2B polyalanine repeat expansion mutation: New twist on a neurocristopathy syndrome

Neuroblastoma in patients with congenital central hypoventilation syndrome (CCHS) as part of a neurocristopathy syndrome is a rare finding and has only been associated with paired‐like homeobox 2b (PHOX2B) non‐polyalanine‐repeat‐expansion mutations. To the best of our knowledge, we report the first case of a child with CCHS and Hirschsprung disease who had a PHOX2B polyalanine‐repeat‐expansion mutation (PARM) (genotype 20/33) and developed high‐risk neuroblastoma. We further describe his treatment including chemotherapy and therapeutic I131‐metaiodobenzylguanidine. This case highlights the need to consider neuroblastoma in patients with CCHS and the longest PHOX2B PARMs and to individualize treatment based on co‐morbidities. Pediatr Blood Cancer

Irinotecan and temozolomide for treatment of neuroblastoma in a patient with renal failure on hemodialysis

Renal failure is a rare complication of neuroblastoma or its therapy. To our knowledge, no reports describe treatment of children with neuroblastoma with chemotherapy in the setting of renal failure and maintenance hemodialysis. We report a 6‐year‐old child with high‐risk neuroblastoma who developed renal failure requiring long‐term hemodialysis. She was subsequently treated with 13 cycles of intravenous irinotecan 20 mg/m2/day and oral temozolomide 100 mg/m2/day for 5 days before disease progression without any dose adjustments, transfusions, febrile neutropenia or diarrhea. This case demonstrates that irinotecan and temozolomide can be safely administered in children with renal failure requiring hemodialysis. Pediatr Blood Cancer 2014;61:949–950.

Soft tissue tumors: Rhabdomyosarcoma

Review on Soft tissue tumors: Rhabdomyosarcoma, with data on clinics, and the genes involved.

Prolonged response to sorafenib in a patient with refractory metastatic osteosarcoma and a somatic PDGFRA D846V mutation

Outcome for patients with metastatic or recurrent/refractory osteosarcoma remains poor. Responses to sorafenib, a multikinase inhibitor, have been seen in recurrent/refractory osteosarcoma, although specific biomarkers of response have not been described. We report a partial response in a 7‐year‐old with refractory osteosarcoma treated with sorafenib 200 mg twice daily. Toxicities included Common Terminology Criteria for Adverse Events Grade 2 skin toxicities and growth suppression. After 51 months of therapy, he suffered a recurrence. Tumor sequencing later revealed a PDGFRA D846V mutation that was not identified in the relapse specimen. This case demonstrates prolonged partial response to sorafenib and provides a potential biomarker for response.