Naomi Balamuth

Ewing's sarcoma

Progress in the treatment of Ewings sarcoma, the second most common bone tumour in children and adolescents, has improved survival from about 10% in the period before chemotherapy was introduced to about 75% today for patients with localised tumours. However, patients with metastases still fare badly, and the therapy carries short-term and long-term toxicities. Multidisciplinary care is indispensable for these patients. Molecular techniques and new imaging modalities are affecting the diagnosis and classification of patients with Ewings sarcoma. Cooperative group studies have led to chemotherapy regimens using the same drugs (vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide), although the exact regimens differ in Europe and North America. The EWS-ETS family of gene fusions and their downstream effects in Ewings sarcomas provide opportunities for new approaches to treatment. These include the inhibition of the fusion gene or its protein product, and pathways related to IGF1 and mTOR. Inhibition of tyrosine kinases, exploitation of non-apoptotic cell death, and interference with angiogenesis are promising new approaches. With many new approaches and relatively few patients, it will be challenging to integrate new and established treatments through clinical trials.

Lestaurtinib Enhances the Antitumor Efficacy of Chemotherapy in Murine Xenograft Models of Neuroblastoma

Purpose: Neuroblastoma, a common pediatric tumor of the sympathetic nervous system, is characterized by clinical heterogeneity. The Trk family neurotrophin receptors play an important role in this behavior. Expression of TrkA is associated with favorable clinical features and outcome, whereas TrkB expression is associated with an unfavorable prognosis. We wanted to determine if the Trk-selective inhibitor lestaurtinib had therapeutic efficacy in a preclinical neuroblastoma model. Experimental Design: We performed intervention trials of lestaurtinib alone or in combination with other agents in TrkB-overexpressing neuroblastoma xenograft models. Results: Lestaurtinib alone significantly inhibited tumor growth compared to vehicle-treated animals [P = 0.0004 for tumor size and P = 0.011 for event-free survival (EFS)]. Lestaurtinib also enhanced the antitumor efficacy of the combinations of topotecan plus cyclophosphamide (P < 0.0001 for size and P < 0.0001 for EFS) or irinotecan plus temozolomide (P = 0.011 for size and P = 0.012 for EFS). There was no additive benefit of combining either 13-cis-retinoic acid or fenretinide with lestaurtinib compared to lestaurtinib alone. There was dramatic growth inhibition combining lestaurtinib with bevacizumab (P < 0.0001), but this combination had substantial systemic toxicity. Conclusions: We show that lestaurtinib can inhibit the growth of neuroblastoma both in vitro and in vivo and can substantially enhance the efficacy of conventional chemotherapy, presumably by inhibition of the Trk/brain-derived neurotrophic factor autocrine survival pathway. It may also enhance the efficacy of selected biological agents, but further testing is required to rule out unanticipated toxicities. Our data support the incorporation of Trk inhibitors, such as lestaurtinib, in clinical trials of neuroblastoma or other tumors relying on Trk signaling pathways for survival. Clin Cancer Res; 16(5); 1478–85

Serial Transcriptome Analysis and Cross-Species Integration Identifies Centromere-Associated Protein E as a Novel Neuroblastoma Target

Cancer genomic studies that rely on analysis of biopsies from primary tumors may not fully identify the molecular events associated with tumor progression. We hypothesized that characterizing the transcriptome during tumor progression in the TH-MYCN transgenic model would identify oncogenic drivers that would be targetable therapeutically. We quantified expression of 32,381 murine genes in nine hyperplastic ganglia harvested at three time points and four tumor cohorts of progressively larger size in mice homozygous for the TH-MYCN transgene. We found 93 genes that showed a linearly increasing or decreasing pattern of expression from the preneoplastic ganglia to end stage tumors. Cross-species integration identified 24 genes that were highly expressed in human MYCN-amplified neuroblastomas. The genes prioritized were not exclusively driven by increasing Myc transactivation or proliferative rate. We prioritized three targets [centromere-associated protein E (Cenpe), Gpr49, and inosine monophosphate dehydrogenase type II] with previously determined roles in cancer. Using siRNA knockdown in human neuroblastoma cell lines, we further prioritized CENPE due to inhibition of cellular proliferation. Targeting CENPE with the small molecular inhibitor GSK923295 showed inhibition of in vitro proliferation of 19 neuroblastoma cell lines (median IC(50), 41 nmol/L; range, 27-266 nmol/L) and delayed tumor growth in three xenograft models (P values ranged from P < 0.0001 to P = 0.018). We provide preclinical validation that serial transcriptome analysis of a transgenic mouse model followed by cross-species integration is a useful method to identify therapeutic targets and identify CENPE as a novel therapeutic candidate in neuroblastoma.

Proton versus photon radiation therapy for patients with high-risk neuroblastoma: The need for a customized approach

Proton therapy for treatment for high‐risk neuroblastoma may offer sparing of organs at risk (OAR) when compared to intensity‐modulated X‐ray therapy (IMXT).

Ectopic production of β-hCG by osteosarcoma: a case report and review of the literature.

Ectopic production of β-human chorionic gonadotropin (β-hCG) by nontrophoblastic tumors has been reported but mostly in carcinomas. We report a case of an adolescent female patient with a epithelioid osteosarcoma that was discovered to secrete β-hCG after routine pregnancy testing. Immunohistochemical staining of her primary tumor biopsy demonstrated immunoreactivity for β-hCG. Levels of serum β-hCG were monitored throughout her therapy and demonstrated normalization with effective systemic therapy and local control. She remains disease free 6 months off therapy, with undetectable hormone levels. A review of the available literature on β-hCG production by sarcomas is also presented.

Musculoskeletal complications following total body irradiation in hematopoietic stem cell transplant patients

Total body irradiation (TBI) is commonly used in conditioning regimens for allogeneic hematopoietic stem cell transplantation (HSCT) to treat benign and malignant disease. Though life‐saving, these therapies place patients at risk for important side effects, including musculoskeletal complications such as short stature, osteonecrosis, slipped capital femoral epiphysis, and the development of benign and malignant bone tumors. With an increasing number of HSCT survivors, there is a growing need for awareness of the musculoskeletal complications of HSCT and TBI.

Reply to: Medication contaminants as a potential cause of anaphylaxis to vincristine: What about drug specific antigens?

To the Editor: We appreciate the informative letter by Dr. Nicholas Kounis and colleagues in response to our manuscript entitled “Medication contaminants as a potential cause of anaphylaxis to vincristine.”1 Kounis et al. propose some questions about our report and discuss it broadly in the context of drug allergy.2 They first note that vincristine has been associated with allergic reactions of the Kounis type, which are characterized by acute myocardial infarction.3–5 This is an important consideration given that one of the patients in our report experienced cardiac arrest following vincristine administration. However, multiple physicians documented circumstances and options that suggest the patient in question experienced a hypoxemic arrest. In addition, an EKG performed just after the event was normal, without signs of cardiac ischemia. Together, these additional considerations make a Kounis-type reaction less likely. The authors also raise the question as to whether premedicating with antihistamines or steroids could contribute to the anaphylaxis events observed in our study. There are rare examples of allergy to these medications.6 However, the four patients in our study who were premedicated after their initial reaction to vincristine tolerated subsequent infusions. As such, allergy to antihistamines or steroids was not a contributing factor in our cases. Lastly, Dr. Kounis and colleagues discuss the value of various testing modalities in the evaluation of drug allergy.We agree that drug provocation testing is the gold standard for establishing the presence of an allergy. In the case of our study, seven of the eight patients tolerated vincristine subsequently, leading us to suspect a contaminant as the etiology of the reactions. Other major testing strategies in the field of allergy include cutaneous testing and evaluation of serum levels of specific IgE molecules. However, commercially available and validated reagents for such testing are only available for penicillin.7 Basophil activation testing has had mixed results, and additional studies with commercially available tests are needed prior to its acceptance as a diagnostic tool.7 In the context of chemotherapeutics, taxanes (paclitaxel, docetaxel), platinum compounds (cisplatin, carboplatin, oxaliplatin), and asparaginase are known to cause allergic reactions. Validated testing approaches for these medications are limited at this time.7 Though not commonly used in the context of chemotherapeutics, primary prevention is another testing modality relevant to drugrelated adverse reactions. Perhaps the best examples of such screening come in the form of HLA typing, which is available for abacavir and carbamazepine hypersensitivity.8,9 Screening is advantageous if, among other things, a valid, rapid, inexpensive, and easily interpretable laboratory test exists, and the population frequency of the allele in question is relatively high.10 In the context of HLA typing, this later criterion is most often achieved by focusing on individuals of similar genetic background.9,11 In sum, the field of drug-related adverse reactions is important and growing. Future research efforts should focus on understanding the immunologic mechanisms that underlie specific reactions. This will facilitate the development of new testing modalities for use in primary prevention, diagnosis, andmanagement.

Pantoprazole, an Inhibitor of the Organic Cation Transporter 2, Does Not Ameliorate Cisplatin‐Related Ototoxicity or Nephrotoxicity in Children and Adolescents with Newly Diagnosed Osteosarcoma Treated with Methotrexate, Doxorubicin, and Cisplatin

Abstract Lessons Learned. Using a randomized crossover design and continuous variables such as change in hearing threshold and biomarkers of acute renal injury as short‐term endpoints, it was determined that pantoprazole, an organic cation transporter 2 inhibitor, did not ameliorate cisplatin‐associated nephrotoxicity or ototoxicity. Cystatin C is a robust method to estimate glomerular filtration rate in patients with cancer. Using a patient‐reported outcome survey, all patients identified tinnitus and subjective hearing loss occurring “at least rarely” after cycle 1, prior to objective high‐frequency hearing loss measured by audiograms. New therapies that improve outcome with less acute and long‐term toxicity are needed. Background. Organic cation transporter 2 (OCT2), which is a cisplatin uptake transporter expressed on renal tubules and cochlear hair cells but not on osteosarcoma cells, mediates cisplatin uptake. Pantoprazole inhibits OCT2 and could ameliorate cisplatin ototoxicity and nephrotoxicity. Using a randomized crossover design, we evaluated audiograms, urinary acute kidney injury (AKI) biomarkers, and glomerular filtration rate (GFR) estimated from cystatin C (GFRcysC) in patients receiving cisplatin with and without pantoprazole. Materials and Methods. Cisplatin (60 mg/m2 × 2 days per cycle) was administered concurrently with pantoprazole (intravenous [IV], 1.6 mg/kg over 4 hours) on cycles 1 and 2 or cycles 3 and 4 in 12 patients with osteosarcoma (OS) with a median (range) age of 12.8 (5.6–19) years. Audiograms, urinary AKI biomarkers, and serum cystatin C were monitored during each cycle. Results. Pantoprazole had no impact on decrements in hearing threshold at 4–8 kHz, post‐treatment elevation of urinary AKI biomarkers, or GFRcysC (Fig. 1, Table 1). Histological response (percent necrosis) after two cycles was similar with or without pantoprazole. All eight patients with localized OS at diagnosis are alive and in remission; three of four patients with metastases at diagnosis have died. Conclusion. Pantoprazole did not ameliorate cisplatin ototoxicity or nephrotoxicity. The decrease in GFRcysC and increase in N‐acetyl‐ß‐glucosaminidase (NAG) and creatinine demonstrate that these biomarkers can quantify cisplatin glomerular and proximal tubular toxicity. OCT2 inhibition by pantoprazole did not appear to alter antitumor response or survival.

Medication contaminants as a potential cause of anaphylaxis to vincristine

Vincristine (VCR) is a vinca alkaloid and common chemotherapeutic that is used to treat multiple pediatric and adult malignancies. Despite its common use, cases of anaphylaxis to VCR are rare and typically isolated to a single individual. We report a series of eight patients with adverse reactions to VCR over the course of 11 months at a single institution, four of which progressed to anaphylaxis and one of which resulted in cardiac arrest. Mass spectrometry analysis of medication lots was performed to test for possible contaminant(s). Our findings highlight the risk of anaphylaxis during therapy with VCR.

Proton therapy for pediatric head and neck malignancies

Pediatric head and neck malignancies are managed with intensive multimodality therapy. Proton beam therapy (PBT) may reduce toxicity by limiting exposure of normal tissue to radiation. In this study, we report acute toxicities and early outcomes following PBT for pediatric head and neck malignancies.