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Purpose To evaluate BSO-mediated glutathione (GSH) depletion in combination with L-PAM for children with recurrent or refractory high-risk neuroblastoma (NB) as a means to enhance alkylator sensitivity. Procedure This pilot study (NCI #T95-0092) administered L-S,R-buthionine sulfoximine (BSO) as a bolus followed by 72 hr continuous infusion of either 0.75 g/m2/hr (level 1) or 1.0 g/m2/hr (level 2) and melphalan (L-PAM) (15 mg/m2 bolus at hour 48 of BSO infusion). GSH in blood mononuclear cells and bone marrow was measured by enzymatic assay, BSO in plasma by HPLC. Results Thirty two patients received 58 courses of therapy (median 1, range 1–4 courses). Blood mononuclear cell GSH decreased (48 hr) to 47% ± 15.7%. Level 2 mean steady-state concentration (Css) for BSO = 524 ± 207 μM and peak L-PAM concentration = 3.32 ± 1.2 μM. Grade 3–4 leukopenia and thrombocytopenia were common. There were two deaths from CNS toxicity and acute tubular necrosis; one had a large, intracranial mass, both were receiving cephalosporin antibiotics. No other significant toxicities were seen. There were six responses (five partial and, one mixed) representing an 18% response rate; four/six responses occurred in patients that relapsed following myeloablative therapy and included a 98% reduction in volume (cm3) of a pelvic mass, and three/five patients with >3 log reduction of tumor in marrow as measured by immunocytology (sensitivity 1/105). Conclusions BSO/L-PAM has activity against recurrent high-risk NB. Exclusion of cephalosporin antibiotics in future clinical trials of BSO may diminish the potential for serious renal and CNS toxicity. Pediatr Blood Cancer 2015;62:1739–1746. © 2015 Wiley Periodicals, Inc.

Background Childhood cancer survivors have an increased risk of developing cardiovascular disease following treatment, yet few interventions have been evaluated to reduce this risk. Purple grape juice (pGJ), a rich source of flavonoids with antioxidant properties, has been shown in adults to reduce oxidative stress and improve endothelial function. We examined the effects of supplementing meals with pGJ on microvascular endothelial function and markers of oxidative stress and inflammation in 24 cancer survivors (ages 10–21 years). Procedure In a randomized controlled crossover trial consisting of two, 4 week intervention periods, each preceded by a 4 week washout period, subjects received in random order 6 ounces twice daily of pGJ and clear apple juice (cAJ; similar in calories but lower in flavonoids). Measurements were obtained before and after each supplementation period; change was evaluated using mixed effects ANOVA. Results pGJ did not improve endothelial function, measured using digital reactive hyperemia, compared with cAJ (mean change: pGJ 0.06, cAJ 0.22; difference of mean change [95% CI]: −0.16 [−0.42 – 0.11], P = 0.25). No significant changes in plasma concentrations of oxidized-LDL, myeloperoxidase, or high sensitivity C-reactive protein were observed. Conclusion After 4 weeks of daily consumption of flavonoid-rich pGJ, no measurable change in vascular function was observed in these childhood cancer survivors. Pediatr Blood Cancer 2014;61:2290–2296. © 2014 Wiley Periodicals, Inc.

Background Therapy for childhood acute myeloid leukemia (AML) has historically included chemotherapy with or without autologous bone marrow transplant (autoBMT) or allogeneic hematopoietic stem cell transplantation (alloBMT). We sought to compare health-related quality-of-life (HRQOL) outcomes between these treatment groups.

Survivors of childhood cancer are at risk for dental late effects. This systematic review summarizes associations between treatment exposures and dental late effects among survivors of childhood cancer. We included investigations with at least 20 study participants conducted for 2 or more years after completion of childhood, adolescent, or young adult cancer therapy. This review suggests both independent and additive effects of radiotherapy and chemotherapy on dental complications, and identifies vulnerable groups with specific host and treatment characteristics. This summary provides information that will assist clinicians to prevent, detect, and facilitate early intervention for dental late effects.

BACKGROUND Estimation of the risk of adverse long-term outcomes such as second malignant neoplasms and infertility often requires reproducible quantification of exposures. The method for quantification should be easily utilized and valid across different study populations. The widely used Alkylating Agent Dose (AAD) score is derived from the drug dose distribution of the study population and thus cannot be used for comparisons across populations as each will have a unique distribution of drug doses.

300mg/m 2 or more of anthracyclines (N ¼14) or treated with multi-agent chemotherapy (with or without cranial radiation) for ALL (N ¼75) compared to healthy controls [11,12]. The complex mechanisms of cardiovascular injury remain poorly defined and additional study is needed to help guide the testing of therapeutic interventions. The objective of this study was to assess markers of vascular injury among survivors of osteosarcoma, a population with intensive, potentially vascular toxic, chemotherapy exposures, typically without radiation exposure. We previously collected the same biomarkers among survivors of Hodgkin lymphoma and found evidence suggestive of vascular inflammation, dyslipidemia, Background. Cardiovascular-related toxicities have been reported among survivors of osteosarcoma. Methods. Fasting blood samples from 24 osteosarcoma survivors were analyzed for highsensitivity C-reactive protein (hsCRP), triglycerides, total cholesterol, high-density lipoprotein (HDL), apolipoprotein-s, lipoprotein (a), fibrinogen, circulating endothelial cells (CECs), and surface expression of vascular cell adhesion molecule-1 (VCAM-1). Values were compared to subjects in the natural history Coronary Artery Risk Development in Young Adults (CARDIA) cohort study except for CECs and VCAM-1 expression, which were compared to controls studied at the University of Minnesota Lillehei clinical trials unit. Procedure. Survivors (54.2% male), median age 18 years (9–32) at diagnosis,36.5years(20–56)atevaluationweretreatedwithavariety of chemotherapeutic exposures, all but one were exposed to doxorubicin (median dose 450mg/m 2 ; range: 90–645mg/m 2 ), 14 (58.3%) received cisplatin, and 3 (12.5%) were exposed to carboplatin. Two survivors (8.3%) received radiation therapy for disease relapse. Compared to CARDIA subjects, mean hsCRP (3.0mg/L � 2.0 vs. 1.6 � 2.3), triglycerides (151mg/dl � 81.7 vs. 95.4 � 101.3),lipoprotein(a)(34.9mg/dl � 17.7vs.13.8 � 22.0),and fibrinogen (315.0mg/dl � 49.3 vs. 252.4 � 61.7) were significantly elevated. The number of CECs (0.47cells/ml � 2.5 vs. 0.92 � 2.5) did not differ while surface expression of VCAM-1 (86.4% � 34.0 vs. 42.1 � 33.8) was significantly elevated compared to controls. Conclusions. Among survivors of osteosarcoma, assessed a median of 14 years from diagnosis, there is evidence of vascular inflammation, dyslipidemia, and early atherogenesis. Pediatr Blood Cancer 2013;60:1703–1708. # 2013 Wiley Periodicals, Inc.

Vascular-related toxicities have been reported among survivors of Hodgkin lymphoma (HL), but their genesis is not well understood.Fasting blood samples from 25 previously irradiated HL survivors were analyzed for biomarkers that can reveal underlying inflammation and/or endothelial cell activation: high-sensitivity C-reactive protein (hsCRP), triglycerides, total cholesterol, high-density lipoprotein (HDL), apolipoprotein ß, lipoprotein (a), fibrinogen, circulating endothelial cells (CECs), and vascular cell adhesion molecule-1 (VCAM-1) expression. Values were compared to subjects in the Coronary Artery Risk Development in Young Adults (CARDIA) study. CECs and VCAM-1 were compared to healthy controls.Survivors (76% male), median age 17.6 years (5-33) at diagnosis, 33.0 years (19-55) at follow-up, included stages IA (n = 6), IIA (n = 10), IIB (n = 2), IIIA (n = 4), and IVA (n = 3) patients. Twenty-four received at least chest radiation therapy (RT) (median dose 3,150 cGy; range: 175-4,650 cGy), one received neck only; 14 (56%) had a history of anthracycline exposure (median dose: 124 mg/m(2) range: 63-200 mg/m2). Compared to CARDIA subjects, mean hsCRP (3.0 mg/L ± 2.0 vs. 1.6 ± 1.9), total cholesterol (194.1 mg/dl ± 33.2 vs. 179.4 ± 32.9), lipoprotein (a) (34.2 mg/dl ± 17.5 vs. 13.8 ± 17.5), and fibrinogen (342.0 mg/dl ± 49.1 vs. 252.6 ± 48.4) were significantly elevated. CECs (2.3 cells/ml ± 1.5 vs. 0.34 ± 1.4) were significantly elevated compared to controls. No difference in VCAM-1 expression (51.1% ± 36.8 vs. 42.3 ± 35.6) was detected.HL survivors exposed to RT have evidence of vascular inflammation, dyslipidemia, and injury suggestive of early atherogenesis.

Background Survivors of childhood acute myeloid leukemia (AML) face increased risks of chronic disease and secondary malignancies. Substance exposure may compound these risks. Procedures Participants were diagnosed with AML at

Background The ability to predict adverse-event occurrences accurately in long-term survivors of childhood cancer is of high importance in late effects research, both clinically and methodologically. Procedure This article considers a statistical prediction of future events in a cohort, taking second malignant neoplasm (SMN) incidence in a large cohort of long-term childhood cancer survivors as an example. The method consists of dividing the follow-up period of the cohort into two non-overlapping periods, using the first period as “training data,” with which we model the patterns of SMN occurrences in the cohort, and the subsequent period as “testing data,” with which we validate the model based on the training data. Future predictions are also applied beyond the testing-data period to calculate the SMN incidence of the cohort in the next five years for overall and specific types of SMNs. Results The proposed statistical prediction is shown empirically to perform well with respect to the prediction accuracy. Overall, the models were able to predict the future second cancers rates very well, with exceptions of a few cancer types that had very small observed counts in the testing period. Conclusions Our proposed statistical method predicts future events in a cohort of long-term childhood cancer survivors and, as such, is a useful tool for late effects research on childhood cancer survivors. Pediatr Blood Cancer 2008;50:1026–1031. © 2007 Wiley-Liss, Inc.

Background The TEL-AML1 fusion in precursor-B ALL is generated by a cryptic 12;21 translocation that is detectable by fluorescence in situ hybridization (FISH). It is generally considered a favorable prognostic indicator. Some TEL-AML1+ ALL patients present at diagnosis with extra copies of the fusion, enumerated by FISH. The aim of the study was to determine whether additional copies of TEL-AML1 have clinical significance. Procedure Charts of all TEL-AML1+ ALL patients at the UM and Children's Hospitals and Clinics of Minnesota between 1996 and 2004 were reviewed. Results Eight patients (7 males/1 female, mean age 46 months) with two or more TEL-AML1 fusion signals and 24 with single TEL-AML1 fusion signals (18 males/6 females, mean age 52 months) were identified. There was no statistically significant difference in age or gender between the two groups. Patients with double TEL-AML1+ had a higher frequency of myeloid markers CD13 (P = 0.04) or CD33 (P = 0.003) than single TEL-AML1+ patients. Single TEL-AML1+ patients had higher WBC (P = 0.04) than double TEL-AML1+ patients. A trend toward slower therapy response was seen in double TEL-AML1+ patients versus single, (1 of 7 [14%]

*INTRODUCTIONPediatric ovarian tumors are an uncommon but impor-tant form of childhood cancer. Ovarian tumors are themost frequent neoplasms of the female genital tract inchildhood [1] and are generally considered to accountfor approximately 1% of all malignancies in patients ages0–17 years [2]. Ovarian masses include neoplastic andnon-neoplastic processes. Non-neoplastic conditions in-clude follicular cysts, corpus luteal cysts, and endome-triomas. Neoplastic processes include both benign tumorssuch as mature cystic teratomas as well as highly malig-nanttumors.Inaddition,therearetumorsoflowmalignantpotential that frequently follow a benign clinical course.Various classification and nomenclature systems havebeen developed to describe the spectrum of ovariantumors. Generally these tumors are classified into threemain categories including epithelial, stromal, and germcell tumors.Previousstudiesofpediatricovariantumorsinchildrenhave noted a predominance of germ cell tumors. This is incontrast to the adult literature, which notes the predomi-nance of tumors of epithelial cell origin [3]. This dif-ference highlights the importance of considering patientage when evaluating ovarian pathology.Germ cell tumors include teratomas and gonadoblas-tomas as well as endodermal sinus tumors, also calledyolk sac tumors, embryonal carcinomas, polyembryomas,and choriocarcinomas. Teratomas include both immature(malignant) and mature (benign) forms. Immature tera-tomas are classified according to their level of differentia-tion [4]. Histologic level of differentiation determines thelevel of malignancy. Gonadoblastomas occur exclusivelyin patients with dysgenetic gonads and are classified asbenign tumors, however, malignant dysgerminomas arefrequently found within these tumors.Children may also present with non-germ cell tumorsincluding sex cord-stromal tumors and epithelial tumors.Sex cord stromal tumors include thecoma–fibroma,Sertoli–Leydig cell tumors and granulosa cell tumors.Juvenile granulosa cell tumors follow a very differentclinical course than granulosa cell tumors in adult womenand although they have malignant potential, they com-monly follow a benign clinical course.Epithelial tumors, including cystadenoma in benign,borderline, and malignant forms, are common in adultwomen, though much less frequent in children. Small cell

We report the case of a child who presented with nonspecific symptoms suggestive of a rheumatologic disorder, whose bone marrow had a complex translocation involving the FGFR1 locus. Hematopathologic findings were subtle and did not definitively indicate malignancy. Because he responded poorly to initial treatment with hydroxyurea, and in light of the progressive clinical course associated with the 8p11 myeloproliferative syndrome, he underwent an unrelated-donor hematopoietic stem cell transplant. This patient's atypical presentation highlights the importance of obtaining cytogenetic analysis at the time of bone marrow sampling and considering this uncommon entity in the differential diagnosis of hematologic disorders.

Deferasirox (Exjade®, Novartis) is a widely used oral iron chelator for the treatment of patients with iron overload due to chronic transfusion therapy for diseases such as β-thalassemia and sickle cell disease. Renal side effects of deferasirox are common and include non-progressive increases in serum creatinine, however, the effect of deferasirox on proximal tubule function is unclear. We report one pediatric patient with reversible Fanconi syndrome associated with long-term deferasirox therapy and one patient with mild proximal tubular dysfunction. Kidney and proximal tubular function should be periodically monitored in patients receiving deferasirox throughout their course of therapy.