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Background Sorafenib,an orally bioavailable, multitarget tyrosine kinase inhibitor, and irinotecan, a topoisomerase I inhibitor, have demonstrated activity in pediatric and adult malignancies. We evaluated the toxicity, pharmacokinetic (PK), and pharmacogenomic (PGX) profile of sorafenib with irinotecan in children with relapsed or refractory solid tumors and assessed the feasibility of incorporating patient-reported outcome (PRO) measures as an adjunct to traditional endpoints. Methods Sorafenib, continuous oral twice daily dosing, was administered with irinotecan, orally, once daily days 1-5, repeated every 21 days (NCT01518413). Based on tolerability, escalation of sorafenib followed by escalation of irinotecan was planned. Three patients were initially enrolled at each dose level. Sorafenib and irinotecan PK analyses were performed during cycle 1. PRO measurements were collected during cycles 1 and 2. Results Fifteen patients were evaluable. Two of three patients at dose level 2 experienced dose-limiting toxicity (DLT), grade 3 diarrhea, and grade 3 hyponatremia. Therefore, dose level 1 was expanded to 12 patients and two patients had DLT, grade 4 thrombocytopenia, grade 3 elevated lipase. Nine of 15 (60%) patients had a best response of stable disease with four patients receiving ≥6 cycles. Conclusions The recommended dose for pediatric patients was sorafenib 150 mg/m2 /dose twice daily with irinotecan 70 mg/m2 /dose daily × 5 days every 21 days. This oral outpatient regimen was well tolerated and resulted in prolonged disease stabilization. There were no significant alterations in the PK profile of either agent when administered in combination. Patients were willing and able to report their subjective experiences with this regimen.

Summary:. Epithelioid sarcoma is a rare, high-grade malignant soft tissue tumor that is often misdiagnosed. Classified as a mesenchymal malignancy, it exhibits both mesenchymal and epithelial markers. Occurrence in children under age 10 is extremely rare. This report describes the clinical course and management of a 5-year-old girl who presented with epithelioid sarcoma in the distal extremity. The lesion was initially misdiagnosed and treated for over a year as a common wart.

Background Patients with relapsed or refractory Wilms tumor (WT) have poor prognoses with limited treatment options.1–3 Immunotherapy offers a promising alternative for targeted therapy but has been limited by immune evasion tactics.4–6 Adoptive cell therapy with patient-derived tumor-associated antigen-specific T cells (TAA-T) targeting 3 antigens (WT1, PRAME, and survivin) has the potential to overcome antigen loss. The objective of this phase I clinical trial is to determine the safety of administering TAA-T to patients with high-risk, relapsed/refractory solid tumors. Secondary objectives include determination of clinical efficacy and immunobiology following infusion. Methods T cells expanded from patient peripheral blood are stimulated weekly with antigen presenting cells expressing an overlapping peptide library spanning the tumor antigens WT1, PRAME, and survivin. Following release testing, patients are infused with TAA-T on a dose escalation study, ranging from a dose of 1 x 107/m2 (dose level 1) to 4 x 107/m2 (dose level 3). Clinical and immunobiological studies performed post-infusion monitor for adverse effects and assess immune and disease responses. Results Therapy with TAA-T was shown to be safe and well-tolerated in patients with high-risk solid tumors on this dose-escalation study.7 A total of 18 patients have been infused, with WT as the predominant diagnosis, accounting for 10 patients. We elucidated a dose-response relationship, with a prolonged median time to progression for patients treated on dose level 3 (recommended dose level [RDL]) compared to those on dose level 1 and 2 combined (5.2 vs 2.8 months, respectively) (figure 1). Patients demonstrated prolonged progression-free survival (PFS) compared to therapy received just prior to TAA-T (figure 2). Best response observed was stable disease. A majority of patients demonstrated improved anti-tumor immunity as evidenced by antigen spreading (figure 3). Conclusions In long-term follow up, the 1-year progression-free survival (PFS) remains improved for patients treated at the recommended dose level compared to the PFS observed with therapy received immediately prior to TAA-T (29% vs 15%, respectively). Three patients are long-term (28–38 months) survivors without disease progression or further therapy. This unique immunotherapeutic has been well-tolerated without life-threatening cytokine release syndrome. To enhance TAA-T activity further in vivo, we will evaluate the safety of prescribed lymphodepletion prior to TAA-T infusion and assess anti-tumor immunity. We expect that lymphodepletion will enhance T cell persistence and expansion and recruit endogenous immune response with altered kinetics. Ethics Approval The study was approved by the Children’s National Hospital Institutional Review Board, approval number NCT02789228. References Dome JS, Graf N, Geller JI, Fernandez CV, Mullen EA, Spreafico F, Van den Heuvel-Eibrink M, Pritchard-Jones K. Advances in Wilms Tumor Treatment and Biology: Progress Through International Collaboration. J Clin Oncol 2015;33(27):2999–3007. Mullen EA, Chi YY, Hibbitts E, Anderson JR, Steacy KJ, Geller JI, Green DM, Khanna G, Malogolowkin MH, Grundy PE and others. Impact of Surveillance Imaging Modality on Survival After Recurrence in Patients With Favorable-Histology Wilms Tumor: A Report From the Children’s Oncology Group. J Clin Oncol 2018:JCO1800076. Malogolowkin MH, Hemmer MT, Le-Rademacher J, Hale GA, Mehta PA, Smith AR, Kitko C, Abraham A, Abdel-Azim H, Dandoy C and others. Outcomes following autologous hematopoietic stem cell transplant for patients with relapsed Wilms’ tumor: a CIBMTR retrospective analysis. Bone Marrow Transplant 2017;52(11):1549–1555. Heczey A, Louis CU. Advances in chimeric antigen receptor immunotherapy for neuroblastoma. Discov Med 2013;16(90):287–94. Park JR, Digiusto DL, Slovak M, Wright C, Naranjo A, Wagner J, Meechoovet HB, Bautista C, Chang WC, Ostberg JR and others. Adoptive transfer of chimeric antigen receptor re-directed cytolytic T lymphocyte clones in patients with neuroblastoma. Mol Ther 2007;15(4):825–33. Lamers CH, Sleijfer S, van Steenbergen S, van Elzakker P, van Krimpen B, Groot C, Vulto A, den Bakker M, Oosterwijk E, Debets R and others. Treatment of metastatic renal cell carcinoma with CAIX CAR-engineered T cells: clinical evaluation and management of on-target toxicity. Mol Ther 2013;21(4):904–12. Hont AB, Cruz CR, Ulrey R, O’Brien B, Stanojevic M, Datar A, Albihani S, Saunders D, Hanajiri R, Panchapakesan K and others. Immunotherapy of relapsed and refractory solid tumors with ex vivo expanded multiantigen-associated specific cytotoxic T lymphocytes: A Phase I Study. J Clin Oncol 2019:JCO1900177.

Purpose Infants with stage 4S neuroblastoma usually have favorable outcomes with observation or minimal chemotherapy. However, young infants with symptoms secondary to massive hepatomegaly or with unfavorable tumor biology are at high risk of death. Our aim was to improve outcomes for patients with symptomatic and/or unfavorable biology 4S neuroblastoma with a uniform treatment approach using a biology- and response-based algorithm. Patients and Methods The subset of patients with 4S disease with MYCN-not amplified tumors with impaired or impending organ dysfunction, or with unfavorable histology and/or diploid DNA index, were eligible. Patients were assigned to receive two, four, or eight cycles of chemotherapy on the basis of histology, diploid DNA index, chromosome arm 1p or 11q loss of heterozygosity (LOH) status, and symptoms. Results Forty-nine eligible patients were enrolled: 41 were symptomatic and 28 had unfavorable biology. Seventeen patients (symptomatic, favorable biology) were assigned two cycles, 21 patients (any unfavorable biologic feature without 1p or 11q LOH) were assigned four cycles, and 11 patients (unfavorable biology including 1p and/or 11q LOH [n = 7] or symptomatic with unknown biology [n = 4]), were assigned eight cycles. The 3-year overall survival was 81.4% ± 5.8%. Eight of nine deaths were in patients younger than 2 months of age at diagnosis (median, 9 days [range, 1 to 68 days]): five acute deaths were a result of hepatomegaly and associated toxicities; two were a result of late relapse in patients with unfavorable biology; and two were a result of treatment complications. No deaths occurred after protocol-mandated pre-emptive treatment of infants younger than 2 months with hepatomegaly, regardless of symptoms. A new scoring algorithm for emergent chemotherapy in patients with 4S disease was developed on the basis of this experience. Conclusion The outcome for 4S neuroblastoma can be improved with pre-emptive chemotherapy for evolving hepatomegaly or other baseline comorbidities in infants younger than 2 months of age.

Children with high-risk neuroblastoma are currently treated with a chimeric monoclonal antibody against GD2 ganglioside (chimeric 14.18). The treatment improves survival but causes transient neuropathic pain-like syndrome. We retrospectively studied 16 children with neuroblastoma receiving GD2 therapy. To manage pain, all patients received morphine via nurse-controlled analgesia or patient-controlled analgesia. Mean daily pain scores ranged from 0 to 5 and all children had a 0 pain score upon discharge. No major side effects were noted, suggesting morphine via nurse-controlled analgesia/patient-controlled analgesia is effective in controlling transient neuropathic pain in children receiving GD2 antibody therapy.

BACKGROUND Pediatric participants on phase 1 or phase 2 clinical trials for incurable cancer are at risk of experiencing toxicities (adverse events [AEs]) related to trial participation. Multiple AEs are subjective; thus, the real impact of trial treatment cannot be known unless patient subjective reports are solicited. METHODS The authors assessed the feasibility and acceptability of soliciting symptom, function, and quality of life (QOL) reports from participants aged 8 to 18 years who were enrolled on phase 1/2 clinical trials at 4 cancer centers during the first course of chemotherapy. The authors also assessed the reliability and validity of 6 self-report Patient-Reported Outcomes Measurement Information System (PROMIS) pediatric measures and 4 open-ended interview questions at 2 time points (at the time of trial enrollment [T1] and 3 to 4 weeks later [T2]). RESULTS The enrollment rate of 75.9% (20 participants) exceeded the feasibility criterion, and missingness of measures by person, measure, and items at T1 and T2 were lower than the acceptability criteria. New QOL themes were limited to the impact of treatment on families and being away from home, family, and friends for treatment. All but one measure at T1 met the reliability criterion and all measures did so at T2. Validity support was limited however because as theorized, mobility decreased and fatigue increased as AEs increased. CONCLUSIONS Soliciting and documenting symptom, function, and QOL reports from patients aged 8 to 18 years who are enrolled on a phase 1/2 clinical trial is feasible and acceptable to participants, particularly when embedded in trials. Reliable and valid findings can result, making patient self-reported outcomes a possible new trial endpoint. Cancer 2017. © 2017 American Cancer Society.

PURPOSE Tumor-associated antigen cytotoxic T cells (TAA-Ts) represent a new, potentially effective and nontoxic therapeutic approach for patients with relapsed or refractory solid tumors. In this first-in-human trial, we investigated the safety of administering TAA-Ts that target Wilms tumor gene 1, preferentially expressed antigen of melanoma, and survivin to patients with relapsed/refractory solid tumors. MATERIALS AND METHODS TAA-T products were generated from autologous peripheral blood and infused over three dose levels: 1, 2, and 4 × 107 cells/m2. Patients were eligible for up to eight infusions administered 4 to 7 weeks apart. We assessed dose limiting toxicity during the first 45 days after infusion. Disease response was determined within the context of a phase I trial. RESULTS There were no dose-limiting toxicities. Of 15 evaluable patients, 11 (73%) with stable disease or better at day 45 postinfusion were defined as responders. Six responders remain without progression at a median of 13.9 months (range, 4.1 to 19.9 months) after initial TAA-Ts. Patients who were treated at the highest dose level showed the best clinical outcomes, with a 6-month progression-free survival of 73% after TAA-T infusion compared with a 38% 6-month progression-free survival with prior therapy. Antigen spreading and a reduction in circulating tumor-associated antigens using digital droplet polymerase chain reaction was observed in patients after TAA-T infusion. CONCLUSION TAA-Ts safely induced disease stabilization, prolonged time to progression, and were associated with antigen spreading and a reduction in circulating tumor-associated antigen DNA levels in patients with relapsed/refractory solid tumors without lymphodepleting chemotherapy before infusion. TAA-Ts are a promising new treatment approach for patients with solid tumors.

Background Carboplatin is often adaptively dosed based on glomerular filtration rate (GFR), usually estimated by nuclear medicine tests. At least five pediatric adaptive dosing formulas have been developed. In an effort to standardize dosing in Children's Oncology Group protocols, we explored methodologic variation in GFR estimation and adaptive-dosing formula performance. Procedure Nuclear medicine GFR data from published series of ≥100 children with cancer were compared. Data from patients for whom body surface area, weight, GFR, and tracer half-life were available were used to compare formulas. Results Differences in methods used to estimate GFR in children with cancer resulted in highly variable population results, with median GFRs ranging from 96 to 150 mL/min/1.73m2 . The choice of adaptive formula had a major impact on calculated dose. When targeting an area under the curve of 7.9 mg/mL • min, the median difference between the formula yielding the lowest and highest carboplatin dose for individual subjects was 289 (range 96-1 737) mg/m2 . Conclusions Wide variation in GFR obtained with nuclear-medicine-based tests in children with cancer primarily results from systematic methodologic errors. Formulas for calculating carboplatin dose produce additional and substantial variation that may place children with cancer at unnecessary risk for excessive toxicity or underdosing. These findings indicate a need for the development of a uniform, validated method for GFR determination in children that should be utilized in all centers. Currently, adaptive dosing of carboplatin based on GFR has serious limitations and in most clinical settings should arguably not be used in place of body-surface-area-based dosing.

Although solitary presentations of infantile myofibromatosis tend toward spontaneous regression, multicentric forms fare worse. Previous case reports have depicted observation, surgical resection, and systemic therapies as treatment options. This paper reports well-tolerated, successful outcomes in a series of patients with high-risk infantile myofibromatosis in need of life-sustaining interventions treated with a combination of vincristine and dactinomycin. The clinical presentation, pathology, and radiographic findings are described.

Background Cellular therapy offers an innovative, personalized alternative to traditional therapeutics aimed to treat cancer and viral infections. Often offered in experimental clinical trials, in 2016 a New York Times article argued that immunotherapy is reserved primarily for white patients due to barriers to access. Two prominent immunotherapy trials cited in the article reported 92% and 88% enrollment of white patients, while minority patients represented 9% and 10% of enrollment, respectively. Purpose To examine the races, ethnicity, and gender of patients enrolled in clinical cell therapy trials at Children's National, Washington DC to determine if the enrollment is representative of the current US population. Methods Demographic data was analyzed from databases obtained from IRB-approved cell therapy clinical trials initiated at our Institution. Results/Conclusions Of the patients (between ages of 1 and 64) enrolled into cell therapy clinical trials, 56% identified racially as white (n=95), while 20% identified as black (n=33), 9% as Asian (n=9), 19% as "other" (n=20), and 3% as "unknown" (n=5). Among the patients who reported race, 18% identified ethnically as Hispanic (n=31). By sex, 50% were male (n=85) and 50% were female (n=84). In the 2015 US census, 77% of participants identified racially as white, 13.3% as black, and 5.6% as Asian. As per the census, 17% of those surveyed identified ethnically as Hispanic. This stands in contrast to 2 published adult centered cell therapy studies mentioned in the New York Times in which 92% and 88% of patients were identified as white and minorities only constituted

BackgroundInternational Neuroblastoma Staging System (INSS) Stage 3 neuroblastoma is a heterogeneous disease. Data from the International Neuroblastoma Risk Group (INRG) database were analyzed to define patient and tumor characteristics predictive of outcome. ProcedureOf 8,800 patients in the INRG database, 1,483 with INSS Stage 3 neuroblastoma and complete follow-up data were analyzed. Secondary analysis was performed in 1,013 patients (68%) with MYCN-non-amplified (NA) tumors. Significant prognostic factors were identified via log-rank test comparisons of survival curves. Multivariable Cox proportional hazards regression model was used to identify factors independently predictive of event-free survival (EFS). ResultsAge at diagnosis (P

Collectively, sarcomas represent 12% of cancers occurring in individuals between birth and 19 years of age; 60% are soft tissue sarcomas and 40% are bone sarcomas. Soft tissue sarcomas may be broadly divided into two groups: rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue sarcomas. The two most common malignant primary bone sarcomas are osteosarcoma and Ewing sarcoma. The treatment of sarcomas has been a challenge in the field of pediatric oncology. Despite the conduct of clinical trials that have introduced new agents into the standard backbones of therapy, there has not been a significant improvement in the overall survival of metastatic sarcomas in the past several decades. This chapter provides an overview of the workup and multidisciplinary treatment of the common pediatric bone and soft tissue sarcomas.

Glomerular hyperfiltration has recently been reported in children with malignancies and has been attributed to increased solute from breakdown of tumor tissues. To evaluate the prevalence of hyperfiltration in the pediatric oncology population and explore its pathophysiological mechanism. Tc-99 m diethylenetriaminepentaacetic acid (DTPA) glomerular filtration rate (GFR) examinations (437 studies) and medical records of 177 patients

Background Individuals with Neurofibromatosis type 1 (NF1) are at risk for developing malignant peripheral nerve sheath tumors (MPNST), which frequently arise in preexisting plexiform neurofibromas (PN). Magnetic resonance imaging (MRI) with volumetric analysis and 18-fluorodeoxyglucose-positron emission tomography (FDG-PET) were utilized to monitor symptomatic nodular lesions. Procedure Patients with NF1 and PN on a NCI natural history trial were monitored for total body tumor volume (TTV) using volumetric MRI. FDG-PET was performed in individuals with a nodular well-demarcated lesion ≥3 cm if they were growing, painful, or there was a prior history of MPNST (target lesions). Asymptomatic nodular lesions were evaluated as non-target lesions. Results Fifteen patients (8m, 7f) median age of 18.3 years (range, 10–45 years) had a single target and non-target (n = 46) nodular lesions identified on MRI. Target lesions arose within (n = 8) or outside (n = 3) a PN, and all but 1 had increased FDG uptake. FDG uptake was increased in non-target lesions but to a lesser degree. FDG uptake in the surrounding PN was low, similar to background activity. Pathologic evaluation performed in 11 patients demonstrated neurofibroma (n = 6), atypical neurofibroma (n = 2) and malignancy (n = 3). Conclusions Nodular target lesions identified on MRI in individuals with NF1 and PN demonstrate increased FDG uptake similar to MPNST, but may be benign on biopsy. Nodular target lesions may be at greater risk for malignant transformation, but their biologic and clinical behavior has not been well studied. Careful longitudinal evaluation will be required to better understand the malignant potential of these lesions. Pediatr Blood Cancer 2013; 60: 59–64. © 2012 Wiley Periodicals, Inc.

Neuroblastoma, a tumor of the sympathetic nervous system, is the most common extra-cranial neoplasm of childhood. Variables with prognostic significance in patients with neuroblastoma, including age at diagnosis, disease stage, tumor histology, MYCN gene amplification, tumor cell ploidy, and the presence of segmental chromosomal aberrations are utilized to classify patients based on risk of disease recurrence. Patients with non-high-risk neuroblastoma, low- and intermediate-risk categories, represent nearly half of all newly diagnosed cases. This group has an excellent event-free and overall survival with current therapy. Over time, the objective in treatment of non-high-risk neuroblastoma has been reduction of therapy intensity to minimize short- and long-term adverse events all the while maintaining excellent outcomes.

The extent to which a drug inhibits a target responsible for a therapeutic effect is a more rational primary endpoint for dose-finding studies of more selective anticancer drugs than the conventional endpoint of dose-limiting toxicity (DLT) used for cytotoxic agents. An adaptive phase I trial design incorporating maximum target inhibition as the primary endpoint was developed to define the optimal dose of talabostat, a dipeptidyl peptidase (DPP) inhibitor, in children with relapsed or refractory solid tumors. The relationship between dose and effect (percent inhibition of serum DPP-4) was assessed using a maximum effect model. Maximum target inhibition was defined as greater than 90% DPP-4 inhibition in five or more of six patients 24 hours post-dose. If DLT was to occur, the trial would adapt to a traditional phase I design with a more conservative dose escalation. At the 600 microg/m(2) dose level, serum DPP-4 inhibition at 24 hours was 85%. No talabostat-related DLT occurred. The maximum effect model predicted that 1200 microg/m(2) of talabostat would maximally inhibit DPP-4. This adaptive trial design appears to be feasible, safe, and efficient and warrants further evaluation for development of molecularly targeted agents.

3042Background: Patients with solid tumors refractory to standard therapies have poor prognoses, and most salvage therapies are toxic and ineffective. Antigen-specific T cell therapies offer a prom...

Background—ABT-751, an orally bioavailable sulfonamide, binds β-tubulin to inhibit microtubule polymerization. To describe response and event free survival (EFS) in children with neuroblastoma and other solid tumors receiving ABT-751, assess in vitro cytotoxicity of ABT-751 and evaluate the effect of ABT-751 on tubulin polymerization in peripheral blood mononuclear cells (PBMC) and pediatric tumor cell lines. Procedure—Patients with neuroblastoma (n=50) or other solid tumors (n=26) enrolled on the ABT-751 pediatric phase I and pilot trials were reviewed. The sulforhodamine B (SRB) and ACEA Real-Time Cell Electronic Sensing (RT-CES) assays were used to determine the in vitro cytotoxicity. Pharmacodynamic effects on tubulin polymerization/depolymerization were assessed by western blot and confocal microscopy using antibodies specific for post-translational modifications of polymerized tubulin. Results—Forty-five patients with neuroblastoma were evaluated for anti-tumor response. No complete or partial responses were documented. The median EFS was 9.3 weeks for children with neuroblastoma and 3.3 weeks for children other solid tumors (P

Tumor necrosis factor (TNF), a peptide produced by macrophages with cytostatic and cytolytic effects, demonstrated single agent antitumor activity and synergistic effect when administered with dactinomycin in in vitro tumor cell lines, in vivo xenograft models, and adult and pediatric phase 1 clinic

Erlotinib hydrochloride is a small molecule inhibitor of epidermal growth factor receptor (EGFR). EGFR is over-expressed in primary brain tumors and solid tumors that metastasize to the central nervous system. We evaluated the plasma and cerebrospinal fluid (CSF) pharmacokinetics of erlotinib and its active metabolite OSI-420 after an intravenous (IV) dose in a non-human primate model.Erlotinib was administered as a 1 h IV infusion to four adult rhesus monkeys. Serial blood and CSF samples were drawn over 48 h and erlotinib and OSI-420 were quantified with an HPLC/tandem mass spectroscopic assay. Pharmacokinetic parameters were estimated using non-compartmental and compartmental methods. CSF penetration was calculated from the AUC(CSF):AUC(plasma).Erlotinib disappearance from plasma after a short IV infusion was biexponential with a mean terminal half-life of 5.2 h and a mean clearance of 128 ml/min per m(2). OSI-420 exposure (AUC) in plasma was 30% (range 12-59%) of erlotinib, and OSI-420 clearance was more than 5-fold higher than erlotinib. Erlotinib and OSI-420 were detectable in CSF. The CSF penetration (AUC(CSF):AUC(plasma)) of erlotinib and OSI-420 was5% relative to total plasma concentration, but CSF drug exposure was approximately 30% of plasma free drug exposure, which was calculated from published plasma protein binding values. The IV administration of erlotinib was well tolerated.Erlotinib and its active metabolite OSI-420 are measurable in CSF after an IV dose. The drug exposure (AUC) in the CSF is limited relative to total plasma concentrations but is substantial relative the free drug exposure in plasma.

Background B43-pokeweed antiviral protein (B43-PAP) is a high-affinity anti-CD19 immunotoxin that is capable of causing apoptotic death in B-lineage leukemic cells with a drug-resistant phenotype. B43-PAP exhibited in vivo antileukemic activity in preclinical studies as well as on a single-agent phase I clinical trial. This pediatric phase I/II study evaluated the toxicity profile and efficacy of B43-PAP immunotoxin in combination with standard induction chemotherapy in children and adolescents with relapsed CD19-positive B-lineage acute lymphoblastic leukemia (B-ALL). Pharmacokinetic profile and immunogenicity of B43-PAP were assessed. Experimental design B43-PAP in combination with standard 3 and 4-drug induction chemotherapy was administered on days 9-13 and 21-25 of a 28-day treatment course with vincristine, prednisone, L-asparaginase, daunomycin, and intrathecal methotrexate. Thirty patients with relapsed B-ALL were enrolled on study CCG-0957. Results Grade III/IV nonhematologic dose-limiting toxicities were encountered in 4 patients evaluable for toxicity and included myalgias, motor dysfunction, pulmonary toxicity, and elevated liver transaminase. Dose-limiting toxicities occurred only with the 4-drug regimen. Fourteen patients achieved a complete remission at the end of induction among the 20 patients evaluable for response. Conclusions B43-PAP in combination with standard induction chemotherapy can be safely administered and exhibits clinical antileukemic activity against relapsed B-ALL.

Objective: To describe the diagnosis and management of a one-year-old male who presented with stridor due to a retropharyngeal neuroblastoma. Method: Retrospective case review. Results: The retropharyngeal neuroblastoma was surgically debulked in the operating room and the stridor improved significantly. The patient continues to be followed with serial MRIs and has no evidence of tumor regrowth or metastasis to this date. Conclusion: Neuroblastoma should be considered in the differential diagnosis of a pediatric retropharyngeal mass. If 50% of the tumor is debulked, the patient can be treated conservatively unless aerodigestive symptoms do not resolve or metastasis is present.

International Neuroblastoma Staging System (INSS) Stage 3 neuroblastoma is a heterogeneous disease. Data from the International Neuroblastoma Risk Group (INRG) database were analyzed to define patient and tumor characteristics predictive of outcome.Of 8,800 patients in the INRG database, 1,483 with INSS Stage 3 neuroblastoma and complete follow-up data were analyzed. Secondary analysis was performed in 1,013 patients (68%) with MYCN-non-amplified (NA) tumors. Significant prognostic factors were identified via log-rank test comparisons of survival curves. Multivariable Cox proportional hazards regression model was used to identify factors independently predictive of event-free survival (EFS).Age at diagnosis (P0.0001), tumor MYCN status (P0.0001), and poorly differentiating/undifferentiated histology (P = 0.03) were independent predictors of EFS. Compared to other Stage 3 subgroups, outcome was inferior for patients ≥ 547 days with MYCN-NA neuroblastoma (P0.0001), and within this cohort, serum ferritin ≥ 96 ng/ml was associated with inferior EFS (P = 0.02). For patients547 days of age with MYCN-NA tumors, serum ferritin levels were prognostic of overall survival (OS) (P = 0.04) and chromosome 11q aberration was prognostic of EFS (P = 0.03).Among patients with INSS Stage 3 neuroblastoma patients, age at diagnosis, MYCN status and histology predict outcome. Patients547 days of age with MYCN-NA tumors that lack chromosome 11q aberrations or those with serum ferritin96 ng/ml have excellent prognosis and should be considered for therapy reduction. Prospective clinical trials are needed to identify optimal therapy for those patients ≥ 547 days of age with undifferentiated histology or elevated serum ferritin.

Renal medullary carcinoma (RMC) was first described over two decades ago as the seventh sickle nephropathy. Survival after diagnosis with metastatic disease still rarely extends beyond 1 year, with recent reports of median overall survival in patients treated with platinum therapy being just 10 months. We describe our experience using platinum-based chemotherapy plus the proteasome inhibitor bortezomib to treat metastatic RMC in two pediatric patients who had complete responses. One patient passed away 7 years after diagnosis, while another remains disease free nearly 2 years from diagnosis.

Malignant peripheral nerve sheath tumors (MPNSTs) are the most common malignancy associated with NF1. At present, complete surgical removal is the only successful treatment for MPNST, and the outcome for unresectable, recurrent, or metastatic MPNST remains poor. Because 50 % of MPNSTs arise in individuals with NF1, and because the prognosis of NF1-associated MPNST appears to be worse than that of sporadic tumors, many studies of MPNST have used NF1 models and comparisons between sporadic and NF1 MPNST. Currently, molecular analyses and preclinical testing are beginning to aid in the identification of promising therapies to target these neoplasms. Knowledge of the epidemiology, clinical presentation, diagnosis, and prognostic factors for MPNST is anticipated to allow for earlier detection of, and more successful treatment for, MPNST.

ABT-751, an orally bioavailable sulfonamide, binds beta-tubulin to inhibit microtubule polymerization. We described response and event-free survival (EFS) in children with neuroblastoma and other solid tumors receiving ABT-751, assessed in vitro cytotoxicity of ABT-751 and evaluated the effect of ABT-751 on tubulin polymerization in peripheral blood mononuclear cells (PBMC) and pediatric tumor cell lines.Patients with neuroblastoma (n = 50) or other solid tumors (n = 26) enrolled on the ABT-751 pediatric phase I and pilot trials were reviewed. The sulforhodamine B (SRB) and ACEA Real-Time Cell Electronic Sensing (RT-CES) assays were used to determine the in vitro cytotoxicity. Pharmacodynamic effects on tubulin polymerization/depolymerization were assessed by Western blot and confocal microscopy using antibodies specific for post-translational modifications of polymerized tubulin.Forty-five patients with neuroblastoma were evaluated for anti-tumor response. No complete or partial responses were documented. The median EFS was 9.3 weeks for children with neuroblastoma and 3.3 weeks for children other solid tumors (P0.0001). The ABT-751 IC(50) was 0.6-2.6 mcM in neuroblastoma and 0.7-4.6 mcM in other solid tumor cell lines. Following drug exposure, polymerized tubulin decreased in a concentration- and time-dependent manner in cell lines.In children treated with ABT-751, the EFS is longer in children with neuroblastoma as compared to other diagnoses. In vitro, ABT-751 was cytotoxic at concentrations tolerable in children. Effects of ABT-751 on polymerization and microtubule structure were time- and dose-dependent but not dependent on tumor type.

Temozolomide pharmacokinetics were evaluated in children receiving concurrent O(6)-benzylguanine (O(6)BG), which enhanced the hematological toxicity of temozolomide.Temozolomide was administered orally, daily for 5 days starting at 28 mg/m(2) per day with escalations to 40, 55, 75 and 100 mg/m(2) per day with O(6)BG intravenously daily for 5 days at doses of 60, 90 or 120 mg/m(2) per day. Plasma samples were drawn over 48 h after the day 5 dose. Temozolomide was quantified with a validated HPLC/tandem mass spectroscopic assay.Temozolomide was rapidly absorbed (mean T (max), 2.1 h). The mean apparent clearance (CL/F) (96 mL/min/m(2)) was similar to the CL/F for temozolomide alone and was not age- or gender-dependent. There was minimal inter-patient variability.The enhanced hematologic toxicity resulting from combining O(6)BG with temozolomide does not appear to be the result of a pharmacokinetic interaction between the agents.

Background Positron emission tomography (PET) differentiates normal from abnormal cells based on metabolic activity. Numerous studies report that PET scan offers increased sensitivity, specificity and predictive values as compared to computed tomography (CT) in adult lymphoma patients. Procedure Twenty-three consecutive pediatric Hodgkin lymphoma (HL) patients were evaluated with PET scan either at diagnosis or during treatment, then at therapy completion and in follow-up. Results Twenty two of the 23 patients had a negative PET scan at the end of therapy; however, ten later developed a positive scan for a total of 11 (47.8%) patients with a positive post treatment PET scan. Six tissue biopsies were performed in five patients; four specimens were negative for disease and two confirmed HL relapse. Six patients were monitored clinically and remained asymptomatic; four had resolution of abnormalities on repeat PET while two had persistently positive, but stable PET scan findings and continue to be in remission at 11 and 40 months following treatment. Twelve (52.2%) patients of the original cohort have had consistently negative PET scans and have not relapsed. Conclusions PET is a sensitive (100%), but not a specific (57.1%) method for evaluating post-treatment pediatric HL patients with a strong negative predictive value (NPV; 100%), but poor positive predictive value (PPV; 18.2%). We do not recommend treatment decisions be based solely on PET scan results. Pediatr Blood Cancer © 2006 Wiley-Liss, Inc.

10052 Background: Sorafenib, an orally bioavailable, multi-target tyrosine kinase inhibitor, and irinotecan, a topoisomerase I inhibitor, have demonstrated single agent activity in various malignan...

9533 Background: Patients with non-high-risk neuroblastoma (low- and intermediate-risk) generally have an excellent event free (EFS) and overall (OS) survival with current therapy. However, within this heterogeneous patient population, there are patients that may benefit from further therapy reduction and patients that may benefit from augmented therapy. Methods: Survival tree regression analysis was performed in patients enrolled on P9641 and A3961 with OS the primary endpoint. Univariate Cox proportional hazards models determined statistically significant prognostic factors. Secondary analysis of cases with MYCN non-amplified, non-high-risk neuroblastoma classified patients by age, INSS stage, Shimada histology and genomic features to determine 5-year EFS and OS. Favorable genomics were defined as hyperdiploid tumors without 1p or 11q loss of heterozygosity (LOH). Those with LOH at 1p or 11q or with a diploid DNA index were considered unfavorable. Patients without genomic data were excluded. Results: In the survival tree analysis, ploidy and genomic features were found to be statistically significant. In the secondary analysis, patients

10027 Background: The optimal dose of less toxic molecularly targeted agents should be defined by target modulation rather than toxicity. Talabostat is an inhibitor of dipeptidyl peptidase 4 (DPP-4...