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Background The Children's Oncology Group (COG) adopted cisplatin, 5-flourouracil, and vincristine (C5V) as standard therapy after the INT-0098 legacy study showed statistically equivalent survival but less toxicity in comparison with cisplatin and doxorubicin. Subsequent experience demonstrated doxorubicin to be effective in patients with recurrent disease after C5V, and this suggested that it could be incorporated to intensify therapy for patients with advanced disease. Methods In this nonrandomized, phase 3 COG trial, the primary aim was to explore the feasibility and toxicity of a novel therapeutic cisplatin, 5-flourouracil, vincristine, and doxorubicin (C5VD) regimen with the addition of doxorubicin to C5V for patients considered to be at intermediate risk. Patients were eligible if they had unresectable, nonmetastatic disease. Patients with a complete resection at diagnosis and local pathologic evidence of small cell undifferentiated histology were also eligible for an assessment of feasibility. Results One hundred two evaluable patients enrolled between September 14, 2009, and March 12, 2012. Delivery of C5VD was feasible and tolerable: the mean percentages of the target doses delivered were 96% (95% CI, 94%-97%) for cisplatin, 96% (95% CI, 94%-97%) for 5-fluorouracil, 95% (95% CI, 93%-97%) for doxorubicin, and 90% (95% CI, 87%-93%) for vincristine. Toxicity was within expectations, with death as a first event in 1 patient. The most common adverse events were febrile neutropenia (n = 55 [54%]), infection (n = 48 [47%]), mucositis (n = 31 [30%]), hypokalemia (n = 39 [38%]), and elevated aspartate aminotransferase (n = 28 [27%]). The 5-year event-free and overall survival rates for the 93 patients who did not have complete resection at diagnosis were 88% (95% CI, 79%-93%) and 95% (95% CI, 87%-98%), respectively. Conclusions The addition of doxorubicin to the previous standard regimen of C5V is feasible, tolerable, and efficacious, and this suggests that C5VD is a good regimen for future clinical trials.

Sorafenib improves outcomes in adult hepatocellular carcinoma; however, hand foot skin reaction (HFSR) is a dose limiting toxicity of sorafenib that limits its use. HFSR has been associated with sorafenib systemic exposure. The objective of this study was to use modeling and simulation to determine whether using pharmacokinetically guided dosing to achieve a predefined sorafenib target range could reduce the rate of HFSR. Sorafenib steady‐state exposures (area under the concentration curve from 0 to 12‐h [AUC0–>12 h]) were simulated using published sorafenib pharmacokinetics at either a fixed dosage (90 mg/m2/dose) or a pharmacokinetically guided dose targeting an AUC0–>12 h between 20 and 55 h µg/ml. Dosages were either rounded to the nearest quarter of a tablet (50 mg) or capsule (10 mg). A Cox proportional hazard model from a previously published study was used to quantify HFSR toxicity. Simulations showed that in‐target studies increased from 50% using fixed doses with tablets to 74% using pharmacokinetically guided dosing with capsules. The power to observe at least 4 of 6 patients in the target range increased from 33% using fixed dosing with tablets to 80% using pharmacokinetically guided with capsules. The expected HFSR toxicity rate decreased from 22% using fixed doses with tablets to 16% using pharmacokinetically guided dosing with capsules. The power to observe less than 6 of 24 studies with HFSR toxicity increased from 51% using fixed dosing with tablets to 88% using pharmacokinetically guided with capsules. Our simulations provide the rationale to use pharmacokinetically guided sorafenib dosing to maintain effective exposures that potentially improve tolerability in pediatric clinical trials.

Introduction Rubinstein-Taybi syndrome (RSTS) is a rare genetic syndrome caused primarily by a mutation in the CREBBP gene found on chromosome 16. Patients with RSTS are at greater risk for a variety of medical problems, including upper airway obstruction and aspiration. Childhood interstitial lung disease (ILD) thus far has not been definitively linked to RSTS. Here we present three patients with RSTS who developed ILD and discuss possible mechanisms by which a mutation in CREBBP may be involved in the development of ILD. Methods Routine hematoxylin and eosin staining was performed on lung biopsy tissue for histological analysis. Immunofluorescent staining was performed on lung biopsy tissue for markers of fibrosis, surfactant deficiency and histone acetylation. Cases 1 and 2 had standard clinical microarray analysis. Case 3 had whole exome sequencing. Bioinformatics analyses were performed to identify possible causative genes using ToppGene. Results CT images in all cases showed consolidated densities overlying ground glass opacities. Lung histopathology revealed accumulation of proteinaceous material within alveolar spaces, evidence of fibrosis, and increased alveolar macrophages. Immunofluorescent staining showed increase in surfactant protein C staining, patchy areas of increased aSMA staining, and increased staining for acetylated histone 2 and histone 3 lysine 9. Discussion Clinical characteristics, radiographic imaging, lung histopathology, and immunofluorescent staining results shared by all cases demonstrated findings consistent with ILD. Immunofluorescent staining suggests two possible mechanisms for the development of ILD: abnormal surfactant metabolism and/or persistent activation of myofibroblasts. These two pathways could be related to dysfunctional CREBBP protein. This article is protected by copyright. All rights reserved.

Recent increased awareness and research studies reflect possible associations between opioid exposure and cancer outcomes. Children with neuroblastoma (NB) often require opioid treatment for pain. However, associations between tumor response to chemotherapy and opioid exposure have not been investigated in clinical settings.This is a single-institution retrospective review of patients with NB treated between 2013 and 2016. We evaluated opioid consumption quantified in morphine equivalent doses (mg/kg) based on nurse- or patient-controlled analgesia during antibody infusions. We also analyzed their associations with change in primary tumor volume and total tumor burden.Of 42 patients given opioids for pain related to anti-disialoganglioside monoclonal antibodies (anti-GD2 mAb), data completion was achieved for 36, and details of statistical analyses were entered. Median total weight-based morphine equivalent (over 8 days) was 4.71 mg/kg (interquartile range 3.49-7.96). We found a statistically insignificant weak negative relationship between total weight-based morphine equivalents and tumor volume ratio (correlation coefficient -.0103, p-value .9525) and a statistically insignificant weak positive relationship between total weight-based morphine equivalent and Curie score ratio (correlation coefficient .1096, p-value .5247).Our study found no statistically significant correlation between opioid consumption and natural killer (NK) cell-mediated killing of NB cells as measured by effects on tumor volume/tumor load.

Background The prognosis for children with recurrent solid tumors generally is poor. Targeting mammalian target of rapamycin (mTOR) and vascular endothelial growth factor A with everolimus and bevacizumab, respectively, synergistically improves progression-free survival and is well tolerated in adults with solid tumors. Methods In the current phase 1 study, a total of 15 children with recurrent or refractory solid tumors were treated with bevacizumab and everolimus to establish the maximum tolerated dose, toxicity, and preliminary antitumor response (ClinicalTrials.gov identifier NCT00756340). The authors also evaluated everolimus-mediated inhibition of the mTOR pathway in the peripheral blood mononuclear cells of treated patients. Results Tumors predominantly were soft tissue and/or bone sarcomas (8 cases) and brain tumors (5 cases). The first 2 patients enrolled at dose level 1 (10 mg/kg of bevacizumab and 4 mg/m2 of everolimus) experienced dose-limiting toxicities (DLTs). The next 5 patients were enrolled at dose level 0 (8 mg/kg of bevacizumab and 4 mg/m2 of everolimus), and DLTs occurred in 2 patients. The authors then modified the protocol to permit expansion of dose 0, and 8 additional patients were added, with no DLTs reported. Of all the patients, stable disease occurred in 4 patients (30.8%; median, 2 courses), and progressive disease occurred in 9 patients (69.2%). Overall survival was 0.59 years (95% CI, 0.24-1.05 years). The mTOR biomarker phospho-4EBP1 Thr/37/46 significantly decreased from baseline to day 27 in peripheral blood mononuclear cells (P = .045). Phospho-AKT levels also decreased from those at baseline. Conclusions The maximum tolerated dose of cotreatment with bevacizumab and everolimus was 8 mg/kg of bevacizumab and 4 mg/m2 of everolimus in a 4-week cycle for children with recurrent solid tumors.

BACKGROUND The objective of this study was to characterize chronic disease, health-related quality of life (HRQOL), emotional distress, and social attainment among long-term survivors of neuroblastoma. METHODS Chronic health conditions among 136 ≥10-year neuroblastoma survivors (median age, 31.9 years; range, 20.2-54.6 years) and 272 community controls (median age, 34.7 years; range, 18.3-59.6 years) were graded with a modified version of the Common Terminology Criteria for Adverse Events (version 4.03). HRQOL and emotional distress were assessed with the Medical Outcomes Study 36-Item Short Form Health Survey and the Brief Symptom Inventory-18. Log-binomial regression and logistic regression were used to compare the prevalence of chronic conditions and the frequency of reduced HRQOL, distress, and social attainment between survivors and controls. The cumulative burden approach was used to estimate multimorbidity. RESULTS By the age of 35 years, survivors had experienced, on average, 8.5 grade 1 to 5 conditions (95% confidence interval [CI], 7.6-9.3), which was higher than the average for controls (3.3; 95% CI, 2.9-3.7). Compared with controls, survivors had a higher prevalence of any pulmonary (P = .003), auditory (P

Background It is possible that the relative lack of progress in treatment outcome among the adolescent and young adult (AYA) group of cancer patients is due to a difference in disease biology compared to the corresponding diseases in younger and older individuals. There is evidence that colon cancer is more aggressive, and has a poorer prognosis in AYA patients than that observed in older adult patients.

BACKGROUND The identification of new therapies for high-risk (HR) hepatoblastoma is challenging. Children's Oncology Group study AHEP0731 included a HR stratum to explore the efficacy of novel agents. Herein, the authors report the response rate to the combination of vincristine (V) and irinotecan (I) and the outcome of patients with high-risk hepatoblastoma. METHODS Patients with newly diagnosed metastatic hepatoblastoma or those with a serum α-fetoprotein (AFP) level 1 log10) decline in their AFP level. Responders were to receive 2 additional cycles of VI intermixed with 6 cycles of the combination of cisplatin, doxorubicin, 5-fluorouracil, and vincristine (C5VD). Nonresponders were to receive 6 cycles of C5VD alone. RESULTS A total of 32 patients with a median age at diagnosis of 26 months (range, 11-159 months) were enrolled between September 2009 and February 2012. Fourteen of 30 evaluable patients were responders (RECIST and AFP in 6 patients, RECIST only in 3 patients, and AFP only in 5 patients). The median AFP decline after 2 cycles of VI for the entire group was 345,565 ng/mL (85% of the initial AFP). The 3-year event-free and overall survival rates were 49% (95% confidence interval, 30%-65%) and 62% (95% confidence interval, 42%-77%), respectively. CONCLUSIONS The VI combination appears to have substantial activity against HR hepatoblastoma. The ultimate impact of this regimen in improving the outcomes of children with HR hepatoblastoma remains to be determined. Cancer 2017;123:2360–2367. © 2017 American Cancer Society.

BACKGROUND Neuroblastoma, the most common extracranial solid tumor of childhood, produces catecholamines that are metabolized within tumor cells. Homovanillic acid (HVA) and vanillylmandelic acid (VMA), the end products of catecholamine metabolism, have limited accuracy for testing of the tumors. This study assessed whether metabolites produced in earlier steps of catecholamine metabolism might offer improved diagnostic accuracy over urinary HVA and VMA. PROCEDURE Plasma concentrations of 3-methoxytyramine, normetanephrine, and metanephrine were measured in two pediatric cohorts: (i) 96 children with confirmed neuroblastoma and (ii) 41 children with signs and symptoms of a catecholamine-producing tumor or other neoplasms and in whom neuroblastoma was excluded. Additional measurements of plasma 3-O-methyldopa and relationships of metabolites to MYCN amplification were examined in patient subgroups. RESULTS Overall, 94 of the 96 patients with neuroblastoma had concentrations of 3-methoxytyramine or normetanephrine above age-specific upper limits of reference intervals, providing a diagnostic sensitivity of 97.9% that was higher (P

Secondary hemophagocytic syndrome (HPS) has been described after autologous hematopoietic cell transplant (AutoHCT). We report two cases of secondary HPS after novel consolidation therapy for high-risk neuroblastoma as part of an institutional phase 2 trial incorporating immunotherapy into a "standard" AutoHCT regimen. Both patients developed liver dysfunction beyond expected course of hepatic veno-occlusive disease, coagulopathy, hyperferritinemia, and when evaluated, elevated soluble interleukin-2 receptor and hemophagocytosis. These cases highlight the need for clinicians to have a high index of suspicion for immune-related complications in patients receiving immune therapies.

Background A total of 5–10% of patients with retinoblastoma (RB) harbor deletion of the long arm (q) chromosome 13 (13q-). The treatment-related toxicities in this population have not been described. Methods Sixty-eight RB patients on a single institutional protocol (RET5) from 2005 to 2010 were reviewed. Genetic screening identified 11 patients (seven female) with 13q-. Patients with early (Reese-Ellsworth [R-E] group I–III) disease (6/23 with 13q-) received eight courses of vincristine/carboplatin (VC). Patients with advanced (R-E group IV-V) bilateral disease (2/27 with 13q-) received two courses of vincristine/topotecan (VT) followed by nine courses of alternating VT/VC. Patients undergoing upfront enucleation received histopathology-based chemotherapy: intermediate risk (2/8 with 13q-) or high risk (1/10 with 13q-). Dose reductions were mandated for >7 day delay in two consecutive courses following hematologic toxicity. Grades 3 and 4 hematologic, infectious, and gastrointestinal toxicities were compared between RET5 patients with and without 13q-. Results Demographics were similar between groups. When present, prolonged neutropenia (median 7 days, range 0–14 days) delayed chemotherapy and resulted in more frequent dose reductions among 13q- patients (5/11) than non-13q- patients (4/57) (P < 0.01). GI toxicity was similar between groups (5/11 13q- vs. 13/57 non-13q-; P = 0.14), but halted chemotherapy in one 13q- patient. Infectious complications and disease outcomes were similar between groups. At follow-up, all patients are alive (median 6.1 years, range 7.6 months–9.5 years). Conclusions 13q- RB patients had a higher incidence of neutropenia requiring chemotherapy dose reductions, but did not have increased treatment failure.

Background Pegylated interferon α-2b (IFN α-2b) improves disease-free survival in adults with resected stage III melanoma. We conducted a study to determine the feasibility and safety of incorporating pegylated IFN α-2b as adjuvant therapy in the treatment of children and adolescents with high-risk melanoma. Pharmacokinetic studies of IFN α-2b and neuropsychological and quality of life (OL) assessments were performed. Patient and Methods Eligible patients with resected American Joint Committee on Cancer Stage IIC, IIIA, and IIIB cutaneous melanoma received nonpegylated IFN α-2b 20 million units/m2/day intravenously 5 days per week for 4 weeks (induction) followed by pegylated IFN α-2b 1 μg/kg/dose weekly subcutaneously (SQ) for 48 weeks (maintenance). Results Twenty-three patients (15 females, median age 10 years) were enrolled. All patients completed induction therapy; five patients did not complete maintenance therapy either because of recurrent disease (n = 2) or toxicity (n = 3). The most common grade 3 and 4 toxicities of pegylated IFN α-2b were neutropenia (35%) and elevated liver transaminases (17%). The median nonpegylated IFN α-2b AUC0-∞ (5,026 pcg⋅hr/ml) was similar to adults. The median pegylated IFN α-2b exposure (48,480 pcg⋅hr/ml) was greater than the cumulative weekly exposure for nonpegylated IFN α-2b administered SQ three times per week (TIW). Validated measures demonstrated an improvement in QOL scores and no decline in psychological functioning over the course of therapy. Conclusions Pegylated IFN α-2b 1 μg/kg/dose SQ weekly as maintenance therapy in children and adolescents with high-risk melanoma is feasible with tolerable toxicity and appears to yield higher exposures than nonpegylated IFN α-2b administered SQ TIW.

Background Esthesioneuroblastoma (ENB) is a rare cancer of the nasal cavity in children. Radical surgery followed by postoperative radiation is considered the standard of care in adults. A similar approach in children can lead to significant long-term morbidity. Procedure A retrospective multi-institutional review of patients less than 21 years of age diagnosed with ENB between 1990 and 2014 was performed. Clinical features, treatment, and outcome were obtained from the medical records. Results Twenty-four patients were identified with a median age of 14 years (range 0.6–20 years) at diagnosis. The majority (75%) were females. Headache was the most common presenting symptom, followed by nasal obstruction and epistaxis. Eight patients had Kadish stage B tumors and 16 had Kadish stage C tumors. Nine patients had metastatic disease. Gross total resection was achieved at diagnosis in eight patients and after neoadjuvant chemotherapy in four patients. Twenty-one patients received radiation therapy (45–68.4 Gy). Thirteen patients received neoadjuvant chemotherapy with 84% objective response rate. Seven patients experienced disease progression or relapse—five in central nervous system, one local, and one in cervical lymph node. Fifteen patients were alive at the last follow-up. The 5-year disease-free survival and overall survival were 74% and 73%, respectively. Late effects were observed in 78% of long-term survivors. Four patients developed subsequent malignant neoplasms. Conclusions Pediatric ENB is a chemosensitive disease. Preoperative chemotherapy-based multimodal approach should be used in patients with advanced stage disease. Radiation therapy is effective for local control, but lower doses should be considered in children.

Background Standardization of imaging obtained in children with neuroblastoma is not well established. This study examines chest CT in pediatric patients with high-risk neuroblastoma. Procedure Medical records and imaging from 88 patients with high-risk neuroblastoma, diagnosed at St. Jude Children's Research Hospital between January, 2002 and December, 2009, were reviewed. Surveillance imaging was conducted through 2013. Ten patients with thoracic disease at diagnosis were excluded. Event free survival (EFS) and overall survival (OS) were estimated. Size specific dose estimates for CT scans of the chest, abdomen, and pelvis were used to estimate absolute organ doses to 23 organs. Organ dosimetry was used to calculate cohort effective dose. Results The 5 year OS and EFS were 51.9% ± 6.5% and 42.6% ± 6.5%, respectively. Forty-six (58.9%) patients progressed/recurred and 41 (52.6%) died of disease. Eleven patients (14%) developed thoracic disease progression/recurrence identified by chest CT (1 paraspinal mass, 1 pulmonary nodules, and 9 nodal). MIBG (metaiodobenzylguanidine) scans identified thoracic disease in six patients. Five of the 11 had normal chest MIBG scans; three were symptomatic and two were asymptomatic with normal chest MIBG scans but avid bone disease. The estimated radiation dose savings from surveillance without CT chest imaging was 42%, 34% when accounting for modern CT acquisition (2011–2013). Conclusions Neuroblastoma progression/recurrence in the chest is rare and often presents with symptoms or is identified using standard non-CT imaging modalities. For patients with non-thoracic high-risk neuroblastoma at diagnosis, omission of surveillance chest CT imaging can save 35–42% of the radiation burden without compromising disease detection. Pediatr Blood Cancer 2015;62:976–981. © 2015 Wiley Periodicals, Inc.

Background Addition of anti-GD2 antibody ch14.18 to the treatment of neuroblastoma has improved outcomes. The most common side effect of ch14.18 is neuropathic pain, which may in part be complement-mediated. Hu14.18K322A is a humanized anti-GD2 antibody designed to diminish complement activation and induce less pain. We compare the pain outcomes in patients treated with ch14.18 and those treated with hu14.18K322A, and explore dose-dependent relationships between pain scores, opioid requirements, and complement levels in patients treated with hu14.18K322A. Procedure Opioid (morphine equivalent mg/kg) and anxiolytic requirements during course 1 (4 days) in patients treated with hu14.18K322A and ch14.18 were reviewed. Correlations between antibody dose and pain scores, opioid requirements, and complement levels were examined for patients receiving hu14.18K322A. Results Patients treated with hu14.18K322A (n = 19) had lower opioid requirements than those who received ch14.18 (n = 9). The differences in median opioid requirements (mg/kg) were statistically significant for the overall course (1.57 vs. 2.41, P = 0.019) as well as for Days 3 (0.34 vs. 0.65, P = 0.005), and 4 (0.32 vs. 0.64, P = 0.010). No difference in anxiolytic use was observed between the two groups. In the group treated with hu14.18K322A, we found a positive correlation between antibody dose administered and pain scores, but no correlation between antibody dose and opioid requirements or changes in complement levels. Conclusions In this retrospective analysis, hu14.18K322A induced less pain than ch14.18 based on opioid requirements. Pediatr Blood Cancer 2015;62:224–228. © 2014 Wiley Periodicals, Inc.

Microarray-based molecular signatures have not been widely integrated into neuroblastoma diagnostic classification systems due to the complexities of the assay and requirement for high-quality RNA. New digital technologies that accurately quantify gene expression using RNA isolated from formalin-fixed paraffin embedded (FFPE) tissues are now available. In this study, we describe the first use of a high-throughput digital system to assay the expression of genes in an “ultra-high risk” microarray classifier in FFPE high-risk neuroblastoma tumors. Customized probes corresponding to the 42 genes in a published multi-gene neuroblastoma signature were hybridized to RNA isolated from 107 FFPE high-risk neuroblastoma samples using the NanoString nCounter™ Analysis System. For classification of each patient, the Pearson's correlation coefficient was calculated between the standardized nCounter™ data and the molecular signature from the microarray data. We demonstrate that the nCounter™ 42-gene panel sub-stratified the high-risk cohort into two subsets with statistically significantly different overall survival ( p = 0.0027) and event-free survival ( p = 0.028). In contrast, none of the established prognostic risk markers (age, stage, tumor histology, MYCN status, and ploidy) were significantly associated with survival. We conclude that the nCounter™ System can reproducibly quantify expression levels of signature genes in FFPE tumor samples. Validation of this microarray signature in our high-risk patient cohort using a completely different technology emphasizes the prognostic relevance of this classifier. Prospective studies testing the prognostic value of molecular signatures in high-risk neuroblastoma patients using FFPE tumor samples and the nCounter™ System are warranted.

Background Neoplasm-related precocious puberty (PP) is a rare presenting feature of childhood cancer. Moreover, evaluation of suspected PP in a child is complex, and cancer is often not considered. We characterized the clinicopathologic features of patients presenting with PP at a large pediatric cancer center, reviewed the relevant literature, and developed an algorithm for the diagnostic work-up of these patients.

Background Locoregional failure is a significant concern in patients with high-risk abdominal neuroblastoma (NB) receiving radiotherapy. Locoregional control outcomes were studied in children with NB receiving intensity modulated radiotherapy (IMRT). Procedure Twenty children (11 females, 9 males) with NB (median age at diagnosis 3.4 years) receiving IMRT were analyzed for locoregional failure, outcomes, and toxicities. IMRT doses were 23.4 Gy (n = 12), 30 Gy (n = 1), 30.6 Gy (n = 5), and 36.0 Gy (n = 2) based on extent of resection. Five patients had tumors with MYCN amplification, and 19 had metastatic disease. All patients were treated consistently using reproducible immobilization techniques; physiological motion was assessed by 4D-CT, and target localization by cone-beam computed tomography. ICRU 62 volumetric conventions were employed based on institutional data for pediatric target volume and organ motion. Results No patient developed primary site infield or locoregional failure at a median follow-up of 2.2 years. Distant failure (median time to distant failure 1.6 years) occurred in the brain, lungs, or skeletal sites in eight patients, five of whom died. The 2-year event-free survival was 58.5 ± 13.3% and cumulative incidence of local and distant failures was 0% and 41.5 ± 11.9%, respectively. Asymptomatic loose stool during RT occurred in nearly all patients, but required no intervention. Conclusions IMRT is feasible, safe in the short term, and yields excellent locoregional control. Despite subtotal resection in some cases, locoregional control appeared to be increased by conformal radiotherapy with ICRU 62-compliant volumes. Dose escalation beyond 30.6 Gy may be unnecessary with improved target volume coverage. Pediatr Blood Cancer 2013; 60: 761–765. © 2012 Wiley Periodicals, Inc.

Background—Administration of an oral cephalosporin allowed advancement of the dosage of oral irinotecan. This study investigates whether administration of an oral cephalosporin increases the maximum tolerated dose (MTD) of intravenous irinotecan. Procedure—Irinotecan was administered intravenously on Days 1– 5 and Days 8 – 12 of a 21day cycle with continuous oral cefpodoxime starting 2 days prior to irinotecan. Cohorts of 3 to 6 pediatric patients with refractory solid tumors were enrolled at 4 dosage levels, starting at the single-agent irinotecan MTD of 20 mg/m 2 /dose. Results—The 17 evaluable patients received 39 courses of therapy. None of the patients treated with 20 mg/m 2 /dose experienced dose-limiting toxicity (DLT). One of 6 patients treated at 30 mg/ m 2 /dose experienced dose-limiting neutropenia. Two of 3 patients treated with 45 mg/m 2 /dose and 2 of 5 treated with 40 mg/m 2 /dose experienced dose-limiting diarrhea, with associated dehydration and anorexia. Two unconfirmed partial responses were observed after one course in a patient with Ewing sarcoma and one with paraganglioma. A child with refractory neuroblastoma had disease stabilization through 12 courses of therapy. Median (range) systemic exposure to SN-38 at the MTD (30 mg/m 2 /dose) was 67 ng-h/mL (36 to 111 ng-h/mL).

Background Severe pandemic influenza A (H1N1) infection can lead to acute respiratory failure (ARF) with associated high mortality. Children with malignancy may be at higher risk of H1N1-associated ARF because of underlying primary disease or immunosuppression associated with chemotherapy. Procedure We describe the clinical course and outcome of critically ill pediatric oncology/hematology patients with H1N1-associated ARF. Results Five patients were admitted to the St. Jude Children's Research Hospital (SJCRH) ICU with H1N1 infection during the 2009–2010 influenza season. Underlying diagnoses included 2 patients with acute lymphoblastic leukemia and one each with neuroblastoma, brainstem glioma, and hemolytic anemia secondary to pyruvate kinase deficiency. All patients were mechanically ventilated secondary to ARF following unsuccessful trials of non-invasive ventilatory support. The majority of patients (4/5) required inotropic support, and none required dialysis. Further measures to support their ARF included high frequency oscillatory ventilation in 2 patients, nitric oxide in 3 patients, and surfactant in 1 patient. Three patients had bronchopleural air leak. All patients received oseltamivir; however, 2 were switched to intravenous zanamivir once resistance to oseltamivir was documented. Mean duration of mechanical ventilation was 24 ± 6.8 days and mean duration of ICU admission was 37 ± 12 days. All patients survived to hospital discharge. Conclusion Our series suggests an overall favorable outcome in immunocompromised children with H1N1-related ARF. Our experience underscores the value of aggressive support during H1N1-related ARF, and early detection and management of oseltamivir-resistant H1N1 infection in this high-risk population. Pediatr Blood Cancer 2011; 57: 625–628. © 2011 Wiley-Liss, Inc.

Background Intensification of systemic therapy for high-risk neuroblastoma (HRNB) has resulted in improved local control and overall survival (OS) leaving potential for de-escalation of primary site radiotherapy. The utility of primary site de-escalation should be evaluated in the context of potential for successful local-regional salvage. We evaluated salvage strategies and outcomes in patients with HRNB with local-regional recurrence as a component of first failure. Methods Twenty of 89 patients with HRNB experienced local-regional recurrence as a component of first relapse after chemotherapy, radiotherapy, surgery, and stem cell transplant from 1997 to 2013. We reviewed salvage therapy strategies and disease control, and report on the impact of local therapy as salvage for local-regional relapse. Results Six of 20 patients with local-regional failure (LRF) were alive after a median follow-up of 13 years (range, 0.9-25.2 years). Median OS was 4.6 years (95% CI, 0.6 to not reached) versus 0.6 years (95% CI, 0.05-2.6) after LRF with and without distant failure, respectively (P = 0.03). OS in patients receiving salvage radiotherapy was comparable to those receiving initial adjuvant but no salvage radiotherapy. Time to first failure and death was significantly impacted by the intensity of frontline systemic therapy (P = 0.03). Salvage radiotherapy reduced the hazard for subsequent LRF (hazard ratio 0.3, 95% CI 0.1-0.9, P = 0.04) but not OS (P = 0.07). Conclusions Our study highlights the potential of local control strategies at first failure in patients with LRF when primary site radiotherapy was initially omitted, and delineates potential selection factors which may further improve the therapeutic ratio.

Background Alveolar soft part sarcoma (ASPS) is a rare mesenchymal tumor characterized by ASPL-TFE3 translocation. Apart from complete surgical resection, there is no standard management strategy. Procedure The clinical data of 69 children and young adults less than 30 years old with ASPS diagnosed from 1980-2014 were retrospectively collected from four major institutions. Results Median age at diagnosis was 17 years (range: 1.5-30). Forty-four (64%) were female. Median follow-up was 46 months (range: 1-409). Most common primary sites were limbs (58%) and trunk (24%). ASPL-TFE3 translocation was present in all 26 patients tested. IRS postsurgical staging was I in 19 (28%), II in 7 (10%), III in 5 (7%), and IV in 38 (55%) patients. The 5-year event-free survival (EFS) and overall survival (OS) were 38% and 72%, respectively. The 5-year EFS and OS were 80% and 87%, respectively, for the 31 patients with localized tumors (IRS-I-II-III), and 7% and 61%, respectively, for the 38 patients with metastatic tumors (IRS-IV). Of 11 IRS-IV patients who received targeted therapy upfront, two had partial response, six had stable disease, and three had progressive disease. Median time to progression for IRS-IV patients was 12 months for those treated with targeted therapy, 7 months for cytotoxic chemotherapy (N = 15), and 4 months for observation only (N = 6). Conclusion Localized ASPS has a good prognosis after gross total resection. ASPS is resistant to cytotoxic chemotherapy. Although there are no curative therapies for patients with metastatic disease, prolonged disease stabilization may be achieved with targeted therapies.

BACKGROUND: For this report, the authors estimated the maximum tolerated dose (MTD) and investigated the toxicities of oxaliplatin combined with irinotecan in children with refractory solid tumors. METHODS: Oxaliplatin was administered on Days 1 and 8 in combination with irinotecan on Days 1 through 5 and Days 8 through 12 of a 21-day cycle. An oral cephalosporin was administered daily to ameliorate irinotecan-associated diarrhea. Pharmacokinetic studies of oxaliplatin and uridine diphosphate glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) genotyping were performed. RESULTS: Thirteen patients were enrolled. Dose-limiting diarrhea (n = 3), serum lipase elevation (n = 3), serum amylase elevation (n = 2), colitis, abdominal pain, and headache (n = 1 each) occurred at the first dose level (oxaliplatin at a dose of 60 mg/m2; irinotecan at a dose of 20 mg/m2). Only 1 of 7 patients who received reduced doses of both agents (40 mg/m2/dose oxaliplatin; 15 mg/m2/dose irinotecan) experienced a dose-limiting toxicity (DLT): diarrhea. When the oxaliplatin dose was re-escalated (60 mg/m2) with irinotecan at a dose of 15 mg/m2, 2 of 3 patients had a DLT (1 episode of diarrhea, 1 episode of hypokalemia). Myelosuppression was minimal. One patient had a complete response, and another patient had stable disease for 6 cycles of therapy. The median oxaliplatin area under the concentration versus time curve (AUC0∞) was 5.9 μg · hour/mL (range, 1.8-7.6 μg · hour/mL). The frequency of the 6/6, 6/7, and 7/7 UGT1A1 promoter genotypes was 5 of 10, 4 of 10, and 1 of 10, respectively. CONCLUSIONS: The oxaliplatin MTD was 40 mg/m2 per dose on Days 1 and 8 in combination with irinotecan 15 mg/m2 per dose on Days 1-5 and Days 8-12. There was some evidence of antitumor activity; however, severe toxicity, both expected (diarrhea) and unexpected (elevation in pancreatic enzymes), was observed. Cancer 2009. © 2009 American Cancer Society.

BACKGROUND: This prospective study was designed to be the first to evaluate the toxicity of radiofrequency ablation (RFA) in patients with recurrent pediatric solid tumors. METHODS: From 2003 through 2008, a phase 1/pilot study of RFA for recurrent pediatric solid tumors was conducted. A multidisciplinary cancer management team selected appropriate candidates for the study. Imaging-guided RFA was performed percutaneously. Repeat RFA was performed for recurrences when appropriate. Toxicity and imaging response was assessed at 1 month and 3 months prospectively. Accrual stopped in 2006, and data collection stopped in 2008. RESULTS: Sixteen patients (ages 4 years-33 years; median age, 15 years) and 56 tumor sites were treated in 37 RFA sessions including 38 pulmonary, 11 musculoskeletal, and 7 hepatic lesions (82 lesion-treatments). Postprocedural pain was moderate (median 5 on a scale from 1 to 10) and lasted a median of 9 days. Prolonged hospitalization (beyond 1 day) occurred 17 times (range, 2 days-25 days; median, 3 days). Hypoxia supported by supplemental oxygen occurred in 8 of 16 patients and resolved within 1 month after each RFA. No patient had tumor lysis syndrome but myoglobinuria/hemoglobinuria occurred in 6 of 16 patients, all without renal damage. Serious complications from pulmonary RFA included 2 diaphragmatic hernias. Of 82 lesions imaged, 24 (29%) remained ablated at the end of the study. CONCLUSIONS: The toxicity from RFA of recurrent pediatric solid tumors was real but limited, and RFA may offer a local tumor control alternative in carefully selected cases. Cancer 2009. © 2009 American Cancer Society.

BACKGROUND: The combination of a platinating agent and etoposide has induced responses in various pediatric tumors. The study estimated the maximum tolerated dose (MTD) of an oxaliplatin and etoposide regimen in children with recurrent solid tumors. METHODS: Oxaliplatin was administered on Day 1 and etoposide on Days 1 to 3 of each 21-day course. Cohorts of 3 to 6 patients were enrolled at 3 dose levels: 1) oxaliplatin at a dose of 130 mg/m2 and etoposide at a dose of 75 mg/m2, 2) oxaliplatin at a dose of 130 mg/m2 and etoposide at a dose of 100 mg/m2, and 3) oxaliplatin at a dose of 145 mg/m2 and etoposide at a dose of 100 mg/m2. Calcium and magnesium infusions were used at dose level 3 in an attempt to escalate the oxaliplatin dose past the single-agent MTD. RESULTS: The 16 patients received a total of 63 courses. At dose level 1, dose-limiting epistaxis, neuropathy, and neutropenia occurred in 1 of 6 patients. No dose-limiting toxicity (DLT) occurred at dose level 2 (n = 6). At dose level 3, 2 of 4 patients experienced dose-limiting neutropenia; none experienced grade 3 or 4 acute neuropathy. Six patients required prolongation of the oxaliplatin infusion because of acute sensory neuropathy. Responses were observed in patients with medulloblastoma (1 complete response) and pineoblastoma (1 partial response); 3 others with atypical teratoid rhabdoid tumor, ependymoma, and soft tissue sarcoma had prolonged disease stabilization. CONCLUSIONS: The MTD of this regimen was found to be oxaliplatin at a dose of 130 mg/m2 given on Day 1 and etoposide at a dose of 100 mg/m2/d given on Days 1 to 3. Neutropenia was found to be the DLT. Calcium and magnesium infusions did not allow escalation of the oxaliplatin dose. The combination was well-tolerated and demonstrated antitumor activity. Cancer 2009. © 2008 American Cancer Society.

BACKGROUND. Current salvage therapy for recurrent high-risk neuroblastoma is rarely curative. Assessment of the effectiveness of new, primarily cytostatic agents requires the redefinition of study endpoints to reflect disease stabilization rather than tumor response or regression. The intervals of disease control in the patients in the current study with recurrent neuroblastoma were characterized to provide comparison criteria for exploratory studies of new agents. METHODS. Disease control intervals, disease-free survival, postrecurrence survival, and median time to treatment failure were estimated in 90 patients with high-risk neuroblastoma treated between January 1991 and June 2002 on 3 St. Jude neuroblastoma protocols. RESULTS. The estimated median time to disease recurrence was 18.3 months (95% confidence interval [95% CI], 15.9–22.4 months) for the first recurrence, 8.7 months (95% CI, 5.0–12.2 months) for the second recurrence, and 3.8 months (95% CI, 2.5–5.4 months) for the third recurrence. The 5-year estimate of survival after the first disease recurrence was 11% ± 4%. Patients with longer initial disease control had a postrecurrence survival advantage:the 5-year estimated postrecurrence survival was 15.3% ± 6.3% for patients with initial disease control ≥16 months and 8.1% ± 5.5% for others (P = .006). The median disease control interval was approximately halved after each disease recurrence. CONCLUSIONS. The previous disease control interval should be considered in stratification schemes for future phase 2 testing of new agents for the treatment of neuroblastoma. For the optimal evaluation of new treatment strategies that incorporate cytostatic agents, study design and selection of endpoints must take into account the current patterns of recurrence or progression of neuroblastoma. Cancer 2008. © 2008 American Cancer Society.

BACKGROUND Intensified chemotherapy may improve the outcome of patients with high-risk pediatric sarcomas. Vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide are highly effective against pediatric sarcomas. The authors investigated the feasibility of administering these agents concomitantly within a defined period. METHODS In the prospective high-risk sarcoma (HIRISA) Phase II trial HIRISA1, pediatric patients with high-risk sarcomas received 3 cycles of intensive vincristine, ifosfamide, etoposide, cyclophosphamide, and doxorubicin (VACIE) before radiotherapy and/or surgery began at Week 9 with concurrent vincristine, cyclophosphamide, and doxorubicin (Week 9) and vincristine and ifosfamide (Week 12). Three additional cycles of VACIE were then given. After delayed hematologic recovery in the first 11 patients, the protocol was modified (HIRISA2) to delay local control therapy until after 5 cycles of VACIE (to be completed within 18 weeks). Patients who responded to the protocols were eligible for myeloablative consolidation with autologous stem cell support. RESULTS Eleven of 24 patients (median age, 14.9 years) had Ewing sarcoma family of tumors, 9 patients had rhabdomyosarcoma, and 4 patients had unresectable desmoplastic small round cell tumors. Seven of 13 patients on HIRISA2, but none of 11 patients on HIRISA1, completed therapy within the specified time. Reversible Grade 4 myelosuppression was the most common toxicity. Major nonhematologic toxic effects were mucositis, nutritional impairment, hypotension, and peripheral neuropathy. Three patients died of toxicity. The 5-year survival and 5-year event-free survival estimates both were 45.8% ± 11.2%. CONCLUSIONS The feasibility of administering intensive chemotherapy regimens like VACIE was dependent in part on the timing of local control therapy. This regimen was associated with significant toxicity. Cancer 2006. © 2006 American Cancer Society.

Although the survival rate for pediatric patients with hepatoblastoma has improved, prognosis is still poor when the disease is unresectable and refractory to chemotherapy. Therefore, novel approaches are warranted. Herein, we describe a patient with recurrent metastatic hepatoblastoma who received a non-myeloablative hematopoietic stem cell transplantation from an HLA-matched unrelated donor. After withdrawal of immunosuppressant and establishment of full donor T-cell engraftment, the tumor regressed and serum alpha-fetoprotein level decreased in concurrence with the onset of graft-versus-host disease (GVHD). Her disease recurred when GVHD resolved. This patient's clinical course provides evidence for the probable existence of allogeneic graft-versus-hepatoblastoma effect.

Background The optimal timing for attempting removal of the primary tumor and regional disease in patients with high-risk neuroblastoma is uncertain. The purpose of this study was to evaluate resectability of the primary tumor and regional disease, as determined radiographically, in children with high-risk neuroblastoma during neoadjuvant chemotherapy. Procedure Patients enrolled in our institutional high-risk neuroblastoma protocol were evaluated prospectively by CT scan and/or MRI to determine the resectability of their primary tumor and regional disease at diagnosis, after two cycles of experimental therapy and after standard induction therapy. Tumors were considered to be unresectable if there was significant involvement with major vascular structures or contiguous organs, or would likely require nephrectomy to remove the entire tumor. Results Twenty-four patients were referred prior to surgery for treatment of high-risk neuroblastoma. Seven of 24 (29%) patients were felt to be resectable at diagnosis, with an additional 9 patients becoming resectable after the initial experimental therapy. Thus, overall, 16 of 24 (67%) patients were felt to be resectable by the completion of the initial therapy. Only four additional patients of the remaining eight were considered resectable after the completion of standard induction therapy. Conclusions Based on these data, we conclude that complete resection of the primary tumor and regional disease in children with high-risk neuroblastoma can be performed after an initial phase therapy in the majority of patients. Since earlier tumor removal may decrease the chance for the subsequent development of chemotherapy-resistant disease, we are recommending surgical resection as soon as the locoregional disease appears to be resectable. © 2004 Wiley-Liss, Inc.

22q11.2 deletion syndrome is the most common microdeletion syndrome. Wilms tumor is one of the most common solid tumors in childhood yet 22q11.2 deletion and Wilms tumor only once have been reported in the same patient. Here we describe a young patient with subtle clinical findings suggestive of 22q11.2 at the time of diagnosis who subsequently developed Wilms tumor. We assert the importance of a low threshold for screening for 22q11.2 deletion and the associated phenotypes and maintaining vigilance in screening for common primary malignancies in patients with known 22q11.2 deletion.

The camptothecin analogs topotecan and irinotecan have shown to be among the most effective anticancer agents and, as S-phase specific agents, their antitumor effect is maximized when they are administered in protracted schedules. The documented activity as single agents in many adult and pediatric malignancies has been followed by their use in combination with other anticancer agents. These studies have shown promising results, and have placed topotecan and irinotecan in the first line treatment for some malignancies. However, studies to better determine the optimal schedules and sequence of combinations are needed.

We used contrast-enhanced three-dimensional magnetic resonance angiography (3D MRA) modified for pediatric use to evaluate the hepatic vasculature prior to partial hepatectomy in five consecutive children with hepatoblastoma. Modifications included non-breath-hold technique in four of the five children who were sedated. The single breath-hold technique was performed in only one awake child. Scan delay times were based on contrast infusion time rather than total infusion time. The hepatic artery, portal vein, and inferior vena cava were identified in all patients. MRA findings were confirmed by conventional angiography in one patient and by surgery in all. Contrast-enhanced 3D MRA is a useful and rapid technique prior to partial hepatectomy in patients with hepatoblastoma.

Background. Standard therapy for pediatric nonrhabdomyosarcoma soft tissue sarcomas (PNRSTS) consists of surgical resection with or without radiotherapy. The role of chemotherapy in the treatment of these tumors has not yet been defined. We investigated the efficacy and toxicity of an ifosfamide-based regimen in controlling disease in children with high-risk PNRSTS. Patients and Methods. Between January 1992 and June 1994 at St. Jude Children's Research Hospital, we treated 11 children and young adults with PNRSTS who were at high risk for treatment failure by using a combined modality regimen that comprised aggressive surgery, radiotherapy, and chemotherapy including vincristine, ifosfamide, and doxorubicin (VID). Nine of these patients had grade 3 disease and one had grade 2 tumor; due to insufficient tissue, the disease grade of the remaining patient could not be established. Metastases were present at diagnosis in 2 children. Results. Therapy was generally well tolerated, with minimal morbidity and no mortality. The most common toxicity was grade 4 neutropenia, which occurred in 51% of evaluable courses. Among 4 patients evaluable for response to chemotherapy alone, 1 child attained a partial response and 3 had stable disease. One child had a response to chemotherapy and concurrent irradiation. At a median follow-up of 30 months, 10 of 11 patients are alive; 8 of 11 patients are alive without evidence of disease. Conclusion. Aggressive multimodality therapy for PNRSTS is well tolerated, despite frequent and profound neutropenia. Although adjuvant chemotherapy for this group of cancers remains unproved, the rate of tumor control achieved in this pilot study encourages further investigation in a multi-institutional setting.

BACKGROUND Neuroblastoma is the most common extracranial solid tumor among pediatric patients, and orbital metastatic disease is not uncommon in these children. Physical signs as a consequence of orbital metastases, such as proptosis and periorbital ecchymosis, frequently are encountered. However, subsequent blindness is rare. METHODS A retrospective study was conducted to determine the incidence, related physical findings, treatment, and outcome of children who developed visual loss during treatment for neuroblastoma. Medical records for a 24-year period (1971-1994) were reviewed to identify these patients. The charts, diagnostic imaging studies, and autopsy material of these patients were reviewed. RESULTS Of the 450 patients treated for neuroblastoma at the study institution during this period, 47 presented with abnormalities in physical examination of the eye. Eight of these 47 patients and 7 others developed visual loss in at least 1 eye during the first week after diagnosis (n = 5), during primary therapy (n = 6), at recurrence (n = 2), or after completion of therapy (n = 2). In ten patients the visual loss was a direct consequence of the primary disease process, whereas a direct relationship between loss of vision and neuroblastoma could not be identified in the remaining five patients. Proptosis and periorbital ecchymosis were the most common associated physical findings. Although ten patients received steroids and eight received radiation, visual loss could not be prevented or reversed in these patients. CONCLUSIONS Early initiation of effective, multiagent chemotherapy remains the primary approach for the treatment of neuroblastoma and its ophthalmologic complications. Radiation therapy and steroids may have benefit but failed to show good effect in this series. The prevention and treatment of blindness is probably most relevant in infants and children age < 2 years because they have the best chance for cure. Cancer 1997; 80:1997-2004. © 1997 American Cancer Society.

Interleukin-1 alpha (IL-1 alpha) is myeloprotective in a variety of animal models of cancer chemotherapy and is similarly beneficial in adults treated with carboplatin, 5-fluorouracil, and after autologous bone marrow transplantation. There are no trials of this agent in children. Our purpose was to determine the toxicity and maximum tolerated dose (MTD) of recombinant human interleukin-1 alpha (rhuIL-1 alpha) in children with solid tumors receiving intensive cancer chemotherapy and to evaluate its myelo-protective effects. Cohorts of patients received rhuIL-1 alpha in doses of 0.1-10 micrograms/m2 for 4 days by subcutaneous injection prior to ICF chemotherapy (ifosfamide, 2 g/m2/day x 3, carboplatin targeted to an area under the curve of 8 mg/ml x min on day 1, and etoposide, 100 mg/m2 daily for 3 days). Patients were randomized to receive rhuIL-1 alpha before either the first or second course of therapy. After the MTD of rhuIL-1 alpha was determined an additional group of patients received rhuIL-1 alpha at the dose immediately following ICE chemotherapy. The dose-limiting toxicities of rhuIL-1 alpha in the 27 children tested comprised systemic symptoms of fever, chills, headache, and hypotension. The MTD was 3 micrograms/m2/day. There were no differences in chemotherapy-induced hematologic toxicity with increasing doses of rhuIL-1 alpha or in comparisons before or after ICE chemotherapy. Although rhuIL-1 alpha can be given safely to children receiving myelosuppressive chemotherapy, clinical usefulness would mandate a significant hematopoietic benefit in view of the trouble some side effects identified. We saw no evidence of a hematoprotective effect.

We report an unusual case of acute lymphoblastic leukemia (ALL) that presented as right lower quadrant pain in a 17-year-old boy. Ultrasonographic findings were consistent with typhlitis. The clinical and imaging symptoms resolved upon treatment with antibiotics and conservative care, only to recur after initiation of chemotherapy. Familiarity with the clinical presentation and imaging findings of typhlitis is important for its correct diagnosis and management.

BACKGROUND The impact of overt testicular disease on survival was assessed among patients treated at the study institution for childhood acute lymphoblastic leukemia (ALL) over a 15-year period. To the authors' knowledge, the frequency of overt testicular involvement at diagnosis of ALL and its impact on treatment outcome have not been reported previously. METHODS The medical records of all 651 boys with ALL enrolled on St. Jude Total Therapy Studies X-XIIIA (May 1979 to December 1993) were reviewed to determine the frequency of overt testicular involvement at diagnosis. The log rank test and sequential Cox regression analyses, adjusted for known adverse features, were used to compare event free and overall survival for patients with and without testicular leukemia. A matched-pairs analysis was then conducted for both outcome measures. RESULTS Thirteen of the 651 male patients (1.9%) presented with overt testicular leukemia. Compared with the other patients, these 13 boys had a significantly higher frequency of infant or adolescent age at diagnosis, hyperleukocytosis, splenomegaly, and mediastinal mass; a poorer 5-year event free survival (38% [95% confidence interval (CI), 15.4-61.4%] vs. 58% [95% CI, 53.6-61.7%], P = 0.06, log rank test); and a significantly poorer 5-year overall survival (37% [95% CI, 14-60.4%] vs. 75% [95% CI, 71.3-78.4%], P = 0.002). The difference in overall, but not event free, survival was supported by sequential Cox regression analyses and by the matched-pairs analysis (P = 0.04). CONCLUSIONS Overt testicular involvement with leukemia at diagnosis was associated with an adverse survival in boys with ALL. Testicular irradiation may not be necessary in those patients who present with overt testicular involvement. This finding merits prospective evaluation in a larger sample of similarly treated patients. Cancer 1996;78:2437-42.

One hundred thirty-eight pediatric patients have received treatment for malignant solid tumors with ifosfamide with mesna, and 71 have received a combination with ifosfamide/carboplatin/etoposide (ICE). Responses were obtained in many types of pediatric tumors, yet comparison of responses was not possible because of inadequate numbers of tumors of differing histiotypes. Comparison of results between patients with all tumors treated with ifosfamide or ICE indicated that there was a higher response rate for patients treated with ICE, with an estimated odds ratio of 2.74 (95% C.I. 1.45-5.179). Excluding patients without prior chemotherapy and radiotherapy, the odds ratio for 2.801 (95% C.I. 1.45-5.4) suggests a similar result. There remain no guarantees that the more costly treatment with ICE, which requires cytokine support, will offer therapeutic benefits against resistant solid tumors.

Mental status changes in an immunosuppressed child can be due to a variety of causes; aluminum toxicity is rarely considered. We report a teenage girl with acute lymphoblastic leukemia who developed mental status changes, speech disturbance, coarse tremor, and abnormal EEG findings following intravesical 1% alum irrigation and administration of aluminum-containing antacids. Her serum aluminum levels were mildly elevated (14–22 μg/L, normal 0–6 μ g/L), and bone marrow biopsy specimens demonstrated aluminum deposition on special staining (Krueger's method). All abnormalities resolved after a nine-week course of intravenous deferoxamine. © 1996 Wiley-Liss, Inc.

BACKGROUND Approximately 30 patients with malignant mesothelioma following radiotherapy have been described. Population-based studies of this occurrence have not been reported. METHODS Patients with malignant mesothelioma of the pleura were collected. All of the patients had a prior cancer and had received radiotherapy to the region in which the malignant mesothelioma developed. Data from the National Cancer Institute's Surveillance, Epidemiology and End Results Program and the Connecticut Tumor Registry were evaluated for cases of malignant mesothelioma of the pleura occurring in patients with a previous cancer. The literature on post-irradiation malignant mesotheliomas was reviewed. RESULTS Eight patients (4 men, 4 women) with malignant mesothelioma occurring in sites of radiotherapy for a prior tumor were identified. The mean age at diagnosis of mesothelioma was 45 years (range: 22–78 years), and the average interval between radiotherapy and the mesothelioma was 21 years (range: 11–29 years). Three of the patients had also received chemotherapy. Histologically, the mesotheliomas were epithelial in five cases, biphasic in one, and sarcomatous in one. One hundred forty-two patients were identified in the epidemiologic survey. The majority were men (89%), with a median age for all patients of 68.5 years (range: 35–86 years) and a median latency between first cancer and mesothelioma of 4.3 years (range: 2 months–29.9 years). CONCLUSIONS Mesotheliomas rarely develop as second malignant neoplasms. Within a large, population-based survey of patients with cancer, temporal patterns and demographic features of most second primary mesotheliomas were similar to asbestos-related tumors, although the late effects of cancer treatment might have contributed to the occurrence of cancer in some patients. Cancer 1996;77:1379-85.

The clinical features and response to therapy of pediatric alveolar soft part sarcoma, a rare soft tissue sarcoma of uncertain histogenesis, have not been previously described in detail in the literature. We retrospectively reviewed the clinical characteristics of all patients with alveolar soft part sarcoma who were seen at our institution over a 32-year period. We found 11 patients with the diagnosis of alveolar soft part sarcoma. Their ages ranged from 2.8-16 years (median 9.8). Staging was determined using the Intergroup Rhabdomyosarcoma Study clinical grouping system and the UICC TNM system. Accordingly, there were six patients with grossly resected tumors (clinical groups I and II) and five with unresected or metastatic disease (clinical groups III and IV). Children with resected disease were more likely to have smaller noninvasive tumors. The main feature predictive of survival was tumor resectability, since chemotherapy in various combinations failed to produce significant tumor responses. Nine patients are disease-free with a median follow-up of 11.9 years. Surgical resection remains the mainstay of therapy for pediatric alveolar soft part sarcoma. Since active chemotherapy agents have not been identified, patients with unresected or metastatic disease may benefit from experimental agents. The survival rate of this cohort is superior to that seen in adults.

Background: The use of interstitial, intracavitary, and permanent placement of radioactive isotopes has become a common practice in adult oncology patients based on numerous reports indicating improved local control and survival when used.1–4 These same irradiation techniques and treatments have been infrequently used for children with malignant disease despite known dose localization properties that allow for highly focal irradiation delivery with rapid reduction of the dose in nearby normal tissues. The noted benefit of decreased late complications noted in the adult series is also attractive, especially when considering the treatment of children. Methods: Between May, 198,1 and December 15, 1992, 46 children with non-CNS primary malignancy received 50 brachytherapy applications for primary therapy (n = 11 sites), as a boost in conjunction with external beam irradiation (n = 16 sites), or as treatment of recurrent disease or a second malignant neoplasm in a previously irradiated region that precluded further external irradiation or for metastatic disease (n = 23 sites). The most common tumor histologies were rhabdomyosarcoma (n = 14), soft tissue sarcoma (n = 10) and retinoblastoma (n = 10). Patient age at implantation ranged from 8 weeks to 24 years; follow-up was maintained in all patients and has ranged from 2–115 months (median, 39 months). Results: Forty-three of 50 sites receiving brachytherapy have maintained continuous disease free intervals, ranging from 2 to 115 months postimplantation (median, 41 months). The seven local failures occurred 2–20 months postimplant (median, 6 months). Severe complications occurred in 12 patients, two which were life threatening but resolved without further incident. Conclusions: Based on this ongoing clinical investigation, the authors recommend brachytherapy for selected pediatric malignancies and continue to evaluate the various factors associated with local control, local failures, and complications. Cancer 1994; 74: 733-9.

To evaluate the clinical characteristics and treatment outcome of childhood non-Hodgkin lymphoma (NHL) cases with bone marrow involvement, we studied 13 lymphoblastic, 15 small noncleaved cell, and 8 large cell cases with tumor cells in their marrow. They represented 16%, 11%, and 9% of consecutive NHL cases with these respective histologic subtypes. The treatment outcome differed significantly according to histologic subtype—the 5-year event-free survivals (EFS ± SE) for large cell NHL, small non-cleaved cell NHL, and lymphoblastic NHL cases were 11 ± 8%, 40 ± 20%, and 62 ± 15%, respectively. Increased serum lactate dehydrogenase (LDH) levels (>500 U/L) were associated with a poorer EFS (5-year EFS, 0% vs. 50 ± 10%; P < 0.001). Children ⩽5 years of age had a poorer EFS survival than older children (5-year EFS, 14 ± 9% vs. 44 ± 10%; P = 0.03). The degree of bone marrow involvement (

Ifosfamide, carboplatin, and etoposide (ICE) chemotherapy has promising activity against various solid tumors but produces significant myelotoxicity that might be ameliorated by hematopoietic growth factors. Twelve patients with relapsed solid tumors were treated with ICE chemotherapy. Carboplatin was given on day 1 at a targeted area under the concentration-time curve (AUC) of 8 mg/mL × min (adjusted for each patient's glomerular filtration rate), followed by ifosfamide 2 g/m2 and etoposide 100 mg/m2 on days 2 through 4. Granulocyte-macrophage colony-stimulating factor (GM-CSF), 1,000 μg/m2/day, was started 24 hours after each course and given for 17 days or until the absolute neutrophil count (ANC) reached 10 × 109/L. Myelotoxicity and responses in these patients were compared to those of eight patients who received the same therapy without GM-CSF. Patients received a median of three courses (range, 1–8). All 20 patients developed grade 4 neutropenia and grade 3 or 4 thrombocytopenia. The median duration of neutropenia was significantly shorter in patients who received GM-CSF (16.75 vs. 10 days, P = 0.005). However, the two groups did not differ in the proportion of courses associated with hospitalization for febrile neutropenia, the duration of hospitalization, or the median duration of thrombocytopenia. There were two complete, four partial, and three objective responses in the 12 patients treated with ICE plus GM-CSF, and two partial and three objective responses in the 8 patients treated with ICE only. GM-CSF did not reduce the occurrence of febrile neutropenia or the duration of thrombocytopenia associated with ICE chemotherapy. Studies of other hematopoietic growth factors in conjunction with this promising combination are merited. © 1994 Wiley-Liss, Inc.

Background. The toxicity of interleukin-2 (IL-2) administered by continuous infusion has not been investigated in children. Methods. This study enrolled 10 boys and 7 girls with refractory malignancy. Recombinant IL-2 was infused continuously for cycles of 120 hours at doses escalating from 3 to 30 x lo6 IU/m2 per day. Results. A total of 45 cycles was administered. The most common toxicities included fever, anemia, hypotension (usually responsive to fluid bolus), hyponatremia, oliguria, hypoalbuminemia, nausea, thrombocytopenia, vomiting, and weight gain. Most side effects were correlated significantly with a dosage of 18 X lo6 IU/mZ or more per day. Respiratory distress was infrequent. Two cycles were interrupted due to severe toxicity (hypotension in one case and confusion in another), but there were no fatalities. During infusion, there was a significant nondose-related increase in serum IL-2 receptor levels. Despite this evidence of immunomodulation, no objective tumor response was noted. Conclusions. Continuous infusion of IL-2 at doses up to 30 x lo6 IU/m2 per day can be administered safely to children by this method. Cancer 1993; 72623-8.

Background. Hypercalcemia complicating malignancy is a frequent complication in adults, but little has been published about the pathogenesis or the true incidence of hypercalcemia in children with cancer. Methods. Hypercalcemia developing in childhood malignancies was studied retrospectively at St. Jude Children's Research Hospital to determine its incidence, the timing of its presentation, and its response to therapy. Results. Over a 29-year period, 25 children (median age, 9.5 years) had been diagnosed and treated for hypercalcemia that occurred during the course of their malignancy. These 25 represented of 0.4% of the total number of children treated for cancer at the institution during that period. Their malignancies comprised acute leukemias (11;0.6%), rhabdomyosarcoma (4;1.2%), malignant rhabdoid tumor (2), Hodgkin disease (1), non-Hodgkin lymphoma (1), hepatoblastoma (2), neuroblastoma (1), brain tumor (1), angiosarcoma (1), and a solid malignant tumor of undetermined type. Conclusions. Patients with acute lymphoblastic leukemia were more likely to present with hypercalcemia at the time of their initial diagnosis and to achieve resolution of this complication, whereas patients with solid tumors presented with hypercalcemia later in the course of their disease and had hypercalcemia that was more resistant to therapy. In contrast to adults with cancer, hypercalcemia of malignancy is extremely rare in children. Cancer 1993; 72:256–60.

Forty-five children with acute lymphoblastic leukemia or non-Hodgkin's lymphoma had cranial nerve palsy (CNP) as a complication of their disease. Twenty-two of these children had CNP initially and 23, at relapse, with or without previous hematologic relapse. Only one of the 23 patients with CNP at relapse was a long-term survivor. In contrast, 11 of the 22 children who had CNP initially survived in remission for 3+ months to 13+ years. Two factors are associated with an improved outcome for patients with CNP at diagnosis: treatment after 1979 (P less than 0.004) and male gender (P less than 0.01). Patients who received radiation therapy fared better than those for whom radiation was not given (disease-free survival at 2 years 53% versus 29%). The authors conclude that CNP signifies an aggressive or advanced disease requiring intensive systemic chemotherapy and that the role of irradiation should be examined for this group of patients.