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Chemoresistance is a major cause of treatment failure and poor outcome in neuroblastoma. In this study, we investigated the expression and function of dual-specificity phosphatase 26 (DUSP26), also known as mitogen-activated protein kinase phophatase-8, in human neuroblastoma. We found that DUSP26 was expressed in a majority of neuroblastoma cell lines and tissue specimens. Importantly, we found that DUSP26 promotes the resistance of human neuroblastoma to doxorubicin-induced apoptosis by acting as a p53 phosphatase to downregulate p53 tumor suppressor function in neuroblastoma cells. Inhibiting DUSP26 expression in the IMR-32 neuroblastoma cell line enhanced doxorubicin-induced p53 phosphorylation at Ser20 and Ser37, p21, Puma, Bax expression as well as apoptosis. In contrast, DUSP26 overexpression in the SK-N-SH cell line inhibited doxorubicin-induced p53 phosphorylation at Ser20 and Ser37, p21, Puma, Bax expression and apoptosis. Using in vitro and in vivo assays, we found that DUSP26 binds to p53 and dephosphorylates p53 at Ser20 and Ser37. In this report, we show that DUSP26 functions as a p53 phosphatase, which suppresses downstream p53 activity in response to genotoxic stress. This suggests that inhibition of this phosphatase may increase neuroblastoma chemosensitivity and DUSP26 is a novel therapeutic target for this aggressive pediatric malignancy. [ABSTRACT FROM AUTHOR]

Introduction: Phenylbutyrate (PB) and its metabolite phenylacetate (PA) demonstrate anticancer activity in vitro through promotion of cell differentiation, induction of apoptosis through the p21 pathway, inhibition of histone deacetylase, and in the case of PB, direct cytotoxicity. We studied the pharmacokinetics, metabolism, and cerebrospinal fluid (CSF) penetration of PA and PB after intravenous (i.v.) administration in the nonhuman primate.Methods: Three animals received 85 mg/kg PA and 130 mg/kg PB as a 30-min infusion. Blood and CSF samples were obtained at 15, 30, 35, 45, 60 or 75 min, and at 1.5, 2.5, 3.5, 5.5, 6.5, 8.5, 10.5 and 24.5 h after the start of the infusion. Plasma was separated immediately, and plasma and CSF were frozen until HPLC analysis was performed.Results: After i.v. PA administration, the plasma area under the concentration-time curve (AUC) of PA (median +/- SD) was 82 +/- 16 mg/ml.min, the CSF AUC was 24 +/- 7 mg/ml.min, clearance (Cl) was 1 +/- 0.3 ml/min per kg, and the AUCCSF:AUCplasma ratio was 28 +/- 19%. After i.v. PB administration, the plasma PB AUC was 19 +/- 3 mg/ml.min, the CSF PB AUC was 8 +/- 11 mg/ml.min, the PB Cl was 7 +/- 1 ml/min per kg, and the AUCCSF:AUCplasma ratio was 41 +/- 47%. The PA plasma AUC after i.v. PB administration was 50 +/- 9 mg/ml.min, the CSF AUC was 31 +/- 24 mg/ml.min, and the AUCCSF:AUCplasma ratio was 53 +/- 46%.Conclusions: These data indicate that PA and PB penetrate well into the CSF after i.v. administration. There may be an advantage to administration of PB over PA, since the administration of PB results in significant exposure to both active compounds. Clinical trials to evaluate the activity of PA and PB in pediatric central nervous system tumors are in progress. [ABSTRACT FROM AUTHOR]

Purpose: Gemcitabine (dFdC) is a difluorine-substituted deoxycytidine analogue that has demonstrated antitumor activity against both leukemias and solid tumors. Pharmacokinetic studies of gemcitabine have been performed in both adults and children but to date there have been no detailed studies of its penetration into cerebrospinal fluid (CSF). The current study was performed in nonhuman primates to determine the plasma and CSF pharmacokinetics of gemcitabine and its inactive metabolite, difluorodeoxyuridine (dFdU) following i.v. administration. Methods: Gemcitabine, 200 mg/kg, was administered i.v. over 45 min to four nonhuman primates. Serial plasma and CSF samples were obtained prior to, during, and after completion of the infusion for determination of gemcitabine and dFdU concentrations. Gemcitabine and dFdU concentrations were measured using high-performance liquid chromatography (HPLC) and modeled with model-dependent and model-independent methods. Results: Plasma elimination was rapid with a mean t1/2 of 8±4 min (mean±SD) for gemcitabine and 83±8 min for dFdU. Gemcitabine total body clearance (ClTB) was 177±40 ml/min per kg and the Vdss was 5.5±1.0 l/kg. The maximum concentrations (Cmax) and areas under the time concentration curves (AUC) for gemcitabine and dFdU in plasma were 194±64 µM and 63.8±14.6 µM·h, and 783±99 µM and 1725±186 µM·h, respectively. The peak CSF concentrations of gemcitabine and dFdU were 2.5±1.4 µM and 32±41 µM, respectively. The mean CSF:plasma ratio was 6.7% for gemcitabine and 23.8% for dFdU. Conclusions: There is only modest penetration of gemcitabine into the CSF after i.v. administration. The relatively low CSF exposure to gemcitabine after i.v. administration suggests that systemic administration of this agent is not optimal for the treatment of overt leptomeningeal disease. However, the clinical spectrum of antitumor activity and lack of neurotoxicity after systemic administration of gemcitabine make this agent an excellent candidate for further studies to assess the safety and feasibility of intrathecal administration. [ABSTRACT FROM AUTHOR]

Purpose: Children undergoing open oncologic surgery can have significant post-operative pain. The purpose of this trial was to compare a surgeon-placed subcutaneous analgesic system (SAS) to epidural analgesia., Methods: Single center randomized controlled trial including children ≤18 years undergoing open tumor resection between October 2018 and April 2021. Randomization to SAS or epidural was done preoperatively and perioperative pain management was standardized. Families were blinded to the modality. Comparisons of oral morphine equivalents (OME) and pain scores for three postoperative days, clinical outcome parameters, and parental satisfaction following unblinding were completed using non-parametric analyses., Results: Of 36 patients (SAS 18, Epidural 18), median age was 5 years (range <1-17). The Epidural cohort had less OME demand on postoperative day one (SAS 0.76 mg/kg, Epidural 0.11 mg/kg; p<0.01) and two (SAS 0.48 mg/kg, Epidural 0.07 mg/kg, p = 0.03). Pain scores were similar on postoperative days 1-3 (0-2 in both groups). The Epidural cohort had more device complications (SAS 11%, Epidural 50%; p = 0.03) and higher urinary catheter use (SAS 50%, Epidural 89%; p = 0.03). More than 80% of parents would use the same device in the future (SAS 100%, Epidural 84%, p = 0.23)., Conclusion: For children undergoing open oncologic abdominal or thoracic surgery, early post-operative pain control appears to be better with epidural analgesia; however, SAS has decreased incidence of device complications and urinary catheter use. Parental satisfaction is excellent with both modalities. SAS could be considered as an alternative to epidural, especially in settings when epidural placement is not available or contraindicated., Type of Study: Treatment study, Randomized controlled trial., Level of Evidence: Level 1., (Copyright © 2022. Published by Elsevier Inc.)

Purpose: Treatment planning for children with neuroblastoma requires accurate assessment of prognosis. The most recent Children's Oncology Group (COG) risk classification system used tumor stage as defined by the International Neuroblastoma Staging System. Here, we validate a revised classifier using the International Neuroblastoma Risk Group Staging System (INRGSS) and incorporate segmental chromosome aberrations (SCA) as an additional genomic biomarker., Methods: Newly diagnosed patients enrolled on the COG neuroblastoma biology study ANBL00B1 between 2007 and 2017 with known age, International Neuroblastoma Staging System, and INRGSS stage were identified (N = 4,832). Tumor MYCN status, ploidy, SCA status (1p and 11q), and International Neuroblastoma Pathology Classification histology were determined centrally. Survival analyses were performed for combinations of prognostic factors used in COG risk classification according to the prior version 1, and to validate a revised algorithm (version 2)., Results: Most patients with locoregional tumors had excellent outcomes except for those with image-defined risk factors (INRGSS L2) with MYCN amplification (5-year event-free survival and overall survival: 76.3% ± 5.8% and 79.9% ± 5.5%, respectively) or patients age ≥ 18 months with L2 MYCN nonamplified tumors with unfavorable International Neuroblastoma Pathology Classification histology (72.7% ± 5.4% and 82.4% ± 4.6%), which includes the majority of L2 patients with SCA. For patients with stage M (metastatic) and MS (metastatic, special) disease, genomic biomarkers affected risk group assignment for those < 12 months ( MYCN ) or 12-18 months ( MYCN , histology, ploidy, and SCA) of age. In a retrospective analysis of patient outcome, the 5-year event-free survival and overall survival using COG version 1 were low-risk: 89.4% ± 1.1% and 97.9% ± 0.5%; intermediate-risk: 86.1% ± 1.3% and 94.9% ± 0.8%; high-risk: 50.8% ± 1.4% and 61.9% ± 1.3%; and using COG version 2 were low-risk: 90.7% ± 1.1% and 97.9% ± 0.5%; intermediate-risk: 85.1% ± 1.4% and 95.8% ± 0.8%; high-risk: 51.2% ± 1.4% and 62.5% ± 1.3%, respectively., Conclusion: A revised 2021 COG neuroblastoma risk classifier (version 2) that uses the INRGSS and incorporates SCAs has been adopted to prospectively define COG clinical trial eligibility and treatment assignment., Competing Interests: Meredith S. IrwinHonoraria: Bayer Arlene NaranjoConsulting or Advisory Role: Novartis Susan L. CohnStock and Other Ownership Interests: Merck, Stryker, Amgen, Pfizer, AbbVie, Lilly, Sanofi, Accelerated Medical Diagnostics, Novo Nordisk, Gilead Sciences, United Health Group, TevaHonoraria: Y-mAbs TherapeuticsResearch Funding: United Therapeutics, MerckOpen Payments Link: https://openpaymentsdata.cms.gov/physician/46569/summaryhttps://openpaymentsdata.cms.gov/physician/46569/summary Wendy B. LondonConsulting or Advisory Role: Jubilant Radiopharma, MerckResearch Funding: Agios, Bristol Myers Squibb, Novartis, Aileron Therapeutics, Bluebird Bio Julie M. Gastier-FosterResearch Funding: Bristol Myers Squibb, Incyte Jed NuchternStock and Other Ownership Interests: Insulet Corporation, Lexicon, Intuitive Surgical John M. MarisStock and Other Ownership Interests: Tantigen BIO IncConsulting or Advisory Role: Auron Therapeutics, Illumina Radiopharmaceuticals, Jubilant DraxImagePatents, Royalties, Other Intellectual Property: GPC2 binders and CARs, Neuroblastoma antigens Rochelle BagatellUncompensated Relationships: Y-mAbs Therapeutics IncNo other potential conflicts of interest were reported.

The myogenic differentiation 1 gene (MYOD1) p.L122R somatic mutation was first discovered in a subset of clinically aggressive embryonal rhabdomyosarcomas and has since been described in both pediatric and adult spindle cell/sclerosing rhabdomyosarcomas. Relatively little is known about the clinical, molecular, and histopathological features of these tumors in children. In order to further characterize the genomic and clinical features of pediatric MYOD1-mutant sarcomas, we evaluated a cohort of soft-tissue sarcoma patients treated at Texas Children's Hospital. Tumor DNA was subjected to next-generation panel sequencing and/or Sanger sequencing of the MYOD1 hotspot mutation. The MYOD1 p.L122R mutation was identified in six tumors, with a variant allele fraction greater than 0.8 in three cases, suggestive of loss of heterozygosity. One sclerosing rhabdomyosarcoma lacking the MYOD1 hotspot mutation was observed to have a MYOD1 copy number gain, also with evidence of loss of heterozygosity. Cancer gene panel sequencing revealed potentially targetable alterations in six of seven (86%) patients with MYOD1 alterations, including four patients with an alteration in the PI3K-AKT pathway: two hotspot PIK3CA mutations and deletions in PTEN and TSC2. On histopathologic review, MYOD1-altered tumors exhibited spindle and/or round cells and varying degrees of hyaline sclerosis. At last follow-up, six patients had died of disease and the seventh progressed early and was subsequently lost to follow-up. Both pre- and post-therapy patient-derived xenograft models were generated from one patient's tumor. These models were confirmed to harbor the MYOD1 and PIK3CA mutations seen in the primary tumor and were shown to be sensitive to PI3K/mTOR inhibition in vitro and in vivo. In conclusion, this study adds to recent reports describing the clinicopathologic and genomic features of MYOD1-altered soft-tissue sarcomas in children, including dismal prognosis and potential molecular targets for therapy. The novel preclinical models developed will facilitate further biological and preclinical study of this rare and aggressive tumor. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (© 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Surgeons caring for patients with neuroblastoma must be familiar with recent developments in assessing risk. In particular, the Children's Oncology Group, along with major international groups, uses the International Neuroblastoma Risk Group Staging System as a risk assessment tool. Accurate risk determination is essential for optimal surgical therapy. Some tumors like neonatal adrenal neuroblastomas and those in the metastatic category can be observed. Very-low-risk and low-risk neuroblastomas can be treated with surgery alone. Intermediate-risk tumors also often require systemic chemotherapy., Competing Interests: Disclosure This research was funded in part by the NIH/NCI Cancer Center Support Grant, P30 CA008748. The authors have no conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Problem: The World Health Organization and the World Bank have identified improvement in access to surgical care as an urgent global health challenge and a cost-effective investment in public health. However, trainees in standard U.S. general surgery programs do not have adequate exposure to the procedures, technical skills, and foundational knowledge essential for providing surgical care in resource-limited settings., Approach: The Michael E. DeBakey Department of Surgery at Baylor College of Medicine (BCM) created a 7-year global surgery track within its general surgery residency in 2014. Individualized rotations equip residents with the necessary skills, knowledge, and experience to operate in regions with low surgeon density and develop sustainable surgical infrastructures. BCM provides a formal, integrated global surgery curriculum-including 2 years dedicated to global surgery-with surgical specialty rotations in domestic and international settings. Residents tailor their individual experience to the needs of their future clinical practice, region of interest, and surgical specialty., Outcomes: There have been 4 major outcomes of the BCM global surgery track: (1) increased exposure for trainees to a broad range of surgeries critical in resource-limited settings, (2) meaningful international partnerships, (3) contributions to global surgery scholarship, and (4) establishment of sustainable global surgery activities., Next Steps: To better facilitate access to safe, timely, and affordable surgical care worldwide, global surgeons should pursue expertise in topics not currently included in U.S. general surgical curricula, such as setting-specific technical skills, capacity building, and organizational collaboration. Future evaluations of the BCM global surgery track will assess the effect of individualized education on trainees' professional identities, clinical practices, academic pursuits, global surgery leadership preparedness, and comfort with technical skills not encompassed in general surgery programs. Increasing availability of quality global surgery training programs would provide a critical next step toward contributing to the delivery of safe surgical care worldwide., (Copyright © 2020 by the Association of American Medical Colleges.)

Background/purpose: To compare the adequacy and safety of percutaneous core needle biopsy and surgical wedge biopsy of neuroblastoma in children., Methods: A retrospective review of patients who underwent biopsy for intermediate- or high-risk neuroblastoma at our institution between 2011 and 2015 was performed (recent cohort). Procedure details and outcomes were collected and analyzed using descriptive statistics and Wilcoxon rank tests; P < 0.05 was considered significant. Published data from 2002 to 2010 were compared (historic cohort)., Results: Since 2011, percutaneous, ultrasound-guided, core needle biopsy has been more commonly utilized (47% (16/34) recent vs. 25% (7/28) historic; P = 0.07), and the number of core needle samples increased from median 7 (historic) to 25 (recent). Complications decreased (21% (7/34) recent vs. 64% (18/28) historic; P < 0.01). Biopsy adequacy in the recent cohort was similar (94% percutaneous vs. 89% surgical; P = 1.00), which is improved from the historic cohort (71% percutaneous vs. 100% surgical; P = 0.06). Larger tumors were more likely to have a percutaneous biopsy (82 ± 37 cm percutaneous vs. 47 ± 29 cm surgical; P = 0.04)., Conclusions: When multiple cores are obtained, percutaneous core needle biopsy is adequate for complete tissue diagnosis of neuroblastoma and can be safely performed. This can be considered as an alternative to open surgical biopsy., Type of Study: Treatment Study., Level of Evidence: III., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Though the volume-outcome relationship has been well-established in adults, low mortality rates and small sample sizes have precluded definitive demonstration in children. This study compares treatment-specific factors for children with nephroblastoma at high (HVC) versus low volume centers (LVC)., Methods: We performed a retrospective cohort study comparing patients ≤18years with unilateral nephroblastoma treated at HVCs and LVCs using the National Cancer Data Base (1998-2012). Definitions of HVCs included performing above the median, the upper two quartiles, and the highest decile of nephroblastoma resections. Outcomes included nodal sampling, margin status, time to chemotherapy and radiation, and survival. Statistical analyses included χ 2 , t-tests, generalized linear, and Cox regression models (p<0.05)., Results: Of 2911 patients from 210 centers, 1443 (49.6%) were treated at HVCs. There was no difference in frequency of preoperative biopsy or days to radiation (p>0.05). High volume centers were more likely to perform nodal sampling (RR 1.04, 95%CI 1.01-1.08) and had fewer days to chemotherapy (RR 0.80, 95%CI 0.69-0.93). Five-year survival was similar (HVC: 0.93, 95%CI 0.92-0.94; LVC: 0.93, 95%CI 0.91-0.94)., Conclusions: HVCs were more likely to perform nodal sampling and had fewer days to chemotherapy. There was no difference in days to radiation or survival between centers., Level of Evidence: Level II (retrospective prognosis study)., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Importance: Melanoma in children is rare, accounting for approximately 2% of all pediatric malignant neoplasms. However, for the past 30 years, the incidence of melanoma in those younger than 20 years has been increasing. Location of the primary tumor has been shown to be an important prognostic factor, with melanomas of the scalp and neck conferring a worse prognosis than those originating at other sites., Objective: To examine the survival, demographic, tumor, and treatment characteristics of pediatric head and neck melanoma., Design, Setting, and Participants: We performed a retrospective cohort study using information from the National Cancer Data Base from January 1, 1998, to December 31, 2012, on pediatric (≤18 years) and adult (>18 years) patients with head and neck melanoma. Data analysis was conducted from August 1, 2015, to June 30, 2016., Exposure: Pediatric age (≤18 years) at diagnosis of head and neck melanoma., Main Outcomes and Measures: Survival differences were estimated using a Cox proportional hazards regression model. Surgical outcomes, including nodal sampling and margin status, were estimated with generalized linear models comparing pediatric and adult patients. Patient demographic, tumor, and treatment characteristics were estimated using t tests and χ2 tests between pediatric and adult patients with head and neck melanoma for continuous and categorical data, respectively., Results: Of the 84 744 patients with head and neck melanoma, 657 (0.8%) were 18 years or younger (mean [SD] age, 13.5 [4.7] years; 285 female and 372 male; 610 white). Pediatric and adult patients had similar demographics but different histologic subtypes (risk difference of pediatric vs adult patients: melanoma, not otherwise specified, 8.5% [95% CI, 4.7%-12.3%]; superficial spreading, 4.2% [95% CI, 0.89%-7.4%]; and lentigo maligna, -13.4% [95% CI, -14.1% to 12.6%]). Pediatric patients had tumors of similar mean depth to those in adult patients (pediatric, 1.54 mm; adult; 1.39 mm; absolute difference, 0.15 mm; [95% CI, -0.32 to 0.008]) and more frequent nodal metastases than did adult patients (risk difference of pediatric vs adult patients for stage T2, 23.9% [95% CI, 14.1%-33.6%]). Five-year survival among pediatric patients was higher for those with stage 1, 2, or 3 disease (absolute difference of pediatric vs adult patients: stage 1, 18% [95% CI, 9.7%-26.3%]; stage 2, 36% [95% CI, 25.3%-46.7%]; stage 3, 39% [95% CI, 26.8%-51.2%]; and stage 4, 2% [95% CI, -8.2% to 12.2%])., Conclusions and Relevance: Although pediatric patients with head and neck melanoma present with similar tumor depth and more frequent nodal metastases than do adult patients, younger patients have higher overall survival.

Importance: Nasopharyngeal carcinoma (NPC) is endemic in some Asian regions but is uncommon in the United States. Little is known about the racial, demographic, and biological characteristics of the disease in pediatric patients., Objectives: To improve understanding of the differences between pediatric and adult NPC and to determine whether race conferred a survival difference among pediatric patients with NPC., Design, Setting, and Participants: This retrospective cohort study included all 17 317 patients with a primary diagnosis of NCP in the National Cancer Data Base from January 1, 1998, to December 31, 2011. Of these, 699 patients were 21 years or younger (pediatric); 16 618 patients, older than 21 years (adult). Data were analyzed after data collection., Exposure: Pediatric age at diagnosis of NPC., Main Outcomes and Measures: Demographic, tumor, and treatment characteristics of pediatric patients with NPC were compared with those of adults using the χ2 test for categorical variables. An adjusted Cox proportional hazards regression model was used to examine survival differences in pediatric patients relative to adult patients. In addition, the risk for pediatric mortality by race was estimated., Results: Of the 17 317 patients, a total of 699 pediatric and 16 618 adult patients were identified with a primary diagnosis of NPC (female, 239 pediatric patients [34.2%] and 5153 adult patients [32.4%]). Pediatric patients were most commonly black (299 of 686 [43.6%]), whereas adults were most likely to be non-Hispanic white (9839 of 16 504 [60.0%]; P < .001). Pediatric patients were less likely to be Asian (39 of 686 [5.7%]) than were adults (3226 of 16 405 [19.7%]; P < .001). Pediatric patients were more likely to have regional nodal evaluation and to present with stage IV disease (227 of 643 [35.3%] and 330 of 565 [58.4%], respectively) than were adult patients (3748 of 15 631 [24.0%] and 6553 of 13 721 [47.8%], respectively; P < .001 for both comparisons). Pediatric patients had a lower risk for mortality relative to adults (hazard ratio, 0.37; 95% CI, 0.25-0.56). No difference in mortality by racial group was found among pediatric patients (hazard ratio, 1.10; 95% CI, 0.82-1.40)., Conclusions and Relevance: Pediatric patients with NPC were more commonly black and presented more frequently with stage IV disease. Pediatric patients had a decreased mortality risk relative to adults, even after adjusting for covariables. Asian race was not associated with increased mortality in pediatric patients with NPC. Racial differences are not associated with an increased risk for mortality among pediatric patients.

Purpose: The International Neuroblastoma Response Criteria (INRC) require serial measurements of primary tumors in three dimensions, whereas the Response Evaluation Criteria in Solid Tumors (RECIST) require measurement in one dimension. This study was conducted to identify the preferred method of primary tumor response assessment for use in revised INRC., Patients and Methods: Patients younger than 20 years with high-risk neuroblastoma were eligible if they were diagnosed between 2000 and 2012 and if three primary tumor measurements (antero-posterior, width, cranio-caudal) were recorded at least twice before resection. Responses were defined as ≥ 30% reduction in longest dimension as per RECIST, ≥ 50% reduction in volume as per INRC, or ≥ 65% reduction in volume., Results: Three-year event-free survival for all patients (N = 229) was 44% and overall survival was 58%. The sensitivity of both volume response measures (ability to detect responses in patients who survived) exceeded the sensitivity of the single dimension measure, but the specificity of all response measures (ability to identify lack of response in patients who later died) was low. In multivariable analyses, none of the response measures studied was predictive of outcome, and none was predictive of the extent of resection., Conclusion: None of the methods of primary tumor response assessment was predictive of outcome. Measurement of three dimensions followed by calculation of resultant volume is more complex than measurement of a single dimension. Primary tumor response in children with high-risk neuroblastoma should therefore be evaluated in accordance with RECIST criteria, using the single longest dimension., (© 2016 by American Society of Clinical Oncology.)

Purpose: Although it is generally accepted that consolidation therapy for neuroblastoma includes irradiation of the primary site and any remaining metaiodobenzylguanidine (MIBG)-avid metastatic sites, limited information has been published regarding the efficacy of this approach., Methods and Materials: Thirty patients with high-risk neuroblastoma were treated at 1 radiation therapy (RT) department after receiving 5 cycles of induction chemotherapy and resection. All patients had at least a partial response after induction therapy, based upon international neuroblastoma response criteria. The primary sites were treated with 24 to 30 Gy whereas the MIBG-avid metastatic sites were treated with 24 Gy. RT was followed by high-dose chemotherapy with autologous stem cell rescue and 6 months of cis-retinoic acid., Results: The 5-year progression-free survival (PFS) and overall survival (OS) rates were 48% and 59%, respectively. The 5-year locoregional control at the primary site was 84%. There were no differences in locoregional control according to degree of primary surgical resection. The 5-year local control rate for metastatic sites was 74%. The 5-year PFS rates for patients with 0, 1, 2, and >3 postinduction MIBG sites were 66%, 57%, 20%, and 0% (P<.0001), respectively, whereas 5-year OS rates were 80%, 57%, 50%, and 0%, respectively (P<.0001)., Conclusions: RT to the primary site and postinduction MIBG-positive metastatic sites was associated with 84% and 74% local control, respectively. The number of MIBG-avid sites present after induction chemotherapy and surgery was predictive of progression-free and overall survival., Competing Interests: none., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: Pemetrexed, a multi-targeted antifolate that disrupts synthesis of both purines and pyrimidines, is approved for use in malignant pleural mesothelioma and non-small cell lung cancer. Pemetrexed is currently being evaluated for anti-tumor activity in a variety of solid and central nervous system tumors. We studied the plasma and cerebrospinal fluid (CSF) pharmacokinetics of pemetrexed in a non-human primate model that is highly predictive of human CSF penetration., Methods: Pemetrexed, 20 mg/kg (400 mg/m2), was administered intravenously to four non-human primates. Serial blood samples were obtained from all animals and serial CSF samples were obtained from three animals. Plasma and CSF concentrations of pemetrexed were measured using LC/MS/MS and the resulting concentration versus time data were evaluated using model independent and dependent methods., Results: Pemetrexed disappearance from plasma was best described by a two compartment model with a mean distribution half-life of 13.8 +/- 3.2 min and an elimination half-life of 70.0 +/- 16.0 min. The volume of distribution of and the clearance from the central compartment were 0.066 +/- 0.017 l/kg and 3.6 +/- 0.6 ml/min/kg, respectively. Peak CSF concentrations occurred 40-71 min after the start of the infusion with an average of 0.26 +/- 0.15 microM., Conclusion: The CSF penetration of pemetrexed was less than 2% (range 0.33-1.58%), suggesting that it should be used in conjunction with other CNS preventive strategies when used in the treatment of malignancies with a predilection for CNS or leptomeningeal metastases.

Purpose: The rebeccamycins, indolocarbazole topoisomerase I poisons originally discovered in actinomycetes, have shown activity in vitro against a range of adult and pediatric tumors. The derivative NSC 655649 (diethylaminoethyl analog of rebeccamycin, or DEAE rebeccamycin) is currently undergoing early-phase human studies and has shown some signs of antitumor activity. We studied the plasma and cerebrospinal fluid (CSF) pharmacokinetics of NSC 655649 after systemic administration in a nonhuman primate model that is predictive of anticancer drug behavior in humans., Design: A dose of 400 mg/m2 was infused over 1 h to three rhesus monkeys. Serial blood and CSF samples were collected. Rebeccamycin concentrations were measured by high-pressure liquid chromatography. Pharmacokinetic analysis was performed using compartmental and noncompartmental methods., Results: A two-compartment or three-compartment model described rebeccamycin pharmacokinetics in plasma adequately. In two animals, the three-compartment model provided a better fit, and in one animal, the two-compartment model was better. The terminal half-life was 730+/-410 min, the AUC was 3130+/-425 microM min, and the clearance was 190+/-25 ml/min/m2. Rebeccamycin was below the limit of quantitation in all CSF samples. The animals had some nausea and agitation during and shortly after the infusion that responded to treatment with prochlorperazine or diazepam. Otherwise, rebeccamycin was well tolerated with minimal toxicity., Conclusion: Rebeccamycin penetrates poorly into the CSF following an intravenous infusion. Therefore, systemically administered rebeccamycin is unlikely to be an important agent for the treatment of leptomeningeal tumors. Because the drug is associated with local irritation at injection sites, it is not an ideal candidate for development as an intrathecal agent. However, the role of rebeccamycin in the treatment of parenchymal brain tumors should be determined in clinical trials.

Purpose: Acetylation of histones by histone acetyl transferases (HATs) leads to transcriptional activation, while histone deacetylase (HDAC) activity leads to transcriptional repression. Abnormalities of histone acetylation are associated with the malignant phenotype. Depsipeptide (FR901228) inhibits HDAC and has shown anticancer activity in preclinical models. We studied the plasma and cerebrospinal fluid (CSF) pharmacokinetics of depsipeptide in a nonhuman primate model that is highly predictive of human CSF penetration., Design: Depsipeptide was administered intravenously at a dose of 10 mg/m(2) over 4 h to three different animals. Serial blood samples were obtained from all animals and serial CSF samples were obtained from two animals. Plasma and CSF concentrations of depsipeptide were measured using liquid chromatography/tandem mass spectrometry. Concentration-versus-time data were modeled using model-independent and model-dependent methods., Results: The peak plasma concentration (median+/-SD) was 245+/-50 n M and occurred within the first 2 h of the infusion. The terminal half-life was 205+/-315 min, the AUC extrapolated to infinity was 50+/-15 micro M.min, and the total body clearance was 350+/-65 ml/min/m(2). In the two animals that had CSF sampling performed, the CSF peak concentration was 3.6 n M in one animal and 2.3 n M in the other, and the CSF half-lives were 250 and 325 min. The CSF penetration of depsipeptide (AUC(CSF):AUC(plasma)) was 2% in each animal. Observed changes included anorexia, fatigue, elevation of creatine phosphokinase (CPK) enzyme levels (muscle fraction), and transient early leukopenia. All animals recovered without sequelae., Conclusions: Although the CSF exposure to depsipeptide after intravenous administration was only 2%, CSF concentrations approached the IC(50) of depsipeptide in vitro for some tumors. Systemic administration of this agent may be useful for the treatment of leptomeningeal tumors.

Genetic engineering of human T lymphocytes to express tumor antigen-specific chimeric immune receptors is an attractive means for providing large numbers of effector cells for adoptive immunotherapy while bypassing major mechanisms of tumor escape from immune recognition. We have applied this strategy to the targeting of a G(D2)-positive tumor, neuroblastoma, which is the commonest extracranial solid tumor of childhood. Chimeric immune receptors were generated by joining an extracellular antigen-binding domain derived from either of the 2 ganglioside G(D2)-specific antibodies sc7A4 and sc14.G2a to a cytoplasmic signaling domain. The variable domains of hybridoma antibody 14.G2a were cloned and selected using a phage display approach. Upon coincubation with G(D2)-expressing tumor cell targets, human T lymphocytes transduced with recombinant retroviruses encoding chimeric receptors based on sc14.G2a, but not sc7A4, secreted significant levels of cytokines in a pattern comparable to the cytokine response obtained by engagement of the CD3 receptor. T cells transduced with the sc14.G2a-based chimeric T-cell receptors also displayed specific lysis of G(D2)-positive neuroblastoma cells, which was blocked in the presence of monoclonal antibody 14.G2a. In the absence of nonspecific stimulation of transduced cells, their functionality declined over time and antigenic stimulation of the chimeric receptor alone did not induce commitment to proliferation. These results support the feasibility of redirecting human T lymphocytes to a tumor-associated ganglioside epitope but emphasize that successful chimeric receptor-mediated adoptive immunotherapy will require additional strategies that overcome functional inactivation of gene-modified primary T lymphocytes., (Copyright 2001 Wiley-Liss, Inc.)

Semipermanent venous catheters remain the most commonly used access for chronic hemodialysis (HD) in pediatric patients. The recent availability of Tesio catheters in 7 and 10 F has expanded available HD catheter options for children and adolescents. We report our experience with Tesio catheter survival, complications, and effect on dialysis adequacy in comparison to standard dual-lumen (DL) catheters in our pediatric HD patients. Demographic data were similar between the two groups. Overall actuarial survival was significantly longer for Tesio versus DL catheters (46% versus 0% at 1 year; P = 0.003). A comparison of smaller catheters (7 F Tesio catheter, 8 or 10 F DL catheter) showed that smaller Tesio catheters had a significantly longer survival (median survival, 244 versus 13 catheter-days; P < 0.01). Tesio 10 F catheters also survived significantly longer than the larger 11.5 and 12 F DL catheters (P < 0.02). Catheter sepsis occurred less frequently with Tesio catheters (one episode/20 catheter-months) than DL catheters (one episode/5 catheter-months) despite the longer duration of Tesio catheters. Adequate dialysis (single-pool Kt/V > 1.2) was delivered with the same frequency, but for a longer duration with Tesio catheters (76% +/- 32% over 100 monthly measurements versus DL catheter, 57% +/- 45% over 54 monthly measurements). Our clinical practice was to replace cuffed catheters when adequate dialysis could not be delivered. We conclude that Tesio catheters provide superior performance compared with DL catheters in terms of catheter survival, infection rates, and duration of adequate performance.

Vigorous host immune reactivity to neuroblastoma may correlate with better prognosis, but identification of human cytotoxic T-lymphocyte (CTL) responses has been relatively unsuccessful. We generated neuroblastoma-reactive CTL lines from two human leukocyte antigen (HLA) A2+ neuroblastoma patients by stimulation of peripheral blood lymphocytes (PBLs) with irradiated autologous tumor cells pretreated with interferon-gamma in the presence of low concentrations of interleukin-2 (5 U/mL). These lines lyse autologous tumor cells but do not kill HLA mismatched allogeneic tumor cells, Epstein-Barr virus-transformed autologous B cells, or standard natural killer cell targets. Cytotoxic T lymphocytes generated from one patient recognize tumor cells from several HLA-A2 matched children, although the other patient's CTLs do not kill tumor cells from other HLA-A2+ individuals. Pretreatment of CTLs or target cells with appropriate standard monoclonal antibodies demonstrates that these CTLs are major histocompatibility complex class I (HLA-A2) restricted and that the effector cell population is CD8+. Our findings suggest that these tumor cells express at least one common HLA-A2 restricted antigen and at least one unique private epitope. Autologous tumor-specific CTLs can be readily generated from patients' PBLs and maintained in long-term culture using standard techniques.

Background/purpose: Ovarian pathology, although rare in children, must be included in the differential diagnosis of all girls who present with abdominal pain, an abdominal mass, or precocious puberty., Methods: To improve clinical appreciation of these lesions, the authors reviewed the presentation, evaluation, and outcome of all patients with ovarian pathology surgically treated at their institution since 1985., Results: One hundred two girls (aged 9.8 +/- 5.5 years; range, 2 days to 20 years) underwent 106 separate ovarian operations (43 salpingo-oophorectomies, 21 oophorectomies, 33 ovarian cystectomies, and 9 ovarian biopsies). Of those presenting with acute abdominal pain (n = 59), 25 (42%) had ovarian torsion (14 associated with a mature teratoma), and only 1 (2%) had a malignant tumor. In contrast, of those presenting with an abdominal mass (n = 23), 6 (26%) had malignancies. There was no age difference between those with benign disease (9.9 +/- 5.6 years; n = 96) and those with malignant tumors (8.6 +/- 3.9 years, n = 10). Nine children had 10 operations for presumed malignant tumors (3 dysgerminomas, 2 immature teratomas with foci of yolk sac tumor, 2 juvenile granulosa cell tumors, 1 yolk sac tumor, and 1 Sertoli-Leydig cell tumor). These patients all had unilateral salpingo-oophorectomy, 4 had chemotherapy, and all are now disease free at 8.4 +/- 4.1 years follow-up., Conclusion: Ovarian pathology remains a rare indication for surgery in girls less than 20 years of age. Because most of these lesions are benign, ovarian-preserving operations should be performed whenever feasible., (Copyright 2001 by W.B. Saunders Company.)

Background/purpose: The aim of this study was to evaluate the usefulness of ultrasonography in the routine management of children with suspected appendicitis in a children's hospital., Methods: Data from surgical, radiologic, and pathologic databases were cross referenced retrospectively to allow for review of all children undergoing appendectomy and all children undergoing an ultrasound scan to rule out appendicitis in the 3-year period August 1, 1996 to July 31, 1999., Results: Pathology reports were available for 1,007 of 1,032 patients undergoing appendectomy. Eighty-four percent had acute appendicitis (26% of these were perforated). Fifty-eight percent of all children undergoing appendectomy had at least 1 preoperative ultrasound scan. Eighty-six percent of those having ultrasound scans had acute appendicitis compared with 82% of those who did not have an ultrasound scan (P <.05 chi(2) Test). During the same period, 2,056 ultrasound examinations were performed by staff radiologists who were available 24 hours a day to rule out appendicitis. Ultrasonography in this setting had a sensitivity of 89%, specificity of 95%, positive predictive value of 86%, and a negative predictive value of 96% (true-positives, n = 496; false-positive, n = 81; true-negative, n = 1,417; false-negative, n = 62). An alternate ultrasound diagnosis was offered in 157 children., Conclusions: Ultrasound scan improves diagnostic accuracy in children with suspected appendicitis. The high negative predictive value of ultrasound scan, especially when used repeatedly, may reduce the need for admission to hospital for clinical observation to rule out appendicitis.

Background: We used phage display technology to clone human recombinant antitumor antibodies from the antibody repertoire of neuroblastoma patients immunized with cytokine-gene transduced tumor cells., Procedure: Lymphocytes obtained from neuroblastoma patients either at diagnosis or after immunization with an autologous interleukin-2 gene transduced tumor vaccine were used to construct two human single-chain Fv (scFV) phage libraries. Tumor-reactive phage were characterized using ELISA, flow cytometry, and sequencing analysis., Results: The initial screening after panning on neuroblastoma cells yielded a substantially higher proportion of selectivity tumor-binding phage clones derived from the immunized patients library (12.9%) than from the unvaccinated patients library (0.8%). The antibodies stained the cells from several additional pediatric malignancies, including Ewing sarcoma and rhabdomyosarcoma, in the absence of binding to any normal tissue cultures or epithelial tumor cell lines. The pattern of reactivity was different from that of antibodies recognizing other widely distributed neuroblastoma-associated antigens, suggesting recognition of a novel shared tumor antigen., Conclusion: The human recombinant scFV antibodies reported here appear to represent a tumor-specific B-cell response induced by autologous tumor immunization and are potentially useful targeting moieties for the treatment of selected childhood tumors., (Copyright 2000 Wiley-Liss, Inc.)

Background/purpose: To better define the indications for peritoneal drainage (PD) in premature babies with intestinal perforation, the authors reviewed their experience with this procedure in a tertiary neonatal intensive care setting., Methods: The charts of all neonates who underwent PD as initial treatment for intestinal perforation between 1996 and 1999 were reviewed. Those patients with pneumatosis intestinalis on abdominal radiograph had perforated necrotizing enterocolitis (NEC) diagnosed; whereas, those infants with no pneumatosis had isolated intestinal perforation diagnosed. The clinical characteristics and outcomes of these 2 groups were compared., Results: Twenty-one premature neonates had primary PD between 1996 and 1999, 10 for isolated intestinal perforation and 11 for perforated NEC. Patients with isolated intestinal perforation had lower birth weights (708 v 949 g; P < .05), were less likely to have started feedings (30% v 91%, P < .05), and the perforation developed at an earlier age (10.6 v 28.0 d, P < .05) compared with the patients who had perforated NEC. Only 2 of 10 infants with isolated perforation required subsequent laparotomy (at 10 weeks for stricture and 12 weeks for a persistent fistula). For these patients, the long-term survival rate was 90%. In contrast, 8 of 11 infants with perforated NEC required laparotomy, and although the 30-day survival rate was 64%, the long-term survival rate was only 27%., Conclusions: Peritoneal drainage provides successful and definitive treatment for most premature babies with isolated intestinal perforation. For neonates with perforation caused by NEC, peritoneal drainage may provide temporary stabilization, but most of these infants require subsequent laparotomy, and few survive.

A nonhuman primate model comprising adult male rhesus monkeys (Macaca mulatta) with chronically indwelling subcutaneous central venous access devices provides a unique opportunity to determine plasma pharmacokinetics of new drugs such as anticancer and anti- retroviral agents. The central venous access we use is a low-profile, single-septum, titanium port that is attached to a radiopaque, indwelling catheter; the catheter is implanted in an internal jugular vein. A common complication following placement of the venous access device was migration of the catheter tip. We therefore modified the standard procedure by cutting the silicone catheter and introducing the rigid connector to secure the catheter to the vessel at the insertion site (approximately 9 to 13 cm from the distal end of the catheter). Prior to the use of the connector, three of five catheters migrated within 4 weeks after placement. In contrast, all 13 internal jugular catheters with connectors have remained patent without migration of the catheter tip. Therefore, incorporation of the catheter connector appears to have eliminated the problem of catheter migration.