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PURPOSE Brentuximab vedotin, an effective anti-CD30 antibody-drug conjugate approved for use in adults with classical Hodgkin lymphoma (HL), was introduced in this frontline trial to reduce prescribed radiation in children and adolescents with classical HL. METHODS Open-label, single-arm, multicenter trial for patients (age ≤ 18 years) with stage IIB, IIIB, or IV classical HL was conducted. Brentuximab vedotin replaced each vincristine in the OEPA/COPDac (vincristine, etoposide, prednisone, and doxorubicin/cyclophosphamide, vincristine, prednisone, and dacarbazine) regimen according to GPOH-HD2002 treatment group 3 (TG3); two cycles of AEPA and four cycles of CAPDac. Residual node radiotherapy (25.5 Gy) was given at the end of all chemotherapy only to nodal sites that did not achieve a complete response (CR) at the early response assessment (ERA) after two cycles of therapy. Primary objectives were to evaluate the safety and efficacy (complete remission at ERA) of this combination and the 3-year event-free (EFS) and overall survival (OS). The trials are registered at ClinicalTrials.gov (identifier: NCT01920932 ). RESULTS Of the 77 patients enrolled in the study, 27 (35%) achieved complete remission at ERA and were spared radiation. Patients who were irradiated received radiation to individual residual nodal tissue. At a median follow-up of 3.4 years, the 3-year EFS was 97.4% (SE 2.3%) and the OS was 98.7% (SE 1.6%). One irradiated patient experienced disease progression at the end of therapy and now remains disease free more than 6 years following salvage therapy, and one unexpected death occurred. Only 4% of patients experienced grade 3 neuropathy. CONCLUSION The integration of brentuximab vedotin in the frontline treatment of pediatric high-risk HL is highly tolerable, facilitated significant reduction in radiation exposure, and yielded excellent outcomes.

PURPOSE Children's Oncology Group (COG) AALL0331 tested whether pegaspargase intensification on a low-intensity chemotherapy backbone would improve the continuous complete remission (CCR) rate in a low-risk subset of children with standard-risk B-acute lymphoblastic leukemia (ALL). METHODS AALL0331 enrolled 5,377 patients with National Cancer Institute standard-risk B-ALL (age 1-9 years, WBC < 50,000/μL) between 2005 and 2010. Following a common three-drug induction, a cohort of 1,857 eligible patients participated in the low-risk ALL random assignment. Low-risk criteria included no extramedullary disease, < 5% marrow blasts by day 15, end-induction marrow minimal residual disease < 0.1%, and favorable cytogenetics ( ETV6-RUNX1 fusion or simultaneous trisomies of chromosomes 4, 10, and 17). Random assignment was to standard COG low-intensity therapy (including two pegaspargase doses, one each during induction and delayed intensification) with or without four additional pegaspargase doses at 3-week intervals during consolidation and interim maintenance. The study was powered to detect a 4% improvement in 6-year CCR rate from 92% to 96%. RESULTS The 6-year CCR and overall survival (OS) rates for the entire low-risk cohort were 94.7% ± 0.6% and 98.7% ± 0.3%, respectively. The CCR rates were similar between arms (intensified pegaspargase 95.3% ± 0.8% v standard 94.0% ± 0.8%; P = .13) with no difference in OS (98.1% ± 0.5% v 99.2% ± 0.3%; P = .99). Compared to a subset of standard-risk study patients given identical therapy who had the same early response characteristics but did not have favorable or unfavorable cytogenetics, outcomes were significantly superior for low-risk patients (CCR hazard ratio 1.95; P = .0004; OS hazard ratio 5.42; P < .0001). CONCLUSION Standard COG therapy without intensified pegaspargase, which can easily be given as an outpatient with limited toxicity, cures nearly all children with B-ALL identified as low-risk by clinical, early response, and favorable cytogenetic criteria.

Background Histiocytic and dendritic cell neoplasms are a diverse group of tumors arising from monocytic or dendritic cell lineage. Whereas the genomic features for Langerhans cell histiocytosis and Erdheim‐Chester disease have been well described, other less common and often aggressive tumors in this broad category remain poorly characterized, and comparison studies across the World Health Organization diagnostic categories are lacking. Methods Tumor samples from a total of 102 patient cases within four major subtypes of malignant histiocytic and dendritic cell neoplasms, including 44 follicular dendritic cell sarcomas (FDCSs), 41 histiocytic sarcomas (HSs), 7 interdigitating dendritic cell sarcomas (IDCSs), and 10 Langerhans cell sarcomas (LCSs), underwent hybridization capture with analysis of up to 406 cancer‐related genes. Results Among the entire cohort of 102 patients, CDKN2A mutations were most frequent across subtypes and made up 32% of cases, followed by TP53 mutations (22%). Mitogen‐activated protein kinase (MAPK) pathway mutations were present and enriched among the malignant histiocytosis (M) group (HS, IDCS, and LCS) but absent in FDCS (72% vs. 0%; p, Histiocytic and dendritic cell neoplasms are a diverse group of tumors arising from the monocytic or dendritic cell lineage. This article presents the molecular characteristics of the four major subtypes of malignant histiocytic and dendritic cell neoplasms, focusing on genomic alterations that could represent therapeutic targets.

Inflammatory bowel diseases (IBD) are often treated with anti-tumor necrosis factor alpha (anti-TNFα) medications. Concomitant treatment of IBD with anti-TNFα agents and immunomodulators appears to be associated with an increased risk for lymphoma. Patients who developed lymphoma while on monotherapy with an anti-TNFα agent were identified at three centers. Institutional Review Board approval was obtained. Five adolescents and young adult patients with pediatric-onset IBD who were treated with infliximab (IFX) without exposure to thiopurines were subsequently diagnosed with lymphoma. Three of the five patients had bone involvement at presentation. Epstein–Barr virus was positive in 2 cases. Median time from diagnosis of IBD and exposure to IFX prior to diagnosis of lymphoma was 5 and 4.3 years, respectively. This case series reports long-term follow-up for young patients with IBD who were treated with IFX monotherapy and developed lymphoma. Three of the five patients had bone involvement. In general, the risk of lymphoma following exposure to anti-TNFα medications alone remains low, but the incidence of primary bone lymphomas in IBD has not been reported. Studies examining longer exposure times may be needed to determine the true lymphoma risk in patients treated with IFX monotherapy.

PURPOSE Children’s Oncology Group (COG) AALL0331 tested whether intensified postinduction therapy that improves survival in children with high-risk B-cell acute lymphoblastic leukemia (ALL) would also improve outcomes for those with standard-risk (SR) ALL. PATIENTS AND METHODS AALL0331 enrolled 5,377 patients between 2005 and 2010. All patients received a 3-drug induction with dexamethasone, vincristine, and pegaspargase (PEG) and were then classified as SR low, SR average, or SR high. Patients with SR-average disease were randomly assigned to receive either standard 4-week consolidation (SC) or 8-week intensified augmented Berlin-Frankfurt-Münster (BFM) consolidation (IC). Those with SR-high disease were nonrandomly assigned to the full COG-augmented BFM regimen, including 2 interim maintenance and delayed intensification phases. RESULTS The 6-year event-free survival (EFS) rate for all patients enrolled in AALL0331 was 88.96% ± 0.46%, and overall survival (OS) was 95.54% ± 0.31%. For patients with SR-average disease, the 6-year continuous complete remission (CCR) and OS rates for SC versus IC were 87.8% ± 1.3% versus 89.1% ± 1.2% ( P = .52) and 95.8% ± 0.8% versus 95.2% ± 0.8% ( P = 1.0), respectively. Those with SR-average disease with end-induction minimal residual disease (MRD) of 0.01% to < 0.1% had an inferior outcome compared with those with lower MRD and no improvement with IC (6-year CCR: SC, 77.5% ± 4.8%; IC, 77.1% ± 4.8%; P = .71). At 6 years, the CCR and OS rates among 635 nonrandomly treated patients with SR-high disease were 85.55% ± 1.49% and 92.97% ± 1.08%, respectively. CONCLUSION The 6-year OS rate for > 5,000 children with SR ALL enrolled in AALL0331 exceeded 95%. The addition of IC to treatment for patients with SR-average disease did not improve CCR or OS, even in patients with higher MRD, in whom it might have been predicted to provide more value. The EFS and OS rates are excellent for this group of patients with SR ALL, with particularly good outcomes for those with SR-high disease.

A Boy with Jaundice A 16-year-old boy was admitted to the hospital in autumn because of malaise, abdominal cramping, and jaundice. Ultrasonography of the abdomen revealed splenomegaly. Atypical lym...

Although melanoma is a rare diagnosis in the pediatric population, advances in the management of adults with melanoma offer the prospect of promising therapeutic options for children. At this time, medical management is not considered curative but may reduce the risk of recurrence or prolong survival. Surgical management remains the mainstay of treatment. Medical therapy of pediatric melanoma is not thought to have a role for in situ, early-stage, or localized disease, but adjuvant therapy may have a role in improving the prognosis of patients with positive sentinel lymph node biopsy (SLNB), spread beyond the regional lymph node basin, metastatic disease, or recurrent disease. Medical treatment options include immunotherapies, particularly checkpoint inhibitors, and targeted therapies, which have provided improved toxicity profiles compared with traditional chemotherapy regimens in the setting of advanced disease. There is a growing body of pediatric-specific data relevant to the use of adjuvant therapies for advanced melanoma in children.

Children's Oncology Group (COG) AALL0331 tested whether pegaspargase intensification on a low-intensity chemotherapy backbone would improve the continuous complete remission (CCR) rate in a low-risk subset of children with standard-risk B-acute lymphoblastic leukemia (ALL). METHODS: AALL0331 enrolled 5,377 patients with National Cancer Institute standard-risk B-ALL (age 1-9 years, WBC < 50,000/μL) between 2005 and 2010. Following a common three-drug induction, a cohort of 1,857 eligible patients participated in the low-risk ALL random assignment. Low-risk criteria included no extramedullary disease, < 5% marrow blasts by day 15, end-induction marrow minimal residual disease < 0.1%, and favorable cytogenetics (ETV6-RUNX1 fusion or simultaneous trisomies of chromosomes 4, 10, and 17). Random assignment was to standard COG low-intensity therapy (including two pegaspargase doses, one each during induction and delayed intensification) with or without four additional pegaspargase doses at 3-week intervals during consolidation and interim maintenance. The study was powered to detect a 4% improvement in 6-year CCR rate from 92% to 96%. RESULTS: The 6-year CCR and overall survival (OS) rates for the entire low-risk cohort were 94.7% ± 0.6% and 98.7% ± 0.3%, respectively. The CCR rates were similar between arms (intensified pegaspargase 95.3% ± 0.8% v standard 94.0% ± 0.8%; P = .13) with no difference in OS (98.1% ± 0.5% v 99.2% ± 0.3%; P = .99). Compared to a subset of standard-risk study patients given identical therapy who had the same early response characteristics but did not have favorable or unfavorable cytogenetics, outcomes were significantly superior for low-risk patients (CCR hazard ratio 1.95; P = .0004; OS hazard ratio 5.42; P < .0001). CONCLUSION: Standard COG therapy without intensified pegaspargase, which can easily be given as an outpatient with limited toxicity, cures nearly all children with B-ALL identified as low-risk by clinical, early response, and favorable cytogenetic criteria.

Inflammatory bowel diseases (IBD) are often treated with anti-tumor necrosis factor alpha (anti-TNFα) medications. Concomitant treatment of IBD with anti-TNFα agents and immunomodulators appears to be associated with an increased risk for lymphoma.Patients who developed lymphoma while on monotherapy with an anti-TNFα agent were identified at three centers. Institutional Review Board approval was obtained.Five adolescents and young adult patients with pediatric-onset IBD who were treated with infliximab (IFX) without exposure to thiopurines were subsequently diagnosed with lymphoma. Three of the five patients had bone involvement at presentation. Epstein-Barr virus was positive in 2 cases. Median time from diagnosis of IBD and exposure to IFX prior to diagnosis of lymphoma was 5 and 4.3 years, respectively.This case series reports long-term follow-up for young patients with IBD who were treated with IFX monotherapy and developed lymphoma. Three of the five patients had bone involvement. In general, the risk of lymphoma following exposure to anti-TNFα medications alone remains low, but the incidence of primary bone lymphomas in IBD has not been reported. Studies examining longer exposure times may be needed to determine the true lymphoma risk in patients treated with IFX monotherapy.

BACKGROUND To the authors' knowledge, health-related quality of life (HRQOL) outcomes are not well described in patients with medulloblastoma. The use of proton radiotherapy (RT) may translate into an improved HRQOL. In the current study, the authors report long-term HRQOL in patients with proton-treated pediatric medulloblastoma. METHODS The current study was a prospective cohort HRQOL study of patients with medulloblastoma who were treated with proton RT and enrolled between August 5, 2002, and October 8, 2015. Both child report and parent-proxy report Pediatric Quality of Life Inventory (PedsQL) surveys were collected at baseline during RT and annually thereafter (score range on surveys of 0-100, with higher scores indicating better HRQOL). Patients were dichotomized by clinical/treatment variables and subgroups were compared. Mixed-model analysis was performed to determine the longitudinal trajectory of PedsQL scores. The Student t test was used to compare long-term HRQOL measures with published means from a healthy child population. RESULTS Survey data were evaluable for 116 patients with a median follow-up of 5 years (range, 1-10.6 years); the median age at the time of diagnosis was 7.6 years (range, 2.1-18.1 years). At baseline, children reported a total core score (TCS) of 65.9, which increased by 1.8 points annually (P

A previously healthy 10-year-old girl presented to the emergency department (ED) with a headache and vomiting which resolved with oral NSAIDs. The patient returned two days later unable to ambulate with mental slowing and lower extremity bruising. Labs demonstrated marked leukocytosis, severe anemia and thrombocytopenia, and disseminated intravascular coagulation (DIC). Brain MRI showed multiple intracranial hemorrhages. A peripheral blood smear demonstrated blasts with many Auer rods. A diagnosis of acute promyelocytic leukemia (APL) was made and therapy including all-transretinoic acid (ATRA) was initiated. Neurologic status returned to baseline within 1 week in the pediatric intensive care unit.

Background/objectives Melanoma in children and adolescents is uncommon, and there are limited data on pediatric outcomes. Several studies have shown comparable survival rates in children and adults, but other research demonstrates that prepubescent children have more favorable outcomes. This study aims to compare childhood and adolescent melanoma. Methods Retrospective cohort study of children who received a melanoma diagnosis at the Massachusetts General Hospital between January 1, 1995, and December 21, 2016. Childhood melanoma is defined as disease occurring in patients younger than 11 years old, and adolescent melanoma is defined as disease occurring in patients 11 to 19 years old. Patients diagnosed with ocular melanoma and borderline tumors of uncertain malignant potential were excluded. This analysis compares clinical, histopathologic, and outcome characteristics of childhood and adolescent melanoma. Results Thirty-two children with melanoma were identified (12 children, 20 adolescents). The spitzoid melanoma subtype was significantly more common in children (6/12) than adolescents (2/20) (P = .01). Four adolescents and no children with melanoma died from melanoma, and survival was significantly different between the age groups (P = .04). Median follow-up time for survivors was 3.6 years. Conclusions These results suggest that children and adolescents present with different melanoma subtypes and that adolescents have a more aggressive disease course than children.

A 14-month-old boy presented with a slow-growing, asymptomatic back plaque, which was biopsied and found to have S100 positivity, sparse CD34 staining, and no significant mitotic activity, nuclear pleomorphism, or necrosis; genetic workup found LMNA-NTRK1 gene fusion, overall consistent with lipofibromatosis-like neural tumor (LPF-NT). LPF-NT is rare, with 14 cases previously reported, and our patient is the first report of this diagnosis in infancy. This case report and literature review includes comparison of similar diagnoses including lipofibromatosis, low-grade malignant peripheral nerve sheath tumor, infantile fibrosarcoma, and dermatofibrosarcoma protuberans and serves to aid detection of LPF-NT presenting in pediatric patients by highlighting similarities and differences that should prompt consideration. LPF-NT shows locally aggressive behavior only and should not be confused with conditions that have potential for distant spread. However, case reports of metastasizing LMNA-NTRK1 tumors draw into question whether growths with this gene fusion exist on a spectrum of disease severity. Our patient was treated with wide local excision and has developed no complications or evidence of recurrence with 6 months of follow-up time.

Background: Brentuximab vedotin is an anti-CD30 antibody-drug conjugate approved for use in adults with newly diagnosed and relapsed/refractory high-risk classical Hodgkin lymphoma (HL). Methods: Open label, single-arm, multicenter trial for patients (age < 18 years) with stage IIB, IIIB or IV classical HL. One dose of brentuximab vedotin (AdcetrisO) replaced each vincristine in the OEPA [vincristine, etoposide, prednisone, and doxorubicin]/COPDac [cyclophosphamide, vincristine, prednisone, and dacarbazine] regimen (2 cycles of AEPA and 4 cycles of CAPDac) according to GPOH-HD2002 treatment group 3 [TG3]. 1 Residual node radiotherapy (25·5 Gy) was given at the end of all chemotherapy only to nodal sites that did not achieve a complete response (CR) at the early response assessment (ERA) after 2 cycles of therapy. Primary objectives were to evaluate the safety and efficacy (complete remission at ERA) of this combination and the 3-year event-free and overall survival. Findings: Of the 77 patients enrolled in the study, 27 (35%) achieved complete remission at ERA and were spared radiation. Patients who were irradiated received radiation to individual residual nodal tissue. At a median follow-up of 3·4 years, the 3 year event-free survival was 97·4% (SE 2·3%) and overall survival 98·7% (SE 1·6%). One irradiated patient experienced disease progression at the end of therapy and now remains disease free more than 6 years following salvage therapy, and one unexpected death occurred. Only 4% patients experienced Grade 3 neuropathy. Interpretation: The integration of brentuximab vedotin in the frontline treatment of pediatric high-risk HL is highly tolerable, facilitated reduction in radiation exposure, and yielded excellent outcomes. Trial Registration: IND (#118603), The trial is registered with www.clinicaltrials.gov, NCT01920932. Funding Statement: Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number P30CA021765. Declaration of Interests: None to declare. Ethics Approval Statement: The trial was approved by the institutional review board of each participating center and monitored by the SJCRH Data, Safety, and Monitoring Board. Informed consent was obtained as per institutional guidelines.

An 8-year-old boy presented with a mass in the right breast that had been present for 18 months and had enlarged during the previous 6 months. On examination, a firm, mobile mass (2 cm by 2 cm) was present under the right areola. Diagnostic procedures were performed.

A 12-year-old boy presented with a 1-month history of fever and abdominal pain. Three months earlier, he had traveled to the Dominican Republic. Laboratory evaluation revealed anemia and an elevated C-reactive protein level. Diagnostic tests were performed.

Background Fever and neutropenia is a common reason for nonelective hospitalization of pediatric oncology patients. Herein we report nearly five years of experience with a clinical pathway designed to guide outpatient management for patients who had low-risk features. Procedures Through a multidisciplinary collaboration, we implemented a clinical pathway at our institution using established low-risk criteria to guide outpatient management of pediatric oncology patients. Comprehensive chart review of all febrile neutropenia episodes was conducted to characterize outcomes of patients with low-risk febrile neutropenia following clinical pathway implementation. Results Between April 1, 2013, and October 1, 2017, there were 169 cases of febrile neutropenia managed in our Pediatric Oncology Unit. Sixty-seven (40%) of these episodes were defined as low risk and managed either entirely in the outpatient setting (41 episodes, 24%) or with a step-down strategy involving a very brief inpatient stay (26 episodes, 15%). There were no intensive care unit admissions or deaths among the low-risk patients. Of those identified as low risk, seven patients (10%) required subsequent hospitalization during the follow-up period, two for inadequate oral intake, two for persistent fevers, one for cellulitis, one for seizure unrelated to the febrile episode, and one for a positive blood culture. Conclusions Following implementation of a clinical pathway, the majority of patients designated as low risk were managed primarily in the outpatient setting without major morbidity or mortality, suggesting that carefully selected low-risk patients can be successfully treated with outpatient management and subsequent admission if warranted.

A 14-year-old boy with a history of type 1 diabetes, learning disabilities, recurrent infections, and leukoplakia had abnormal results on liver-function tests. On evaluation, he had thrombocytopenia, anemia, splenomegaly, and liver nodularity. Diagnostic tests were performed.

Background Esthesioneuroblastoma (EN) of the paranasal sinus comprises less than 3% of tumors of in pediatric and adolescent patients [1]. The collective adult literature indicates a critical role for radiotherapy in attaining cure [2], yet pediatric outcome data is limited. Radiation in pediatric patients with EN can cause significant morbidity due to the proximity of critical structures. Proton radiotherapy offers a potential dosimetric benefit that may improve long-term survival and toxicity outcomes in the pediatric population [3]. Methods We retrospectively identified eight patients treated for EN with proton radiotherapy from 2000-2013. Times to event clinical endpoints are summarized using the Kaplan–Meier methods and are from the date of radiotherapy completion. Toxicities are reviewed and graded according to CTCAE v. 4.0. Results Median follow up was 4.6 years for survivors (range 0.8–9.4 years). The 4 year overall survival was 87.5%. Four of eight patients (one elective) had comprehensive neck radiotherapy. No local or regional failures were observed. Two patients failed distantly with diffuse leptomeningeal disease and intraparenchymal brain metastases, at 0.6 and 1.3 months respectively. Four patients developed radiation related late toxicities including endocrine dysfunction, two cases of grade 2 retinopathy and one case of grade 3 optic neuropathy. Conclusions In a limited cohort, proton radiotherapy appears to provide excellent locoregional disease control even in those patients with locally advanced disease and intracranial extension. Distant failure determined overall survival in our cohort. Toxicities were acceptable given disease location and extent. Pediatr Blood Cancer 2015;62:1523–1528. © 2015 Wiley Periodicals, Inc.

Pediatric rhabdomyosarcoma (RMS) is highly curable, however, cure may come with significant radiation related toxicity in developing tissues. Proton therapy (PT) can spare excess dose to normal structures, potentially reducing the incidence of adverse effects.Between 2005 and 2012, 54 patients were enrolled on a prospective multi-institutional phase II trial using PT in pediatric RMS. As part of the protocol, intensity modulated radiation therapy (IMRT) plans were generated for comparison with clinical PT plans.Target coverage was comparable between PT and IMRT plans with a mean CTV V95 of 100% for both modalities (p=0.82). However, mean integral dose was 1.8 times higher for IMRT (range 1.0-4.9). By site, mean integral dose for IMRT was 1.8 times higher for HN (p0.01) and GU (p=0.02), 2.0 times higher for trunk/extremity (p0.01), and 3.5 times higher for orbit (p0.01) compared to PT. Significant sparing was seen with PT in 26 of 30 critical structures assessed for orbital, head and neck, pelvic, and trunk/extremity patients.Proton radiation lowers integral dose and improves normal tissue sparing when compared to IMRT for pediatric RMS. Correlation with clinical outcomes is necessary once mature long-term toxicity data are available.

Study NCT01519323 (A study of vemurafenib in pediatric patients with stage IIIC or stage IV melanoma harbouring BRAFV600 mutations) was included in a table listing ongoing clinical trials of adjuvant therapies for pediatric melanoma (Table 1) in error. The study was in fact closed early due to low enrollment as correctly noted in section 4 of the article.

Background: The outcome of treatment for pediatric Hodgkin lymphoma (HL) is excellent using chemotherapy and radiation. However, a minority of patients will relapse after treatment, but additionaltherapy achieves durable second remission in many cases. The optimal surveillance strategy after modern therapy for HL has not been well defined. Procedures: We reviewed the outcomes of pediatric patients with HL treated between 1990 and 2006 to determine the primary event that led to the detection of relapse. We determined the probability of relapse detection by routine follow-up procedures, including history,physical examination, laboratorytests, and imaging, and determined the impact of each of these screening methods on the likelihood of survival after relapse. Results: Relapse occurred in 64 of 402 evaluable patients (15.9%) at a median of 1.7 years from the time of diagnosis. The majority of relapses (60%) were diagnosed at a routine visit, and patient complaint was the most common initial finding that led to a diagnosis of relapse (47% of relapses). An abnormal finding on physical examination was the primary event in another 17% of relapses, and imaging abnormalities led to the diagnosis in the remaining 36%. Laboratory abnormalities were never the primary finding. The method of detection of relapse andtiming(whetherdetectedataroutinevisitoranextravisit)didnot impact survival. Conclusions: In pediatric HL, most relapses are identified through history and physical examination. Frequent imaging of asymptomatic patients does not appear to impact survival and is probably not warranted. Pediatr Blood Cancer 2013;60:1458‐ 1463. # 2013 Wiley Periodicals, Inc.

A 4-year-old boy was admitted to this hospital because of fever and abdominal pain. Imaging revealed a periappendiceal mass; purulent fluid was aspirated, and symptoms resolved with antibiotics. One week later, pain recurred. A diagnostic procedure was performed.

To compare whole-body magnetic resonance (MR) imaging with conventional imaging for detection of distant metastases in pediatric patients with common malignant tumors.This institutional review board-approved, HIPAA-compliant, multicenter prospective cohort study included 188 patients (109 male, 79 female; mean age, 10.2 years; range,1 to 21 years) with newly diagnosed lymphoma, neuroblastoma, or soft-tissue sarcoma. Informed consent was obtained and all patients underwent noncontrast material-enhanced whole-body MR imaging and standard-practice conventional imaging. All images were reviewed centrally by 10 pairs of readers. An independent panel verified the presence or absence of distant metastases. Detection of metastasis with whole-body MR and conventional imaging was quantified by using the area under the receiver operating characteristic curve (AUC). The effects of tumor subtype, patient age, and distant skeletal and pulmonary disease on diagnostic accuracy were also analyzed.Of the 134 eligible patients, 66 (33 positive and 33 negative for metastasis) were selected for image review and analysis. Whole-body MR imaging did not meet the noninferiority criterion for accuracy when compared with conventional imaging for detection of metastasis (difference between average AUCs was -0.03 [95% confidence interval: -0.10, 0.04]); however, the average AUC for solid tumors was significantly higher than that for lymphomas (P = .006). More skeletal metastases were detected by using whole-body MR imaging than by using conventional imaging (P = .03), but fewer lung metastases were detected (P.001). Patient age did not affect accuracy.The noninferior accuracy for diagnosis of distant metastasis in patients with common pediatric tumors was not established for the use of whole-body MR imaging compared with conventional methods. However, improved accuracy was seen with whole-body MR imaging in patients with nonlymphomatous tumors.

Epstein-Barr virus-related lymphoproliferative disease (EBV-LPD) rarely occurs in patients with acute lymphoblastic leukemia (ALL), who have not received hematopoietic transplantation. We describe EBV-LPD manifesting as facial lesions in two children with ALL in remission. One patient was a 16-year-old male with T-cell ALL with an EBV-positive angiocentric polymorphous lip lesion presenting as right-sided facial swelling. The other patient was a 12-year-old male with B-cell ALL with an EBV-positive polymorphous lymphoplasmacytic infiltrate presenting as bilateral dacryoadenitis. Neither patient had known primary immunodeficiencies. Both cases improved with immunosuppressant de-escalation. These cases suggest that immunosuppression induced by maintenance chemotherapy is sufficient to promote EBV-LPD.

Purpose To report the early outcomes for children with high-risk neuroblastoma treated with proton radiotherapy (RT) and to compare the dose distributions for intensity-modulated photon RT (IMRT), three-dimensional conformal proton RT (3D-CPT), and intensity-modulated proton RT to the postoperative tumor bed. Methods and Materials All patients with high-risk (International Neuroblastoma Staging System Stage III or IV) neuroblastoma treated between 2005 and 2010 at our institution were included. All patients received induction chemotherapy, surgical resection of residual disease, high-dose chemotherapy with stem cell rescue, and adjuvant 3D-CPT to the primary tumor sites. The patients were followed with clinical examinations, imaging, and laboratory testing every 6 months to monitor disease control and side effects. IMRT, 3D-CPT, and intensity-modulated proton RT plans were generated and compared for a representative case of adjuvant RT to the primary tumor bed followed by a boost. Results Nine patients were treated with 3D-CPT. The median age at diagnosis was 2 years (range 10 months to 4 years), and all patients had Stage IV disease. All patients had unfavorable histologic characteristics (poorly differentiated histologic features in 8, N-Myc amplification in 6, and 1p/11q chromosomal abnormalities in 4). The median tumor size at diagnosis was 11.4 cm (range 7–16) in maximal dimension. At a median follow-up of 38 months (range 11–70), there were no local failures. Four patients developed distant failure, and, of these, two died of disease. Acute side effects included Grade 1 skin erythema in 5 patients and Grade 2 anorexia in 2 patients. Although comparable target coverage was achieved with all three modalities, proton therapy achieved substantial normal tissue sparing compared with IMRT. Intensity-modulated proton RT allowed additional sparing of the kidneys, lungs, and heart. Conclusions Preliminary outcomes reveal excellent local control with proton therapy for high-risk neuroblastoma, although distant failures continu to occur. Dosimetric comparisons demonstrate the advantage of proton RT compared with IMRT in this setting, allowing more conformal treatment and better normal tissue sparing.

Purpose In this study, we report the clinical outcomes of 7 children with bladder/prostate rhabdomyosarcoma (RMS) treated with proton radiation and compare proton treatment plans with matched intensity-modulated radiation therapy (IMRT) plans, with an emphasis on dose savings to reproductive and skeletal structures. Methods and Materials Follow-up consisted of scheduled clinic appointments at our institution or direct communication with the treating physicians for referred patients. Each proton radiotherapy plan used for treatment was directly compared to an IMRT plan generated for the study. Clinical target volumes and normal tissue volumes were held constant to facilitate dosimetric comparisons. Each plan was optimized for target coverage and normal tissue sparing. Results Seven male patients were treated with proton radiotherapy for bladder/prostate RMS at the Massachusetts General Hospital between 2002 and 2008. Median age at treatment was 30 months (11–70 months). Median follow-up was 27 months (10–90 months). Four patients underwent a gross total resection prior to radiation, and all patients received concurrent chemotherapy. Radiation doses ranged from 36 cobalt Gray equivalent (CGE) to 50.4 CGE. Five of 7 patients were without evidence of disease and with intact bladders at study completion. Target volume dosimetry was equivalent between the two modalities for all 7 patients. Proton radiotherapy led to a significant decrease in mean organ dose to the bladder (25.1 CGE vs. 33.2 Gy; p = 0.03), testes (0.0 CGE vs. 0.6 Gy; p = 0.016), femoral heads (1.6 CGE vs. 10.6 Gy; p = 0.016), growth plates (21.7 CGE vs. 32.4 Gy; p = 0.016), and pelvic bones (8.8 CGE vs. 13.5 Gy; p = 0.016) compared to IMRT. Conclusions This study provides evidence of significant dose savings to normal structures with proton radiotherapy compared to IMRT and is well tolerated in this patient population. The long-term impact of these reduced doses can be tested in future studies incorporating extended follow-up, objective outcome measures, and quality-of-life analyses.

A 4-year-old boy was admitted to this hospital because of a 1-week history of back pain, with sleepiness, constipation, and refusal to walk. The serum calcium level was elevated. Initial radiographs and MRI studies were interpreted as normal. Diagnostic tests were performed.

Although numerous quantitative trait loci (QTL) mapping studies involving milk protein percent (PP), milk yield (MY), and protein yield (PY) have been carried out, there has not been any systematic evaluation of the effects of individual QTL on these 3 interrelated traits. Consequently, the aim of the present study was to investigate the effects on MY and PY of QTL for PP previously mapped in various laboratories. The study, based on selective DNA pooling of milk samples, included 10 Israeli Holstein artificial insemination bulls, each the sire of 1,800 or more milk-recorded daughters. For each sire-trait combination across the 10 sires, milk samples of the highest and lowest daughters with respect to estimated breeding values for PP, PY, and MY were collected for pooling. A total of 134 dinucleotide microsatellites distributed over 25 bovine autosomes were used. An empirical standard error for marker-QTL linkage testing was calculated based on the variation among split samples within the same tail. Threshold comparison-wise error rate P-values were set to control proportion of false positives at P = 0.10 level for declaring significant effects at the marker-trait level. Estimates of the number of true null hypotheses for each trait were obtained from the histogram of marker comparison-wise error rate P-values. Based on these estimates, effective power of the experiment at the marker-trait level was estimated as 0.75, 0.41, and 0.73 for PP, PY, and MY. The proportion of heterozygosity at the QTL was estimated as 0.46, 0.39, and 0.40, respectively. After correcting for incomplete power and proportion of false positives, it was estimated that 38.7 and 37.5% of the markers affecting PP and MY, respectively, also affected PY. Of the markers affecting PY, 68.9 and 76.5%, respectively, also affected PP and MY. Apparently, none of the significant markers affected PY exclusively, and only 6.5 and 16.0%, respectively, affected PP or MY exclusively. Thus, almost all significant markers, and by inference almost all QTL, had effects on at least 2 of the 3 traits.

1. Alison M. Friedmann, MD, MSc* 1. *Department of Hematology/Oncology, Massachusetts General Hospital, Boston, Mass After completing this article, readers should be able to: 1. Define lymphadenopathy. 2. Develop a systematic approach to the evaluation and management of lymphadenopathy. 3. Discuss the differential diagnosis of localized and generalized lymphadenopathy. 4. Recognize worrisome features of lymphadenopathy that should prompt a referral for a biopsy. Examining the lymph nodes is an important aspect of the general physical examination of both well and ill children and adolescents. Lymph nodes are normal structures, and certain lymph nodes may be palpable in a healthy patient, particularly in a young child. Conversely, the presence of abnormally enlarged lymph nodes (“lymphadenopathy”) can be a clue to a serious underlying systemic disease, and the differential diagnosis of lymphadenopathy can be broad. Thus, the challenge for the general pediatrician is to learn how to distinguish pathologic from nonpathologic lymph nodes and to develop a rational approach to the evaluation of lymphadenopathy. Because of its association with malignancy, lymphadenopathy can be a major source of parental anxiety. Therefore, it is crucial to know when to provide reassurance and to recognize when concern is sufficient to warrant referral to a subspecialist. The lymphatic system is an open circulatory system that is a component of the immune system. It includes lymph, lymphatic vessels, lymph nodes, spleen, tonsils, adenoids, Peyer patches, and the thymus. Lymph contains lymphocytes and is an ultrafiltrate of blood that is collected in lymphatic capillaries present throughout the body in all organs except the brain and heart. Lymph moves slowly, without a central pump and under low pressure, via peristalsis and through the milking action of skeletal muscles. Lymph is transported from the head and extremities to progressively larger lymphatic vessels and ultimately into either the right lymphatic duct (lymph from the right upper body) or the thoracic duct (lymph from the rest of the body). These ducts …

Quantitative trait loci (QTL) mapping projects have been implemented mainly in the Holstein dairy cattle breed for several traits. The aim of this study is to map QTL for milk yield (MY) and milk protein percent (PP) in the Brown Swiss cattle populations of Austria, Germany, and Italy, considered in this study as a single population. A selective DNA pooling approach using milk samples was applied to map QTL in 10 paternal half-sib daughter families with offspring spanning from 1,000 to 3,600 individuals per family. Three families were sampled in Germany, 3 in Italy, 1 in Austria and 3 jointly in Austria and Italy. The pools comprised the 200 highest and 200 lowest performing daughters, ranked by dam-corrected estimated breeding value for each sire-trait combination. For each tail, 2 independent pools, each of 100 randomly chosen daughters, were constructed. Sire marker allele frequencies were obtained by densitometry and shadow correction analyses of 172 genome-wide allocated autosomal markers. Particular emphasis was placed on Bos taurus chromosomes 3, 6, 14, and 20. Marker association for MY and PP with a 10% false discovery rate resulted in nominal P-values of 0.071 and 0.073 for MY and PP, respectively. Sire marker association tested at a 20% false discovery rate (within significant markers) yielded nominal P-values of 0.031 and 0.036 for MY and PP, respectively. There were a total of 36 significant markers for MY, 33 for PP, and 24 for both traits; 75 markers were not significant for any of the traits. Of the 43 QTL regions found in the present study, 10 affected PP only, 8 affected MY only, and 25 affected MY and PP. Remarkably, all 8 QTL regions that affected only MY in the Brown Swiss, also affected MY in research reported in 3 Web-based QTL maps used for comparison with the findings of this study (http://www.vetsci.usyd.edu.au/reprogen/QTL_Map/; http://www.animalgenome.org/QTLdb/cattle.html; http://bovineqtl.tamu.edu/). Similarly, all 10 QTL regions in the Brown Swiss that affected PP only, affected only PP in the databases. Thus, many QTL appear to be common to Brown Swiss and other breeds in the databases (mainly Holstein), and an appreciable fraction of QTL appears to affect MY or PP primarily or exclusively, with little or no effect on the other trait. Although QTL information available today in the Brown Swiss population can be utilized only in a within family marker-assisted selection approach, knowledge of QTL segregating in the whole population should boost gene identification and ultimately the implementation and efficiency of an individual genomic program.

Background Local control remains a challenge in pediatric parameningeal rhabdomyosarcoma (PM-RMS), and survival after local failure (LF) is poor. Identifying patients with a high risk of LF is of great interest to clinicians. In this study, we examined whether tumor response to induction chemotherapy (CT) could predict LF in embryonal PM-RMS. Methods We identified 24 patients with embryonal PM-RMS, age 2 to 18 years, with complete magnetic resonance imaging and gross residual disease after surgical resection. All patients received proton radiation therapy (RT), median dose 50.4 Gy RBE (50.4-55.8 Gy RBE ). Tumor size was measured before initial CT and before RT. Results With a median follow-up time of 4.1 years for survivors, LF was seen in 9 patients (37.5%). The median time from the initiation of CT to the start of RT was 4.8 weeks. Patients with LF had a similar initial (pre-CT) tumor volume compared with patients with local controlled (LC) (54 cm 3 vs 43 cm 3 , P =.9) but a greater median volume before RT (pre-RT) (40 cm 3 vs 7 cm 3 , P =.009) and a smaller median relative percent volume reduction (RPVR) in tumor size (0.4% vs 78%, P P =.05), larger pre-RT tumor volume ( P =.03), and smaller RPVR ( P =.003) were significantly associated with actuarial LF on univariate Cox analysis. Conclusions Poor response to induction CT appears to be associated with an increased risk of LF in pediatric embryonal PM-RMS.

Purpose To evaluate the efficacy of vinblastine, doxorubicin, methotrexate, and prednisone (VAMP) and cyclophosphamide, vincristine, and procarbazine (COP) chemotherapy and response-based, involved-field radiation, a combined-modality regimen that limits doses of alkylating agents, anthracyclines, and radiation, in children with advanced and unfavorable Hodgkin's disease. Patients and Methods From 1993 to 2000, 159 children and adolescents with unfavorable Hodgkin's disease received three alternating cycles (total of six cycles) of VAMP/COP chemotherapy followed by response-based, involved-field radiation therapy: 15 Gy was administered to patients achieving a complete response, and 25.5 Gy was administered to those achieving a partial response after the first two cycles of chemotherapy and to all sites of bulky lymphadenopathy. Unfavorable disease was defined as clinical stage I and II with bulky peripheral nodal disease greater than 6 cm, initial bulky mediastinal mass 33% or more of the intrathoracic diameter, and/or “B” symptoms and all stage III and IV. Results Study enrollment was closed after an interim analysis estimated a 5-year event-free survival (EFS) rate below a predefined level. Disease presentation was localized (stage I/II) in 77 patients (48.4%) and advanced (stage III/IV) in 82 patients (51.6%). At a median follow-up of 5.8 years (range, 1.3 to 10.0 years), 38 patients had events, including relapse/progression (n = 35), second malignancy (n = 2), and accidental death (n = 1); nine relapses (25.7%) occurred greater than 4 years from diagnosis. Five-year survival and EFS estimates are 92.7% ± 2.5% and 75.6% ± 4.1%, respectively. Conclusion Risk-adapted combined-modality therapy with VAMP/COP and response-based, involved-field radiation therapy results in an unsatisfactory outcome for pediatric patients with unfavorable presentations of Hodgkin's disease.

From the Division of Pediatric Hematology–Oncology, Pediatric Service (A.M.F.), and the Departments of Radiation Oncology (N.J.T.), Radiology (P.W.S.), and Pathology (B.L.H.), Massachusetts General Hospital; and the Departments of Pediatrics (A.M.F.), Radiation Oncology (N.J.T.), Radiology (P.W.S.), and Pathology (B.L.H.), Harvard Medical School.

Presentation of Case An 18-year-old man was admitted to the hospital because of back and leg pain and a nondiagnostic biopsy specimen from a paravertebral mass. The patient had been well until eight months earlier, when the back pain began. Despite the use of ibuprofen and local application of ice, the pain increased, and three months before admission, pain developed in the right lower leg. A chiropractor obtained a radiograph of the spine, which revealed a compression fracture at the L3 vertebra. About one month before admission, a computed tomographic (CT) scan of the lumbosacral spine, obtained at another facility, . . .

This study was designed to determine if low doses of oral sodium phenylbutyrate (SPB) induce hemoglobin F (HbF) synthesis in children with hemoglobin SS (HbSS). We treated 8 children with HbSS over a period of 5-30 weeks. The initial dose (1.0 g/d) was increased weekly (by 1.0 g/d) until F-reticulocytes doubled. All patients showed an increase in F-reticulocytes (P = 0.002) that was dose-dependent (P = 0.001). Three of 5 patients who continued oral SPB for more than 10 weeks had substantial increases in HbF. We conclude that lower dose SPB is effective in inducing HbF synthesis in some children with HbSS. Further trials are warranted to determine the optimal treatment regimen.

PURPOSE: Between January 1990 and April 1993, 56 pediatric patients with Hodgkin’s disease were treated on a single-arm trial at three institutions with a regimen designed to maintain high cure rates while minimizing the potential late effects of treatment, such as infertility, second malignant neoplasms, and cardiopulmonary injury. PATIENTS AND METHODS: The regimen used combined-modality therapy with six cycles of vinblastine, etoposide, prednisone, and doxorubicin (VEPA) chemotherapy and low-dose, involved-field radiation. Unfavorable features comprised bulky presentations of localized (stage I or II) disease or advanced (stage III or IV) Hodgkin’s disease. RESULTS: Of 56 patients enrolled, 26 (46%) had unfavorable presentations of stage I/II disease and 30 (54%) had advanced (stage III/IV) disease. Seventy-nine percent of the patients are alive without disease at a median follow-up time of 8.9 years from diagnosis. Nineteen patients had events at a median of 1.5 years (range, 0.4 to 7.9 years) from diagnosis; 17 patients relapsed, one died of cardiomyopathy, and one died of accidental injuries. Survival and event-free survival (EFS) estimates at 5 years for the entire cohort were 81.9% (SE, 5.2%) and 67.8% (SE, 6.3%), respectively. Five-year EFS by stage was 100% for stage I, 79.2% (SE, 8.3%) for stage II, 70% (SE, 14.5%) for stage III, and 49.5% (SE, 11.3%) for stage IV patients. CONCLUSION: Combined-modality therapy with VEPA chemotherapy and low-dose, involved-field radiation is adequate for disease control of early-stage patients with unfavorable features, but it is inferior to other standard regimens for advanced-stage patients.

The purpose of this study was to determine which clinical and laboratory features correlate with serious hemorrhage in thrombocytopenic oncology patients. A retrospective review was conducted of all thrombocytopenic adult patients admitted to the Johns Hopkins Oncology Center, Baltimore, MD, over the last 10 years. We performed multiple logistic regression analysis on 2942 patients looking at the frequency of serious bleeding as a function of platelet count and numerous features that may correlate with hemorrhage. Multivariate analyses showed no relationship between either the first morning platelet count or the lowest platelet count of the day and the risk of hemorrhage. Of the other features we examined, several correlated independently with bleeding, including uremia (odds ratio [OR] 1.64; 95% confidence interval [CI], 1.40 to 1.92), hypoalbuminemia (OR 1.54; 95% CI, 1.33 to 1.79), recent bone marrow transplantation (OR 1.32; 95% CI, 1.22 to 1.43), and recent hemorrhage (OR 6.72; 95% CI, 5.53 to 8.18). Leukopenia was associated with a decreased risk of bleeding (OR 0.70; 95% CI, 0.60 to 0.82). Although this large study identified a number of clinical and laboratory features that correlated significantly with bleeding, the ORs of these factors were not large and all were much less than previous bleeding. These findings suggest that the major goal of transfusion support should be the aggressive therapeutic use of blood products rather than prophylactic use based on such weak clinical correlates and on the platelet count, which was not a correlate at all in multivariate analysis.