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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.

Recent methodological advances in solution NMR allow the determination of multi-state protein structures and provide insights into correlated motion at atomic resolution as demonstrated here for the well-studied PDZ2 domain of protein human tyrosine phosphatase 1E for which protein allostery was predicted. Two-state protein structures were calculated for both the free form and in complex with the RA-GEF2 peptide using the exact nuclear Overhauser effect (eNOE) method. In the apo protein states an allosteric conformational preselection step comprising almost 60% of the domain was detected with an “open” ligand welcoming state and a “closed” state that obstructs the binding site by the distance between the β-sheet, α-helix 2 and sidechains of residues Lys38 and Lys72. Observed apo-holo structural rearrangements of induced fit-type are in line with previously published evolution-based analysis covering ~25% of the domain with only a partial overlap with the protein allostery of the open form. These presented structural studies highlight the presence of a dedicated highly optimized dynamic interplay of the complexity of the PDZ2 domain owed by the structure-dynamics landscape.

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.

Case Tibio-talar-calaneal fusion nails can be used to treat acute ankle fractures in patients with diabetes, Charcot arthropathy, or other comorbidities. Recently, Paragon28 released the Phantom Hindfoot Fusion Nail (Phantom nail) with a unique design feature-a proximal coil. We present a case of an ankle fracture-dislocation in a diabetic patient treated with the Paragon28 nail who experienced early implant failure. Conclusion It is important for surgeons to understand that the proximal coil in the Phantom nail should not be considered part of the working length of the nail and may introduce a stress riser that may lead to early implant failure.

We present a statistical analysis of the first four seasons from a "second-generation" microlensing survey for extrasolar planets, consisting of near-continuous time coverage of 8 deg$^2$ of the Galactic bulge by the OGLE, MOA, and Wise microlensing surveys. During this period, 224 microlensing events were observed by all three groups. Over 12% of the events showed a deviation from single-lens microlensing, and for $\sim$1/3 of those the anomaly is likely caused by a planetary companion. For each of the 224 events we have performed numerical ray-tracing simulations to calculate the detection efficiency of possible companions as a function of companion-to-host mass ratio and separation. Accounting for the detection efficiency, we find that $55^{+34}_{-22}\%$ of microlensed stars host a snowline planet. Moreover, we find that Neptunes-mass planets are $\sim10$ times more common than Jupiter-mass planets. The companion-to-host mass ratio distribution shows a deficit at $q\sim10^{-2}$, separating the distribution into two companion populations, analogous to the stellar-companion and planet populations, seen in radial-velocity surveys around solar-like stars. Our survey, however, which probes mainly lower-mass stars, suggests a minimum in the distribution in the super-Jupiter mass range, and a relatively high occurrence of brown-dwarf companions., Comment: 24 pages, 13 figures, 2 tables. 2016, MNRAS, 457, 4089

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.

We present the analysis of the binary-lens microlensing event OGLE-2013-BLG-0911. The best-fit solutions indicate the binary mass ratio of q~0.03 which differs from that reported in Shvartzvald+2016. The event suffers from the well-known close/wide degeneracy, resulting in two groups of solutions for the projected separation normalized by the Einstein radius of s~0.15 or s~7. The finite source and the parallax observations allow us to measure the lens physical parameters. The lens system is an M-dwarf orbited by a massive Jupiter companion at very close (M_{host}=0.30^{+0.08}_{-0.06} M_{Sun}, M_{comp}=10.1^{+2.9}_{-2.2} M_{Jup}, a_{exp}=0.40^{+0.05}_{-0.04} au) or wide (M_{host}=0.28^{+0.10}_{-0.08} M_{Sun}, M_{comp}=9.9^{+3.8}_{-3.5}M_{Jup}, a_{exp}=18.0^{+3.2}_{-3.2} au) separation. Although the mass ratio is slightly above the planet-brown dwarf (BD) mass-ratio boundary of q=0.03 which is generally used, the median physical mass of the companion is slightly below the planet-BD mass boundary of 13M_{Jup}. It is likely that the formation mechanisms for BDs and planets are different and the objects near the boundaries could have been formed by either mechanism. It is important to probe the distribution of such companions with masses of ~13M_{Jup} in order to statistically constrain the formation theories for both BDs and massive planets. In particular, the microlensing method is able to probe the distribution around low-mass M-dwarfs and even BDs which is challenging for other exoplanet detection methods., Comment: 22 pages, 10 figures, Accepted for publication in The Astronomical Journal

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.

著者人数: 49名ほか (所属. 宇宙航空研究開発機構宇宙科学研究所 (JAXA)(ISAS): 鈴木, 大介), 資料番号: SA1180374000

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.

著者人数: 47名ほか（所属. 宇宙航空研究開発機構宇宙科学研究所(JAXA)(ISAS): 鈴木, 大介), Accepted: 2018-07-22, 資料番号: SA1180098000

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.

The observed delay-time distribution (DTD) of Type-Ia supernovae (SNe Ia) is a valuable probe of SN Ia progenitors and physics, and of the role of SNe Ia in cosmic metal enrichment. The SN Ia rate in galaxy clusters as a function of cluster redshift is an almost-direct measure of the DTD, but current estimates have been limited out to a mean redshift z=1.1, corresponding to time delays, after cluster star-formation, of over 3.2 Gyr. We analyze data from a Hubble Space Telescope monitoring project of 12 galaxy clusters at z=1.13-1.75, where we discover 29 SNe, and present their multi-band light curves. Based on the SN photometry and the apparent host galaxies, we assess cluster membership and SN type, finding 11 cases that are likely SNe Ia in cluster galaxies and 4 more cases which are possible but not certain cluster SNe Ia. We conduct simulations to estimate the SN detection efficiency, the experiment's completeness, and the photometric errors, and perform photometry of the cluster galaxies to derive the cluster stellar masses. Separating the cluster sample into high-z and low-z bins, we obtain rest-frame SN Ia rates per unit formed stellar mass of $2.2 ^{+2.6}_{-1.3}\times 10^{-13}{\rm yr}^{-1}{\rm M}_\odot^{-1}$ at a mean redshift z=1.25, and $3.5^{+6.6}_{-2.8} \times 10^{-13}{\rm yr}^{-1}{\rm M}_\odot^{-1}$ at z=1.58. Combining our results with previous cluster SN Ia rates, we fit the DTD, now down to delays of 1.5 Gyr, with a power-law dependence, $t^\alpha$, with $\alpha=-1.30^{+0.23}_{-0.16}$. We confirm previous indications for a Hubble-time-integrated SN Ia production efficiency that is several times higher in galaxy clusters than in the field, perhaps caused by a peculiar stellar initial mass function in clusters, or by a higher incidence of binaries that will evolve into SNe Ia., Comment: MNRAS, in press

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.

Purpose: To establish normal values of the optic nerve sheath diameter (ONSD) in children and adolescents for transbulbar sonography and magnetic resonance imaging. Materials and Methods: In 99 children and adolescents (age: 5.6 – 18.6 years, mean: 12 years) without neurologic or ophthalmologic disease, measurements of the ONSD with transbulbar sonography were performed. For comparison 59 children and adolescents (age: 5.1 – 17.4 years, mean 12.3 years) with a normal MR examination of the brain had measurements of the ONSD on a T2-weighted thin section sequence of the orbit. Besides establishing modality-related normal values, age dependency, accuracy and reproducibility of measurements were assessed. Results: Overall the mean ONSD was 5.75 ± 0.52 mm for transbulbar sonography and 5.69 ± 0.31 mm for MRI. There was no statistical significance between the 95 % percentiles and age for both transbulbar sonography (p = 0.332) and MRI (p = 0.336). As a parameter for the reproducibility of measurements, the repeatability coefficient (RC) was between 0.34 mm and 0.46 mm. The concordance correlation coefficient (CCC) values revealed a high agreement between readers both for transbulbar sonography (0.868) and MRI (0.796). Conclusion: Normal values for ONSD in children and adolescents found in this study are significantly higher than assumed. The values found for transbulbar sonography are confirmed by comparable results for MR measurements. A precise sonographic measurement technique and the consideration of normal values found hereby are essential for correct interpretation of ONSD measurements in children and adolescents.

We detect a cold, terrestrial planet in a binary-star system using gravitational microlensing. The planet has low mass (2 Earth masses) and lies projected at $a_{\perp,ph}$ ~ 0.8 astronomical units (AU) from its host star, similar to the Earth-Sun distance. However, the planet temperature is much lower, T, Published in Science, Main and supplementary material combined

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.

Spitzer microlensing parallax observations of OGLE-2015-BLG-1212 decisively breaks a degeneracy between planetary and binary solutions that is somewhat ambiguous when only ground-based data are considered. Only eight viable models survive out of an initial set of 32 local minima in the parameter space. These models clearly indicate that the lens is a stellar binary system possibly located within the bulge of our Galaxy, ruling out the planetary alternative. We argue that several types of discrete degeneracies can be broken via such space-based parallax observations., Comment: 27 pages, 6 figures, accepted by ApJ

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.