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Three-dimensional non-oxidic extended frameworks offer the possibility to design novel materials with unique properties, which can be different from their oxide analogues. Here, we present first experimental results concerning unusual magnetic properties of FeNCN, investigated using Mössbauer spectroscopy and magnetometry between 5 and 380 K. This study reveals an unconventional behaviour of the magnetic parameters below the Néel temperature of 350 K, i.e., the hyperfine field on iron decreases with decreasing temperature. At room temperature, quadrupole and hyperfine magnetic field interaction energies are comparable in magnitude, which leads to a rare five-line absorption spectrum. We suggest that these features in the hyperfine field are caused by the combination of a small Fermi contact term and a temperature-dependent contribution from the orbital momentum and the dipole term. One additional spectral component is observed, which exhibits a magnetic relaxation behaviour and slows down at low temperatures to yield a sextet. The magnetometry data suggest that the antiferromagnetic FeNCN is rich in structural distortions, which results in a splitting of the field-cooled and zero-field-cooled curves. The lattice dynamics of FeNCN were investigated using nuclear inelastic scattering. The comparison of the obtained data with literature data of iron monoxide reveals very similar iron phonon modes with a small softening and a slightly reduced sound velocity. [ABSTRACT FROM AUTHOR]

Purpose: In preclinical studies, thioguanine (TG) has been shown to be more potent than the standard acute lymphoblastic leukemia (ALL) maintenance agent, mercaptopurine (MP), suggesting that TG may be more efficacious than MP in the treatment of childhood ALL. As part of a pilot trial in which TG was used in place of MP, we studied the plasma pharmacokinetics of oral TG and measured steady-state plasma and CSF TG concentrations during a continuous intravenous infusion (CIVI) in children with newly diagnosed standard-risk ALL.Methods: Nine plasma samples were collected after each patient's first 60 mg/m2 oral TG dose during maintenance. CIVI TG (20 mg/m2/h over 24 h) was administered during the consolidation phase of therapy, and simultaneous plasma and CSF samples were collected near the end of the infusion. TG was measured by reverse-phase HPLC with ultraviolet detection. Erythrocyte TG nucleotide (TGN) concentrations were measured 7 days after a course of CIVI TG and prior to the start of each maintenance cycle.Results: After oral TG (n = 35), the mean (+/- SD) peak plasma concentration was 0.46 +/- 0.68 microM and the AUC ranged from 0.18 to 9.5 microM.h (mean 1.5 microM.h). Mean steady-state plasma and CSF TG concentrations during CIVI (n = 33) were 2.7 and 0.5 microM, respectively. The mean (+/- SD) TG clearance was 935 +/- 463 ml/min per m2. Plasma TG concentrations did not correlate with erythrocyte TGN concentrations after oral or CIVI TG. The 8-OH-TG metabolite was detected in plasma and CSF.Conclusions: TG concentrations that are cytotoxic to human leukemia cell lines can be achieved in plasma after a 60 mg/m2 oral dose of TG and in plasma and CSF during CIVI of TG. [ABSTRACT FROM AUTHOR]

Abstract Background High-resolution magnetic resonance imaging (cine-MRI) is well suited for determining global cardiac function longitudinally in genetically or surgically manipulated mice, but in practice it is seldom used to its full potential. In this study, male and female guanidinoacetate N-methyltransferase (GAMT) knockout, and wild type littermate mice were subjected to a longitudinal cine-MRI study at four time points over the course of one year. GAMT is an essential enzyme in creatine biosynthesis, such that GAMT deficient mice are entirely creatine-free. Since creatine plays an important role in the buffering and transfer of high-energy phosphate bonds in the heart, it was hypothesized that lack of creatine would be detrimental for resting cardiac performance during ageing. Methods Measurements of cardiac structure (left ventricular mass and volumes) and function (ejection fraction, stroke volume, cardiac output) were obtained using high-resolution cine-MRI at 9.4 T under isoflurane anaesthesia. Results There were no physiologically significant differences in cardiac function between wild type and GAMT knockout mice at any time point for male or female groups, or for both combined (for example ejection fraction: 6 weeks (KO vs. WT): 70 ± 6% vs. 65 ± 7%; 4 months: 70 ± 6% vs. 62 ± 8%; 8 months: 62 ± 11% vs. 62 ± 6%; 12 months: 61 ± 7% vs. 59 ± 11%, respectively). Conclusion These findings suggest the presence of comprehensive adaptations in the knockout mice that can compensate for a lack of creatine. Furthermore, this study clearly demonstrates the power of cine-MRI for accurate non-invasive, serial cardiac measurements. Cardiac growth curves could easily be defined for each group, in the same set of animals for all time points, providing improved statistical power, and substantially reducing the number of mice required to conduct such a study. This technique should be eminently useful for following changes of cardiac structure and function during ageing.

Background and objectives: In progressive multiple sclerosis (MS) patients, CNS inflammation trapped behind a closed blood brain barrier drives continuous neuroaxonal degeneration, thus leading to deterioration of neurological function. Therapeutics in progressive MS are limited. High-dose intravenous glucocorticosteroids (HDCS) can cross the blood-brain barrier and may reduce inflammation within the CNS. However, the treatment efficacy of HDCS in progressive MS remains controversial. Serum neurofilament light chains (sNfL) are an established biomarker of neuroaxonal degeneration and are used to monitor treatment responses. We aimed to investigate whether repeated cycles of intravenous HDCS reduce the level of sNfL in progressive MS patients. Methods: We performed a monocentric observational study of 25 patients recruited during ongoing clinical routine care who were treated with repeated cycles of intravenous HDCS as long-term therapy for their progressive MS. sNfL were measured in 103 repeated blood samples (median time interval from baseline 28 weeks, range 2-55 weeks) with the Single Molecular Array (SiMoA) technology. The Expanded Disability Status Score (EDSS) was documented at baseline and follow-up. Results: The median age of patients was 55 years (range 46-77 years) with a median disease duration of 26 years (range 11-42 years). sNfL baseline levels at study inclusion were significantly higher in progressive MS patients compared to age-matched healthy controls (median 16.7 pg/ml vs 11.5 pg/ml, p=0.002). sNfL levels showed a positive correlation with patient age (r=0.2, p=0.003). The majority of patients (72%, 16/23) showed reduced sNfL levels ≥20 weeks after HDCS compared to baseline (median 13.3 pg/ml, p=0.03). sNfL levels correlated negatively with the time interval from baseline HDCS therapy (r=-0.2, p=0.03). This association was also evident after correction for treatment with disease-modifying drugs (adjusted R 2 =0.10, p=0.001). The EDSS remained stable (median 6.5) within a median treatment duration of 26 weeks (range 13-51 weeks). Conclusion: Although larger studies are needed to confirm our findings, we were able to demonstrate that HDCS treatment reduces sNfL levels and therefore may slow down neuroaxonal damage in a subgroup of patients with progressive MS. Moreover, a stable EDSS was observed during therapy. Findings suggest that HDCS may be beneficial for the treatment of progressive MS.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease associated with axonal injury, and neurofilament light chains in serum (sNfL) are considered a biomarker for this damage. We aimed to investigate the relationship between sNfL and the axonal damage in early MS lesions in a special cohort of biopsied patients. sNfL from 106 biopsied patients with 26 follow-up samples were analyzed using single-molecule array (SiMoA) technology. Findings were correlated with clinical parameters and histological findings of acute axonal damage (APP-positive spheroids) and axonal loss in different lesion stages. A median of 59 pg/ml sNfL was found (range 8-3101 pg/ml). sNfL levels correlated with APP-positive spheroids in early active demyelinating lesions that represent the earliest lesion stages (p < 0.01). A significant negative correlation between sNfL levels in follow-up blood samples and axonal density in normal-appearing white matter was also observed (p = 0.02). sNfL levels correlated with the Expanded Disability Status Score at biopsy (p < 0.01, r = 0.49) and at last clinical follow-up (p < 0.01, r = 0.66). In conclusion, sNfL likely represent a compound measure of recent and ongoing neuroaxonal damage. We found that sNfL in biopsied MS patients correlate with acute axonal damage in the earliest MS lesion stages. Determination of sNfL levels thus allows insight into brain pathology and underlines the relevance of relapse-associated lesional pathology. Axonal loss in normal-appearing white matter contributes to sNfL levels independent of relapses. Since sNfL levels correlate with clinical disability, they may predict the future disability of patients and help with individual treatment decisions., (© 2022. The Author(s).)

Bruising or bleeding in a child can raise the concern for child abuse. Assessing whether the findings are the result of trauma and/or whether the child has a bleeding disorder is critical. Many bleeding disorders are rare, and not every child with bruising/bleeding that may raise a concern for abuse requires an evaluation for bleeding disorders. However, in some instances, bleeding disorders can present in a manner similar to child abuse. Bleeding disorders cannot be ruled out solely on the basis of patient and family history, no matter how extensive. The history and clinical evaluation can be used to determine the necessity of an evaluation for a possible bleeding disorder, and prevalence and known clinical presentations of individual bleeding disorders can be used to guide the extent of laboratory testing. This clinical report provides guidance to pediatricians and other clinicians regarding the evaluation for bleeding disorders when child abuse is suspected., (Copyright © 2022 by the American Academy of Pediatrics.)

Spindle cell/sclerosing rhabdomyosarcoma (ssRMS) is a rare subtype of rhabdomyosarcoma, commonly harboring a gain-of-function L122R mutation in the muscle-specific master transcription factor MYOD1. MYOD1 -mutated ssRMS is almost invariably fatal, and development of novel therapeutic approaches based on the biology of the disease is urgently needed. MYOD1 L122R affects the DNA-binding domain and is believed to confer MYC-like properties to MYOD1, driving oncogenesis. Moreover, the majority of the MYOD1 -mutated ssRMS harbor additional alterations activating the PI3K/AKT pathway. It is postulated that the PI3K/AKT pathway cooperates with MYOD1 L122R. To address this biological entity, we established and characterized a new patient-derived ssRMS cell line OHSU-SARC001, harboring MYOD1 L122R as well as alterations in PTEN , PIK3CA , and GNAS We explored the functional impact of these aberrations on oncogenic signaling with gain-of-function experiments in C2C12 murine muscle lineage cells. These data reveal that PIK3CA I459&#95;T462del , the novel PIK3CA variant discovered in this patient specimen, is a constitutively active kinase, albeit to a lesser extent than PI3KCA E545K , a hotspot oncogenic mutation. Furthermore, we examined the effectiveness of molecularly targeted PI3K/AKT/mTOR and RAS/MAPK inhibitors to block oncogenic signaling and suppress the growth of OHSU-SARC001 cells. Dual PI3K/mTOR (LY3023414, bimiralisib) and AKT inhibitors (ipatasertib, afuresertib) induced dose-dependent reductions in cell growth. However, mTOR-selective inhibitors (everolimus, rapamycin) alone did not exert cytotoxic effects. The MEK1/2 inhibitor trametinib did not impact proliferation even at the highest doses tested. Our data suggest that molecularly targeted strategies may be effective in PI3K/AKT/mTOR-activated ssRMS. Taken together, these data highlight the importance of utilizing patient-derived models to assess molecularly targetable treatments and their potential as future treatment options., (© 2022 Choo et al.; Published by Cold Spring Harbor Laboratory Press.)

Purpose: Our goal was to evaluate the comparative effectiveness of robot-assisted laparoscopic prostatectomy (RALP) and open radical prostatectomy (ORP) in a multicenter study., Materials and Methods: We evaluated men with localized prostate cancer at 11 high-volume academic medical centers in the United States from the PROST-QA (2003-2006) and the PROST-QA/RP2 cohorts (2010-2013) with a pre-specified goal of comparing RALP (549) and ORP (545). We measured longitudinal patient-reported health-related quality of life (HRQOL) at pre-treatment and at 2, 6, 12, and 24 months, and pathological and perioperative outcomes/complications., Results: Demographics, cancer characteristics, and margin status were similar between surgical approaches. ORP subjects were more likely to undergo lymphadenectomy (89% vs 47%; p <0.01) and nerve sparing (94% vs 89%; p <0.01). RALP vs ORP subjects experienced less mean intraoperative blood loss (192 vs 805 mL; p <0.01), shorter mean hospital stay (1.6 vs 2.1 days; p <0.01), and fewer blood transfusions (1% vs 4%; p <0.01), wound infections (2% vs 4%; p=0.02), other infections (1% vs 4%; p <0.01), deep venous thromboses (0.5% vs 2%; p=0.04), and bladder neck contractures requiring dilation (1.6% vs 8.3%; p <0.01). RALP subjects reported less pain (p=0.04), less activity interference (p <0.01) and higher incision satisfaction (p <0.01). Surgical approach (RALP vs ORP) was not a significant predictor of longitudinal HRQOL change in any HRQOL domain., Conclusions: In high-volume academic centers, RALP and ORP patients may expect similar long-term HRQOL outcomes. Overall, RALP patients have less pain, shorter hospital stays, and fewer post-surgical complications such as blood transfusions, infections, deep venous thromboses, and bladder neck contractures.

Natalizumab, a recombinant humanized monoclonal antibody directed against the α4 subunit of the integrins α4ß1 and α4ß7, has been approved for the treatment of active relapsing-remitting MS. Although natalizumab is a highly beneficial drug that effectively reduces the risk of sustained disability progression and the rate of clinical relapses, some patients do not respond to it, and some are at higher risk of developing progressive multifocal leukoencephalopathy (PML). The histopathological effects after natalizumab therapy are still unknown. We, therefore, performed a detailed histological characterization of the CNS inflammatory cell infiltrate of 24 brain specimens from natalizumab treated patients, consisting of 20 biopsies and 4 autopsies and 21 MS controls. To complement the analysis, immune cells in blood and cerebrospinal fluid (CSF) of 30 natalizumab-treated patients and 42 MS controls were quantified by flow cytometry. Inflammatory infiltrates within lesions were mainly composed of T cells and macrophages, some B cells, plasma cells, and dendritic cells. There was no significant difference in the numbers of T cells or macrophages and microglial cells in lesions of natalizumab-treated patients as compared to controls. A shift towards cytotoxic T cells of a memory phenotype was observed in the CSF. Plasma cells were significantly increased in active demyelinating lesions of natalizumab-treated patients, but no correlation to clinical disability was observed. Dendritic cells within lesions were found to be reduced with longer ongoing therapy duration. Our findings suggest that natalizumab does not completely prevent immune cells from entering the CNS and is associated with an accumulation of plasma cells, the pathogenic and clinical significance of which is not known. As B cells are considered to serve as a reservoir of the JC virus, the observed plasma cell accumulation and reduction in dendritic cells in the CNS of natalizumab-treated patients may potentially play a role in PML development., (© 2021 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)

Background: Within pediatric oncology, parental decision making regarding participation in clinical trials that aim to reduce therapy to mitigate side effects is not well studied. The recently completed Children's Oncology Group trial for standard-risk acute lymphoblastic leukemia (AALL0932) included a reduction in maintenance therapy, and required consent for randomization immediately prior to starting maintenance. At our institution, 40% of children enrolled on AALL0932 were withdrawn from protocol therapy prior to randomization due to parental choice. This study sought to identify factors that impacted parental decision making regarding randomization on AALL0932., Procedure: Parents of children enrolled on AALL0932 at our institution were eligible if their child met criteria for the average-risk randomization. Parents were invited to participate in a 30-50-minute phone interview. Questions focused on factors that shaped parental decision making about randomization, as well as their perspectives about the clinical trial experience more generally., Results: Fear of receiving less therapy and subsequent relapse was the predominant reason to decline randomization. Reasons given for consenting to randomization included trust in the physician, altruism, hope for less therapy, and potential for fewer side effects. Parents also reflected on ways to support future families making decisions about clinical trial participation., Conclusion: While many parents recognize the importance of clinical trials aiming to mitigate side effects, the fear of their own child relapsing with less than standard therapy may dissuade them from study participation. Recognizing and addressing these concerns will be important for enrollment and retention in future clinical trials., (© 2021 Wiley Periodicals LLC.)

Early active multiple sclerosis (MS) lesions can be classified histologically into three main immunopathological patterns of demyelination (patterns I-III), which suggest pathogenic heterogeneity and may predict therapy response. Patterns I and II show signs of immune-mediated demyelination, but only pattern II is associated with antibody/complement deposition. In pattern III lesions, which include Baló's concentric sclerosis, primary oligodendrocyte damage was proposed. Serum antibody reactivities could reflect disease pathogenesis and thus distinguish histopathologically defined MS patterns. We established a customized microarray with more than 700 peptides that represent human and viral antigens potentially relevant for inflammatory demyelinating CNS diseases, and tested sera from 66 patients (pattern I n = 12; II n = 29; III n = 25, including 8 with Baló's), healthy controls, patients with Sjögren's syndrome and stroke patients. Cell-based assays were performed for aquaporin 1 (AQP1) and AQP4 antibody detection. No single peptide showed differential binding among study cohorts. Because antibodies can react with different peptides from one protein, we also analyzed groups of peptides. Patients with pattern II showed significantly higher reactivities to Nogo-A peptides as compared to patterns I (p = 0.02) and III (p = 0.02). Pattern III patients showed higher reactivities to AQP1 (compared to pattern I p = 0.002, pattern II p = 0.001) and varicella zoster virus (VZV, compared to pattern II p = 0.05). In patients with Baló's, AQP1 reactivity was also significantly higher compared to patients without Baló's (p = 0.04), and the former revealed distinct antibody signatures. Histologically, Baló's patients showed loss of AQP1 and AQP4 in demyelinating lesions, but no antibodies binding conformational AQP1 or AQP4 were detected. In summary, higher reactivities to Nogo-A peptides in pattern II patients could be relevant for enhanced axonal repair and remyelination. Higher reactivities to AQP1 peptides in pattern III patients and its subgroup of Baló's patients possibly reflect astrocytic damage. Finally, latent VZV infection may cause peripheral immune activation.

Febrile neutropenia is a potentially life-threatening complication of chemotherapy in pediatric oncology patients. Prompt initiation of antibiotic therapy may minimize morbidity and mortality associated with this condition, and time to antibiotic (TTA) administration <60 minutes is used as a quality benchmark by many institutions. We implemented a quality improvement initiative to achieve TTA < 60 minutes in >80% of eligible patients in the pediatric emergency department., Methods: After collecting baseline data, we employed consecutive PDSA cycles to (i) reduce time to antibiotic order after patient arrival; (ii) expedite the preparation of antibiotic by pharmacy; and (iii) enable antibiotic ordering before patient arrival. Statistical process control methodologies were used for key outcome measures to compare pre-intervention, post-intervention, and maintenance periods., Results: Comparing pre-intervention and post-intervention years, mean TTA decreased from 64 to 53 minutes and the percentage of patients receiving antibiotics in <60 minutes increased from 59% to 84%. Improvements were sustained in the maintenance period of the project, with mean TTA administration of 44 minutes and 85% of patients receiving antibiotics within our stated goal., Conclusion: Through a series of PDSA cycles, we decreased TTA and increased the percentage of febrile neutropenia patients receiving antibiotics in <60 minutes., (Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Daclizumab is a monoclonal antibody that binds the high-affinity interleukin-2 receptor and was approved for the treatment of relapsing multiple sclerosis. Due to severe inflammatory brain disorders, the approval was suspended in March 2018., Objective and Methods: This retrospective cohort study summarizes clinical, laboratory, radiological, and histological findings of seven patients who developed meningo-/encephalitis after daclizumab therapy., Results: Patients presented with encephalitis and/or meningitis and suffered from systemic symptoms such as fever (5/7), exanthema (5/7), or gastrointestinal symptoms (4/7). Secondary autoimmune diseases developed. Blood analysis revealed an increase in eosinophils (5/7). Six patients fulfilled the diagnostic criteria for a drug reaction with eosinophilia and systemic symptoms (DRESS). Magnetic resonance imaging (MRI) showed multiple contrast-enhancing lesions, and enhancement of the ependyma (6/7), meninges (5/7), cranial or spinal nerves (2/7), and a vasculitic pattern (3/7). Histology revealed a pronounced inflammatory infiltrate consisting of lymphocytes, plasma cells and eosinophils, and densely infiltrated vessels. Most patients showed an insufficient therapeutic response and a high disability at last follow-up (median Expanded Disability Status Scale (EDSS) 8). Two patients died., Conclusion: Meningoencephalitis and DRESS may occur with daclizumab therapy. This potential lethal side effect is characterized by a dysregulated immune response. Our findings underline the importance of postmarketing drug surveillance.

Background: Delirium affects 10% to 30% of patients in pediatric intensive care units (PICU) and is associated with increased length of stay and prolonged late sequela. There are no prospective trials evaluating delirium in the pediatric hematology, oncology, and bone marrow transplant (PHO) population. Hypothesizing that delirium is underrecognized in this population, our study aimed to identify the prevalence of delirium in hospitalized PHO patients and associated risk factors., Procedure: PHO and PICU nurses were trained to use the Cornell Assessment for Pediatric Delirium and to record scores once every 12-hour shift. Predetermined demographic and clinical variables were collected daily on all hospitalized PHO patients during the year-long prospective study., Results: Prior to initiating routine delirium screening, 1.1% of PHO admissions and 2.4% of unique patients had delirium mentioned in a progress note. This study included 807 consecutive admissions: 671 oncology, 49 hematology, and 87 bone marrow transplant (BMT) hospitalizations among 223 unique PHO patients. The prevalence of delirium among hospitalizations was 5% and among unique patients was 13%. Among BMT hospitalizations, the prevalence was 23%. Multiple logistic regression identified significant association of delirium with increased length of stay, admission to the BMT service, patient location (PICU vs PHO unit), benzodiazepine, opioid, and anticholinergic administration., Conclusions: Before routine screening, delirium was underrecognized in this PHO-hospitalized population. Patients at highest risk had prolonged hospital stays, PICU admissions, BMT, and/or frequent use of benzodiazepines, opioids, or anticholinergics. Routine screening is feasible and may improve our recognition of delirium., (© 2019 Wiley Periodicals, Inc.)

Background: Doxorubicin, cisplatin, and high-dose methotrexate (HDMTX) are the backbone of pediatric osteosarcoma treatment. However, due to toxicity concerns and the lack of data regarding efficacy in adults, high-dose methotrexate is rarely used in the adult population., Methods: This single-center retrospective study examined 33 patients who received HDMTX (12 g/m 2 , maximum 20 g) for the treatment of osteosarcoma at Oregon Health and Science University (OHSU) from 2011 to 2017. Time to serum methotrexate level ≤0.1 µmol/L was the primary outcome. Secondary outcomes included number of HDMTX doses received, methotrexate-related toxicities, and disease outcomes including histologic response at resection and metastasis-free survival., Results: Median age was 20 years [range 7-38]; 14 patients ≤18 years old and 19 patients >18 years old. Median time to clearance for patients ≤18 years was 79 hours (range 63-116) compared to 120 hours (range 77-315) for patients >18 years (P < 0.001). No correlation between age and histologic response at resection was observed (P = 0.50), but there was a significant positive correlation between the number of HDMTX doses received before resection and histologic response (r = 0.49, P = 0.006). There was no significant difference in metastasis-free survival between age groups, although a trend toward improved survival was noted for patients who received at least seven doses of HDMTX., Conclusion: Age over 18 years correlates with delayed methotrexate clearance and fewer administered doses of methotrexate, without increased toxicity. The potential benefit of HDMTX in young adults with osteosarcoma may outweigh toxicity risks., (© 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objective: To report on 2 women with multiple sclerosis (MS) who developed severe neurologic deterioration and a drug reaction with eosinophilia and systemic symptoms (DRESS) after treatment with 2 and 4 subcutaneous injections of daclizumab, respectively., Methods: This report includes clinical, MRI, and histopathologic data., Results: Daclizumab is a humanized monoclonal antibody that binds the interleukin-2 receptor. It was approved for the treatment of relapsing MS. DRESS is an immunologic reaction to various medications that is characterized by eosinophilia as well as cutaneous and visceral manifestations. Following daclizumab treatment, both patients showed fulminant neurologic deterioration along with blood eosinophilia and skin changes, and both fulfilled the clinical criteria for the diagnosis of DRESS. They presented with multiple gadolinium-enhancing supra- and infratentorial lesions, with lesions in the basal ganglia, mesencephalon, and cerebellum. Brain biopsies revealed a pronounced inflammatory infiltrate including numerous eosinophils infiltrating demyelinating lesions, a feature that is atypical for MS but compatible with DRESS. In addition, numerous plasma cells and changes reminiscent of vasculitis were evident., Conclusions: Neurologic deterioration and DRESS occurred as severe adverse drug effects of daclizumab treatment. Early diagnosis and treatment of DRESS are essential because it is associated with complications such as new autoimmune diseases and liver failure, and may even be lethal. Because of its potential serious side effects, daclizumab was recently suspended for use in the European Union., (© 2018 American Academy of Neurology.)

Importance: Plasma exchange and immunoadsorption are second-line apheresis therapies for patients experiencing multiple sclerosis relapses. Early active multiple sclerosis lesions can be classified into different histopathological patterns of demyelination. Pattern 1 and 2 lesions show T-cell- and macrophage-associated demyelination, and pattern 2 is selectively associated with immunoglobulin and complement deposits, suggesting a humoral immune response. Pattern 3 lesions show signs of oligodendrocyte degeneration. Thus it is possible that pathogenic heterogeneity might predict therapy response., Objective: To evaluate the apheresis response in relation to histopathologically defined immunopathological patterns of multiple sclerosis., Design, Setting and Participants: This single-center cohort study recruited 69 patients nationwide between 2005 and 2016. All included patients had a diagnosis of early active inflammatory demyelination consistent with multiple sclerosis; were classified into patterns 1, 2, or 3 based on brain biopsy analysis; and underwent apheresis treatments. Patients who had concomitant severe disease, neuromyelitis optica, or acute disseminated encephalomyelitis were excluded., Main Outcomes and Measures: The primary therapy outcome was a functionally relevant improvement of the relapse-related neurological deficit. Radiological and Expanded Disability Status Scale changes were secondary outcome parameters., Results: The mean (SD) age of patients was 36.6 (13.3) years; 46 of the 69 participants (67%) were female. Overall, 16 patients (23%) exhibited pattern 1 lesions, 40 (58%) had pattern 2 lesions, and 13 (19%) had pattern 3 lesions. A functional therapy response was observed in 5 of the 16 patients with pattern 1 disease (31%) and 22 of the 40 patients with pattern 2 disease (55%), but none of the 13 patients with pattern 3 disease exhibited improvement (pattern 2 vs 3 P < .001). Radiological improvements were found in 4 (25%), 22 (56%), and 1 (11%) of patients with patterns 1, 2, and 3, respectively. The respective rates of response measured by changes in Expanded Disability Status Scale scores were 25%, 40%, and 0%. Brainstem involvement was a negative predictive factor for the functional therapy response (logarithmic odds ratio [logOR], -1.43; 95% CI, -3.21 to 0.17; P = .03), while immunoadsorption (as compared with plasma exchange) might be a positive predictive factor (logOR, 3.26; 95% CI, 0.75 to 8.13; P = .01)., Conclusions and Relevance: This cohort study provides evidence that the response to apheresis treatment is associated with immunopathological patterns. Patients with both patterns 1 and 2 improved clinically after apheresis treatment, but pattern 2 patients who showed signs of a humoral immune response benefited most. Apheresis appears unlikely to benefit patients with pattern 3 lesions.

Purpose: To assess the uptake, accumulation, temporal stability, and spatial localization of isoflurane (ISO) in the C57BL/6 mouse, and to identify its potential interference with the detection of labeled cardiac progenitor cells using 19 F MRI/MR spectroscopy (MRS)., Materials and Methods: Objectives are demonstrated using (a) in vitro ISO tests, (b) in vivo temporal accumulation/spatial localization C57BL/6 studies (n = 3), and (c) through injections of perfluoro-crown-ether (PFCE) labeled cardiac progenitor cells into femoral muscle areas of the murine hindlimb post-mortem (n = 1) using 1 H/ 19 F MRI/MRS at 9.4 Tesla. Data were acquired using double-gated spoiled gradient echo images and pulse-acquire spectra. For the in vivo study, the temporal stability of ISO resonances was quantified using coefficient of variability (CV) (5 min) estimates., Results: Two ISO resonances were observed in vivo that correspond to the -CF 3 and -OCHF 2 moieties. CV values ranged between 3.2 and 6.4% (-CF 3 ) and 6.4 and 11.2% (-OCHF 2 ). Reductions of the ISO dose (2.0 to 1.7%) at 80 min postinduction had insignificant effects on ISO signals (P = 0.23; P = 0.71). PFCE-labeled cells exhibited a resonance at -16.25 ppm in vitro that did not overlap with the ISO resonances, a finding that is confirmed with MRS post-mortem using injected, labeled cells. Based on 19 F MRI, similar in vivo/post-mortem ISO compartmentalization was also confirmed in peripheral and thoracic skeletal muscles., Conclusion: Significant ISO accumulation was observed by 19 F MRS in vivo with temporally stable signals over 90 min postinduction. ISO effects on PFCE labels are anticipated to be minimal but may be more prominent for perfluoropolyether or perfluorooctyl bromide labels., Level of Evidence: 1 Technical Efficacy: Stage 1 J. MAGN. RESON. IMAGING 2017;45:1659-1667., (© 2016 The Authors Journal of Magnetic Resonance Imaging published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine.)

Introduction: EPA and DHA cause different physiological effects, which are in many cases mediated via their oxidative metabolites (oxylipins). However, metabolism studies investigating the effect of either EPA or DHA on comprehensive oxylipin patterns are lacking., Material and Methods: The short and long term (1, 3, 6, and 12 week) effect of 1076mg/d DHA (free of EPA) on free (unesterified) oxylipin concentrations in plasma and lipopolysacharid (LPS) stimulated blood of 12 healthy men (mean age 25.1 ± 1.5 years) was investigated., Results: After DHA supplementation, plasma levels of all DHA-oxylipins (HDHAs, EpDPEs, DiHDPEs) significantly increased (up to 600%) in a time-dependent fashion. Oxylipins of EPA and arachidonic acid (AA) were also affected. Whereas a slight increase in several EPA-derived hydroxy-FAs (including the RvE1 precursor 18-HEPE) and dihydroxy-FAs was observed after DHA supplementation, a trend to a slight decline in AA-derived oxylipin levels was found. In LPS stimulated blood, it is shown that DHA supplementation significantly reduces the ability of immune cells to form AA-derived COX (TXB2 and PGB2) and 12-LOX (12-HETE) eicosanoids. While no increase in EPA COX metabolites was found, n-3 PUFA 12-LOX metabolites of EPA (12-HEPE) and DHA (14-HDHA) were highly induced., Conclusion: We demonstrated that DHA supplementation causes a time-dependent shift in the entire oxylipin profile suggesting a cross-linked metabolism of PUFAs and subsequent formation of oxygenated lipid mediators., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Introduction: Polyunsaturated fatty acids (PUFA) are metabolized in a complex network of elongation, desaturation and beta oxidation., Material and Methods: The short (1 and 3 wk), and long term (6 and 12 wk) effect of 1076mg/d docosahexaenoic acid (DHA, free of eicosapentaenoic acid (EPA)) on (absolute) PUFA concentrations in plasma and red blood cells (RBC) of 12 healthy men (mean age 25.1±1.5 years) was investigated., Results: RBC DHA concentrations significantly (p<0.001) increased from 28±1.6µg/mL to 38±2.0µg/mL (wk 1), 52±3.3µg/mL (wk 3), 68±2.6µg/mL (wk 6), and 79±3.5µg/mL (wk 12). Arachidonic acid (AA) concentrations declined in response to DHA treatment, while the effect was more pronounced in plasma (wk 0: 183±9.9µg/mL, wk 12: 139±8.0µg/mL, -24%, p<0.001) compared to RBC (wk 0: 130±3.7µg/mL, wk 12: 108±4.0µg/mL, -16%, p=0.001). Furthermore, an increase of EPA concentrations in plasma (wk 0: 15±1.5µg/mL, wk 1:19±1.6µg/mL, wk 3: 27±2.3µg/mL, wk 6: 23±1.2µg/mL, wk 12: 25±1.7µg/mL, p<0.001) and RBC (wk 0: 4.7±0.33µg/mL, wk 1: 6.7±1.3µg/mL, wk 3: 8.0±0.66µg/mL, wk 6: 6.9±0.44µg/mL, wk 12: 6.7±0.45µg/mL, n.s.) was observed suggesting a retroconversion of DHA to EPA., Conclusion: Based on PUFA concentrations we showed that DHA supplementation results in increased EPA levels, whereas it is not known if this impacts the formation of EPA-derived lipid mediators. Furthermore, shifts in the entire PUFA pattern after supplementation of EPA or DHA should be taken into account when discussing differential physiological effects of EPA and DHA., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: The 70-gene signature test (MammaPrint) has been shown to improve prediction of clinical outcome in women with early-stage breast cancer. We sought to provide prospective evidence of the clinical utility of the addition of the 70-gene signature to standard clinical-pathological criteria in selecting patients for adjuvant chemotherapy., Methods: In this randomized, phase 3 study, we enrolled 6693 women with early-stage breast cancer and determined their genomic risk (using the 70-gene signature) and their clinical risk (using a modified version of Adjuvant! Online). Women at low clinical and genomic risk did not receive chemotherapy, whereas those at high clinical and genomic risk did receive such therapy. In patients with discordant risk results, either the genomic risk or the clinical risk was used to determine the use of chemotherapy. The primary goal was to assess whether, among patients with high-risk clinical features and a low-risk gene-expression profile who did not receive chemotherapy, the lower boundary of the 95% confidence interval for the rate of 5-year survival without distant metastasis would be 92% (i.e., the noninferiority boundary) or higher., Results: A total of 1550 patients (23.2%) were deemed to be at high clinical risk and low genomic risk. At 5 years, the rate of survival without distant metastasis in this group was 94.7% (95% confidence interval, 92.5 to 96.2) among those not receiving chemotherapy. The absolute difference in this survival rate between these patients and those who received chemotherapy was 1.5 percentage points, with the rate being lower without chemotherapy. Similar rates of survival without distant metastasis were reported in the subgroup of patients who had estrogen-receptor-positive, human epidermal growth factor receptor 2-negative, and either node-negative or node-positive disease., Conclusions: Among women with early-stage breast cancer who were at high clinical risk and low genomic risk for recurrence, the receipt of no chemotherapy on the basis of the 70-gene signature led to a 5-year rate of survival without distant metastasis that was 1.5 percentage points lower than the rate with chemotherapy. Given these findings, approximately 46% of women with breast cancer who are at high clinical risk might not require chemotherapy. (Funded by the European Commission Sixth Framework Program and others; ClinicalTrials.gov number, NCT00433589; EudraCT number, 2005-002625-31.).

Objective: To assess in an observational study whether serum peptide antibody reactivities may distinguish aquaporin-4 (AQP4) antibody (Ab)-positive and -negative neuromyelitis optica spectrum disorders (NMOSD) and relapsing-remitting multiple sclerosis (RRMS)., Methods: We screened 8,700 peptides that included human and viral antigens of potential relevance for inflammatory demyelinating diseases and random peptides with pooled sera from different patient groups and healthy controls to set up a customized microarray with 700 peptides. With this microarray, we tested sera from 66 patients with AQP4-Ab-positive (n = 16) and AQP4-Ab-negative (n = 19) NMOSD, RRMS (n = 11), and healthy controls (n = 20)., Results: Differential peptide reactivities distinguished NMOSD subgroups from RRMS in 80% of patients. However, the 2 NMOSD subgroups were not well-discriminated, although those patients are clearly separated by their antibody reactivities against AQP4 in cell-based assays. Elevated reactivities to myelin and Epstein-Barr virus peptides were present in RRMS and to AQP4 and AQP1 peptides in AQP4-Ab-positive NMOSD., Conclusions: While AQP4-Ab-positive and -negative NMOSD subgroups are not well-discriminated by peptide antibody reactivities, our findings suggest that peptide antibody reactivities may have the potential to distinguish between both NMOSD subgroups and MS. Future studies should thus concentrate on evaluating peptide antibody reactivities for the differentiation of AQP4-Ab-negative NMOSD and MS.

Background: Children with T-lineage acute lymphoblastic leukemia ALL (T-ALL) historically have had inferior outcomes compared with the children with precursor-B ALL (B-ALL). After 1995, the Children's Cancer Group (CCG) treated patients with B- and T-ALL according to the National Cancer Institute (NCI) risk criteria, basing risk stratification on age and white blood cell (WBC) count regardless of immunophenotype. The Pediatric Oncology Group (POG) treated all the patients with T-ALL on separate, generally more intensive protocols than those used to treat the patients with B-ALL., Procedure: We compared the outcomes of children with T-ALL and NCI standard-risk (SR) criteria treated on CCG and POG trials between 1996 and 2005. CCG SR-ALL 1952 and 1991 enrolled 80 and 86 patients with T-ALL, respectively, utilizing a reduced intensity Berlin-Frankfurt-Münster backbone. Treatment was intensified for slow early responders and only patients with overt central nervous system leukemia received cranial irradiation. Eighty-four patients with T-ALL and SR features were enrolled on POG 9404 comprising more intensive therapy with all patients receiving cranial irradiation., Results: The 7-year event-free survival (EFS) for patients with SR T-ALL on CCG 1952, CCG 1991, and POG 9404 were 74.1 ± 5.8%, 81.8 ± 5.3%, and 84.2 ± 4.3%, respectively (P = 0.18). Overall 7-year survivals were 86.1 ± 4.6%, 88.3 ± 4.4%, 89.1 ± 3.6%, respectively (P = 0.84)., Conclusions: Comparable high rates of EFS and long-term survival were achieved with all three regimens, with the CCG regimens utilizing a less intensive chemotherapy backbone without prophylactic cranial irradiation for patients with SR T-ALL., (© 2015 Wiley Periodicals, Inc.)

Genetic variation in drug detoxification pathways may influence outcomes in pediatric acute lymphoblastic leukemia (ALL). We evaluated relapse risk and 24 variants in 17 genes in 714 patients in CCG-1961. Three TPMT and 1 MTR variant were associated with increased risks of relapse (rs4712327, OR 3.3, 95%CI 1.2-8.6; rs2842947, OR 2.7, 95%CI 1.1-6.8; rs2842935, OR 2.5, 95%CI 1.1-5.0; rs10925235, OR 4.9, 95%CI 1.1-25.1). One variant in SLC19A1 showed a protective effect (rs4819128, OR 0.5, 95%CI 0.3-0.9). Our study provides data that relapse risk in pediatric ALL is associated with germline variations in TPMT, MTR and SLC19A1.

Background: Treatment of acute myeloid leukemia (AML) comes with a significant risk of life-threatening infection during periods of prolonged severe neutropenia. We studied the impact of preventive intravenous (IV) antibiotic administration at onset of absolute neutropenia on the incidence and outcome of life-threatening infections during treatment of childhood AML., Procedures: This is a retrospective study on pediatric patients (aged 0-18 years) consecutively diagnosed with de novo AML and treated at a single institution from April 2005 through February 2013. Patients were treated on the Children's Oncology Group (COG) AAML0531 protocol or with a modified United Kingdom Medical Research Council (UK MRC) AML 10 regimen. Pertinent data were extracted from hard copy or electronic chart review., Results: A total of 76 chemotherapy phases were analyzed from 29 patients. In each phase reported, preventive antibiotics were initiated when the daily absolute neutrophil count was <500 cells/mcl, before onset of fever. Seven episodes of bacteremia were documented with predominantly coagulase-negative staphylococci and viridans group streptococci. One infection-related death occurred, attributed to progressive respiratory failure occurring months after documented candidal pneumonia., Conclusions: Initiation of preventive antibiotics at the onset of absolute neutropenia was associated with no mortality from bacteremia. This preventive approach appears feasible and safe., (© 2015 Wiley Periodicals, Inc.)

Background: Despite higher cure rates, childhood acute lymphoblastic leukemia (ALL) may continue to result in considerable family strain. We sought to (i) measure incidence of divorce, reduced career opportunities, changes to work hours, home relocation, and changes to family planning at one year after ALL diagnosis; and (ii) Identify family and patient factors associated with these events., Procedure: We conducted a prospective cohort study of 159 children with average risk-ALL enrolled and treated on COG protocol AALL0331 at 31 selected sites. Eligibility criteria included age ≥2 years and English or Spanish comprehension. Parents completed surveys at three time points during the first 12 months of therapy., Results: Parents were at significantly increased risk of loss of employment (46% vs. 9.1%, P ≤ 0.001) than peers nationally. 13% divorced/separated, 27% relocated homes, 22% decided not to have more children, 51% declined occupational opportunities, and 68% decreased work hours. In adjusted analyses, relocation correlated with less maternal education (OR: 4.27 [95% CI: 1.43-12.82]). Declining parental opportunities associated with family income <$50,000 (OR: 4.25 [95% CI: 1.50-12.02]) and child <5 years old (OR: 4.21 [95% CI: 1.73-10.25]). Deciding not to have more children correlated with smaller family size 2-3 versus 4-5 (OR: 3.62 [95% CI: 1.10-11.96])., Conclusion: Families experience a high incidence of major life changes in the first year of ALL treatment. Understanding these burdens helps health care providers to provide appropriate anticipatory guidance and support. No unifying factor was associated with the different family events. Ongoing follow-up is planned to measure long-term outcomes., (© 2014 Wiley Periodicals, Inc.)

Sinusoidal obstruction syndrome is a complication of therapy for pediatric ALL and may be modified by thiopurine methyltransferase activity as well as by MTHFR genotype. We assessed TPMT *3A, *3B, *3C, and MTHFR C677T and A1298C germline genetic polymorphisms among 351 patients enrolled in the thioguanine treatment arm of CCG-1952 clinical trial. TPMT and MTHFR C677T genotypes were not associated with SOS risk. The combination of MTHFR and TPMT variant genotypes was not associated with SOS risk. These suggest that germline genetic variation in TPMT and MTHFR do not significantly alter SOS risk in patients exposed to thioguanine., (© 2014 Wiley Periodicals, Inc.)

Background: Existing therapies for recurrent or refractory histiocytoses, including Langerhans cell histiocytosis (LCH), juvenile xanthogranuloma (JXG), and Rosai-Dorfman disease (RDD), have limited effectiveness. We report our experience with using clofarabine as therapy in children with recurrent or refractory histiocytic disorders, including LCH (11 patients), systemic JXG (4 patients), and RDD (3 patients)., Methods: Patients treated with clofarabine for LCH, JXG, or RDD by Texas Children's Hospital physicians or collaborators between May 2011 and January 2013 were reviewed for response and toxicity., Results: Patients were treated with a median of three chemotherapeutic regimens prior to clofarabine. Clofarabine was typically administered at 25 mg/m(2) /day for 5 days. Cycles were administered every 28 days for a median of six cycles (range: 2-8 cycles). Seventeen of 18 patients are alive. All surviving patients showed demonstrable improvement after two to four cycles of therapy, with 11 (61%) complete responses, 4 (22%) partial responses, and 2 patients still receiving therapy. Five patients experienced disease recurrence, but three of these subsequently achieved complete remission. All patients with JXG and RDD had complete or partial response at conclusion of therapy. Side effects included neutropenia in all patients. Recurring but sporadic toxicities included prolonged neutropenia, severe vomiting, and bacterial infections., Conclusion: Clofarabine has activity against LCH, JXG, and RDD in heavily pretreated patients, but prospective multi-center trials are warranted to determine long-term efficacy, optimal dosing, and late toxicity of clofarabine in this population., (© 2013 Wiley Periodicals, Inc.)