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• Immune checkpoint inhibitor (ICI) therapy is commonly used in the second line setting in patients with mesothelioma. • Among real-world patients with mesothelioma, second-line ICI therapy improved overall survival compared to chemotherapy. • Our findings are in contrast with a recent clinical trial, highlighting the importance of real-world evidence. Second-line immune checkpoint inhibition (ICI) was recently shown to have a survival advantage over placebo in malignant pleural mesothelioma (MPM), but the survival comparison to chemotherapy in patients with MPM receiving routine clinical care is unknown. Our objective was to examine the effectiveness of second-line ICI versus chemotherapy on overall survival (OS) outcomes in real-world patients with advanced MPM. We performed a multicenter retrospective cohort study of real-world adult patients with advanced MPM who received first-line platinum-based chemotherapy and at least two total lines of systemic therapy. Patients received either second-line chemotherapy (gemcitabine and/or vinorelbine) or ICI therapy (pembrolizumab or nivolumab ± ipilimumab). The primary outcome was OS, defined as the time from second-line therapy initiation to death or end of the observation period. We used Kaplan-Meier methods and Cox proportional hazards modeling with adjustment for relevant patient demographic and clinical variables to compare OS between the two second-line treatment groups. Of the 176 patients with MPM, the median age was 75 years (IQR: 69–79.5 years), and most were white (77%), male (74%), and had epithelioid histology (67%). Thirty-five percent (61) received second-line chemotherapy and 65% (1 1 5) ICI therapy (80 pembrolizumab, 31 nivolumab, and 4 nivolumab + ipilimumab). Treatment with ICI was associated with significantly longer median OS compared to chemotherapy (8.7 vs 5.0 months, p=0.001; adjusted hazard ratio: 0.52, 95% CI: 0.34–0.81). The estimated 12-month OS probability was 36.7% (95% CI: 27.6%-45.8%) and 15.6% (95% CI: 7.7%-26.1%) in the ICI and chemotherapy groups, respectively. In this "real-world" population of patients with MPM, treatment with ICI was associated with improved OS outcomes compared to chemotherapy in the second-line setting, in contrast with a recent clinical trial. Our findings suggest that ICI may benefit patients with advanced MPM and progression after initial platinum-based chemotherapy. [ABSTRACT FROM AUTHOR]

The development of normal tissue radiation dose-response models for children with cancer has been challenged by many factors, including small sample sizes; the long length of follow-up needed to observe some toxicities; the continuing occurrence of events beyond the time of assessment; the often complex relationship between age at treatment, normal tissue developmental dynamics, and age at assessment; and the need to use retrospective dosimetry. Meta-analyses of published pediatric outcome studies face additional obstacles of incomplete reporting of critical dosimetric, clinical, and statistical information. This report describes general methods used to address some of the pediatric modeling issues. It highlights previous single- and multi-institutional pediatric dose-response studies and summarizes how each PENTEC taskforce addressed the challenges and limitations of the reviewed publications in constructing, when possible, organ-specific dose-effect models. [ABSTRACT FROM AUTHOR]

• Protaetia brevitarsis larvae effectively converted spent mushroom substrate from Auricularia auricula (SMS-AA) and Lentinula edodes (SMS-LE). • The larvae produced nutrient-enriched organic fertilizer with a phytotoxicity-free. • The larvae were able to efficiently digest and thus utilize lignocellulose. • We present a new strategy for the use of woodchip-derived spent mushroom substrates. The edible mushroom industry produces massive amounts of spent mushroom substrate (SMS). Thus, there is an urgent need for high-value utilization technology to process the SMS, especially SMSs originating from woodchips. Protaetia brevitarsis larvae (PBL) can feed on various types of organic matter and can produce organic fertilizer and insect protein. In this study, we investigated the potential of PBL to utilize and convert SMSs from Auricularia auricula (SMS-AA) and Lentinula edodes (SMS-LE) cultivation. The results showed that the PBL were able to feed on SMS-AA and SMS-LE and form nutrient-enriched organic fertilizer with a low phytotoxicity and high humic acid content. Further analysis of the organic carbon dynamics suggested that PBL can efficiently digest and utilize lignin. This study demonstrates a new strategy for the utilization of SMSs originating from woodchips, and provides a new model for further investigations on the mechanism of lignin decomposition. [ABSTRACT FROM AUTHOR]

• The study cohort comprised children with leukemia who underwent partially CD3+-depleted peripheral stem cell transplantation (PSCT). • Three-year overall survival was 61.8% (95% confidence interval [CI], 50.2% to 71.4%) and event-free survival was 52.0% (95% CI, 40.3% to 62.4%). • Age ≥15 years and second complete remission were associated with worse outcomes. • The incidence of severe chronic graft-versus-host disease was lower in CD3+-depleted PSCTthan in T cell-replete PSCT. Most children who may benefit from stem cell transplantation lack a matched related donor. Alternative donor transplantations with an unrelated donor (URD) or a partially matched related donor (PMRD) carry an increased risk of graft-versus-host-disease (GVHD) and mortality compared with matched related donor transplantations. We hypothesized that a strategy of partial CD3+/CD19+ depletion for URD or PMRD peripheral stem cell transplantation (PSCT) would attenuate the risks of GVHD and mortality. We enrolled 84 pediatric patients with hematologic malignancies at the Children's Hospital of Philadelphia and the Children's Hospital of Wisconsin between April 2005 and February 2015. Two patients (2.4%) experienced primary graft failure. Relapse occurred in 23 patients (27.4%; cumulative incidence 26.3%), and 17 patients (20.2%) experienced nonrelapse mortality (NRM). Grade III-IV acute GVHD was observed in 18 patients (21.4%), and chronic GVHD was observed and graded as limited in 24 patients (35.3%) and extensive in 8 (11.7%). Three-year overall survival (OS) was 61.8% (95% confidence interval [CI], 50.2% to 71.4%) and event-free survival (EFS) was 52.0% (95% CI, 40.3% to 62.4%). Age ≥15 years was associated with decreased OS (P =.05) and EFS (P =.05). Relapse was more common in children in second complete remission (P =.03). Partially CD3+-depleted alternative donor PSCT NRM, OS, and EFS compare favorably with previously published studies of T cell-replete PSCT. Historically, T cell-replete PSCT has been associated with a higher incidence of extensive chronic GVHD compared with limited chronic GVHD, which may explain the comparatively low relapse and NRM rates in our study cohort despite similar overall rates of chronic GVHD. Partial T cell depletion may expand donor options for children with malignant transplantation indications lacking a matched related donor by mitigating, but not eliminating, chronic GVHD. [ABSTRACT FROM AUTHOR]

Highlights • P. brevitarsis larvae can convert agricultural residues to organic manure. • Maize and sawdust were converted to manure by larvae. • Larval digestion produced non-phytotoxic manure with high quality humic acids. • Manure humic acids shared structural similarities with soil humic acids. • P. brevitarsis offers a solution to the buildup of agricultural residues in China. Abstract Utilization of the organic residues produced after crop harvesting is currently an important issue across the world. The edible insect Protaetia brevitarsis larvae can feed various organic matters. In this paper, we investigated the potential to utilize the insect to convert herbaceous and ligneous plant residues. We feed the insect larvae with maize straw and sawdust and analyzed the produced insect manure. P. brevitarsis larval was found to be able to digest both herbaceous and ligneous straw and insect manure extract shown no phytotoxicity. The mass fractions of humic acids (HAs) in the insect manure derived from maize straw and sawdust digestion were 24.37% and 14.46%, respectively. The 13C cross-polarization magic-angle spinning nuclear magnetic resonance (CP–MAS NMR) spectra data indicated that the HAs in the insect manure were similar to those found in the soil. These data suggested that P. brevitarsis larvae can be used to convert agricultural residues and produce organic fertilizers. [ABSTRACT FROM AUTHOR]

Abstract: Impaired immunologic recovery (IR) after hematopoietic stem cell transplantation (HSCT) is associated with increased risk for infections and relapse. Stem cell source and graft manipulation influence the kinetics of IR. Partial T cell depletion of peripheral blood stem cell (PBSC) grafts is a novel alternative method of graft manipulation for children. We compared IR in children undergoing HSCT for hematologic malignancies receiving either T cell–depleted (TCD)-PBSCs (n = 55) or umbilical cord blood (UCB) (n = 21) over a 7-year period at a single institution. PBSC grafts underwent ex vivo negative selection for CD3+ cells using the CliniMACS system with partial T cell add-back. Recovery of CD4+ T cells was significantly delayed in TCD-PBSC recipients compared with UCB recipients, owing to impaired CD4+/CD45RA+ (naïve) T cell lymphopoiesis. Recovery of total CD3+ cells and CD3+/CD8+ cells was similar in the 2 groups. The TCD-PBSC recipients had a marked deficit in CD19+ and, to a lesser extent, IgA/IgM, owing to the need for B cell depletion of these grafts to attenuate the risk of lymphoproliferative disease after TCD HSCT. There were no significant between-group differences in response to mitogen stimulation, time to independence from intravenous immunoglobulin supplementation, or incidence of viral reactivation. Transplantation outcomes of relapse, transplantation-related mortality, event-free survival, and overall survival were similar in the 2 groups. Efforts to enhance IR after partial TCD-PBSC transplantation, such as selective αβ T cell depletion, hold promise for further improvement of this transplantation approach. [Copyright &y& Elsevier]

This paper is devoted to the fractional Laplacian system with critical exponents. We use the method of moving spheres to derive a Liouville Theorem with at most three radial solutions, and then prove the solutions in R n ∖ { 0 } are radially symmetric and monotonically decreasing. Together with blow up analysis, we get the upper bound of the local solutions in B 1 ∖ { 0 }. Our results is an extension of the classical works by Caffarelli et al. (1989), Caffarelli et al. (2014), Chen and Lin (2015) and Guo and Liu (2008). [ABSTRACT FROM AUTHOR]

Context: Parents of seriously ill children hold personal beliefs about what they should do to be good parents. How these beliefs change over time is unknown.Objectives: The objectives of this study were to describe the pattern of Good-Parent Beliefs over time, and determine whether parents' hopeful patterns of thinking, affect, and perceived child's health are associated with changes in beliefs at 12 and 24 months.Methods: Our longitudinal sample included 124 parents of 100 children hospitalized with serious illness. We used latent transition models to classify parents into groups with similar Good-Parent Beliefs during the baseline and follow-up periods and modeled the change in good-parent beliefs over time as a function of covariates using generalized linear mixed models.Results: Two parent belief profiles emerged from the latent transition model: Loved ("Making sure my child feels loved," n = 61 at baseline) and Informed ("Making informed decisions," n = 63 at baseline). At 12 months, 21 parents (20.4%) had moved into the Loved group and no parents transitioned to the Informed group. By 24 months, eight parents transitioned to the Loved group and four to the Informed group (13.04%). Transition into the Loved group was associated with parents' baseline degree of hopeful thinking and positive perceptions of child's health at baseline.Conclusion: Some parents change their parenting priorities over time. Hopeful patterns of thinking and perception of child health appear to predict change. Clinicians should regularly reevaluate Good-Parent Beliefs over time to promote priority-congruent dialogue. [ABSTRACT FROM AUTHOR]

Cu foils are physically heavy and chemically inappropriate for lithium metal rechargeable batteries with lithium-metal-free negatrode (LMFRBs). Physically light carbon-based current collectors (CBCCs) with high conductivity and strong resistance toward corrosion by air or electrolyte can replace Cu foil as a preferable deposition substrate for Li. However, welding problems, lithiation or electrolyte penetration-induced mechanical strength reduction, and lithiophobility-induced fragile SEI largely limit the application of CBCCs. In this work, we prepare lightweight graphene/polyvinylidene fluoride (PVDF) composite sheet via a coating and etching process to address the above issues. Cu tabs are bonded firmly to this CBCC with acceptable resistance, guaranteeing practical application. Tightly stacked graphene nanosheets mitigate lithiation and extra Li consumption (SEI), while PVDF as the binder reinforces the mechanical strength of CBCC by hindering the electrolyte penetration. Therefore, this composite CBCC satisfies the basic requirements i.e., sufficient conductivity and mechanical strength, and viable tab welding, needed for pouch cell application. In addition, as a film-forming polymer with a low Fermi level, PVDF helps form Li–F-rich and highly insulating SEI and suppresses electron transfer to the electrolyte, which induces uniform Li+ flux and alleviates electrolyte decomposition. The stable interface and robust SEI give rise to uniform and more reversible Li plating/stripping. The assembled LMFRB using this composite CBCC achieves remarkable capacity retention of 80% after ∼50 cycles with a high plating capacity of 4 mAh cm−2. [Display omitted] • Stacked graphene nanosheets mitigate lithiation and extra Li consumption. • PVDF enhances structural stability by hindering electrolyte penetration. • PVDF helps form Li–F-rich and insulating SEI, facilitating dense Li deposition. • Cu tabs can be easily bonded to the current collector with low resistance. • Practical pouch cells with this current collector shows improved cycle stability. [ABSTRACT FROM AUTHOR]

Purpose: Patients with high-risk neuroblastoma (HR-NBL) require radiation to the primary tumor site and sites of persistent metastatic disease. Proton radiation therapy (PRT) may promote organ sparing, but long-term outcomes have not been studied.Methods and Materials: Sequential patients with HR-NBL received PRT: 2160 cGy (relative biological effectiveness) to primary tumor bed and persistent metastatic sites, with 3600 cGy (relative biological effectiveness) to gross residual disease.Results: From September 2010 through September 2015, 45 patients with HR-NBL received PRT after systemic therapy, primary tumor resection, and high-dose chemotherapy with stem cell rescue. Median age was 46 months at the time of PRT (range, 10 months to 12 years); 23 patients (51%) were male. Primary tumors were adrenal in 40 (89%); 11 (24%) received boost. Ten metastatic sites in 8 patients were radiated. Double scattered proton beams were used for 19 (42%) patients, in combination with x-rays for 2 (5%). The remaining 26 (58%) received pencil beam scanning, available since January 2013. We observed 97% freedom from primary site recurrence at 3, 4, and 5 years. Overall survival rates were 89%, 80%, and 80% and disease-free survival rates were 77%, 70%, and 70%, at 3, 4, and 5 years, respectively. With median follow-up of 48.7 months from diagnosis (range, 11-90 months) for all patients (57.4 months for those alive), 37 (82%) patients are alive, and 32 (71%) are without evidence of disease. One patient experienced locoregional recurrence; the remaining 12 (27%) experienced relapse at distant, nonradiated sites. Acute toxicities during treatment were mainly grade 1. No patient has experienced World Health Organization grade 3 or 4 long-term renal or hepatic toxicity. Pencil beam scanning plans required less planning time and resources than double scattered plans.Conclusions: We observe excellent outcomes in patients treated with PRT for HR-NBL from 2010 through 2015, with 82% of patients alive and 97% free of primary site recurrence. No patient has experienced long-term renal or liver toxicity. This treatment maximizes normal tissue preservation and is appropriate for this patient population. [ABSTRACT FROM AUTHOR]

Compared with photon therapy, proton therapy reduces exposure of normal brain tissue in patients with craniopharyngioma, which might reduce cognitive deficits associated with radiotherapy. Because there are known physical differences between the two methods of radiotherapy, we aimed to estimate progression-free survival and overall survival distributions for paediatric and adolescent patients with craniopharyngioma treated with limited surgery and proton therapy, while monitoring for excessive CNS toxicity. In this single-arm, phase 2 study, patients with craniopharyngioma at St Jude Children's Research Hospital (Memphis TN, USA) and University of Florida Health Proton Therapy Institute (Jacksonville, FL, USA) were recruited. Patients were eligible if they were aged 0–21 years at the time of enrolment and had not been treated with previous radiotherapeutic or intracystic therapies. Eligible patients were treated using passively scattered proton beams, 54 Gy (relative biological effect), and a 0·5 cm clinical target volume margin. Surgical treatment was individualised before proton therapy and included no surgery, single procedures with catheter and Ommaya reservoir placement through a burr hole or craniotomy, endoscopic resection, trans-sphenoidal resection, craniotomy, or multiple procedure types. After completing treatment, patients were evaluated clinically and by neuroimaging for tumour progression and evidence of necrosis, vasculopathy, permanent neurological deficits, vision loss, and endocrinopathy. Neurocognitive tests were administered at baseline and once a year for 5 years. Outcomes were compared with a historical cohort treated with surgery and photon therapy. The coprimary endpoints were progression-free survival and overall survival. Progression was defined as an increase in tumour dimensions on successive imaging evaluations more than 2 years after treatment. Survival and safety were also assessed in all patients who received photon therapy and limited surgery. This study is registered with ClinicalTrials.gov , NCT01419067. Between Aug 22, 2011, and Jan 19, 2016, 94 patients were enrolled and treated with surgery and proton therapy, of whom 49 (52%) were female, 45 (48%) were male, 62 (66%) were White, 16 (17%) were Black, two (2%) were Asian, and 14 (15%) were other races, and median age was 9·39 years (IQR 6·39–13·38) at the time of radiotherapy. As of data cutoff (Feb 2, 2022), median follow-up was 7·52 years (IQR 6·28–8·53) for patients who did not have progression and 7·62 years (IQR 6·48–8·54) for the full cohort of 94 patients. 3-year progression-free survival was 96·8% (95% CI 90·4–99·0; p=0·89), with progression occurring in three of 94 patients. No deaths occurred at 3 years, such that overall survival was 100%. At 5 years, necrosis had occurred in two (2%) of 94 patients, severe vasculopathy in four (4%), and permanent neurological conditions in three (3%); decline in vision from normal to abnormal occurred in four (7%) of 54 patients with normal vision at baseline. The most common grade 3–4 adverse events were headache (six [6%] of 94 patients), seizure (five [5%]), and vascular disorders (six [6%]). No deaths occurred as of data cutoff. Proton therapy did not improve survival outcomes in paediatric and adolescent patients with craniopharyngioma compared with a historical cohort, and severe complication rates were similar. However, cognitive outcomes with proton therapy were improved over photon therapy. Children and adolescents treated for craniopharyngioma using limited surgery and post-operative proton therapy have a high rate of tumour control and low rate of severe complications. The outcomes achieved with this treatment represent a new benchmark to which other regimens can be compared. American Lebanese Syrian Associated Charities, American Cancer Society, the US National Cancer Institute, and Research to Prevent Blindness. [ABSTRACT FROM AUTHOR]

Purpose: To characterize respiration-induced abdominal organ motion in children receiving radiation treatment with a 4-dimensional (4D) magnetic resonance imaging (MRI) method.Methods and Materials: We analyzed free-breathing coronal 4D MRI datasets acquired from 35 patients (aged 1-20 years) with abdominal tumors. A deformable image registration of the 4D MRI datasets was performed to derive motion trajectories of selected anatomic landmarks, from which organ motions were quantified. The association between organ motion and patient characteristics was investigated and compared with previous studies. The relation between patient height and organ motion was further investigated to predict organ motion in prospective patients.Results: Organ motion and its individual variation were reduced in younger patients (eg, kidney peak-to-peak motion <5 mm for all but 1 patient aged ≤8 years), although special motion management may be warranted in some adolescents. The liver and spleen exhibited greater motion than did the kidneys, while intraorgan variation was present. The motions in the liver and kidneys agreed with those reported by the previous 4D computed tomography studies. Individual variations of organ motion in younger patients were due, in part, to changes in respiration rate, which ostensibly reflected the effect of anesthesia. The prediction of organ motion was limited by large individual variations, particularly for older patients.Conclusions: The 4D MRI acquisition method and motion analysis described in this study provide a nonionizing approach to understand age-associated organ motion, which aids in the planning of abdominal radiation therapy for pediatric patients. Use of 4D MRI facilitates monitoring of changes in target motion patterns during treatment courses and in various studies of the effect of organ motion on radiation treatment. [ABSTRACT FROM AUTHOR]

Purpose: Pediatric patients with craniopharyngioma risk cognitive deficits when treated with radiation therapy. We investigated cognitive outcomes after conformal photon radiation therapy (CRT) and the effect of visual deficits and hormone deficiencies.Methods and Materials: One hundred one pediatric patients were enrolled on a single institutional protocol beginning in 1998 (n = 76) or followed a similar nonprotocol treatment plan (n = 25). CRT (54 Gy) was administered using a 1.0- or 0.5-cm clinical target volume margin. Median age at CRT was 9.50 years (range, 3.20-17.63 years). Patients were followed for 10 years with assessment of hearing, vision, hormone deficiencies, and cognitive performance.Results: Intellectual functioning (intelligence quotient) was significantly lower in children treated at a younger age and those who received higher doses to temporal lobes and hippocampi. Black race (-17.77 points, P = .002) and cerebrospinal fluid shunting (-11.52 points, P = .0068) were associated with lower baseline intelligence quotient. Reading scores were lower over time in models incorporating age, shunt, and dose to specific brain structures. Patients treated for growth hormone deficiency within 12 months of CRT had better intelligence and attention outcomes. Among patients with normal baseline vision, the 10-year cumulative incidence of change in visual acuity was 4.00% ± 2.82% and in visual field 10.42% ± 4.48%. Reading scores decreased after treatment (0.7873 points/y, P = .0451) in those with impaired baseline vision.Conclusions: Cognitive outcomes are selectively affected by dose to brain subvolumes, comorbidities of visual deficits, and treatment of endocrinopathy in pediatric craniopharyngioma. Improved treatment selection, normal tissue sparing methods of irradiation, and posttreatment management of endocrinopathy should be considered. [ABSTRACT FROM AUTHOR]

Due to its woven structure, rich inner voids and high electrical conductivity, carbon fiber cloth (CFC) is considered as a promising three-dimensional (3D) current collector for lithium metal anode. However, it is usually inevitable that metallic Li plates on top of CFC as Li ions are instantaneously reduced when they reach the upper surface of CFC, which impedes the utilization of the inner space of CFC for accommodating Li deposition and causes poor cyclic stability of Li anode. In this study, by decorating a thin layer of graphene oxide (GO) on the surface of CFC using an electrophoresis method, an all-carbon 3D current collector with electrical conductivity differences in the vertical direction is fabricated. The graphene oxide layer with poor electrical conductivity induces downward electroplating of metallic Li into the inner voids of CFC, which fully exploits the effect of CFC as a 3D current collector in governing the plating/stripping behaviors of Li. As a result, the full cell using the GO modified CFC as the negative electrode and NCM811 positive electrodes can maintain 80% of its initial capacity after 460 cycles at a high current of 0.5C charge and 1C discharge. An all-carbon 3D current collector with vertical electro-conductivity differences is prepared by coating a thin graphene oxide layer on the surface of carbon fiber cloth to avoid the "top-growth" phenomenon of Li metal. [Display omitted] • A layer of graphene oxide is assembled on carbon fiber cloths by electrophoresis. • The 3D current collector inhibits "top-growth" phenomenon of lithium metal. • A long lifespan of 460 cycles is achieved in a full cell. [ABSTRACT FROM AUTHOR]

Purpose: Clinically effective measurement of cognitive toxicity from photon radiation therapy (XRT) should be accurate, sensitive, and specific. This pilot study tested translational findings on phasic changes in children's memory systems that are sensitive and insensitive to toxic XRT effects to identify a possible neuroplastic effect.Methods and Materials: Memory processes were prospectively tested before XRT and at 3 later time points up to 2 years in 35 children with mixed primary brain tumors who had not experienced recurrence. Memory processes were verbal-semantic, visual-semantic, and visual-perceptual, including accuracy, speed to recall, encoding, retrieval, and recognition. The mixed-effects model included time (to estimate slope), covariates (age, tumor locus, XRT field, and medications) as fixed effects, and individual random intercepts. A sensitivity analysis examined the influence of XRT dose to the hippocampi on memory.Results: Retrieval from long-term verbal-semantic memory declined 2 months after completing XRT, as seen in adults, and was lowest at 1 year, which was delayed in comparison with adults. Double dissociation from visual-perceptual memory at baseline and 2 months was found, consistent with adults. Recovery was demonstrated 2 years after XRT. Patterns were unchanged when dose to hippocampus was included in the model.Conclusions: Verbal and semantic long-term retrieval is specifically sensitive to XRT-related cognitive dysfunction, without effect on visual-perceptual memory. Children reached nadir in XRT-sensitive memory 1 year after XRT and recovered by 2 years, which is later than that observed in adults. The protracted period of post-XRT injury may represent the maturation of the human hippocampus and white matter into late adolescence. [ABSTRACT FROM AUTHOR]

Purpose The purpose of this study was to determine radiation dose effect on the structural integrity of cerebral white matter in craniopharyngioma patients receiving surgery and proton therapy. Methods and Materials Fifty-one patients (2.1-19.3 years of age) with craniopharyngioma underwent surgery and proton therapy in a prospective therapeutic trial. Anatomical magnetic resonance images acquired after surgery but before proton therapy were inspected to identify white matter structures intersected by surgical corridors and catheter tracks. Longitudinal diffusion tensor imaging (DTI) was performed to measure microstructural integrity changes in cerebral white matter. Fractional anisotropy (FA) derived from DTI was statistically analyzed for 51 atlas-based white matter structures of the brain to determine radiation dose effect. FA in surgery-affected regions in the corpus callosum was compared to that in its intact counterpart to determine whether surgical defects affect radiation dose effect. Results Surgical defects were seen most frequently in the corpus callosum because of transcallosal resection of tumors and insertion of ventricular or cyst catheters. Longitudinal DTI data indicated reductions in FA 3 months after therapy, which was followed by a recovery in most white matter structures. A greater FA reduction was correlated with a higher radiation dose in 20 white matter structures, indicating a radiation dose effect. The average FA in the surgery-affected regions before proton therapy was smaller ( P =.0001) than that in their non–surgery-affected counterparts with more intensified subsequent reduction of FA ( P =.0083) after therapy, suggesting that surgery accentuated the radiation dose effect. Conclusions DTI data suggest that mild radiation dose effects occur in patients with craniopharyngioma receiving surgery and proton therapy. Surgical defects present at the time of proton therapy appear to accentuate the radiation dose effect longitudinally. This study supports consideration of pre-existing surgical defects and their locations in proton therapy planning and studies of treatment effect. [ABSTRACT FROM AUTHOR]

Purpose: Vasculopathy (VAS) is a significant complication associated with radiation therapy in patients treated for brain tumors. We studied the type, location, severity, timing, and resolution of VAS in children with craniopharyngioma treated with proton radiation therapy (PRT) and evaluated predictors of stenosis (STN) using a novel patient and imaging-based modeling approach.Methods and Materials: Children with craniopharyngioma (n = 94) were treated with 54 Gy relative biological effectiveness PRT in a clinical trial, NCT01419067. We evaluated VAS type, location, severity, and resolution. VAS events were segmented and related to their location, operative corridor, PRT dose, and vascular territory to facilitate mixed effect logistic regression modeling of spatial predictors of STN events.Results: Forty-five (47.9%) patients had 111 instances of confirmed VAS (pre-PRT n = 37, 33.3%). The median time to post-PRT VAS was 3.41 years (95% confidence interval, 1.86-6.11). STN events were observed post-PRT in 23.4% (n = 22) of patients. Post-PRT VAS was detected by cerebral angiogram in 9.6% (n = 9), severe in 4.3% (n = 4), and compensated on perfusion in 2.1% (n = 2). Revascularization was required for 5 (5.3%) patients. Postsurgical, pre-PRT VAS, and PRT dose to unperturbed vessels were predictive of STN. The effect of PRT on STN was negligible within the surgical corridor.Conclusions: VAS often precedes PRT and was the strongest predictor of post-PRT STN. The adverse effect of PRT on STN was only apparent in unperturbed vasculature beyond the operative corridor. [ABSTRACT FROM AUTHOR]

BK virus (BKV) infection is associated with hemorrhagic cystitis (HC) in hematopoietic stem cell transplantation (HSCT) recipients and nephropathy after kidney transplantation. We assessed the association between BKV and kidney and bladder complications in children developing HC by retrospectively reviewing 221 consecutive pediatric allogeneic HSCT recipients at the Children's Hospital of Philadelphia from 2005 to 2011. We included all patients with BKV PCR testing performed for clinical indication from day 0 until 1 year post-HSCT (N = 68). We assessed the association of any BKV infection (urine and/or blood) or peak BK viremia ≥ 10,000 copies/mL (high viremia) with severe HC (defined as grade IV—bladder catheterization or surgical intervention); the need for dialysis; serum creatinine–estimated glomerular filtration rate at the time of BKV testing, day 100, and day 365; and death. Children with high viremia more likely developed severe HC compared with those with peak viremia < 10,000 copies/mL (21% versus 2%; P = .02). BKV infection of the blood or urine was not associated with the need for dialysis, change in estimated glomerular filtration rate, or mortality. BKV infection is common after pediatric allogeneic HSCT, and plasma testing in those with HC may predict patients who will develop severe bladder injury. [Copyright &y& Elsevier]

Purpose: To determine whether radiation-induced changes in white matter tracts are uniform across the brainstem. Methods and Materials: We analyzed serial diffusion tensor imaging data, acquired before radiation therapy and over 48 to 72 months of follow-up, from 42 pediatric patients (age 6-20 years) with medulloblastoma. FSL software (FMRIB, Oxford, UK) was used to calculate fractional anisotropy (FA) and axial, radial, and mean diffusivities. For a consistent identification of volumes of interest (VOIs), the parametric maps of each patient were transformed to a standard brain space (MNI152), on which we identified VOIs including corticospinal tract (CST), medial lemniscus (ML), transverse pontine fiber (TPF), and middle cerebellar peduncle (MCP) at the level of pons. Temporal changes of DTI parameters in VOIs were compared using a linear mixed effect model. Results: Radiation-induced white matter injury was marked by a decline in FA after treatment. The decline was often accompanied by decreased axial diffusivity, increased radial diffusivity, or both. This implied axonal damage and demyelination. We observed that the magnitude of the changes was not always uniform across substructures of the brainstem. Specifically, the changes in DTI parameters for TPF were more pronounced than in other regions (P<.001 for FA) despite similarities in the distribution of dose. We did not find a significant difference among CST, ML, and MCP in these patients (P>.093 for all parameters). Conclusions: Changes in the structural integrity of white matter tracts, assessed by DTI, were not uniform across the brainstem after radiation therapy. These results support a role for tract-based assessment in radiation treatment planning and determination of brainstem tolerance. [ABSTRACT FROM AUTHOR]

Purpose: The use of stereotactic body radiation therapy (SBRT) in pediatric patients has been underreported. We reviewed practice patterns, outcomes, and toxicity of SBRT in this population.Methods and Materials: In this multi-institutional study, 55 patients with 107 non-central nervous system lesions treated with SBRT between 2010 and 2016 were reviewed. Treatment response was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and modified RECIST v1.1 criteria for soft-tissue and bone lesions, respectively. Patterns of local failure (LF) were assessed dosimetrically. The cumulative incidence of LF and toxicity were estimated accounting for the competing risk event of death. Predictors of LF were identified through joint frailty models for clustered competing risks.Results: The median (range) dose/fraction was 7 (4.5-25) Gy, the total (range) dose/site was 35 (12-45), and the median (range) number of fractions was 5 (1-9). The radiographic response rates of bone and soft-tissue lesions were 90.6% and 76.7%, respectively. Symptom improvement was observed for 62% of symptomatic sites. A total of 27 LFs were documented, with 14 in-field, 9 marginal, and 4 out-of-field LFs. The 1-year estimated cumulative LF rate, progression-free survival, and overall survival were 25.2% (95% confidence interval [CI], 17.2%-36.1%), 17.5% (95% CI, 9.0%-34.1%), and 61% (95% CI, 48.9%-76.1%), respectively. Lesion type (soft tissue vs bone) was the only significant predictor of LF on multivariable analysis (P = .04), with increased hazard for soft-tissue lesions. No acute or late toxicity of grade 4 or higher was observed; the estimated 1-year cumulative incidence of late toxicity of any grade was 7.5% (95% CI, 3.6%-12.1%).Conclusions: The SBRT was well tolerated and resulted in radiographic response and symptom palliation in most pediatric patients with advanced disease. The 1-year cumulative LF rate of 25% will serve as a benchmark for further modifications to radiation therapy indications, parameters, and combination therapy. [ABSTRACT FROM AUTHOR]

Purpose: To determine the preirradiation baseline association of white matter integrity with neurocognitive function and to assess posttreatment changes in pediatric patients with craniopharyngioma treated with proton therapy.Methods and Materials: Ninety children and adolescents (2-20 years old) with craniopharyngioma were treated with proton therapy (54 Gy[RBE]) in a prospective therapeutic trial. Neurocognitive performance at the postoperative baseline before proton therapy and diffusion tensor imaging (DTI) data acquired at baseline and at annual follow-up were analyzed. Tract-based spatial statistics and structural connectomics were used to derive global and local white matter features from DTI. Baseline DTI features were compared for patients with average and below-average neurocognitive performance. Longitudinal DTI data were analyzed to determine the proton dose effect on white matter structures in relation to the irradiated brain volume and baseline age.Results: Before proton therapy, patients with below-average working memory, processing speed, verbal fluency, verbal learning, or fine motor dexterity exhibited more globally degraded white matter structures compared with their counterparts with average performance, as indicated by lower mean fractional anisotropy, decreased global efficiency, or higher modularity. Surgery, obstructive hydrocephalus, and preoperative hypothalamic involvement appeared to be related to this degradation. In local analyses, tract-based spatial statistics revealed left-lateralized associations with verbal and motor functions, which supported surgical approaches to midline tumors via the right hemisphere. The mean fractional anisotropy of the brain and the global efficiency derived from DTI increased over the 5 years after proton therapy. The rate of increase was lower with larger irradiated brain volumes and in older children.Conclusions: Below-average baseline neurocognitive performance in patients with craniopharyngioma before proton therapy appeared to be related to structural degradation of white matter tracts. Posttherapy longitudinal DTI showed improving trends in global integrity and efficiency measures, particularly in children in whom a smaller brain volume was irradiated. [ABSTRACT FROM AUTHOR]

Among various technologies that go beyond lithium-ion batteries, lithium metal batteries (LMBs) have been intensively studied as the next generation of high-energy battery technology. However, achieving scalable production of dendrite-free lithium metal anodes (LMAs) for practical application is still a formidable challenge. Herein, we propose a simple and feasible method to modify lithium foil with graphene coatings, which is expected to be used in practical applications on a large scale. Graphene has a high specific surface area and excellent electrical conductivity, which can disperse current density, induce uniform Li deposition, and reduce the generation of dendrites and dead lithium. Meanwhile, the porous graphene coating layer is beneficial to the continuous compensation of irreversible active Li loss by the Li foil underneath the graphene coating. As a result, pouch cells using graphene coated Li anode display superior cyclic stability comparing to the cell with bare Li anode. The cell with a high areal capacity of 4 mAh cm−2 reaches a high capacity retention of 76% after 470 charge/discharge cycles at a current density of 0.1C. Modifying lithium foil with graphene coatings by a simple and feasible method enables long cycle life (470 cycles with 76% capacity retention) of Li metal pouch cells. [Display omitted] • A simple and feasible method to modify lithium foil with graphene coatings. • Graphene coating guides reversible Li plating/stripping. • The loose stacking of graphene sheets facilitates migration of Li+. • A long life of 470 cycles is achieved in a pouch cell using graphene coated Li. [ABSTRACT FROM AUTHOR]

• Matched sibling donor transplants have a survival and cost advantage over unrelated donor transplants. • Matched unrelated donor and unrelated cord blood transplants have similar survival outcomes. • Among unrelated donor transplants, matched unrelated donor transplants have a cost advantage. Allogeneic hematopoietic stem cell transplantation (alloHCT) may be associated with significant morbidity and mortality, resulting in increased healthcare utilization (HCU). To date, no multicenter comparative cost analyses have specifically evaluated alloHCT in children with acute leukemia. In this retrospective cohort study, we examined the relationship between survival and HCU while investigating the hypothesis that matched sibling donor (MSD) alloHCT has significantly lower inpatient HCU with unrelated donor (URD) alloHCT, and that among URDs, umbilical cord blood (UCB) alloHCT will have higher initial utilization but lower long-term utilization. Clinical and transplantation outcomes data from the Center for International Blood and Marrow Transplant Research (CIBMTR) were merged with inpatient cost data from the Pediatric Health Information System (PHIS) database using a probabilistic merge methodology. The merged dataset comprised US patients age 1 to 21 years who underwent alloHCT for acute leukemia between 2004 and 2011 with comprehensive CIBMTR data at a PHIS hospital. AlloHCT was analyzed by donor type, with specific analysis of utilization and costs using PHIS claims data. The primary outcomes of overall survival (OS), leukemia-free survival (LFS), and inpatient costs were evaluated using Kaplan-Meier curves and Cox and Poisson models. A total of 632 patients were identified in both the CIBMTR and PHIS data. The 5-year LFS was 60% for MSD alloHCT, 47% for well-matched matched unrelated donor bone marrow (MUD) alloHCT, 48% for mismatched unrelated donor alloHCT, and 45% for UCB alloHCT (P =.09). Total adjusted costs were significantly lower for MSD alloHCT versus MUD alloHCT by day 100 (adjusted cost ratio [ACR],.73; 95% confidence interval [CI],.62 to.86; P <.001), and higher for UCB alloHCT versus MUD alloHCT (ACR, 1.27; 95% CI, 1.11 to 1.45; P <.001). By 2 years, total adjusted costs remained significantly lower for MSD alloHCT compared with MUD alloHCT (ACR,.67; 95% CI,.56 to.81; P <.001) and higher for UCB alloHCT compared with MUD alloHCT (ACR, 1.25; 95% CI, 1.02 to 1.52; P =.0280). Our data show that UCB and MUD alloHCT provide similar survival outcomes; however, MUD alloHCT has a significant advantage in cost by day 100 and 2 years. More research is needed to determine whether the cost difference among URD alloHCT approaches remains significant with a larger sample size and/or beyond 2 years post-alloHCT. [ABSTRACT FROM AUTHOR]

Graft versus host disease (GVHD) causes significant morbidity and mortality after allogeneic stem cell transplant (SCT). Little is known about genetic determinants of GVHD risk, including human leukocyte antigen (HLA) genotypes outside of HLA-mismatch. HLA-DQ2 and DQ8 genotypes are associated with celiac disease (CD) and are present in ≥90% of patients with CD. Both GVHD and CD are systemic inflammatory conditions that may have T cell-mediated enteropathy. We hypothesized HLA-DQ alleles associated with CD risk would confer increased risks of acute (a) and chronic (c) GVHD in pediatric SCT recipients. We performed a retrospective cohort study of children aged 0-21 years undergoing first allogeneic SCT at the Children's Hospital of Philadelphia from 10/1/12 — 7/1/16. Patients with primary graft failure or missing HLA-DQ genotypes were excluded. We grouped patients by low, moderate or high CD risk (Clin Gastroenterol Hepatol 2009, 7:966). Primary outcomes were 1) 100-day aGVHD incidence; 2) day 100 — 1-year cGVHD incidence; and 3) time to GVHD with relapse, death, secondary graft failure, second SCT, or donor lymphocyte infusion as competing risks. Logistic regressions were used to calculate odds ratios (OR) and 95% confidence intervals (CI). Sub-distribution hazard models were used to estimate crude and adjusted sub-distribution hazard ratios (sHR) in time-to-event analyses. Multivariate models were adjusted for race-ethnicity, malignant/nonmalignant SCT indication, donor/mismatch, and graft source. We identified 167 patients (mean age 9.2 ±6.2 years). Proportions by CD risk were: low-risk n=108 (64.7%), moderate n=33 (19.8%), and high n=26 (15.6%). Day 100 incidence of ≥grade 2 aGVHD was 14.4% (8.4% had ≥grade 3). cGVHD 1-year incidence was 42.7% (14% had extensive). CD risk was protective against GVHD but did not reach statistical significance (Table 1). Risk of clinically significant GVHD (≥grade 2 or any chronic) was reduced in children with CD risk in the adjusted time-to-event model (moderate: sHR 0.42, 95% CI 0.18 — 0.95, p=0.037; high: sHR 0.31, 95% CI 0.12 – 0.8, p=0.016; Figure 1A). The protective effect of high CD risk was more pronounced for severe GVHD (≥grade 3 or chronic extensive) but did not reach statistical significance (adjusted sHR 0.14, 95%CI 0.02-1.09, P = 0.061; Figure 1B). In contrast to our hypothesis, CD risk by HLA-DQ is protective against GVHD in a dose-responsive manner. Reports of HLA-DQ2 and DQ8 protecting against other non-CD autoimmune diseases (rheumatoid arthritis and inflammatory bowel disease) support our observations. These results require confirmation and evaluation in a larger patient sample to define this novel GVHD risk modifier more robustly. [ABSTRACT FROM AUTHOR]

Patients (pts) receiving CTL019 (tisagenlecleucel) for B-ALL with high tumor burden (HTB) are at high risk for developing severe CRS. Tocilizumab, an IL-6 receptor antibody, is a vital component of severe CRS management; however, its role in preventing severe CRS is not known. We sought to determine the effectiveness of preemptive tocilizumab (PT) administration in decreasing the rate of grade (gr) 4 CRS in HTB pts. We conducted a pilot trial of risk-adapted PT after CTL019 (NCT02906371). HTB pts, defined as ≥40% bone marrow (BM) blasts immediately before infusion, received a single dose of PT for high persistent fever (2 temperatures ≥38.5C in 24hr). The primary endpoint was frequency of gr4 CRS (Penn scale), with an observed rate of ≤5/15 predefined as clinically meaningful. Secondary endpoints included complete remission (CR) rate and ICU length of stay (LOS). A comparator cohort with HTB who received standard CRS management (stdCRS) was identified from the initial CTL019 trial (NCT01626495). Characteristics of the PT (n=15) and stdCRS (n=26) HTB cohorts are shown in Table 1. All pts developed gr≥2 CRS; median time to fever was longer in the PT cohort [PT, 3d (IQR 2-9); stdCRS, 2d (IQR 1-7), p=0.03]. Gr4 CRS was observed in 4/15 (27%) pts in the PT cohort vs. 13/26 (50%) in the prior stdCRS cohort [RR 0.53 (95% CI, 0.21-1.34), p=0.18]. In the stdCRS cohort, gr4 CRS was associated with earlier onset of fever (p=0.04). In patients with earlier CRS onset (fever by day +4), gr4 CRS was observed in 4/9 (44%) vs. 13/21 (62%) in the PT and stdCRS cohorts [RR 0.72 (95% CI, 0.32-1.60), p=0.42]. Except for a trend toward fewer vasoactive days in the PT cohort, ICU LOS and resource utilization were not significantly different (Table 2). The CR rate at day 28 was similar in the PT and stdCRS cohorts (87% vs. 85%, p=1.00). Risk-adapted PT administration reduced gr4 CRS, meeting the predefined study endpoint, without impacting the CR rate. A secondary comparison to a prior trial showed a clinically meaningful decrease in the rate of gr4 CRS from 50% to 27%; however, the analysis was not powered to detect a statistically significant difference. Ongoing analyses will evaluate CAR T cell expansion, duration of remission, and additional safety endpoints, including rates of neurotoxicity. [ABSTRACT FROM AUTHOR]

Purpose: Optimal radiation therapy (RT) target margins for diffuse intrinsic pontine glioma (DIPG) are unknown. We sought to define disease progression patterns in a contemporary cohort treated with conformal RT using different clinical target volume (CTV) margins.Methods and Materials: We reviewed 105 patients with newly diagnosed DIPG treated with conformal conventionally fractionated RT at our institution from 2006 to 2014. CTV margins were classified as standard (1 cm) for 60 patients and extended (2-3 cm) for 45 patients. Survival and cumulative incidence of progression in treatment groups were compared by log-rank and Gray's tests, respectively. Cox proportional hazard models identified predictors of survival.Results: For 97 patients evaluated with magnetic resonance imaging at progression, the cumulative incidences of isolated local, isolated distant, and synchronous disease progression at 1 year were 62.6%, 12.3%, and 7.2%, respectively, and did not differ significantly according to the CTV margin. Central dosimetric progression (Vprogression95% ≥95%) was observed in 80 of 81 evaluable patients. Median progression-free survival and overall survival (OS) were 7.6 months (95% confidence interval, 6.9-8.2) and 11.3 months (95% confidence interval, 10.0-12.8), respectively, and did not differ significantly according to margin status. DIPG survival prediction risk group (standard vs high, P = .02; intermediate vs high, P = .009) and development of distant metastasis (P = .003) were independent predictors of OS. For the 41 patients (39%) with a pathologic diagnosis, H3.3 K27M mutation was associated with shorter OS (hazard ratio [HR], 0.41; P =.02), whereas H3.1 K27M and ACVR1 mutations were associated with longer OS (HR, 3.56; P =.004 and HR, 2.58; P =.04, respectively).Conclusions: All patients who experienced local failure showed progression within the high-dose volume, and there was no apparent survival or tumor-control benefit to extending the CTV margins beyond 1 cm. Given the increasing use of reirradiation, standardizing the CTV margin to 1 cm may improve retreatment tolerance. [ABSTRACT FROM AUTHOR]

Pipecolic acid (Pip) and N-hydroxypipecolic acid (NHP) have been found to accumulate during the ripening of multiple types of fruits; however, the function and mechanism of pipecolate pathway in fruits remain unclear. Here study was conducted on fruits produced by the model plant tomato, wherein the NHP biosynthesis-related genes, Slald1 and Slfmo1 , were mutated. The results showed that the fruits of both the Slald1 and the Slfmo1 mutants exhibited a delayed onset of ripening, decreased fruit size, nutrition and flavor. Exogenous treatment with Pip and NHP promoted fruit ripening and improved fruit quality. Transcriptomic analysis combined with weighted gene co-expression network analysis revealed that the genes involved in the biosynthesis of amino acids, carbon metabolism, photosynthesis, starch and sucrose metabolism, flavonoid biosynthesis, and plant hormone signal transduction were affected by SlFMO1 gene mutation. Transcription factor prediction analysis revealed that the NAC and AP2/ERF-ERF family members are notably involved in the regulation pathway. Overall, our results suggest that the pipecolate biosynthesis pathway is involved in the simultaneous regulation of fruit ripening and quality and indicate that a regulatory mechanism at the transcriptional level exists. However, possible roles of endogenously synthesized Pip and NHP in these processes remain to be determined. The biosynthesis pathway genes SlALD1 and SlFMO1 may be potential breeding targets for promoting fruit ripening and improving fruit quality with concomitant yield increases. • Pipecolate biosynthesis pathway promotes the onset of tomato fruit ripening. • Pipecolate biosynthesis pathway improves the nutrition and flavor quality of fruit. • Pip and NHP can promote fruit ripening and improve fruit quality simultaneously. • Multiple metabolic processes are involved in the process regulation. • The NAC and AP2/ERF family members are notably involved in the process regulation. [ABSTRACT FROM AUTHOR]

Purpose: The predictive value of Image-Defined Risk Factors (IDRFs) developed by the International Neuroblastoma Risk Group Task Force as it relates to primary-site management is undefined and may aid patient selection for de-escalation of adjuvant radiation therapy to the primary site in high-risk neuroblastoma.Methods and Materials: Patients (N = 76) with high-risk neuroblastoma treated on prospective trials at our institution from 1997 to 2014 were eligible for inclusion. IDRFs were defined based on pretherapy imaging. Overall survival, progression-free survival, and locoregional failure-free survival (LRFFS) were described using the Kaplan-Meier estimator and tested across strata by using the log-rank test.Results: Twenty of 76 patients (26%) experienced local (n = 6), regional (n = 6), or combined locoregional failure (n = 8) with or without distant failure. Ten (50%) of the locoregional failures had concurrent distant relapse. Of patients who completed all therapy, both those with no IDRFs and those with >90% resection had a 3-year LRFFS of 100%, with or without radiation therapy. Patients with either ≥1 IDRF or Conclusions: Patients with >90% tumor resection and no primary site IDRFs at diagnosis may be candidates for de-escalation of adjuvant primary-site radiation therapy, although validation of these findings in future studies is required. [ABSTRACT FROM AUTHOR]

Purpose: We sought to investigate the pattern of treatment failure with respect to anatomic extent, radiation dose, and criteria for failure according to the Response Assessment in Neuro-Oncology (RANO). We evaluated the corresponding prognostic significance of these factors in patients with pediatric high-grade glioma (pHGG).Methods and Materials: Fifty-six patients with pHGG were enrolled in an institutional phase 1 to 2 prospective trial that included maximal safe resection and radiation therapy with concurrent and adjuvant erlotinib. The radiation therapy dose administered was 54 to 59.4 Gy at 1.8 Gy/d. Tumor progression was defined according to clinical symptoms and imaging features and was classified in relation to the original extent of the tumor, radiation prescription target volume coverage, and RANO criteria (RANOc).Results: With a median follow-up period of 90 months (range, 70-124 months), progression occurred in 48 patients (85.7%) while 8 (14.3%) were without progression. Central failure represented 42.6% of the total cohort, while in-field, marginal, and distant failures occurred in 7.4%, 9.3%, and 22.2%, respectively. Patients with biopsy or subtotal resection had increased rates of central failure and represented 14.81% and 16.67% of the total cohort, respectively. Tumor progression was classified as local, local plus distant, or distant. Among patients with local failure as a component of failure, 5 were considered to have marginal failure. Patients with frontal, temporal, and parietal disease had the highest rates of multifocal failure. A comparison between responses defined by RANOc demonstrated varied time to death (TTD) from progression.Conclusions: Pediatric high-grade glioma was shown to have high rates of central failure, particularly in cases with limited resection. Patients with central failure had a trend toward more prolonged TTD from failure relative to other failure patterns. The low marginal failure rates seen in this group suggest that less conservative radiation target margins may be possible. TTD from failure varied according to RANO type, suggesting that adult RANOc require modification before being applied to pHGG. [ABSTRACT FROM AUTHOR]

Various parametric and nonparametric modeling approaches exist for real-time prediction in time-to-event clinical trials. Recently, Chen (2016 BMC Biomedical Research Methodology 16 ) proposed a prediction method based on parametric cure-mixture modeling, intending to cover those situations where it appears that a non-negligible fraction of subjects is cured. In this article we apply a Weibull cure-mixture model to create predictions, demonstrating the approach in RTOG 0129, a randomized trial in head-and-neck cancer. We compare the ultimate realized data in RTOG 0129 to interim predictions from a Weibull cure-mixture model, a standard Weibull model without a cure component, and a nonparametric model based on the Bayesian bootstrap. The standard Weibull model predicted that events would occur earlier than the Weibull cure-mixture model, but the difference was unremarkable until late in the trial when evidence for a cure became clear. Nonparametric predictions often gave undefined predictions or infinite prediction intervals, particularly at early stages of the trial. Simulations suggest that cure modeling can yield better-calibrated prediction intervals when there is a cured component, or the appearance of a cured component, but at a substantial cost in the average width of the intervals. [ABSTRACT FROM AUTHOR]

Flower-like brookite TiO 2 nanostructures were controllable prepared by a one-step hydrothermal method by changing experimental conditions, such as hydrothermal temperature, reaction time and the amount of polyvinylpyrrolidone. The photocatalytic activities of the samples were investigated by degradation of methylene blue (MB) in aqueous solution under UV light irradiation. It was found that the formation of brookite TiO 2 nanostructures with various morphologies could be well controlled by the adjustment of hydrothermal temperature, reaction time and the amount of surfactant, and the morphology of the products changed from spindle-like structures to flower-like structures with the increase of hydrothermal temperature, reaction time and the amount of surfactant. The photocatalytic tests indicate that the flower-like brookite TiO 2 nanostructures shows high photocatalytic activity in degradation of methylene blue (MB) under UV light irradiation. The formation mechanism of flower-like brookite TiO 2 nanostructures was also discussed in detail based on the above investigations. [ABSTRACT FROM AUTHOR]

Introduction: Sickle cell disease (SCD) research is hampered by disparities in participation due in part to mistrust of research among racial/ethnic minorities. Beyond the historic context of research misconduct, little is known about the associations of social ecologic factors with mistrust and of mistrust with SCD clinical trials enrollment. This study evaluated proximal (age, gender, disease severity, perceived stress, SES) and distal (religious beliefs, social support, instrumental support) factors related to mistrust of research among caregivers of children with SCD and adolescents and young adults (AYAs) with SCD.Methods: Over an 18-month period (2009-2010), participants completed questionnaires of perceived barriers and benefits to clinical trials enrollment, perceived stress, and self-reported demographic and disease-related information. Analyses (January-June 2015) used multivariable linear regressions to evaluate predictors of mistrust.Results: Data were analyzed for 154 caregivers (mean age, 38.75 years; SD=9.56 years; 90.30% female) and 88 AYAs (mean age, 24.76 years; SD=7.25 years; 46.40% female). Among caregivers (full model, R(2)=0.14, p≤0.001), greater mistrust was explained by higher perceived stress (β=0.04, p=0.052); religious beliefs (β=0.61, p≤0.001); and greater instrumental support (β=0.07, p=0.044). Among AYAs (full model, R(2)=0.18, p≤0.001), higher mistrust was explained by being male (β=-0.56, p≤0.001) and lower instrumental support (β=-0.11, p=0.016). Mistrust was significantly greater among caregivers that reported no prior involvement in medical research (p=0.003).Conclusions: By understanding the complexity through which social ecologic factors contribute to mistrust, researchers may create targeted strategies to address mistrust and increase engagement in SCD research for caregivers and AYAs. [ABSTRACT FROM AUTHOR]

Acquired aplastic anemia (aAA) results from the T cell-mediated autoimmune destruction of hematopoietic stem cells. Factors predicting response to immune suppression therapy (IST) or development of myelodysplastic syndrome (MDS) are beginning to be elucidated. Our recent data suggest most patients with aAA treated with IST develop clonal somatic genetic alterations in hematopoietic cells. One frequent acquired abnormality is copy-number neutral loss of heterozygosity on chromosome 6p (6p CN-LOH) involving the human leukocyte antigen (HLA) locus. We hypothesized that because 6p CN-LOH clones may arise from selective pressure to escape immune surveillance through deletion of HLA alleles, the development of 6p CN-LOH may affect response to IST. We used single nucleotide polymorphism array genotyping and targeted next-generation sequencing of HLA alleles to assess frequency of 6p CN-LOH, identity of HLA alleles lost through 6p CN-LOH, and impact of 6p CN-LOH on response to IST. 6p CN-LOH clones were present in 11.3% of patients, remained stable over time, and were not associated with development of MDS-defining cytogenetic abnormalities. Notably, no patient with 6p CN-LOH treated with IST achieved a complete response. In summary, clonal 6p CN-LOH in aAA defines a unique subgroup of patients that may provide insights into hematopoietic clonal evolution. [ABSTRACT FROM AUTHOR]

Acquired aplastic anemia (aAA) is a nonmalignant disease caused by autoimmune destruction of early hematopoietic cells. Clonal hematopoiesis is a late complication, seen in 20–25% of older patients. We hypothesized that clonal hematopoiesis in aAA is a more general phenomenon, which can arise early in disease, even in younger patients. To evaluate clonal hematopoiesis in aAA, we used comparative whole exome sequencing of paired bone marrow and skin samples in 22 patients. We found somatic mutations in 16 patients (72.7%) with a median disease duration of 1 year; of these, 12 (66.7%) were patients with pediatric-onset aAA. Fifty-eight mutations in 51 unique genes were found primarily in pathways of immunity and transcriptional regulation. Most frequently mutated was PIGA , with seven mutations. Only two mutations were in genes recurrently mutated in myelodysplastic syndrome. Two patients had oligoclonal loss of the HLA alleles, linking immune escape to clone emergence. Two patients had activating mutations in key signaling pathways (STAT5B (p.N642H) and CAMK2G (p.T306M)). Our results suggest that clonal hematopoiesis in aAA is common, with two mechanisms emerging—immune escape and increased proliferation. Our findings expand conceptual understanding of this nonneoplastic blood disorder. Future prospective studies of clonal hematopoiesis in aAA will be critical for understanding outcomes and for designing personalized treatment strategies. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To evaluate perceived benefits and barriers to pediatric clinical trials participation to improve decision-making and enhance recruitment and retention among minority youth with chronic health conditions (sickle cell disease, asthma) and their caregivers. Methods: A questionnaire was developed based on the social ecological model using input from medical experts and community-based public health organizations. Parallel caregiver, adolescent/young adult (AYA; 16–39years old), and child (8–15years old) versions were field tested. Patients and caregivers completed the questionnaire, which included demographic items, perceived life stress and social desirability measures. Results: Exploratory factor analysis rendered a four-factor solution for the caregiver version (direct treatment benefit, mistrust of research/researchers, trust in healthcare team to engage in safe research, and opportunity cost) and the AYA version (mistrust/no direct benefit, safety, direct treatment benefit/practical considerations, and social support for research). Factor structures differed for SCD and asthma caregivers; results were equivocal for the child version. Summated subscales were not significantly associated with patient demographics or social desirability, but significant correlations with perceived life stress and prior participation in research were identified. Conclusions: While the factor structure should be confirmed with larger samples, findings indicate potential benefit, perceived harm due to mistrust of researchers, and logistics are primary factors in decision-making about participation in pediatric clinical trials. By addressing these benefits/barriers through adjustments to recruitment and informed consent procedures, researchers may address misperceptions of research, improve decision-making, and increase recruitment and retention particularly for ethnic minority children with chronic health conditions. [Copyright &y& Elsevier]

Purpose: To characterize therapy-induced changes in normal-appearing brainstems of childhood brain tumor patients by serial diffusion tensor imaging (DTI). Methods and Materials: We analyzed 109 DTI studies from 20 brain tumor patients, aged 4 to 23 years, with normal-appearing brainstems included in the treatment fields. Those with medulloblastomas, supratentorial primitive neuroectodermal tumors, and atypical teratoid rhabdoid tumors (n = 10) received postoperative craniospinal irradiation (23.4–39.6 Gy) and a cumulative dose of 55.8 Gy to the primary site, followed by four cycles of high-dose chemotherapy. Patients with high-grade gliomas (n = 10) received erlotinib during and after irradiation (54–59.4 Gy). Parametric maps of fractional anisotropy (FA) and apparent diffusion coefficient (ADC) were computed and spatially registered to three-dimensional radiation dose data. Volumes of interest included corticospinal tracts, medial lemnisci, and the pons. Serving as an age-related benchmark for comparison, 37 DTI studies from 20 healthy volunteers, aged 6 to 25 years, were included in the analysis. Results: The median DTI follow-up time was 3.5 years (range, 1.6–5.0 years). The median mean dose to the pons was 56 Gy (range, 7–59 Gy). Three patterns were seen in longitudinal FA and apparent diffusion coefficient changes: (1) a stable or normal developing time trend, (2) initial deviation from normal with subsequent recovery, and (3) progressive deviation without evidence of complete recovery. The maximal decline in FA often occurred 1.5 to 3.5 years after the start of radiation therapy. A full recovery time trend could be observed within 4 years. Patients with incomplete recovery often had a larger decline in FA within the first year. Radiation dose alone did not predict long-term recovery patterns. Conclusions: Variations existed among individual patients after therapy in longitudinal evolution of brainstem white matter injury and recovery. Early response in brainstem anisotropy may serve as an indicator of the recovery time trend over 5 years after radiation therapy. [ABSTRACT FROM AUTHOR]

Abstract: Background: Influenza vaccination is recommended for immunocompromised patients. Methods: Children (6 months to 21 years) with cancer, HIV infection, or sickle cell disease (SCD) received 1 or 2 doses of pandemic 2009 H1N1 monovalent influenza vaccine (H1N1 MIV). Safety and tolerability, hemagglutination inhibition (HI) and microneutralization (MN) antibody titers were measured against 2009 H1N1 influenza A virus after each dose. Seroprotection (SP) and seroconversion (SC) rates were determined. Results: 103 participants were enrolled and 99 were evaluable (39 with HIV, 37 with cancer and 23 with SCD). Mean age (±SD) was 7.9 (±5.4) years for cancer participants, 18.0 (±3.5) for HIV, and 13.3 (±4.2) for SCD. 54% were males; 65% black; and 96% had received seasonal influenza vaccine. HIV-infected participants had a median CD4 count of 625cells/mm3 (range, 140–1260). 46% had an undetectable HIV viral load and 41% were perinatally infected. No participant had vaccine-related serious adverse events. None developed influenza A proven illness during the 6 months after the vaccine. Local injection reactions were reported in 29% and systemic reactions in 42% after the first dose of vaccine. SC and SP were achieved after the last dose in 48% and 52%, respectively, of participants with leukemia or lymphoma, 50% and 75% of participants with solid tumors, 63% and 92% of HIV-infected participants, and 74% and 100% of participants with SCD. Conclusion: H1N1 MIV was safe and well tolerated. H1N1 MIV resulted in an adequate immune response in children with SCD. It was only modestly immunogenic in cancer or HIV participants. [Copyright &y& Elsevier]

Acute lung injury is a fatal condition characterized by excessive inflammation responses. Salidroside, the active constituent of Rhodiola rosea , possesses properties including anti-oxidation, anti-aging, anti-inflammatory, anti-hypoxia, and anti-cancer activities. In the present study, Salidroside attenuated acute lung injury via inhibition of inflammatory cytokine production. Rats pre-treated with Salidroside showed attenuated lipopolysaccharide (LPS)-induced pathological damage and suppressed tumor necrosis factor-alpha (TNFα) and interleukin 6 (IL-6) secretion in the lung. Furthermore, flow cytometry showed that Salidroside reduced the production of TNFα and IL-6 in NR8383 alveolar macrophages. These findings suggest that Salidroside may attenuate LPS-induced acute lung injury. • Sal attenuates LPS-induced pathological damage and decreases the W/D lung ratio. • Sal suppresses TNFα, IL-6, and GM-CSF secretion in the ALI model. • Sal inhibits TNFα, IL-6, and GM-CSF transcription in lung tissues in the ALI model. • Sal reduces TNFα and IL-6 production induced by LPS in NR8383 cells. [ABSTRACT FROM AUTHOR]

CART19-related toxicities may require treatment inpatient or in the ICU. We sought to describe inpatient/ICU resource utilization within 30 days of CART19 infusion and evaluate trends in resource utilization from 2012-2019. We identified patients (pts) with ALL treated with CART19 on a clinical trial (NCT01626495, NCT02906371, and NCT02374333) or with the commercial product, tisagenlecleucel, at Children's Hospital of Philadelphia. Demographic, pharmacy, and inpatient data were extracted from the EHR from day of infusion (d0) to d+30 using a semi-automated EPIC data query tool. The Virtual Pediatric Systems database was queried for resource utilization data and PRISM 3 and PIM 2 severity of illness scores. Log-binomial and linear regression were used to estimate the association of patient characteristics with inpatient/ICU admission and inpatient/ICU length of stay (LOS). Similar models were used to estimate trends over time. The analyses included 213 pts. Median age was 12y (range 1-29y); 60% were male. Prior to CART19, 42% had an alloHCT. Pre-infusion, 19% had high tumor burden (HTB), defined as bone marrow blasts ≥40%. From 2012-2019, the proportion of pts with prior alloHCT or HTB decreased (Table 1). CART19 was infused in the outpatient setting in 198 (93%) pts. From d0 to d+30, 149 (70%) had ≥1 inpatient admission, starting at a median of d+2 (IQR +1 to +6). Among admitted pts, median cumulative inpatient LOS was 7d (IQR 4-13). From 2012-2019, there were linear trends toward decreases in proportion of pts admitted (p <.001) and in inpatient LOS (p <.001, Figure 1). These decreases persisted after adjustment for HTB (p =0.03 and p <.001). ICU admission was required for 49 (23%) pts, starting at a median of day +5 (IQR +4 to +7). ICU admission was more frequent for pts with HTB [HTB, 68% (95% CI, 52-81) vs. low burden, 11% (95% CI, 7-17), p <.001]. Among ICU pts, resources utilized included tocilizumab (n=36, 75%), vasoactives (n=36, 75%), invasive mechanical ventilation (n=18, 8%), and dialysis (n=4, 8%). In the 30d follow-up period, median ICU LOS was 7d (IQR 3-12), but 6 (13%) pts remained in the ICU after d+30. Median duration of vasoactive, mechanical ventilation, and dialysis use was 5d, 7d and 2d, respectively. Predicted median risk of mortality was 6% (IQR 5-7) by PIM 2 and 11% (IQR 7-27) by PRISM 3 scores. However, observed 30d mortality was 1% (n=2) across the cohort, or 4% among ICU pts. From 2012-2019, there was a decrease in ICU admissions (p <.01), but no significant change in ICU LOS (Figure 1). Other than HTB, baseline characteristics were not associated with inpatient/ICU admission or LOS. In a cohort of 213 pediatric pts, over 90% were safely infused with CART19 in the outpatient setting. Though 70% required at least one admission, the proportion of pts admitted to the hospital or ICU and cumulative inpatient LOS decreased over the past 7 years. [ABSTRACT FROM AUTHOR]

Background CD19-targeted chimeric antigen receptor (CAR) T cell therapy has demonstrated remarkable clinical efficacy in treating relapsed/refractory B-cell acute lymphoblastic leukemia (ALL). However, there are potential treatment-related toxicities, which may be severe. Acute kidney injury (AKI) has been reported after CD19 CAR T cells, but not systematically evaluated. We sought to describe AKI incidence, severity, outcome, and risk factors in the first 30 days after CTL019, a CD19 CAR T cell therapy, for ALL in pediatric patients. Methods We studied patients treated with CTL019 through two clinical trials (NCT01626495 and NCT02906371) at Children's Hospital of Philadelphia between April 2012 and April 2018. Demographic, laboratory and pharmacy data were automatically extracted from the electronic medical record using an EPIC data query tool. The primary outcome was AKI within 30 days after CTL019 infusion. AKI was defined using the Kidney Disease: Improving Global Outcomes criteria. Stage 1 (serum creatinine (SCr) >= 1.5 times the baseline) was classified as mild AKI. Stage 2 or 3 (SCr >=2 times the baseline) were classified as severe AKI. Renal recovery was defined as improvement in SCr to within 1.5 times the baseline by day +30. Log-binomial regression was used to estimate risk ratios for the association of cytokine release syndrome (CRS) and other patient characteristics with the development of AKI. Results A total of 125 patients and 3231 creatinine values were analyzed. Median patient age was 11.2 (range: 1.4-29.1) years at CTL019 infusion; 57.6% were male, 72% were Caucasian, and 82.4% were non-Hispanic. AKI developed in 26 patients (21.0%; 95% CI, 14.5 to 28.9), severe AKI developed in 15 patients (12%; 95% CI 7.3 to 19.1), and 3 patients (2.4%; 95% CI 0.7 to 7.3) required renal-replacement therapy. Among patients who developed AKI, 22 (88%: 95% CI 66.7 to 96.4) recovered renal function by day +30. Patients with Grade 3/4 CRS had a 4.9 times greater risk of developing AKI (95% CI, 2.4 to 9.9; p<.001) and a 10.3 times greater risk of developing severe AKI (95% CI 3.1 to 34.3; p<.001) than patients with no or Grade 1/2 CRS (Figure 1). The median time to CRS start, AKI onset, and maximum SCr level was 2, 7 and 9 days after infusion, respectively. History of hematopoietic cell transplant prior to CTL019 was not significantly associated with AKI, nor were age, sex, race, and ethnicity. Conclusion In the first 30 days after CTL019 infusion, 21% of patients developed AKI, but most recovered renal function by day +30. AKI was strongly associated with Grades 3 and 4 CRS and developed at a median of 5 days after the start of CRS. Additional analyses will compare the trajectories of CRS biomarkers and tumor lysis labs with the trajectory of AKI in order to better elucidate mechanisms of renal injury and identify opportunities for intervention. [ABSTRACT FROM AUTHOR]