bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison between the Hamiltonian Monte Carlo method and the Metropolis–Hastings method for coseismic fault model estimation
Authors: Yamada Taisuke , Ohno Keitaro , Ohta Yusaku
Published: June 2022

A rapid source fault estimation and quantitative assessment of the uncertainty of the estimated model can elucidate the occurrence mechanism of earthquakes and inform disaster damage mitigation. The Bayesian statistical method that addresses the posterior distribution of unknowns using the Markov chain Monte Carlo (MCMC) method is significant for uncertainty assessment. The Metropolis–Hastings method, especially the Random walk Metropolis–Hastings (RWMH), has many applications, including coseismic fault estimation. However, RWMH exhibits a trade-off between the transition distance and the acceptance ratio of parameter transition candidates and requires a long mixing time, particularly in solving high-dimensional problems. This necessitates a more efficient Bayesian method. In this study, we developed a fault estimation algorithm using the Hamiltonian Monte Carlo (HMC) method, which is considered more efficient than the other MCMC method, but its applicability has not been sufficiently validated to estimate the coseismic fault for the first time. HMC can conduct sampling more intelligently with the gradient information of the posterior distribution. We applied our algorithm to the 2016 Kumamoto earthquake (MJMA 7.3), and its sampling converged in 2 × 104 samples, including 1 × 103 burn-in samples. The estimated models satisfactorily accounted for the input data; the variance reduction was approximately 88%, and the estimated fault parameters and event magnitude were consistent with those reported in previous studies. HMC could acquire similar results using only 2% of the RWMH chains. Moreover, the power spectral density (PSD) of each model parameter's Markov chain showed this method exhibited a low correlation with the subsequent sample and a long transition distance between samples. These results indicate HMC has advantages in terms of chain length than RWMH, expecting a more efficient estimation for a high-dimensional problem that requires a long mixing time or a problem using nonlinear Green’s function, which has a large computational cost.

Graphical Abstract
Efficiency of 124I radioisotope production from natural and enriched tellurium dioxide using 124Te(p,xn)124I reaction
Authors: Bzowski Paweł , Borys Damian , Gorczewski Kamil , Chmura Agnieszka , Daszewska Kinga , Gorczewska Izabela , Kastelik-Hryniewiecka Anna , Szydło Marcin , d’Amico Andrea , Sokół Maria
Published: June 2022

Background

124I Iodine (T$$_{1/2}$$

1
/
2

= 4.18 d) is the only long-life positron emitter radioisotope of iodine that may be used for both imaging and therapy as well as for 131I dosimetry. Its physical characteristics permits taking advantages of the higher Positron Emission Tomography (PET) image quality, whereas the availability of new molecules to be targeted with 124I makes it a novel innovative radiotracer probe for a specific molecular targeting.

Results

In this study Monte Carlo and SRIM/TRIM modelling was applied to predict the nuclear parameters of the 124I production process in a small medical cyclotron IBA 18/9 Cyclone. The simulation production yields for 124I and the polluting radioisotopes were  calculated for the natural and enriched 124TeO2  +  Al2O3  solid targets irradiated with 14.8 MeV protons. The proton beam was degraded energetically from 18 MeV with 0.2 mm Havar foil. The 124Te(p,xn)124I reactions were taken into account in the simulations. The optimal thickness of the target material was calculated using the SRIM/TRIM and Geant4 codes. The results of the simulations were compared with the experimental data obtained for the natural TeO2 +Al2O3 target. The dry distillation technique of the 124-iodine was applied.

Conclusions

The experimental efficiency for the natural Te target was better than 41% with an average thick target (>0.8 mm) yield of 1.32 MBq/μAh. Joining the Monte Carlo and experimental approaches makes it possible to optimize the methodology for the 124I production from the expensive Te enriched targets.
Susceptibility areas identification and risk assessment of debris flow using the Flow-R model: a case study of Basu County of Tibet
Authors: Xu Huange , Su Peng , Chen Qiong , Liu Fenggui , Zhou Qiang , Liu Linshan
Published: June 2022

Background

Uncertainties exist in the magnitude and outbreak of debris flow disasters, resulting in significant loss of lives and property to human society. Improved identification of debris flow susceptibility areas can help to predict the location and sphere of influence of debris flow disaster, thus accurately assessing the risk of debris flow disaster and reducing losses caused by such a disaster. The dry-hot valleys of Basu County in the Eastern Qinghai-Tibet Plateau are typical areas of high debris flow incidence, mapping of debris flow susceptibility identification and regional risk assessment is needed in this area.

Results

The parameters improved Flow-R model was first applied to identify debris flow susceptibility areas in Basu county using the digital elevation model, flow accumulation, slope, plan curvature, and land use data, followed by debris flow risk assessment. The Flow-R model can output high result accuracy of high-resolution susceptibility to debris flow identification on a regional scale with less data, and its accuracy value is 87.6%, indicating that the susceptibility to regional debris flow disaster is credible. This study provides a useful basis for effective prevention of regional debris flow disasters in the future, and provides a useful method for effectively identifying the debris flow susceptibility areas and assessing the related risk in large-scale areas.

Conclusions

(1) The debris flow susceptibility areas in Basu County covered 97.04 km2 (0.79% of the study area), distributed mainly in the Nujiang River Valley, Lengqu tributaries, and both sides of National Highway 318. (2) The debris flow susceptibility areas were dominant in zones characterized by an altitude range of 3000–4000 m, a plane curvature of − 2/100 m−1 to 1/100 m−1, and a low slope of 20°–40°. In addition, the susceptibility areas were dominant in the unused land and less prevalent in the water area. The highest and lowest susceptibility values were observed for cultivated and unused lands, respectively. (3) The debris flow risk in the study areas accounted for 0.82 km2 and revealed a distribution of high-risk debris flow along roads. The areas with a high debris flow risk were mainly distributed along the mainstream of the Nujiang River, which is the main future protected area.
A case in which the ileocolic vein draining into the gastrocolic trunk of Henle could be diagnosed preoperatively: a rare anatomical case report
Authors: Mizumoto Rie , Tei Mitsuyoshi , Mori Soichiro , Nishida Kentaro , Yasuyama Akinobu , Nomura Masatoshi , Yoshikawa Yukihiro , Sueda Toshinori , Matsumura Tae , Koga Chikato , Miyagaki Hiromichi , Tsujie Masanori , Akamaru Yusuke
Published: June 2022

Background

Numerous variations in vascular anatomy have been reported in the right colon. The ileocolic vein (ICV) generally drains directly into the superior mesenteric vein (SMV), and is an important landmark for laparoscopic surgery in right colon cancer. We present here a patient with a vascular anomaly of the ICV that was diagnosed on preoperative imaging.

Case presentation

A 65-year-old woman was diagnosed with transverse colon cancer by colonoscopy. Preoperative computed tomography scan showed that the ICV drained into the gastrocolic trunk of Henle (GCT) rather than the SMV. Single-incision laparoscopic transverse colectomy with D3 lymph node dissection was performed, dividing the middle colic vein (MCV) and preserving the right gastroepiploic vein (RGEV), anterior superior pancreaticoduodenal vein (ASPDV), GCT and ICV. The intraoperatively identified venous anatomy was consistent with the preoperative evaluation, and the RGEV, ASPDV and ICV were found to form the GCT.

Conclusion

We report a rare vascular anatomical anomaly that was diagnosed preoperatively, facilitating safe and successful single-incision laparoscopic surgery with D3 lymph node dissection.
DeepPricing: pricing convertible bonds based on financial time-series generative adversarial networks
Authors: Tan Xiaoyu , Zhang Zili , Zhao Xuejun , Wang Shuyi
Published: June 2022

Convertible bonds are an important segment of the corporate bond market, however, as hybrid instruments, convertible bonds are difficult to value because they depend on variables related to the underlying stock, the fixed-income part, and the interaction between these components. Besides, embedded options, such as conversion, call, and put provisions are often restricted to certain periods, may vary over time, and are subject to additional path-dependent features of the state variables. Moreover, the most challenging problem in convertible bond valuation is the underlying stock return process modeling as it retains various complex statistical properties. In this paper, we propose DeepPricing, a novel data-driven convertible bonds pricing model, which is inspired by the recent success of generative adversarial networks (GAN), to address the above challenges. The method introduces a new financial time-series generative adversarial networks (FinGAN), which is able to reproduce risk-neutral stock return process that retains the unique statistical properties such as the fat-tailed distributions, the long-range dependence, and the asymmetry structure etc., and then transit to its risk-neutral distribution. Thus it is more flexible and accurate to capture the dynamics of the underlying stock return process and keep the rich set of real-world convertible bond specifications compared with previous model-driven models. The experiments on the Chinese convertible bond market demonstrate the effectiveness of DeepPricing model. Compared with the convertible bond market prices, our model has a better convertible bonds pricing performance than both model-driven models, i.e. Black-Scholes, the constant elasticity of variance, GARCH, and the state-of-the-art GAN-based models, i.e. FinGAN-MLP, FinGAN-LSTM. Moreover, our model has a better fitting capacity for higher-volatility convertible bonds and the overall convertible bond market implied volatility smirk, especially for equity-liked convertible bonds, convertible bonds trading in the bull market, and out-of-the-money convertible bonds. Furthermore, the Long-Short and Long-Only investment strategies based on our model earn a significant annualized return with 41.16% and 31.06%, respectively, for the equally-weighted portfolio during the sample period.
HLA-A*03, the hemochromatosis ancestral haplotype, and phenotypes of referred hemochromatosis probands with HFE p.C282Y homozygosity
Authors: Barton James C. , Barton J. Clayborn , Acton Ronald T.
Published: June 2022

Background

Human leukocyte antigen (HLA)-A*03, hemochromatosis ancestral haplotype marker, was associated with greater iron overload in hemochromatosis cohorts reported before discovery of theHFEgene. We sought to learn whether an A*03-linked locus influences phenotypes in referredHFEp.C282Y homozygotes.

Methods

We tabulated these phenotypes in probands with p.C282Y homozygosity: age, transferrin saturation (TS), serum ferritin (SF), conditions related to iron overload, fibrosis-four variables (FIB-4) index and aspartate aminotransferase-to-platelet ratio index (APRI) predictors of severe hepatic fibrosis, and iron removed to achieve depletion (QFe/age). We analyzed phenotypes of men and women separately across three A*03 subgroups.

Results

There were 104 men (57.8%) and 76 women (42.2%). Mean age (SD) was 49 ± 13 y. Mean TS was 79 ± 17%. Median SF (range) was 715 µg/L (28, 6103). Related conditions included: hemochromatosis arthropathy (21.7%); type 2 diabetes (18.9%); hypogonadotropic hypogonadism (5.8% of men); cardiomyopathy (0%); and cirrhosis (10.0%). Median QFe/age was 61 mg/y (0, 714). A*03 homozygosity, heterozygosity, and no A*03 occurred in 37 (20.6%), 104 (57.8%), and 39 probands (21.7%), respectively. In men, mean TS and median SF were significantly higher in A*03 homozygotes than heterozygotes but not A*03-negative probands. In men, median APRI was significantly lower in A*03 heterozygotes than homozygotes and A*03-negative probands. No other phenotypes, including QFe/age, differed significantly across A*03 subgroups in either men or women.

Conclusions

Our results suggest that an A*03-linked locus does not influence phenotypes in referredHFEp.C282Y homozygotes. It is unlikely that heritable factors that modify phenotypes of p.C282Y homozygotes are linked to the hemochromatosis ancestral haplotype.
Exploring the relationships between composite scores of disease severity, seizure-freedom and quality of life in Dravet syndrome
Authors: Strzelczyk Adam , Kurlemann Gerhard , Bast Thomas , Bettendorf Ulrich , Kluger Gerhard , Mayer Thomas , Neubauer Bernd A. , Polster Tilman , von Spiczak Sarah , Trollmann Regina , Wolff Markus , Toward Toby , Gruenert Jens , Gibson Eddie , Pritchard Clive , Carroll Joe , Rosenow Felix , Schubert-Bast Susanne
Published: June 2022

Background

In Dravet syndrome (DS), a rare epileptic and developmental encephalopathy, the effectiveness of a new treatment is predominantly measured in terms of seizure frequency. However, this may not fully capture the impact of a treatment on the broader aspects of the syndrome and patients’ health-related quality of life (HRQoL). Using a previously published survey which collected data from DS patients and their carers on the broader manifestations of their syndrome, their HRQoL, and their experience of seizures, this study created composite measures of symptom severity to offer new perspectives on the multifaceted aspects of this rare condition.

Methods

Survey responses on the severity of physical and psychosocial symptoms were combined with independent assessments of disability and care need, to generate three composite symptom scores assessing the manifestations of DS (physical, psychosocial and care requirements). Variation in HRQoL was investigated in multiple regression analyses to assess the strength of association between each of these composite measures and three forms of seizure measures (seizure frequency, days with no seizures and longest interval without seizures), as experienced over a 4- and 12-week period.

Results

Composite scores were calculated for a cohort of 75 primarily paediatric patients who were enrolled in the study. Strong associations were found between each of the three composite symptom scores and each of the three seizure measures, with the regression coefficient on symptom score highly significant (p ≤ 0.001) in all nine comparisons. Separate regressions using predictors of HRQoL (Kiddy KINDL and Kid KINDL) as the dependent variable were inconclusive, identifying only behavioural/attention problems and status epilepticus as significant predictors of HRQoL.

Conclusions

These results allow the development of a composite score that may be useful in developing a clinical understanding of the severity of DS for an individual patient and establishing their treatment goals. Where measurement of long-term sequalae of disease is not feasible, such as clinical trials, correlation of the composite score with experience of seizures and seizure-free periods may allow a better contextualisation of the results of short-term assessments.

Trial registration

German Clinical Trials Register (DRKS), DRKS00011894. Registered 16 March 2017, http://www.drks.de/ DRKS00011894.
Reducing PAPR of OFDM signals using a tone reservation method based on $$\ell_{\infty }$$-norm minimization
Authors: Kiambi Stephen , Mwangi Elijah , Kamucha George
Published: June 2022

Orthogonal frequency division multiplexing (OFDM) continues to be the most preferred signal-multiplexing scheme for high-speed data communication. However, OFDM signals are known to have the problem of high peak-to-average power ratio (PAPR), especially when the number of subcarriers is large, which leads to nonlinear amplification in the high power amplifier and consequently to bit-error rate degradation and out-of-band radiation. In this paper, we propose a new optimal tone reservation method for reducing high PAPR in OFDM signals in order to avoid nonlinear amplification effects. The method employs Chebyshev-norm minimization to determine peak-reduction coefficients for OFDM signal. Simulation results show that the proposed method can achieve high PAPR reduction at the expense of a small loss in data rate and a slight increase in average transmit power. For example, with 4 out of 64 subcarriers reserved for peak-reduction coefficients, which represents 6.25% data-rate loss, the method can achieve 4.06 dB of PAPR reduction with only a 0.46 dB increase in average transmit power. Similarly, when 8 subcarriers or 12.5% of the total number of subcarriers are reserved, a PAPR reduction of 5.75 dB is achieved with a paltry 0.19 dB rise in transmit power.
Trash Taxonomy Tool: harmonizing classification systems used to describe trash in environments
Authors: Hapich Hannah , Cowger Win , Gray Andrew , Tangri Neil , Hale Tony , Magdy Amr , Vermilye Antoinette , Yu Walter , Ayres Dick , Moore Charles , Vermilye John , Singh Samiksha , Haiman Aaron N. K. , Youngblood Kathryn , Kang Yunfan , McCauley Margaret , Lok Trevor , Moore Shelly , Baggs Eric , Lippiatt Sherry , Kohler Peter , Conley Gary , Taing Janna , Mock Jeremiah
Published: June 2022

Despite global efforts to monitor, mitigate against, and prevent trash (mismanaged solid waste) pollution, no harmonized trash typology system has been widely adopted worldwide. This impedes the merging of datasets and comparative analyses. We addressed this problem by 1) assessing the state of trash typology and comparability, 2) developing a standardized and harmonized framework of relational tables and tools, and 3) informing practitioners about challenges and potential solutions. We analyzed 68 trash survey lists to assess similarities and differences in classification. We created comprehensive harmonized hierarchical tables and alias tables for item and material classes. On average, the 68 survey lists had 20.8% of item classes in common and 29.9% of material classes in common. Multiple correspondence analysis showed that the 68 surveys were not significantly different regarding organization type, ecosystem focus, or substrate focus. We built the Trash Taxonomy Tool (TTT) web-based application with query features and open access at openanalysis.org/trashtaxonomy. The TTT can be applied to improve, create, and compare trash surveys, and provides practitioners with tools to integrate datasets and maximize comparability. The use of TTT will ultimately facilitate improvements in assessing trends across space and time, identifying targets for mitigation, evaluating the effectiveness of prevention measures, informing policymaking, and holding producers responsible.
Anesthetic management of carotid endarterectomy: an update from Italian guidelines
Authors: Bevilacqua Sergio , Ticozzelli Giulia , Orso Massimiliano , Alba Giuseppe , Capoccia Laura , Cappelli Alessandro , Cernetti Carlo , Diomedi Marina , Dorigo Walter , Faggioli Gianluca , Giannace Giovanni , Giannandrea David , Giannetta Matteo , Lessiani Gianfranco , Marone Enrico Maria , Mazzaccaro Daniela , Migliacci Rino , Nano Giovanni , Pagliariccio Gabriele , Petruzzellis Marco , Plutino Andrea , Pomatto Sara , Pulli Raffaele , Sirignano Pasqualino , Vacirca Andrea , Visco Emanuele , Moghadam Shadeh Parsapour , Lanza Gaetano , Lanza Jessica
Published: June 2022

Background and aims

In order to systematically review the latest evidence on anesthesia, intraoperative neurologic monitoring, postoperative heparin reversal, and postoperative blood pressure management for carotid endarterectomy. The present review is based on a single chapter of the Italian Health Institute Guidelines for diagnosis and treatment of extracranial carotid stenosis and stroke prevention.

Methods and results

A systematic article review focused on the previously cited topics published between January 2016 and October 2020 has been performed; we looked for both primary and secondary studies in the extensive archive of Medline/PubMed and Cochrane library databases.

We selected 14 systematic reviews and meta-analyses, 13 randomized controlled trials, 8 observational studies, and 1 narrative review. Based on this analysis, syntheses of the available evidence were shared and recommendations were indicated complying with the GRADE-SIGN version methodology.

Conclusions

From this up-to-date analysis, it has emerged that any type of anesthesia and neurological monitoring method is related to a better outcome after carotid endarterectomy. In addition, insufficient evidence was found to justify reversal or no-reversal of heparin at the end of surgery. Furthermore, despite a low evidence level, a suggestion for blood pressure monitoring in the postoperative period was formulated.
A systematic review and mixed-methods synthesis of the experiences, perceptions and attitudes of prison staff regarding adult prisoners who self-harm
Authors: Hewson Thomas , Gutridge Kerry , Bernard Zara , Kay Kathryn , Robinson Louise
Published: June 2022

Background

Self-harm, including suicide, is common among prisoners. Staff attitudes and perceptions regarding self-harm may affect quality of care and patient safety.

Aims

To systematically review the experiences, perceptions and attitudes of staff in adult prisons regarding self-harm.

Method

Systematic searches of EMBASE, Medline, PsycINFO and CINAHL databases were conducted, and supplemented by hand-searching and grey literature review, to identify relevant English-language articles published since the year 2000. Articles were screened by two authors and evaluated with standardised quality appraisal tools. Qualitative data were analysed thematically, whereas quantitative data were narratively synthesised because of high study heterogeneity.

Results

Two thousand articles were identified, of which 32 were included, involving 6389 participants from five countries. Most studies were moderate (n = 15) or poor (n = 10) quality, and seven were rated as good quality. Staff frequently witnessed self-harm and described multiple perceived risk factors and causes of this. Perceptions that self-harm is ‘manipulative’ or ‘attention-seeking’ were associated with hostility toward prisoners and lower quality of care. Perceived barriers to preventing and managing self-harm included low staffing levels, prison environments and culture, poor staff confidence and insufficient training. The importance of multidisciplinary teamwork and building staff–prisoner relationships were highlighted. Staff occasionally experienced intense psychological reactions to self-harm, which resulted in adaptive or maladaptive coping that influenced their capacity to care.

Conclusions

There are mixed attitudes and perceptions toward self-harm among prison staff. Further training, support and resources are required to protect staff's well-being and improve self-harm prevention and management in prisons.
Racial, ethnic, and socioeconomic survival disparities among children with high-risk neuroblastoma treated on upfront Children’s Oncology Group clinical trials.
Authors: Umaretiya Puja J , Naranjo Arlene , Zhang Fan , Park Julie R. , Weiss Brian D. , Granger Meaghan , DuBois Steven G. , Bagatell Rochelle , Bona Kira
Published: June 2022

10005

Background: Racial and socioeconomic disparities have not been comprehensively investigated in high-risk neuroblastoma (HR NBL). Prior Children’s Oncology Group (COG) investigations have demonstrated population-based disparities in late relapse rates among Black children, and trial-based disparities in relapse and survival among children living in poverty receiving post-consolidation immunotherapy. It is unknown whether these disparities persist in upfront trials for newly diagnosed patients. We leveraged COG data to investigate race, ethnicity, and socioeconomic disparities in a cohort of children with HR NBL treated on upfront clinical trials from 2007-2016. Methods: Retrospective cohort study of children enrolled on upfront COG HR NBL trials ANBL0532, ANBL09P1, and ANBL12P1. Race and ethnicity were the primary exposures categorized as: Black Non-Hispanic (BNH); Hispanic; Other Non-Hispanic (ONH); or White Non-Hispanic (WNH). Poverty was the secondary exposure, defined as household (public insurance only vs others), area (census-defined high-poverty ZIP code with >20% of population living below 100% Federal Poverty Level (FPL) vs <20% below 100% FPL), and rural (Census-defined rurality measures linked to ZIP code). Overall (OS) and event-free (EFS) survival from time of trial enrollment were plotted by Kaplan-Meier methods; associations with race/ethnicity and poverty were evaluated by log-rank tests. Results: Among 696 children, 16% were BNH, 11% Hispanic, 4% ONH, and 69% WNH. One-third (33%) of children were household poverty-exposed, 26% area poverty-exposed, and 15% rural-exposed. Tumor stage and biology did not differ by race/ethnicity or poverty measures. Five-year OS differed significantly by race/ethnicity (47% Hispanic vs. 50% ONH vs. 61% WNH vs. 62% BNH; p=0.047). Five-year OS was inferior among children exposed to household-poverty (53% vs. 63%; p=0.036) and neighborhood-poverty (54% vs. 62%; p=0.050) compared to unexposed children. There was no difference in OS by rurality. Similar directionality in 5-year EFS outcomes by race/ethnicity and poverty were observed without statistical significance. Conclusions: Race/ethnicity and poverty-exposure are associated with inferior OS outcomes among children with HR NBL despite uniform planned treatment on upfront COG trials. Investigation of mechanisms driving these disparities, including disparate early phase trial enrollment are ongoing to inform targeted health equity interventions to improve outcomes.
Securing access to innovative anticancer therapies for children, adolescents, and young adults outside clinical trials: The SACHA study of the French Society of Pediatric Oncology (SFCE).
Authors: Berlanga Pablo , Ndounga-Diakou Lee Aymar , Corradini Nadege , Ducassou Stephane , Strullu Marion , De Carli Emilie , Andre Nicolas , Entz-Werle Natacha , Defachelles Anne Sophie , Roumy Marianne , Valteau-Couanet Dominique , Gandemer Virginie , Laghouati Salim , Vassal Gilles
Published: June 2022

10006

Background: Access to innovative anticancer therapies for children, adolescents and young adults within clinical trials in France is steadily increasing in the last years. However, current clinical trials portfolios are still inadequate and thus pediatric hemato-oncologists regularly prescribe innovative medicines outside their marketing authorization, and/or experimental drugs through compassionate use. Methods: The Secured Access to innovative medicines for CHildren with cAncer (SACHA) is a French prospective observational study developed by the French Society of Pediatric Oncology (SFCE) with Gustave Roussy as the legal sponsor to prospectively collect real-world safety and activity data of innovative therapies administered to patients ≤ 25 years-old with pediatric malignancies (solid tumor or leukemia) or other related conditions, either on compassionate use of experimental drugs or off-label use of anti-cancer medicines that have been first approved in adults after 2007. Prior to SACHA inclusion, multicenter tumor board discussion defining best available therapeutic options for each patient with a relapsed malignancy is mandatory. Results: The SACHA study opened in March 2020 and by February 2022, 283 patients have been included from 29/31 SFCE recruiting centers; median age: 11.0 years (range: 0.3-24.4). Main cancer types were central nervous system (CNS) tumors (47%), followed by non-CNS tumors (40%) and leukemias (13%). Innovative therapies prescribed in > 10 patients with reported objective response rate (ORR) and related CTCAE v.5 grade ≥2 clinical and/or grade ≥3 biological adverse drug reactions (ADRs) are described in Table. Conclusions: SACHA confirms the feasibility of this type of prospective real word registry, with a high participation of French centers. Based on this French experience, the Innovative Therapies for Children with Cancer (ITCC) consortium is currently developing a “SACHA International Project” to be opened in ITCC and collaborating countries. [Table: see text]
STRIVE-02: A first-in-human phase 1 trial of systemic B7H3 CAR T cells for children and young adults with relapsed/refractory solid tumors.
Authors: Pinto Navin R. , Albert Catherine Michelle , Taylor Mallory , Wilson Ashley , Rawlings-Rhea Stephanie , Huang Wenjun , Seidel Kristy , Narayanaswany Prabha , Wu Vicky , Brown Christopher , Vitanza Nicholas A. , Orentas Rimas , Gardner Rebecca Alice , Jensen Michael C. , Park Julie R.
Published: June 2022

10011

Background: B7H3 (CD276) has limited expression in normal tissues and high cell-surface expression in pediatric solid malignancies providing rationale for immunologic therapeutic targeting. We present a first-in-human experience of B7H3 chimeric antigen receptor T cells (CAR-T) for children and young adults (CYA) with relapsed or refractory solid tumors (R/RST). Methods: CYA patients with R/RST were enrolled onto a Phase 1 trial (NCT04483778) to examine the safety of autologous T cells genetically modified to express scFV-IgG4hinge-CD28tm-4-1BB-zeta B7H3-specific CAR with the methotrexate resistance/selection cassette DHFRdm and the tracking/suicide construct EGFRt. All patients received lymphodepleting fludarabine and cyclophosphamide prior to infusion of cryopreserved CAR-T at the prescribed dose level. The maximal tolerated dose or biologically effective dose (BED) was determined based upon observed toxicity through day 28 from initial CAR-T infusion and using a 3+3 statistical design. Results: Sixteen subjects (age 11-24, median 17 years) enrolled and received dose level (DL) 1 (0.5 x 106 CAR-T/kg, n = 3) or DL2 (1 x 106 CAR-T cells/kg, n = 6). No dose limiting toxicity was observed following first infusion, most common toxicities were fatigue and cytokine release syndrome (CRS) (n = 2, maximum CTCAE grade 2). Maximum circulating CAR-T expansion on first infusion was 4.98 cells/uL (range 0.23-4.98 cells/uL) with median persistence of 28 days (range 14-90). Best overall response of Stable Disease was observed in 3 of the 9 subjects infused. Given observed expansion and persistence, DL2 was determined to be the BED. A second infusion at DL2 in one subject demonstrated CAR T expansion to 1590 cells/uL (86% of circulating CD3 cells) with CTCAE grade 2 CRS and transient dose limiting CTCAE grade 4 liver enzyme elevation. A partial metabolic response on FDG-PET by PERCIST criteria was observed in this subject at Day 28. Conclusions: B7H3 CAR T cells are safe and demonstrate anti-tumor activity in CYA with R/RST. CAR-T cell expansion and persistence may be necessary to achieve objective responses. STRIvE-02 Arm B will explore dual expression of CD19 CAR with B7H3 CAR, using lymphocytic CD19 expression to drive CAR expansion and persistence. Clinical trial information: NCT04483778.
Modulation of radiation biomarkers in a randomized phase II study of 131I-MIBG with or without radiation sensitizers for relapsed or refractory neuroblastoma: A report from the NANT Consortium.
Authors: Campbell Kevin M. , Groshen Susan G. , Marachelian Araz , Armant Myriam , Pal Sharmistha , Haas-Kogan Daphne A. , Evans Angela Clare , Coleman Matthew A. , Park Julie R. , Granger Meaghan , Matthay Katherine K. , DuBois Steven G.
Published: June 2022

10026

Background: 131I-metaiodobenzylguanidine (131I-MIBG) has demonstrated efficacy as a single agent for patients with neuroblastoma. Recent trials have focused on 131I-MIBG combination strategies, though little is known about the impact of combination agents on markers of radiation exposure. Methods: NANT11-01 (NCT02035137) was a multicenter, open label, randomized phase II clinical trial that evaluated 131I-MIBG therapy alone (Arm A) or in combination with vincristine/irinotecan (Arm B) or vorinostat (Arm C) for patients with resistant/relapsed neuroblastoma. We collected blood samples at baseline, 72 hours, 96 hours, and 15 days after 131I-MIBG infusion and determined levels of plasma FLT3 ligand, serum amylase, and gene expression for selected RNA transcripts (apoptosis, DNA damage response and cell cycle related). We evaluated marker association with treatment arm, clinical response using NANT response criteria, toxicity, and whole-body radiation dose. Results: The cohort included 99 patients who had at least one biomarker available for analysis (32 Arm A; 35 Arm B; 32 Arm C). We observed both positive and negative significant modulation in most biomarkers between baseline, 72 hours, and 96 hours following 131I-MIBG. Patients in Arm C had the lowest degree of modulation in FLT3 ligand. Elevated baseline levels of FLT3 ligand were significantly associated with improved Curie response but not overall response. Lower baseline BCL2 levels were associated with higher overall and Curie response. Patients with increased FLT3 ligand at 96 hours after 131I-MIBG therapy were significantly more likely to have grade 4 thrombocytopenia.Peripheral blood gene expression of the BCL2 family of apoptotic markers (BCL2/L1 and BAX) was significantly associated with grade 4 hematological toxicity. Whole-body radiation dose and PRKDC fold change at 72 hours were significantly correlated. No other individual biomarkers were correlated with whole body radiation dose at 72 or 96 hours post 131I-MIBG. Conclusions: Peripheral blood biomarkers relevant to radiation exposure demonstrate significant modulation over time after 131I-MIBG treatment. Biomarkers related to hematopoietic damage and apoptosis were associated with hematological toxicity. Patients treated with vorinostat and 31I-MIBG had differential modulation of FLT3-ligand Further use of these biomarkers may improve our ability to care for patients treated with 131I-MIBG.
Impact of diagnostic and end-of-induction Curie scores in tandem autologous hematopoietic cell transplant for patients with high-risk neuroblastoma: A report from the Children’s Oncology Group.
Authors: Streby Keri A. , Parisi Marguerite T. , Shulkin Barry L. , LaBarre Brian , Bagatell Rochelle , Diller Lisa , Grupp Stephan A. , Matthay Katherine K. , Voss Stephan D. , Yu Alice L. , London Wendy B. , Park Julie R. , Yanik Gregory A. , Naranjo Arlene
Published: June 2022

10027

Background: Diagnostic mIBG (meta-iodobenzylguanidine) scans are an integral component of response assessment in children with high-risk neuroblastoma. The role of end of induction (EOI) Curie Scores (CS) has been previously described in patients undergoing a single autologous hematopoietic cell transplant (AHCT) as consolidation therapy. We now examine the prognostic significance of CS in patients randomized to tandem or single AHCT on the Children’s Oncology Group (COG) trial ANBL0532. Methods: A retrospective analysis of mIBG scans obtained from patients enrolled in COG ANBL0532 (n = 652) was performed. Evaluable patients (n = 179) had mIBG-avid, International Neuroblastoma Staging System (INSS) stage 4 disease, did not progress during induction therapy, consented to consolidation randomization, and received either a single (n = 99) or tandem AHCT (n = 80). In addition, evaluable patients had paired mIBG scans at time of initial diagnosis and EOI. Optimal CS cut points maximized the outcome difference (≤ vs > CS cut-off) according to the Youden index. Log-rank tests compared EFS subgroups, with p < 0.05 considered statistically significant. 3-year EFS is presented ± standard error. EFS was estimated for relative reductions in CS of 50% and 75% from diagnosis to EOI. Results: For recipients of tandem AHCT, the optimal cut point at diagnosis was CS = 12, with superior EFS from study enrollment for patients with CS<12 (74.2±7.9%; n = 31) vs CS > 12 (59.2±7.1%; n = 49) (p = 0.002). At EOI, the optimal cut point was CS = 0, with superior EFS from EOI for patients with CS = 0 (72.9±6.4%; n = 48) vs CS > 0 (46.5±9.1%; n = 32) (p = 0.002). The cut point at diagnosis for recipients of single AHCT was CS = 21 (p = 0.04), while the EOI CS had an optimal cut point of 2, but without a significant difference in EFS (p = 0.29). Absolute CS at diagnosis and at EOI had a greater impact on outcome than the relative reduction in CS between diagnosis and EOI, for both single and tandem AHCT. Conclusions: In the setting of tandem transplantation for children with high-risk neuroblastoma, Curie scores at diagnosis and end-induction may identify a more favorable patient group. Patients treated with tandem AHCT who exhibited a CS<12 at diagnosis or CS = 0 at EOI had superior EFS compared to those with CS above these cut points. Similar to prior reports, a CS<2 was the optimal cut point for single transplant recipients. Clinical trial information: NCT00567567.
Phase II trial of gemcitabine and nab-paclitaxel for recurrent osteosarcoma: A report from the National Pediatric Cancer Foundation.
Authors: Wagner Lars M. , Mascarenhas Leo , Isakoff Michael , Setty Bhuvana , Lagmay Joanne P. , Caywood Emi , Sandler Eric Stuart , Pratilas Christine A. , Borinstein Scott C. , Trucco Matteo M. , Fridley Brooke , Reed Damon R. , Oesterheld Javier E.
Published: June 2022

10042

Background: The combination of gemcitabine and docetaxel is often used to treat patients with recurrent osteosarcoma. A retrospective study of 35 such patients has reported an objective response rate of 17% and 4-month progression-free survival (PFS) of 56% with this combination (BMC Cancer 2016;16:280). Nab-paclitaxel is a nanoparticle taxane that has activity against osteosarcoma xenografts and may have less myelosuppression than docetaxel. The combination of gemcitabine and nab-paclitaxel is now frontline therapy for pancreatic cancer. We conducted a prospective multi-institutional phase II trial of this drug combination for patients with recurrent osteosarcoma. Methods: Patients with relapsed/refractory osteosarcoma with measurable disease and age ≥ 12 years and adequate organ function were included. A Simon’s two-stage design was used to identify a 4-month progression-free survival (PFS) of > 35%. Patients received nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2 weekly x 3 in 4-week cycles. Results: Eighteen patients with a median age 16 years (range 12- 26) received a total of 56 total cycles.(median 2, range 1 - 12). The median number of prior treatment regimens was 3 (range 1-7). Two patients (11%) experienced a partial response, and 6 (33%) received more than 2 cycles. The 4-month PFS was 30% (95% CI 14-62 %). Six patients required dose reductions for neutropenia (n = 4), pleural effusion (1), or neuropathy (1). Two patients were removed from study secondary to neutropenia despite dose reduction and myeloid growth factor support, and one patient came off study due to severe peripheral edema. Conclusions: In this prospective study, the combination of gemcitabine and nab-paclitaxel administered on this schedule showed only limited activity for patients with heavily pretreated recurrent osteosarcoma. Toxicity led to dose modifications in 33% and discontinuation in 17% of patients. When compared to a historical retrospective study, the substitution of nab-paclitaxel for docetaxel did not appear to increase activity or decrease toxicity for this patient population. Clinical trial information: NCT02945800.
The relationship between chronic health conditions and employment transitions among survivors of childhood cancer: A report from the Childhood Cancer Survivor Study (CCSS).
Authors: Bhatt Neel S. , Goodman Pamela J. , Leisenring Wendy M. , Armstrong Gregory T. , Chow Eric Jessen , Hudson Melissa M. , Krull Kevin R. , Nathan Paul C. , Oeffinger Kevin C. , Robison Leslie L. , Kirchhoff Anne C. , Mulrooney Daniel A.
Published: June 2022

10051

Background: Chronic health conditions are prevalent among adult survivors of childhood cancer. The impact of health on maintaining full-time (FT) employment, a common indicator of socioeconomic independence, has not been studied in this population. Methods: Self-reported employment status (FT, part-time [PT], unemployed [any reason], not in labor force) was assessed at two timepoints (2002-04 [T1] and 2015-16 [T2]) in adult (≥25y old) survivors of childhood cancer diagnosed between 1970-86. Sex-stratified Poisson regression, adjusted for race and ages at diagnosis and T2, was used to study associations between timing and severity of chronic health conditions (graded per the CTCAE v4.03) and transitions from FT to PT or unemployed. Results: Survivors employed FT at T1 (males=1712, median age [min-max]: 34y [25-53]; females=1337, 33y [25-53]) who reported employment status at T2 were included. At T2 (median time from T1 11.5y [9.4-13.8]), 83% males and 70% females remained employed FT, but 4% and 10% transitioned to PT, and 11% and 12% to unemployed (additional 2% and 8% left the labor force), respectively. Male and female survivors with grade 2 or 3-4 neurologic conditions acquired before T1 or between T1-T2 were at a higher risk of moving from FT to PT or unemployed compared to those with grade 0-1 conditions. Males and females with grade 3-4 respiratory conditions prior to T1 and cardiac and musculoskeletal conditions acquired between T1-T2 were also at higher risk for moving to PT or unemployed (Table). Additional predictors for males included grade 2 vision (before T1 RR 2.3, 95% CI 1.5-3.3; between T1-T2 RR 1.7, 95% CI 1.1-2.7) and endocrine (before T1 RR 1.4, 95% CI 1.1-1.9; between T1-T2 RR 1.7, 95% CI 1.3-2.3) conditions. Conclusions: A substantial portion of adult survivors of childhood cancer with health conditions of varying severity leave FT employment. Increased awareness of all stakeholders may facilitate access to clinical counseling and occupational provisions for flexible and supportive work accommodations to reduce work-related barriers for childhood cancer survivors. [Table: see text]
Long-term medical and functional outcomes of medulloblastoma survivors: A population-based, matched cohort study.
Authors: Coltin Hallie , Pequeno Priscila , Liu Ning , Tsang Derek S. , Taylor Michael D. , Bouffet Eric , Nathan Paul C. , Ramaswamy Vijay
Published: June 2022

10053

Background: Most medulloblastoma survivors suffer from late treatment-related sequelae. There are no population-based studies examining such late effects in a dedicated cohort of medulloblastoma survivors. Methods: Using a provincial pediatric cancer registry, all 5+ year medulloblastoma survivors diagnosed between 1987-2015 at <18 years of age in Ontario, Canada were identified and matched to cancer-free population controls based on age, sex, and geographical location. Cases were followed from the index date (five years from latest of diagnosis, or relapse/subsequent malignancy prior to age 18 years) until December 31, 2020 or censorship (death, or relapse/new cancer after age 18 years). Clinical data were linked to administrative health databases to estimate the cumulative incidences and cause-specific hazard ratios (HR) of mortality, hospitalizations, strokes, hearing loss requiring a hearing aid, and receipt of homecare services between cohorts, accounting for matching and competing risks. We evaluated demographic, disease, and treatment predictors of mortality using Cox proportional hazards models. Results: Of 389 medulloblastoma diagnoses in the study period, 159 (40.9%) were excluded, most commonly due to early death prior to the index date. Two hundred thirty cases were matched to 1150 controls (Table). Ten-year survival probability after index was 92.4% in cases and 99.4% in controls (HR 21.5, 95% CI 9.8-54.0). Cases were at higher risk for hospitalizations (HR 3.4, 95% CI 2.7-4.3), stroke (HR 45.6, 95% CI 12.8-289.8), hearing loss (HR 96.3, 95% CI 39.7-317.3), and requiring homecare services (HR 7.9, 95% CI 5.8-10.9). By 10 years after index, 4.8% (95% CI 2.2-9.0) of survivors had experienced a stroke compared to 0.1% (95% CI 0.01-0.7) of controls. None of the candidate predictors were significantly associated with mortality on univariate analyses. Conclusions: Survivors of childhood medulloblastoma experienced an increased risk of mortality and serious morbidity compared to population controls. Consideration for mitigation strategies or early interventions for preventing neurovascular sequelae and hearing loss is warranted, as is dedicated supports for survivors. [Table: see text]
The impact of clinical trial enrollment on specialty palliative care utilization in pediatric patients with high-grade gliomas.
Authors: Roberts Holly , Franson Andrea Flynn
Published: June 2022

10057

Background: In pediatric oncology patients, palliative care has been shown to provide numerous benefits, including less intense clinical care in the last month of life, improved symptom management, and dedicated family communication. Pediatric patients with high grade glioma (HGG) represent a patient population particularly well suited for early involvement of palliative care given their high symptom burden and relatively poor prognosis. However, a recent study revealed that pediatric patients with primary malignant central nervous system (CNS) tumors missed multiple opportunities for appropriate palliative care involvement throughout their disease courses. We hypothesize that clinical trial enrollment may lead to a lack of or delay in involvement of palliative care in children and young adults with HGG. Methods: We identified a cohort of 43 deceased pediatric patients with HGG who received care at our institution. IRB exemption was obtained. For each patient, the electronic medical record was reviewed to collect patient demographics, cancer diagnoses and outcomes, clinical trial enrollment, non-clinical trial treatments, and palliative care involvement. Statistical analysis was performed comparing patients enrolled in trials to those not enrolled, employing Fisher’s exact tests for categorical data and t tests for numerical data. Results: Overall, 72% (31/43) of patients had at least one visit with a specialty palliative care provider. 56% (24/43) of patients enrolled in a clinical trial with HGG-directed therapy. 71% (17/24) of patients who enrolled in a clinical trial received specialty palliative care compared to 74% (14/19) of non-trial participants (p = 1.000). Similarly, among patients who received palliative care there was no statistically significant difference in the timing of palliative care involvement, measured from the date of first palliative care contact to date of death, for patients who enrolled in a clinical trial (mean = 177 days) compared to those who did not (mean = 113 days, p = 0.180). Of the 24 patients enrolled in clinical trials, only 7 (29%) had palliative care involvement prior to initiation of study treatment. Conclusions: As our understanding of the genomic landscape of pediatric brain tumors increases, it can be expected that patients electing to enroll in targeted therapy clinical trials will also increase. As such, it is reassuring that our data suggest that trial participation does not interfere with the receipt of specialty palliative care in children with HGG. While not statistically significant, initial palliative care involvement trends toward occurring in closer proximity to death in the patients who are not enrolled on a clinical trial. Overall, it is encouraging that in our pediatric HGG patient cohort, enrollment in clinical trials does not appear to have an adverse impact on specialty palliative care involvement.