Unlocking the Potential: A Systematic Review of Master Protocol in Pediatrics.

The use of master protocols allows for innovative approaches to clinical trial designs, potentially enabling new approaches to operations and analytics and creating value for patients and drug developers. Pediatric research has been conducted for many decades, but the use of novel designs such as master protocols in pediatric research is not well understood. This study aims to provide a systematic review on the utilization of master protocols in pediatric drug development. A search was performed in September 2022 using two data sources (PubMed and ClinicalTrials.gov) and included studies conducted in the past10 years. General study information was extracted such as study type, study status, therapeutic area, and clinical trial phase. Study characteristics that are specific to pediatric studies (such as age of the participants and pediatric drug dosing) and important study design elements (such as number of test drug arms and whether randomization and/or concurrent control was used) were also collected. Our results suggest that master protocol studies are being used in pediatrics, with platform and basket trials more common than umbrella trials. Most of this experience is in oncology and early phase studies. There is a rise in the use starting in 2020, largely in oncology and COVID-19 trials. However, adoption of master protocols in pediatric clinical research is still on a small scale and could be substantially expanded. Work is required to further understand the barriers in implementing pediatric master protocols, from setting up infrastructure to interpreting study findings.

Follicle-stimulating hormone orchestrates glucose-stimulated insulin secretion of pancreatic islets.

Follicle-stimulating hormone (FSH) is involved in mammalian reproduction via binding to FSH receptor (FSHR). However, several studies have found that FSH and FSHR play important roles in extragonadal tissue. Here, we identified the expression of FSHR in human and mouse pancreatic islet ß-cells. Blocking FSH signaling by Fshr knock-out led to impaired glucose tolerance owing to decreased insulin secretion, while high FSH levels caused insufficient insulin secretion as well. In vitro, we found that FSH orchestrated glucose-stimulated insulin secretion (GSIS) in a bell curve manner. Mechanistically, FSH primarily activates Gαs via FSHR, promoting the cAMP/protein kinase A (PKA) and calcium pathways to stimulate GSIS, whereas high FSH levels could activate Gαi to inhibit the cAMP/PKA pathway and the amplified effect on GSIS. Our results reveal the role of FSH in regulating pancreatic islet insulin secretion and provide avenues for future clinical investigation and therapeutic strategies for postmenopausal diabetes.

Performance of hippocampal radiomics models based on T2-FLAIR images in mesial temporal lobe epilepsy with hippocampal sclerosis.

PURPOSE: Preoperative identification of hippocampal sclerosis (HS) is crucial to successful surgery for mesial temporal lobe epilepsy (MTLE). We aimed to investigate the diagnostic performance of hippocampal radiomics models based on T2 fluid-attenuated inversion recovery (FLAIR) images in MTLE with HS. METHODS: We analysed 210 cases, including 172 HS pathology-confirmed cases (100 magnetic resonance imaging [MRI]-positive cases [MRI + HS], 72 MRI-negative HS cases [MRI - HS]), and 38 healthy controls (HC). The hippocampus was delineated slice by slice on an oblique coronal plane by a T2-FLAIR sequence, perpendicular to the hippocampus's long axis, to obtain a three-dimensional region of interest. Radiomics were processed using Artificial Intelligence Kit software; logistic regression radiomics models were constructed. The model evaluation indexes included the area under the curve (AUC), accuracy, sensitivity, and specificity. RESULTS: The respective AUC, accuracy, sensitivity, and specificity were 0.863, 81.4%, 78.0%, and 84.6% between the MRI - HS and HC groups in the training set and 0.855, 75.0%, 68.2%, and 81.8% in the test set; 0.975, 95.0%, 92.9%, and 98.0% between the MRI + HS and HC groups in the training set and 0.954, 88.7%, 90.0%, and 87.0% in the test set; and 0.912, 84.3%, 83.3%, and 86.5% between the MTLE and HC groups in the training set and 0.854, 79.7%, 80.8%, and 77.3% in the test set. The AUC values of the comparative radiomics models were > 0.85, indicating good diagnostic efficiency. CONCLUSION: The hippocampal radiomics models based on T2-FLAIR images can help diagnose MTLE with HS. They can be used as biological markers for MTLE diagnosis.

Examining the influence of pain and fatigue on neurocognitive functioning in adolescents and young adults with sickle cell disease.

Pain and fatigue are among the most common and impactful complications of sickle cell disease (SCD). Individuals with SCD are also more likely to have neurocognitive deficits. Previous studies have suggested that pain and fatigue might influence neurocognitive functioning in patients with SCD. However, these studies are limited by small sample sizes and inadequate measurement of cognitive performance. The present study aimed to investigate the relationship between pain and fatigue with neurocognitive functioning using performance-based measures of neurocognition. Pain and fatigue were not associated with neurocognitive performance. Implications and directions for future research are discussed.

Phosphorylation of 53BP1 by ATM enforce neurodevelopmental programs in cortical organoids.

53BP1 is a well-established DNA damage repair factor recently shown to regulate gene expression and critically influence tumor suppression and neural development. For gene regulation, how 53BP1 is regulated remains unclear. Here, we showed that 53BP1-serine 25 phosphorylation by ATM is required for neural progenitor cell proliferation and neuronal differentiation in cortical organoids. 53BP1-serine 25 phosphorylation dynamics controls 53BP1 target genes for neuronal differentiation and function, cellular response to stress, and apoptosis. Beyond 53BP1, ATM is required for phosphorylation of factors in neuronal differentiation, cytoskeleton, p53 regulation, and ATM, BNDF, and WNT signaling pathways for cortical organoid differentiation. Overall, our data suggest that 53BP1 and ATM control key genetic programs required for human cortical development.

Xuanfei Baidu formula alleviates impaired mitochondrial dynamics and activated NLRP3 inflammasome by repressing NF-κB and MAPK pathways in LPS-induced ALI and inflammation models.

BACKGROUND: Xuanfei Baidu Formula (XBF) is an effective traditional Chinese medicine (TCM) remedy for treating coronavirus disease 2019 (COVID-19) in China. This herbal medicine has shown effects in reducing clinical symptoms and shortening the average length of hospital stay for COVID-19 patients. Previous studies have demonstrated that XBF alleviates acute lung injury (ALI) by regulating macrophage-mediated immune inflammation, but the mechanisms of action remain elusive. PURPOSE: This study aimed to evaluate the lung-protective and anti-inflammatory effects of XBF and its underlying mechanisms. METHODS: Here, XBF's effects were investigated in an ALI mouse model induced by inhalation of atomized lipopolysaccharide (LPS). Besides, the LPS-induced inflammation model in RAW264.7 cells was used to clarify the underlying mechanisms of XBF against ALI. RESULTS: Our results showed that XBF treatment alleviated LPS-induced lung injury, as evidenced by reduced histopathological changes, pulmonary alveoli permeability, fibrosis, and apoptosis in the lung tissues. In addition, inflammation was alleviated as shown by decreased levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1ß in serum and bronchoalveolar lavage fluid (BALF), and reduced white blood cell (WBC) count in BALF. Furthermore, consistent with the in vivo assay, XBF inhibited LPS-induced inflammatory cytokines release and pro-inflammatory polarization in RAW264.7 cells. Mechanistically, XBF increased mitochondrial fusion by upregulating Mfn1 and attenuated NLRP3 inflammasome activation by repressing Casp11, respectively, to inhibit NF-κB and MAPK pathways, thus repressing pro-inflammatory macrophage polarization. CONCLUSION: In this study, we demonstrate that XBF exerts anti-ALI and -inflammatory effects by recovering mitochondrial dynamics and reducing inflammasome activation, providing a biological illustration of the clinical efficacy of XBF in treating COVID-19 patients.

Pediatric Craniopharyngioma: The Effect of Visual Deficits and Hormone Deficiencies on Long-Term Cognitive Outcomes After Conformal Photon Radiation Therapy.

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.

A software tool for both the maximum tolerated dose and the optimal biological dose finding trials in early phase designs.

Background: Phase I and/or I/II oncology trials are conducted to find the maximum tolerated dose (MTD) and/or optimal biological dose (OBD) of a new drug or treatment. In these trials, for cytotoxic agents, the primary aim of the single-agent or drug-combination is to find the MTD with a certain target toxicity rate, while for the cytostatic agents, a more appropriate target is the OBD, which is often defined by considering of toxicity and efficacy simultaneously. Accessible software packages to achieve both these aims are needed. Results: The objective of this study is to develop a software package that can provide tools for both MTD- and OBD-finding trials, which implements the Keyboard design for single-agent MTD-finding trials as reported by Yan et al. (2017), the Keyboard design for drug-combination MTD-finding trials by Pan et al. (2020), and a phase I/II OBD-finding method by Li et al. (2017) in a single R package, called Keyboard. For each of the designs, the Keyboard package provides corresponding functions such as get.boundary ( ⋯ ) for deriving the optimal dose escalation and de-escalation boundaries, select.mtd ( ⋯ ) for selecting the MTD when the trial is completed, select.obd ( ⋯ ) for selecting the OBD at the end of a trial, and get.oc ( ⋯ ) for generating the operating characteristics. Conclusion: The Keyboard R package developed herein provides convenient tools for designing, conducting and analyzing single-agent, drug-combination, phase I/II OBD-finding trials.

Research on the Springback Behavior of 316LN Stainless Steel in Micro-Scale Bending Processes.

Hydrogen fuel cells have been used worldwide due to their high energy density and zero emissions. The metallic bipolar plate is the crucial component and has a significant effect on a cell's efficiency. However, the springback behavior of the metallic bipolar plate will greatly influence its forming accuracy in the micro-scale sheet metal forming process. Therefore, accurate calculation of the springback angle of the micro-scale metallic bipolar plate is urgent but difficult given the state of existing elastoplastic theory. In this paper, a constitutive model that simultaneously considers grain size effect and strain gradient is proposed to analyze micro-scale bending behavior and calculate springback angles. The specialized micro-scale four-point bending tool was designed to better calculate the springback angle and simplify the calculation step. A pure micro-bending experiment on a 316LN stainless steel sheet with a thickness of 0.1 mm was conducted to verify the constitutive model's accuracy.

A semi-mechanistic dose-finding design in oncology using pharmacokinetic/pharmacodynamic modeling.

While a number of phase I dose-finding designs in oncology exist, the commonly used ones are either algorithmic or empirical model-based. We propose a new framework for modeling the dose-response relationship, by systematically incorporating the pharmacokinetic (PK) data collected in the trial and the hypothesized mechanisms of the drug effects, via dynamic PK/PD modeling, as well as modeling of the relationship between a latent cumulative pharmacologic effect and a binary toxicity outcome. This modeling framework naturally incorporates the information on the impact of dose, schedule and method of administration (e.g., drug formulation and route of administration) on toxicity. The resulting design is an extension of existing designs that make use of pre-specified summary PK information (such as the area under the concentration-time curve [AUC] or maximum serum concentration [Cmax ]). Our simulation studies show, with moderate departure from the hypothesized mechanisms of the drug action, that the performance of the proposed design on average improves upon those of the common designs, including the continual reassessment method (CRM), Bayesian optimal interval (BOIN) design, modified toxicity probability interval (mTPI) method, and a design called PKLOGIT that models the effect of the AUC on toxicity. In case of considerable departure from the underlying drug effect mechanism, the performance of the design is shown to be comparable with that of the other designs. We illustrate the proposed design by applying it to the setting of a phase I trial of a γ-secretase inhibitor in metastatic or locally advanced solid tumors. We also provide R code to implement the proposed design.

Two-stage screened selection designs for randomized phase II trials with time-to-event endpoints.

Phase II exploratory multiarm studies that randomize among new treatments are found to be broadly useful and appear to be of value both scientifically and logistically, especially in the areas of unmet needs, for example, pediatric cancer. This multiarm design also has a faster recruitment rate because it provides patients with more treatment choices than traditional two-arm randomized controlled trials do. In contrast to direct formal comparisons in multiarm multistage designs, for example, umbrella or platform designs, the screened selection design (SSD) recommends using a promising treatment arm by ranking according to the effect size, which often needs lesser sample sizes than the former. In this paper, the usefulness of the phase II SSD design is exemplified by three real trials. However, the existing SSD methods can only deal with binary endpoints. Motivated by the real trials in the authors' respective institutions, we propose using the two-stage SSD and its variant for randomized phase II trials with the time-to-event endpoint. The proposed methods not only provide a high probability of selecting a superior treatment arm but also control the type I error rate for testing the efficacy of each treatment arm versus a common external control. Sample size calculations have been derived and simulation studies demonstrate desirable operating characteristics. The proposed design has been used for designing three real trials. An R package frequentistSSD has been developed and is freely accessible for practitioners.

Blood DNA methylation signatures are associated with social determinants of health among survivors of childhood cancer.

Social epigenomics is an emerging field in which social scientist collaborate with computational biologists, especially epigeneticists, to address the underlying pathway for biological embedding of life experiences. This social epigenomics study included long-term childhood cancer survivors enrolled in the St. Jude Lifetime Cohort. DNA methylation (DNAm) data were generated using the Illumina EPIC BeadChip, and three social determinants of health (SDOH) factors were assessed: self-reported educational attainment, personal income, and an area deprivation index based on census track data. An epigenome-wide association study (EWAS) was performed to evaluate the relation between DNAm at each 5'-cytosine-phosphate-guanine-3' (CpG) site and each SDOH factor based on multivariable linear regression models stratified by ancestry (European ancestry, n = 1,618; African ancestry, n = 258). EWAS among survivors of European ancestry identified 130 epigenome-wide significant SDOH-CpG associations (P < 9 × 10-8), 25 of which were validated in survivors of African ancestry (P < 0.05). Thirteen CpGs were associated with all three SDOH factors and resided at pleiotropic loci in cigarette smoking-related genes (e.g., CLDND1 and CPOX). After accounting for smoking and body mass index, these associations remained significant with attenuated effect sizes. Seven of 13 CpGs were associated with gene expression level based on 57 subsamples with blood RNA sequencing data available. In conclusion, DNAm signatures, many resembling the effect of tobacco use, were associated with SDOH factors among survivors of childhood cancer, thereby suggesting that biologically distal SDOH factors influence health behaviours or related factors, the epigenome, and subsequently survivors' health.

Light Therapy for QoL/Depression in AYA With Cancer: A Randomized Trial.

OBJECTIVE: Secondary outcomes from a published feasibility and acceptability trial were examined to explore the effect of bright white light (BWL) on quality of life (QoL) and depressive symptoms compared to dim red light (DRL) control in adolescents and young adults (AYAs) receiving cancer-directed therapy. METHODS: Fifty-one AYAs (12-22 years, 51% male) newly diagnosed with cancer were randomized to receive 8 weeks of BWL (n = 26) or DRL (n = 25). The CDI-2 (total score, negative mood/physical symptoms, interpersonal problems, ineffectiveness, and negative self-esteem) and parent- and self-report PedsQL (total score and subscales of physical, emotional, social, and school QoL) were completed at multiple timepoints. RESULTS: BWL produced improvements in self-reported total depression (d = -.64; 95% confidence interval [CI] = -1.26, -0.01), negative self-esteem (d = -.80; 95% CI = -1.43, -.14), negative mood/physical symptoms (d = -.73; 95% CI = -1.36, -0.08), ineffectiveness (d = -.43; 95% CI = -1.04, .19), total self-reported QoL (d = .41; 95% CI = -.16, .96), emotional (d = .78; 95% CI = .19, 1.37), school functioning (d = .48; 95% CI = -.09, 1.04), and parent-reported school functioning (d = .66; 95% CI = 0.02, 1.33). BWL reported a greater rate of improvement than DRL for total depression (ß = .49, p < .05) and self-esteem (ß = .44, p < .05), and parent-reported school functioning (ß = -1.68, p < .05). CONCLUSIONS: BWL improved QoL and depressive symptoms for AYAs with cancer. These findings will inform larger randomized controlled trials.

Improved Outcome in Children With Newly Diagnosed High-Risk Neuroblastoma Treated With Chemoimmunotherapy: Updated Results of a Phase II Study Using hu14.18K322A.

PURPOSE: We evaluated whether combining a humanized antidisialoganglioside monoclonal antibody (hu14.18K322A) throughout therapy improves early response and outcomes in children with newly diagnosed high-risk neuroblastoma. PATIENTS AND METHODS: We conducted a prospective, single-arm, three-stage, phase II clinical trial. Six cycles of induction chemotherapy were coadministered with hu14.18K322A, granulocyte-macrophage colony-stimulating factor (GM-CSF), and low-dose interleukin-2 (IL-2). The consolidation regimen included busulfan and melphalan. When available, an additional cycle of parent-derived natural killer cells with hu14.18K322A was administered during consolidation (n = 31). Radiation therapy was administered at the end of consolidation. Postconsolidation treatment included hu14.18K322A, GM-CSF, IL-2, and isotretinoin. Early response was assessed after the first two cycles of induction therapy. End-of-induction response, event-free survival (EFS), and overall survival (OS) were evaluated. RESULTS: Sixty-four patients received hu14.18K322A with induction chemotherapy. This regimen was well tolerated, with continuous infusion narcotics. Partial responses (PRs) or better after the first two chemoimmunotherapy cycles occurred in 42 of 63 evaluable patients (66.7%; 95% CI, 55.0 to 78.3). Primary tumor volume decreased by a median of 75% (range, 100% [complete disappearance]-5% growth). Median peak hu14.18K322A serum levels in cycle one correlated with early response to therapy (P = .0154, one-sided t-test). Sixty of 62 patients (97%) had an end-of-induction partial response or better. No patients experienced progressive disease during induction. The 3-year EFS was 73.7% (95% CI, 60.0 to 83.4), and the OS was 86.0% (95% CI, 73.8 to 92.8), respectively. CONCLUSION: Adding hu14.18K322A to induction chemotherapy improved early objective responses, significantly reduced tumor volumes in most patients, improved end-of-induction response rates, and yielded an encouraging 3-year EFS. These results, if validated in a larger study, may be practice changing.

Radiotherapy alone for pediatric patients with craniopharyngioma.

PURPOSE: Radiotherapy alone, without tumor-directed surgery, may be appropriate for selected patients with craniopharyngioma reducing the risks associated with neurosurgery. Understanding outcomes for patients with craniopharyngioma treated with radiotherapy alone will further refine patient selection and treatment options. METHODS: Since 2002, 13 children, adolescents and young adults, with craniopharyngioma were treated with radiotherapy alone and followed for disease control and functional outcomes at a single institution. The median age at treatment was 13 years (range, 3-21 years). All patients received 54 Gy/54 Gy(RBE) in 30 fractions. Five patients were treated with intensity-modulated photon therapy, four with passively scattered proton therapy, and four with intensity-modulated proton therapy. RESULTS: With a median follow-up of 5 years (range 3 months-14 years), all patients were alive. One experienced tumor progression 8.5 years after treatment. No significant changes in vision, hearing or neurologic function attributed to radiotherapy. Hormone deficiencies and body mass index were within the expected range at baseline and 5 years after treatment. There was no evidence of cognitive decline based on assessment of IQ, memory and attention. Unexpected complications included single cases of out-of-field malignancy, white matter changes, large vessel narrowing, and pontine capillary telangiectasia. Six patients had sphenoid bone abnormalities on follow-up imaging attributed to radiotherapy. CONCLUSION: Radiotherapy alone is an important treatment option to consider when radical resection is contraindicated, or surgical intervention is not required to alleviate symptoms. Disease control and functional outcomes are excellent after radiation therapy alone in appropriately selected patients.

Trajectories of resilience and posttraumatic stress in childhood cancer: Consistency of child and parent outcomes.

OBJECTIVE: Childhood cancer represents a potentially traumatic experience for both patients and caregivers. We examined trajectories of posttraumatic stress symptoms (PTSS) across a 5-year period in children with a history of cancer and their parents/caregivers. Medical, demographic, and dispositional variables were examined as predictors of PTSS trajectories. METHOD: Using a longitudinal design, children with cancer history (n = 254, age 8-17 years at baseline) and one parent or caregiver (n = 255) completed measures of PTSS at baseline, and 1-, 3-, and 5-years poststudy entry. Children and caregivers completed dispositional measures including optimism, positive or negative affect, and Five-Factor Inventories. Latent class growth analysis (LCGA) was used to identify latent trajectories of PTSS, and univariate logistic regression models were conducted to predict LCGA class membership from medical, demographic, and disposition factors Results: Very similar trajectories were observed in children and caregivers, with two-class solutions providing the best fit: a "resilient" class, with low PTSS at baseline, which declined significantly over time (83.5% in children; 71.5% in parents), and an "elevated PTSS" class, which was moderately high at baseline and increased significantly over time. There was a small, but significant relationship between child and caregiver trajectories. Latent trajectories observed in children and parents were more strongly associated with dispositional variables than medical factors. CONCLUSIONS: Resilience, depicted by low PTSS, is by far the most common outcome observed in both children and caregivers. However, the smaller subset with elevated PTSS do not show recovery over time, and are identified as a group in need of targeted interventions. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

An adaptive gBOIN design with shrinkage boundaries for phase I dose-finding trials.

BACKGROUND: With the emergence of molecularly targeted agents and immunotherapies, the landscape of phase I trials in oncology has been changed. Though these new therapeutic agents are very likely induce multiple low- or moderate-grade toxicities instead of DLT, most of the existing phase I trial designs account for the binary toxicity outcomes. Motivated by a pediatric phase I trial of solid tumor with a continuous outcome, we propose an adaptive generalized Bayesian optimal interval design with shrinkage boundaries, gBOINS, which can account for continuous, toxicity grades endpoints and regard the conventional binary endpoint as a special case. RESULT: The proposed gBOINS design enjoys convergence properties, e.g., the induced interval shrinks to the toxicity target and the recommended dose converges to the true maximum tolerated dose with increased sample size. CONCLUSION: The proposed gBOINS design is transparent and simple to implement. We show that the gBOINS design has the desirable finite property of coherence and large-sample property of consistency. Numerical studies show that the proposed gBOINS design yields good performance and is comparable with or superior to the competing design.

iTRAQ-based quantitative proteomic analysis of thoracic aortas from adult rats born to preeclamptic dams.

BACKGROUND: Preeclampsia and gestational hypertension can cause vascular function impairment in offspring. In our previous work, we described the protein expression profiles of umbilical artery tissues from patients with preeclampsia. METHODS: To gain insights into the mechanisms of vascular dysfunction in adult rats born to preeclamptic dams, we analyzed thoracic aorta tissues by using iTRAQ isobaric tags and 2D nano LC-MS/MS. RESULTS: By using the iTRAQ method, we analyzed 1825 proteins, of which 106 showed significantly different expression in the thoracic aortic. Ingenuity pathway analysis (IPA) showed that the majority of differentially expressed proteins (DEPs) were associated with cardiovascular function. Further analysis indicated that glucose-6-phosphate dehydrogenase (G6PD), which is inhibited by miR-423-5p and activated by TP53, had the strongest effect on cardiovascular function. The expression of G6PD was upregulated in thoracic aorta tissues, as confirmed by Western blotting. The expression of two other vascular function-related proteins, cysteine- and glycine-rich protein 2 (CSRP2) and tubulin alpha-4 A (TUBA4A), was upregulated, as demonstrated by mass spectrometry (MS). CONCLUSIONS: Although the results require further functional validation, these data provide novel findings related to vascular function impairment in the adult offspring of preeclamptic mothers.

A prospective, comprehensive registry that integrates the molecular analysis of pediatric and adolescent melanocytic lesions.

BACKGROUND: Childhood melanocytic tumors represent a diagnostic and therapeutic challenge, and additional research is needed to better define the natural history of these tumors. METHODS: The authors developed a comprehensive, prospective registry called Molecular Analysis of Childhood Melanocytic Tumors for children and adolescents with an atypical Spitz tumor/Spitz melanoma (AST/SM), conventional or adult-type melanoma (CM), melanoma arising in a giant congenital nevus (MCM), or atypical melanocytic proliferation of other types (OT) to better define the clinical behavior of these lesions by incorporating an integrated clinicopathologic and molecular analysis using centralized pathology review and various platforms, including fluorescence in situ hybridization; array comparative genomic hybridization; and whole genome, exome, and capture targeted panels. RESULTS: From May 2016 to November 2019, 70 children were enrolled with a median age at diagnosis of 9.1 years. Thirty-seven had AST/SM, 17 had CM, 4 had MCM, and 12 had OT. Patients with AST/SM were younger (median age, 7 years), and their tumor most commonly arose in the extremities and trunk. The most common gene rearrangements included MAP3K8 and ALK. None of the 33 patients who underwent a TERT promoter mutation analysis had a mutation, and all patients were alive. Among the CM patients, the median age was 13 years; 11 had a BRAFV600E mutation, and 7 had a TERT promoter mutation. Three patients died of their disease. All 4 patients with MCM harbored an NRASQ61 mutation and died of their disease. The OT group was heterogenous, and all patients survived. CONCLUSIONS: The incorporation of an integrated clinicopathologic and genomic analysis identifies distinct subgroups of pediatric melanocytic lesions that have different clinical behaviors. The integration of this combined diagnostic modality can help to individualize diagnoses and treatments for these patients.

Bayesian single-arm phase II trial designs with time-to-event endpoints.

For the cancer clinical trials with immunotherapy and molecularly targeted therapy, time-to-event endpoint is often a desired endpoint. In this paper, we present an event-driven approach for Bayesian one-stage and two-stage single-arm phase II trial designs. Two versions of Bayesian one-stage designs were proposed with executable algorithms and meanwhile, we also develop theoretical relationships between the frequentist and Bayesian designs. These findings help investigators who want to design a trial using Bayesian approach have an explicit understanding of how the frequentist properties can be achieved. Moreover, the proposed Bayesian designs using the exact posterior distributions accommodate the single-arm phase II trials with small sample sizes. We also proposed an optimal two-stage approach, which can be regarded as an extension of Simon's two-stage design with the time-to-event endpoint. Comprehensive simulations were conducted to explore the frequentist properties of the proposed Bayesian designs and an R package BayesDesign can be assessed via R CRAN for convenient use of the proposed methods.