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Introduction: Zucker diabetic fatty (ZDF) rats are used widely as an animal model of metabolic syndrome and insulin resistance. Our study focused on the effects of high versus low dietary fat on the development of Type 2 diabetes in obese male ZDF rats (fa/fa), including biomarkers to detect early signs of hypercoagulability and vascular injury in the absence of overt thrombosis. Methods: In this study, male (5/group) 10-week-old CRL:ZDF370(obese) rats were fed low (LFD, 16.7% fat) or high fat (HFD, 60% fat) diet for 12 or 15 weeks. Cohorts of 5 rats within diet groups were scheduled for sample collection after weeks 12 and 15. Results: HFD–fed ZDF rats had oily coats, lower rates of food consumption, more accelerated weight gain and increased serum cholesterol (+15%) and triglyceride concentrations (+75%) vs. LFD–fed ZDF rats. Urinary ketones were observed only in HFD–fed ZDF rats and greater urine glucose and protein concentrations in HFD–fed ZDF vs. LFD–fed ZDF rats were seen. Hemostasis testing showed ~2-fold greater fibrinogen concentration, increased von Willebrand factor concentration, and high thrombin generation in HFD–fed ZDF vs LFD–fed ZDF rats. Increased mortality in the HFD–fed ZDF rat was attributed to exacerbations of altered carbohydrate metabolism as evidenced by ketonuria and nephropathy leading to renal failure. Discussion: This characterization shows that the ZDF rat at the age, sex and weight used in this study is highly sensitive to dietary fat content that can exacerbate prothrombotic, metabolic and renal disturbances and increase mortality. [ABSTRACT FROM AUTHOR]

Importance: Biomarkers would greatly assist decision-making in the diagnosis, prevention, and treatment of chronic pain., Objective: To undertake analytical validation of a sensorimotor cortical biomarker signature for pain consisting of 2 measures: sensorimotor peak alpha frequency (PAF) and corticomotor excitability (CME)., Design, Setting, and Participants: This cohort study at a single center (Neuroscience Research Australia) recruited participants from November 2020 to October 2022 through notices placed online and at universities across Australia. Participants were healthy adults aged 18 to 44 years with no history of chronic pain or a neurological or psychiatric condition. Participants experienced a model of prolonged temporomandibular pain with outcomes collected over 30 days. Electroencephalography to assess PAF and transcranial magnetic stimulation (TMS) to assess CME were recorded on days 0, 2, and 5. Pain was assessed twice daily from days 1 through 30., Exposure: Participants received an injection of nerve growth factor (NGF) to the right masseter muscle on days 0 and 2 to induce prolonged temporomandibular pain lasting up to 4 weeks., Main Outcomes and Measures: The predictive accuracy of the PAF/CME biomarker signature was determined using a nested control-test scheme: machine learning models were run on a training set (n = 100), where PAF and CME were predictors and pain sensitivity was the outcome. The winning classifier was assessed on a test set (n = 50) comparing the predicted pain labels against the true labels., Results: Among the final sample of 150 participants, 66 were female and 84 were male; the mean (SD) age was 25.1 (6.2) years. The winning classifier was logistic regression, with an outstanding area under the curve (AUC = 1.00). The locked model assessed on the test set had excellent performance (AUC = 0.88; 95% CI, 0.78-0.99). Results were reproduced across a range of methodological parameters. Moreover, inclusion of sex and pain catastrophizing as covariates did not improve model performance, suggesting the model including biomarkers only was more robust. PAF and CME biomarkers showed good to excellent test-retest reliability., Conclusions and Relevance: This study provides evidence for a sensorimotor cortical biomarker signature for pain sensitivity. The combination of accuracy, reproducibility, and reliability suggests the PAF/CME biomarker signature has substantial potential for clinical translation, including predicting the transition from acute to chronic pain.

Breast magnetic resonance imaging (MRI) has the highest sensitivity for breast cancer detection compared to other breast imaging modalities such as mammography and ultrasound. As a functional modality, it captures the increased angiogenic activity of breast cancer through gadolinium-based contrast enhancement. Normal breast tissue also enhances, albeit in distinct patterns termed background parenchymal enhancement (BPE). Asymmetric enhancement, i.e., when one breast enhances more prominently than the other, can pose a diagnostic challenge for interpreting radiologists as distinguishing suspicious nonmass enhancement (NME) versus benign asymmetric BPE can be difficult. Correlating with patient history and imaging findings can help differentiate benign versus suspicious patterns of asymmetric enhancement. We present a collection of cases illustrating clues helpful for assessing asymmetric enhancement encountered on breast MRI., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier Inc.)

Abstract: Repetitive transcranial magnetic stimulation (rTMS) has shown promise as an intervention for pain. An unexplored research question is whether the delivery of rTMS prior to pain onset might protect against a future episode of prolonged pain. The present study aimed to determine whether (1) 5 consecutive days of rTMS delivered prior to experimentally induced prolonged jaw pain has a prophylactic effect on future pain intensity and (2) whether these effects were accompanied by increases in corticomotor excitability (CME) and/or sensorimotor peak alpha frequency (PAF). On each day from day 0 to 4, 40 healthy individuals received a single session of active (n = 21) or sham (n = 19) rTMS over the left primary motor cortex. Peak alpha frequency and CME were assessed on day 0 (before rTMS) and day 4 (after rTMS). Prolonged pain was induced via intramuscular injection of nerve growth factor in the right masseter muscle after the final rTMS session. From days 5 to 25, participants completed twice-daily electronic diaries including pain on chewing and yawning (primary outcomes), as well as pain during other activities (eg, talking), functional limitation in jaw function and muscle soreness (secondary outcomes). Compared to sham, individuals who received active rTMS subsequently experienced lower pain on chewing and yawning. Furthermore, active rTMS led to an increase in PAF. This is the first study to show that rTMS delivered prior to prolonged pain onset can protect against future pain. Our findings suggest that rTMS may hold promise as a prophylactic intervention for pain., (Copyright © 2024 International Association for the Study of Pain.)

Purpose: Antibodies to select Epstein-Barr virus proteins can diagnose early-stage nasopharyngeal carcinoma (NPC). We have previously shown that IgA against Epstein-Barr virus nuclear antigen 1 (EBNA1) can predict incident NPC in high- and intermediate-risk cohorts 4 years before diagnosis. Here, we tested EBNA1 variants, with mutants, to define the sequence requirements for an NPC risk assay., Experimental Design: Mammalian-expressed constructs were developed to represent EBNA1 variants 487V and 487A, which can differ by ≥15 amino acids in the N- and C-termini. Denatured lysates were evaluated by a refined IgA and IgG immunoblot assay in a case-control study using prediagnostic NPC sera from two independent cohorts in Singapore and Shanghai, the People's Republic of China., Results: At 95% sensitivity, 487V yielded a 94.9% specificity compared with 86.1% for 487A. EBNA1 deleted for the conserved glycine-alanine repeats (GAr) reduced false positives by 22.8%. NPC sera reacted more strongly to the C-terminus than healthy controls, but the C-terminal construct (a.a. 390-641) showed lower specificity (84.8%) than the EBNA1 GAr-deleted construct (92.4%) at 95% sensitivity., Conclusions: Although EBNA1 IgA was present in healthy sera, most epitopes localized to the immunodominant GAr. We conclude that a refined EBNA1 antigen deleted for the GAr, but with residues consistently detected in Southeast Asian NPC tumors, is optimized for risk prediction with an extended sojourn time of 7.5 years. Furthermore, distinct EBNA1 serologic profiles enhanced the utility of the EBNA1 IgA assay for risk stratification. This illustrates the importance of serologically relevant EBNA1 sequences for NPC risk prediction and early detection., (©2024 American Association for Cancer Research.)

Importance: Biomarkers would greatly assist decision making in the diagnosis, prevention and treatment of chronic pain., Objective: The present study aimed to undertake analytical validation of a sensorimotor cortical biomarker signature for pain consisting of two measures: sensorimotor peak alpha frequency (PAF) and corticomotor excitability (CME)., Design: In this cohort study (recruitment period: November 2020-October 2022), participants experienced a model of prolonged temporomandibular pain with outcomes collected over 30 days. Electroencephalography (EEG) to assess PAF and transcranial magnetic stimulation (TMS) to assess CME were recorded on Days 0, 2 and 5. Pain was assessed twice daily from Days 1-30., Setting: Data collection occurred at a single centre: Neuroscience Research Australia., Participants: We enrolled 159 healthy participants (through notices placed online and at universities across Australia), aged 18-44 with no history of chronic pain, neurological or psychiatric condition. 150 participants completed the protocol., Exposure: Participants received an injection of nerve growth factor (NGF) to the right masseter muscle on Days 0 and 2 to induce prolonged temporomandibular pain lasting up to 4 weeks., Main Outcomes and Measures: We determined the predictive accuracy of the PAF/CME biomarker signature using a nested control-test scheme: machine learning models were run on a training set (n = 100), where PAF and CME were predictors and pain sensitivity was the outcome. The winning classifier was assessed on a test set (n = 50) comparing the predicted pain labels against the true labels., Results: The final sample consisted of 66 females and 84 males with a mean age of 25.1 ± 6.2. The winning classifier was logistic regression, with an outstanding area under the curve (AUC=1.00). The locked model assessed on the test set had excellent performance (AUC=0.88[0.78-0.99]). Results were reproduced across a range of methodological parameters. Moreover, inclusion of sex and pain catastrophizing as covariates did not improve model performance, suggesting the model including biomarkers only was more robust. PAF and CME biomarkers showed good-excellent test-retest reliability., Conclusions and Relevance: This study provides evidence for a sensorimotor cortical biomarker signature for pain sensitivity. The combination of accuracy, reproducibility, and reliability, suggests the PAF/CME biomarker signature has substantial potential for clinical translation, including predicting the transition from acute to chronic pain.

Chimeric antigen receptor (CAR) T-cell therapy is a human gene therapy product where T cells from a patient are genetically modified to enable them to recognize desired target antigen(s) more effectively. In recent years, promising antitumor activity has been seen with autologous CAR T cells. Since 2017, six CAR T-cell therapies for the treatment of hematological malignancies have been approved by the Food and Drug Administration (FDA). Despite the rapid progress of CAR T-cell therapies, considerable statistical challenges still exist for this category of products across all phases of clinical development that need to be addressed. These include (but not limited to) dose finding strategy, implementation of the estimand framework, use of real-world data in contextualizing single-arm CAR T trials, analysis of safety data and long-term follow-up studies. This paper is the first step in summarizing and addressing these statistical hurdles based on the development of the six approved CAR T-cell products., (© 2024. The Author(s), under exclusive licence to The Drug Information Association, Inc.)

Repetitive transcranial magnetic stimulation (rTMS) has shown promise as an intervention for pain. An unexplored research question is whether the delivery of rTMS prior to pain onset might protect against a future episode of prolonged pain. The present study aimed to determine i) whether 5 consecutive days of rTMS delivered prior to experimentally-induced prolonged jaw pain could reduce future pain intensity and ii) whether any effects of rTMS on pain were mediated by changes in corticomotor excitability (CME) and/or sensorimotor peak alpha frequency (PAF). On each day from Day 0-4, forty healthy individuals received a single session of active (n = 21) or sham (n = 19) rTMS over the left primary motor cortex. PAF and CME were assessed on Day 0 (before rTMS) and Day 4 (after rTMS). Prolonged pain was induced via intramuscular injection of nerve growth factor (NGF) in the right masseter muscle after the final rTMS session. From Days 5-25, participants completed twice-daily electronic dairies including pain on chewing and yawning (primary outcomes), as well as pain during other activities (e.g. talking), functional limitation in jaw function and muscle soreness (secondary outcomes). Compared to sham, individuals who received active rTMS subsequently experienced lower pain on chewing and yawning. Although active rTMS increased PAF, the effects of rTMS on pain were not mediated by changes in PAF or CME. This study is the first to show that rTMS delivered prior to pain onset can protect against future pain and associated functional impairment. Thus, rTMS may hold promise as a prophylactic intervention for persistent pain., Competing Interests: Conflict of Interest: The authors have no conflicts of interests to declare.

Nasopharyngeal carcinoma (NPC), a cancer that is etiologically associated with the Epstein-Barr virus (EBV), is endemic in Southern China and Southeast Asia. The scarcity of representative NPC cell lines owing to the frequent loss of EBV episomes following prolonged propagation and compromised authenticity of previous models underscores the critical need for new EBV-positive NPC models. Herein, we describe the establishment of a new EBV-positive NPC cell line, designated NPC268 from a primary non-keratinizing, differentiated NPC tissue. NPC268 can undergo productive lytic reactivation of EBV and is highly tumorigenic in immunodeficient mice. Whole-genome sequencing revealed close similarities with the tissue of origin, including large chromosomal rearrangements, while whole-genome bisulfite sequencing and RNA sequencing demonstrated a hypomethylated genome and enrichment in immune-related pathways, respectively. Drug screening of NPC268 together with six other NPC cell lines using 339 compounds, representing the largest high-throughput drug testing in NPC, revealed biomarkers associated with specific drug classes. NPC268 represents the first and only available EBV-positive non-keratinizing differentiated NPC model, and extensive genomic, methylomic, transcriptomic, and drug response data should facilitate research in EBV and NPC, where current models are limited., Significance: NPC268 is the first and only EBV-positive cell line derived from a primary non-keratinizing, differentiated nasopharyngeal carcinoma, an understudied but important subtype in Southeast Asian countries. This model adds to the limited number of authentic EBV-positive lines globally that will facilitate mechanistic studies and drug development for NPC., (© 2024 The Authors; Published by the American Association for Cancer Research.)

Our goal was to analyze radiology report text for chest radiographs (CXRs) to identify imaging findings that have the most impact on report length and complexity. Identifying these imaging findings can highlight opportunities for designing CXR AI systems which increase radiologist efficiency. We retrospectively analyzed text from 210,025 MIMIC-CXR reports and 168,949 reports from our local institution collected from 2019 to 2022. Fifty-nine categories of imaging finding keywords were extracted from reports using natural language processing (NLP), and their impact on report length was assessed using linear regression with and without LASSO regularization. Regression was also used to assess the impact of additional factors contributing to report length, such as the signing radiologist and use of terms of perception. For modeling CXR report word counts with regression, mean coefficient of determination, R 2 , was 0.469 ± 0.001 for local reports and 0.354 ± 0.002 for MIMIC-CXR when considering only imaging finding keyword features. Mean R 2 was significantly less at 0.067 ± 0.001 for local reports and 0.086 ± 0.002 for MIMIC-CXR, when only considering use of terms of perception. For a combined model for the local report data accounting for the signing radiologist, imaging finding keywords, and terms of perception, the mean R 2 was 0.570 ± 0.002. With LASSO, highest value coefficients pertained to endotracheal tubes and pleural drains for local data and masses, nodules, and cavitary and cystic lesions for MIMIC-CXR. Natural language processing and regression analysis of radiology report textual data can highlight imaging targets for AI models which offer opportunities to bolster radiologist efficiency., (© 2024. The Author(s) under exclusive licence to Society for Imaging Informatics in Medicine.)

Transcranial magnetic stimulation (TMS) has been used to examine inhibitory and facilitatory circuits during experimental pain and in chronic pain populations. However, current applications of TMS to pain have been restricted to measurements of motor evoked potentials (MEPs) from peripheral muscles. Here, TMS was combined with electroencephalography (EEG) to determine whether experimental pain could induce alterations in cortical inhibitory/facilitatory activity observed in TMS-evoked potentials (TEPs). In Experiment 1 (n=29), multiple sustained thermal stimuli were administered to the forearm, with the first, second, and third block of thermal stimuli consisting of warm but non-painful (pre-pain block), painful (pain block) and warm but non-painful (post-pain block) temperatures, respectively. During each stimulus, TMS pulses were delivered while EEG (64 channels) was simultaneously recorded. Verbal pain ratings were collected between TMS pulses. Relative to pre-pain warm stimuli, painful stimuli led to an increase in the amplitude of the frontocentral negative peak ~45 ms post-TMS (N45), with a larger increase associated with higher pain ratings. Experiments 2 and 3 (n=10 in each) showed that the increase in the N45 in response to pain was not due to changes in sensory potentials associated with TMS, or a result of stronger reafferent muscle feedback during pain. This is the first study to use combined TMS-EEG to examine alterations in cortical excitability in response to pain. These results suggest that the N45 TEP peak, which indexes GABAergic neurotransmission, is implicated in pain perception and is a potential marker of individual differences in pain sensitivity., Competing Interests: NC, AC, SM, PS, WC, DS, SS No competing interests declared, (© 2023, Chowdhury et al.)

Abemaciclib is an orally administered, potent, and selective small molecule inhibitor of cyclin-dependent kinases 4 and 6, approved for advanced or metastatic breast cancer. This study aimed to use an exposure-response approach to investigate the effect of abemaciclib and its active metabolites (M2 and M20) on QTc interval and delay in cardiac repolarization at clinically relevant exposures. This was a single-blind, randomized, and placebo-controlled study of ascending doses of abemaciclib. Thirty-five healthy participants were administered a single dose of 200-600 mg abemaciclib. Twelve-lead electrocardiogram tracings and pharmacokinetic samples were collected serially pre- and post-dose. The primary objective was to study the relationship between abemaciclib and its active metabolites (M2 and M20) and QTc interval following ascending oral doses of abemaciclib. The secondary objective included evaluating the safety and tolerability of single ascending doses of abemaciclib in healthy participants. Exposure-response analysis demonstrated that there was no significant relationship between placebo-corrected change from baseline QTcF (ΔΔQTcF), abemaciclib, and metabolite plasma concentrations. Additionally, the ΔΔQTcF slopes of abemaciclib, its metabolites, and total analyte concentrations were not statistically different from zero. Single doses of abemaciclib, up to 400 mg, were well-tolerated by healthy participants; however, at the 600 mg dose (three times the highest registered dose), the frequency and severity of treatment-related gastrointestinal events (primarily diarrhea, nausea, and vomiting) increased. In conclusion, single doses of abemaciclib, up to 400 mg, had no statistically or clinically relevant effects on QTc, and abemaciclib was well tolerated up to a dose of 400 mg in this study., (© 2023 Eli Lilly and Company. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Transcranial magnetic stimulation (TMS) has been used to examine inhibitory and facilitatory circuits during experimental pain and in chronic pain populations. However, current applications of TMS to pain have been restricted to measurements of motor evoked potentials (MEPs) from peripheral muscles. Here, TMS was combined with electroencephalography (EEG) to determine whether experimental pain could induce alterations in cortical inhibitory/facilitatory activity observed in TMS-evoked potentials (TEPs). In Experiment 1 (n = 29), multiple sustained thermal stimuli were administered to the forearm, with the first, second and third block of thermal stimuli consisting of warm but non-painful (pre-pain block), painful (pain block) and warm but non-painful (post-pain block) temperatures respectively. During each stimulus, TMS pulses were delivered while EEG (64 channels) was simultaneously recorded. Verbal pain ratings were collected between TMS pulses. Relative to pre-pain warm stimuli, painful stimuli led to an increase in the amplitude of the frontocentral negative peak ~45ms post-TMS (N45), with a larger increase associated with higher pain ratings. Experiments 2 and 3 (n = 10 in each) showed that the increase in the N45 in response to pain was not due to changes in sensory potentials associated with TMS, or a result of stronger reafferent muscle feedback during pain. This is the first study to use combined TMS-EEG to examine alterations in cortical excitability in response to pain. These results suggest that the N45 TEP peak, which indexes GABAergic neurotransmission, is implicated in pain perception and is a potential marker of individual differences in pain sensitivity., Competing Interests: Disclosures The authors have no conflicts of interest to declare.

Background: Survival of children and adolescents with high-risk, mature B-cell non-Hodgkin lymphoma is improved by the addition of rituximab to chemotherapy. The effect of rituximab on immune reconstitution after therapy has not been well described. Herein, we evaluate the immune effects of the addition of rituximab to intensive chemotherapy, a prespecified secondary aim of the Inter-B-NHL Ritux 2010 trial., Methods: The Inter-B-NHL Ritux 2010 trial was an international, open-label, randomised, phase 3 trial in children (age 6 months to 18 years) with high-risk, mature B-cell non-Hodgkin lymphoma, comparing chemotherapy alone or chemotherapy with rituximab. Measures of immune status were completed at baseline, 1 month from the end of treatment, and 1 year from the start of therapy, and yearly thereafter until normalised. For this secondary analysis, we report on the proportions of patients with low lymphocyte counts and immunoglobulin concentrations at these timepoints with total lymphocyte count, B-cell count, and IgG concentration as the main endpoints. Other endpoints of interest included exposure to immunoglobulin replacement therapy and vaccine serologies. The population assessed for immune endpoints was the eligible per-protocol population with at least one immune parameter at one timepoint. Comparisons of immune status were made between the randomised treatment groups. Safety in the post-therapy period was assessed in the population eligible for the immunity study who were followed up at least 3 months after the end of treatment and without cancer-related events. The Inter-B-NHL Ritux 2010 study was registered with ClinicalTrials.gov, NCT01516580; status completed, with analyses of secondary aims ongoing., Findings: From Dec 19, 2011, to June 13, 2017, 421 patients (344 [82%] boys and 77 [18%] girls; mean age was 8·8 years [SD 4·1]) were enrolled and had immune data at baseline during follow-up, or both. The study population included randomly assigned patients (n=289) and a non-randomised cohort enrolled after the planned interim analysis (n=132). At baseline, 99 (34%) of 290 patients with available data (excluding patients with bone marrow disease with peripheral blast cells) had lymphopenia, and 178 (48%) of 368 had hypogammaglobulinemia. 1 month from the end of therapy, patients who received chemotherapy with rituximab were more likely than those who received chemotherapy alone to have lymphopenia (86 [81%] of 106 vs 53 (60%) of 89, odds ratio [OR] 2·92 [95% CI 1·53-5·57], p=0·0011), B-cell lymphopenia (72 [96%] of 75 vs 36 [64%] of 56, OR 13·33 [3·71-47·84], p<0·0001), and hypogammaglobulinemia (67 [71%] of 95 vs 37 [47%] of 79, OR 2·72 [1·45-5·07], p=0·0017). Differences remained at 1 year for hypogammaglobulinemia only (52 [55%] of 94 vs 16 [25%] of 63, OR 3·64 [1·81-7·31], p=0·0003). Patients in the chemotherapy with rituximab group were more likely than those in the chemotherapy group to receive immunoglobulin replacement (26 [16%] 164 vs nine [7%] of 158, hazard ratio [HR] 2·63 [95% CI 1·23-5·62], p=0·010), mainly due to low immunoglobulin concentration. In the combined treatment groups, including non-randomly assigned patients, the proportion of patients who had loss of protective serologies to a vaccine preventable infection varied from four (9%) of 47 for polio to 21 (42%) of 50 for Streptococcus pneumoniae (pneumococcus). One patient (chemotherapy with rituximab group) had a life-threatening infectious event of polymicrobial bacterial sepsis reported 2 months after the final chemotherapy administration., Interpretation: Children with high-risk mature B-cell non-Hodgkin lymphoma receiving chemotherapy with rituximab were at risk of prolonged hypogammaglobulinemia, although severe infections were rare. Strategies for immunoglobulin replacement and revaccination are needed., Funding: Clinical Research Hospital Program of the French Ministry of Health, Cancer Research UK, National Institute for Health Research Clinical Research Network in England, Children's Cancer Foundation Hong Kong, US National Cancer Institute, F Hoffmann-La Roche., Competing Interests: Declaration of interests GAAB provides consultancy to Roche, Novartis, Merck, and Janssen. AA, CP, and VM-C received grant support for the present study, paid to their institution, from F Hoffmann–La Roche. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The European Intergroup for Childhood Non-Hodgkin Lymphoma (EICNHL) was established 25 years ago with the goal to facilitate clinical trials and research collaborations in the field both within Europe and worldwide. Since its inception, much progress has been made whereby major improvements in outcomes have been achieved. In this Review, we describe the different diagnostic entities of non-Hodgkin lymphoma in children and young adults describing key features of each entity and outlining clinical achievements made in the context of the EICNHL framework. Furthermore, we provide an overview of advances in biopathology with an emphasis on the role of biological studies and how they have shaped available treatments. Finally, for each entity, we describe future goals, upcoming clinical trials, and highlight areas of research that require our focus going forward., Competing Interests: Declaration of interests LB has sat on advisory boards for the BrigaPed study for Takeda and has received support from Bristol Myers Squibb for the nivoALCL clinical trial. GAAB has received institutional payments for consultancies from Novartis, Roche, Takeda, straZeneca, and Janssen. AA has sat on a board for MSD. All other authors have no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

This topical review is focused on the clinical breast x-ray imaging applications of the rapidly evolving field of artificial intelligence (AI). The range of AI applications is broad. AI can be used for breast cancer risk estimation that could allow for tailoring the screening interval and the protocol that are woman-specific and for triaging the screening exams. It also can serve as a tool to aid in the detection and diagnosis for improved sensitivity and specificity and as a tool to reduce radiologists' reading time. AI can also serve as a potential second 'reader' during screening interpretation. During the last decade, numerous studies have shown the potential of AI-assisted interpretation of mammography and to a lesser extent digital breast tomosynthesis; however, most of these studies are retrospective in nature. There is a need for prospective clinical studies to evaluate these technologies to better understand their real-world efficacy. Further, there are ethical, medicolegal, and liability concerns that need to be considered prior to the routine use of AI in the breast imaging clinic., (Copyright © 2022 Elsevier Inc. All rights reserved.)

This brief report aims to evaluate the treatment outcome of transarterial embolization in ruptured hepatoblastoma complicated with acute intra-abdominal hemorrhage. Three children (mean age 6 years) with high-risk hepatoblastoma presented with rupture and acute intra-abdominal hemorrhage. In addition to aggressive fluid resuscitation and blood product support, super-selective embolization of the arteries with active bleeding or pseudoaneurysm was performed using calibrated gelfoam particles, with a technical success rate of 100%. Hemodynamic status and hemoglobin level were normalized in all patients within 2 days postembolization. The 30-day survival rate was 100%. No major complication was detected apart from mild elevation of alanine transaminase., (© 2022 Wiley Periodicals LLC.)

An accurately identified maximum tolerated dose (MTD) serves as the cornerstone of successful subsequent phases in oncology drug development. Bayesian logistic regression model (BLRM) is a popular and versatile model-based dose-finding design. However, BLRM with original overdose control strategy has been reported to be safe but "excessively conservative." In this article, we investigate the reason for conservativeness and point out that a major reason could be the lack of appropriate underdose control. We propose designs that balance overdose and underdose control to improve the performance over the original BLRM. Simulation results reveal that the new designs have better accuracy and treat more patients at MTD., (© 2022 John Wiley & Sons Ltd.)

Despite the expanding portfolio of targeted therapies for adults with acute myeloid leukemia (AML), direct implementation in children is challenging due to inherent differences in underlying genetics. Here we established the pharmacologic profile of pediatric AML by screening myeloblast sensitivity to approved and investigational agents, revealing candidates of immediate clinical relevance. Drug responses ex vivo correlated with patient characteristics, exhibited age-specific alterations, and concorded with activities in xenograft models. Integration with genomic data uncovered new gene-drug associations, suggesting actionable therapeutic vulnerabilities. Transcriptome profiling further identified gene-expression signatures associated with on- and off-target drug responses. We also demonstrated the feasibility of drug screening-guided treatment for children with high-risk AML, with two evaluable cases achieving remission. Collectively, this study offers a high-dimensional gene-drug clinical data set that could be leveraged to research the unique biology of pediatric AML and sets the stage for realizing functional precision medicine for the clinical management of the disease., Significance: We conducted integrated drug and genomic profiling of patient biopsies to build the functional genomic landscape of pediatric AML. Age-specific differences in drug response and new gene-drug interactions were identified. The feasibility of functional precision medicine-guided management of children with high-risk AML was successfully demonstrated in two evaluable clinical cases. This article is highlighted in the In This Issue feature, p. 476., (©2022 The Authors; Published by the American Association for Cancer Research.)

Objective: It remains unclear to what extent Transcranial Magnetic Stimulation-evoked potentials (TEPs) reflect sensory (auditory and somatosensory) potentials as opposed to cortical excitability. The present study aimed to determine; a) the extent to which sensory potentials contaminate TEPs using a spatially-matched sham condition, and b) whether sensory potentials reflect auditory or somatosensory potentials alone, or a combination of the two., Methods: Twenty healthy participants received active or sham stimulation, with the latter consisting a sham coil click combined with scalp electrical stimulation. Two additional conditions i) electrical stimulation and ii) auditory stimulation alone, were included in a subset of 13 participants., Results: Signals from active and sham stimulation were correlated in spatial and temporal domains > 55 ms post-stimulation. Relative to auditory or electrical stimulation alone, sham stimulation resulted in a) larger potentials, b) stronger correlations with active stimulation and c) a signal that was not a linear sum of electrical and auditory stimulation alone., Conclusions: Sensory potentials can confound interpretations of TEPs at timepoints > 55 ms post-stimulation. Furthermore, TEP contamination cannot be explained by auditory or somatosensory potentials alone, but instead reflects a non-linear interaction between both., Significance: Future studies may benefit from controlling for sensory contamination using spatially-matched sham conditions, and which consist of combined auditory and somatosensory stimulation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Rationale: There are widespread histaminergic projections throughout the brain, including hypoglossal nuclei, that modulate pharyngeal muscle tone and respiratory control. Hence, histaminergic stimulation pharmacologically may increase pharyngeal muscle tone and stabilize respiratory control (loop gain) to reduce obstructive sleep apnea (OSA) severity. Antimuscarinics also increase REM pharyngeal muscle tone in rats. Thus, a combination of histaminergic and anti-muscarinic drugs may be a novel target for OSA pharmacotherapy. However, this has not been investigated. Accordingly, we aimed to test the effects of betahistine (Beta), an H3-autoreceptor antagonist which thereby increases histamine levels, in combination with the antimuscarinic oxybutynin (Oxy), on OSA severity, OSA endotypes, polysomnography parameters and next-day sleepiness and alertness., Methods: Thirteen adults with OSA received either Beta-Oxy (96-5mg) or placebo according to a randomized, crossover, double-blind design, prior to polysomnography. Participants completed the Karolinska Sleep Scale and Leeds Sleep Evaluation Questionnaire and a driving simulation task to quantify next-day sleepiness and alertness. OSA endotypes were estimated through validated algorithms using polysomnography., Results: Compared to placebo, Beta-Oxy increased respiratory control sensitivity (loop gain) (0.52[0.24] vs 0.60[0.34], median [IQR], P = 0.021) without systematically changing OSA severity (34.4±17.2 vs 40.3±27.3 events/h, mean±SD, P = 0.124), sleep efficiency, arousal index or markers of hypoxemia. Beta-Oxy was well tolerated and did not worsen next-day sleepiness/alertness., Conclusion: Rather than stabilize breathing during sleep, Beta-Oxy increases loop gain, which is likely to be deleterious for most people with OSA. However, in certain conditions characterized by blunted respiratory control (eg, obesity hypoventilation syndrome), interventions to increase loop gain may be beneficial., Competing Interests: Alan Chiang reports grants from Cooperative Research Centre Project Grant (Australian Government, Academia and Industry collaboration, Industry partner: Oventus Medical), outside the submitted work. Luigi Taranto-Montemurro is Chief Scientific Officer of Apnimed and has a financial interest in Apnimed, a company developing pharmacologic therapies for sleep apnea. His interests were reviewed and are managed by Brigham and Women’s Hospital and Partners HealthCare in accordance with their conflict of interest policies; and reports personal fees from Apnimed, outside the submitted work. Danny J Eckert reports grants from National Health and Medical Research Council of Australia, during the conduct of the study; research grants and personal fees from Bayer, Apnimed, Takeda, and Invicta Medical, and a Collaborative Research Centre (CRC-P) Consortium Grant between the Australian Government, Academia and Industry (Industry partner: Oventus Medical) and serves on the Scientific Advisory Boards for Invicta Medical and Apnimed, outside the submitted work. The authors report no other potential conflicts of interest in relation to this work., (© 2022 Messineo et al.)

Purpose: Children with mediastinal masses often present with insidious symptoms to nonspecialist centers and require interhospital transport to oncology centers for definitive care. We evaluated clinical characteristics and patient outcomes and proposed a management protocol., Materials and Methods: This is a retrospective review of all children with mediastinal mass at the pediatric intensive care unit of the Hong Kong Children's Hospital between April 2019 and March 2020., Results: Ten children with a median age of 14.5 years (interquartile range, 9.3-17.0 years) were included. Leukemia and lymphoma accounted for the majority of cases (n = 6, 60%). Nearly all patients (n = 9, 90%) required interhospital transport before definitive treatment could be instituted. There were no deaths, but 2 patients were transported with significant respiratory compromise. Among patients requiring more than 1 interhospital transport, there was a higher incidence of shortness of breath (100% vs 40%; odds ratio, 33; P = 0.048) and orthopnea (80% vs 0%; odds ratio, 33; P = 0.048), whereas none had a neck mass (0% vs 80%; odds ratio, 0.03; P = 0.048)., Conclusions: Children with mediastinal mass are at risk of life-threatening cardiorespiratory compromise. Pretransport assessment, planning, and stabilization along with clear management plans for deterioration during transport are crucial especially for patients who are symptomatic at time of presentation, to reduce risks associated with delays in arriving at the specialist point of care for definitive treatment., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Hematopoietic stem cell transplantation, despite being a curative treatment for various pediatric disorders, is associated with significant acute and chronic complications., Methods: This retrospective review of 196 hematopoietic stem cell transplantation episodes (144 allogeneic, 52 autologous) performed in a tertiary pediatric unit focused on neurological symptoms and complications occurred from the start of conditioning to within 3 years of transplantation. Indications for transplantation included both benign and malignant diseases. For episodes involving allogeneic transplantation, 42% of donors were matched-unrelated, 19% were matched-sibling, and 12% were haploidentical.  RESULTS: Neurological complications developed in 17% of all hematopoietic stem cell transplantation episodes. Tumors of central nervous system and leukemia or lymphoma were two indications reported to have higher incidence of 42% and 21%, respectively. The occurrence of neurological complications was significantly associated with primary diagnosis (p = 0.01), central nervous system involvement by underlying disease (p = 0.001), and radiation-based conditioning (p = 0.018). Upon multivariate analysis, central nervous system involvement by underlying disease remained to be the only significant factor (p = 0.019), while radiation-based containing conditioning (p = 0.029) is revealed to be associated when considering allogeneic transplantation alone. Pre-transplant central nervous system-directed treatment, allogeneic versus autologous donor, stem cell source, donor type, busulfan use, and cyclosporin use were not significantly associated with neurological complications. Patients with neurological complications were also found to have an inferior 2-year overall survival (53.9% ± 8.8% versus 63.8% ± 4.2%; p = 0.016)., Conclusion: Neurological complications were common in pediatric hematopoietic stem cell transplantation and were associated with adverse outcome; non-radiation containing conditioning regimens might be beneficial in mitigating the risk of such complications., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: A dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine and prednisone plus rituximab (DA-EPOCH-R) regimen has been shown to deliver excellent survival for adults with primary mediastinal large B-cell lymphoma (PMLBL) without the use of radiotherapy. No international prospective evaluation of this regimen has previously been reported in children and adolescents., Patients and Methods: We conducted an international single-arm phase II trial involving patients younger than age 18 years with PMLBL who were to receive six courses of DA-EPOCH-R. The primary end point was event-free survival (EFS). Overall survival and toxicity were also assessed. This trial was registered (ClinicalTrials.gov identifier: NCT01516567)., Results: Analyses were based on 46 patients. The median age was 15.4 years (interquartile range: 14-16 years). The median follow-up was 59.0 months (interquartile range: 52.6-69.2 months). Fourteen events were observed (eight relapses or progressions (including three parenchymal CNS relapses), four residual lymphoma, and two second malignancies). The 4-year EFS was 69.6% (95% CI, 55.2 to 80.9), which did not differ from the rate observed historically ( P = .59). Seven deaths occurred (six disease-related and one second malignancy). The overall survival was 84.8% (95% CI, 71.8 to 92.4). Twenty-two patients (48%) reached dose levels ≥ 4. Nonhematologic adverse events grade ≥ 3 or cardiac adverse events grade ≥ 2 occurred in 47 of 276 (17%) courses and 30 of 46 patients (65%)., Conclusion: DA-EPOCH-R did not improve the EFS compared with a historical control in this first prospective multisite international study of children and adolescents with PMLBL. Further studies are required to determine the optimum therapy for children and adolescents with this lymphoma., Competing Interests: G. A. Amos BurkeConsulting or Advisory Role: Roche, Takeda, Oxford Immune Algorithmics, Novartis Veronique Minard-ColinResearch Funding: F. Hoffmann-La Roche-GenentechConsulting or Advisory Role: Novartis, Roche, BMS, Pfizer Anne AupérinConsulting or Advisory Role: MSDResearch Funding: F. Hoffmann-La Roche-Genentech Catherine M. BollardLeadership: Cabaletta BioConsulting or Advisory Role: Mana Therapeutics, Catamaran Bio Keith WheatleyResearch Funding: Bio-Cancer Treatment International, EUSA Pharma, Bayer Donald A. BarkauskasEmployment: Genentech (I)Stock and Other Ownership Interests: Genentech (I)Patents, Royalties, Other Intellectual Property: US patent on the basis of PhD research in glioblastoma (I) Peter C. AdamsonEmployment: SanofiStock and Other Ownership Interests: Gilead Sciences, McKesson, Molina Healthcare, Thermo Fisher Scientific, UnitedHealthcare, AbbVie, Medtronic, Sanofi Gilles VassalConsulting or Advisory Role: Bayer, Roche/Genentech, AstraZeneca, Bristol Myers Squibb, Lilly, Ipsen, NovartisTravel, Accommodations, Expenses: Bristol Myers Squibb, RocheNo other potential conflicts of interest were reported.

Germline adenomatous polyposis coli (APC) gene mutation is a cancer-predisposing condition commonly presenting as familial adenomatous polyposis. We describe a patient first diagnosed at the age of 3 years with metastatic hepatoblastoma. With a positive family history, germline testing confirmed maternally inherited APC mutation (p.Thr899Ansfs*13). The patient was subsequently diagnosed at 8 years with colonic adenocarcinoma in the absence of macroscopic polyposis. Total colectomy with adjuvant chemotherapy was delivered and the patient remained disease-free for 5 years since the second diagnosis. This report demonstrates the importance of considering germline APC mutation in children with hepatoblastoma, who may benefit from the early institution of colonoscopic surveillance., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Objective: Atomoxetine combined with oxybutynin (Ato-Oxy) has recently been shown to reduce obstructive sleep apnoea (OSA) severity by >60%. However, Ato-Oxy also modestly reduced the respiratory arousal threshold, which may decrease sleep quality/efficiency. We sought to investigate the additional effect of zolpidem with Ato-Oxy on sleep efficiency (primary outcome), the arousal threshold, OSA severity, other standard polysomnography (PSG) parameters, next-day sleepiness and alertness (secondary outcomes)., Methods: Twelve participants with OSA received 10 mg zolpidem plus Ato-Oxy (80-5 mg, respectively) or Ato-Oxy plus placebo prior to overnight in-laboratory PSG according to a double-blind, randomized, crossover design (1-week washout). Participants were fitted with an epiglottic catheter, a nasal mask and pneumotachograph to quantify arousal threshold and airflow. Next-day sleepiness and alertness were assessed via the Karolinska Sleepiness Scale and a driving simulation task., Results: The addition of zolpidem increased sleep efficiency by 9% ± 13% (80.9% ± 16.9% vs. 88.2% ± 8.2%, p = 0.037) and the respiratory arousal threshold by 17% ± 18% (-26.6 ± 14.5 vs. -33.8 ± 20.3 cm H 2 O, p = 0.004) versus Ato-Oxy + placebo. Zolpidem did not systematically change OSA severity. Combination therapy was well tolerated, and zolpidem did not worsen next-day sleepiness. However, median steering deviation during the driving simulator task increased following the zolpidem combination., Conclusion: Zolpidem improves sleep efficiency via an increase in the respiratory arousal threshold to counteract potential wake-promoting properties of atomoxetine in OSA. These changes occur without altering the rate of respiratory events or overnight hypoxaemia. However, while the addition of zolpidem does not increase next-day perceived sleepiness, caution is warranted given the potential impact on next-morning objective alertness., (© 2021 Asian Pacific Society of Respirology.)

Allogeneic hematopoietic stem cell transplantation is curative for transfusion-dependent thalassemia, but mixed chimerism (MC) may herald graft rejection. We report a child who failed bone marrow transplant (BMT) from matched unrelated donor (MUD) successfully salvaged with haploidentical peripheral blood stem cell transplant (PBSCT), but had MC in T-lymphocyte compartment despite near-complete donor chimerism in myeloid compartment. MC was successfully improved by repeated CD45RA-depleted donor lymphocyte infusion (DLI). A 2-year-old Chinese girl with beta-thalassemia major underwent 12/12-MUD BMT with HU/AZA/Cy/Flu/Bu/TT conditioning resulted in graft rejection. As donor refused second donation, rescue haploidentical PBSCT was performed with alemtuzumab/fludarabine/treosulfan conditioning. Harvest product was CD3/CD45RA depleted with extra products cryopreserved. Split cell chimerism performed 1-month after haplo-transplant showed 97% mother, 3% MUD, and 0% host for granulocytes but 38% mother, 62% MUD, and 0% host for CD3 + T cells. In view of low haploidentical donor chimerism in T-lymphocyte compartment, CD45RA-depleted DLI using cryopreserved product was performed on day + 38, after thymoglobulin 3 mg/kg given as T-cell depletion 3 days beforehand. T-cell chimerism improved to 51% mother and 49% MUD post-DLI. Second cryopreserved CD45RA-depleted DLI was given 17 days after the first DLI (day + 55), and 100% full chimerism of mother's T cells was gradually established without significant graft-versus-host disease (GVHD) or viral reactivation. To conclude, split lineage chimerism determination is beneficial to guide management strategy. For MC in T-cell compartment, CD45RA-depleted DLI is a potential alternative to unselected T cells as it carries lower risk of GVHD and infection., (© 2020 Wiley Periodicals LLC.)

Primary central nervous system (CNS) post-transplant lymphoproliferative disorder (PTLD) in childhood is rare. Twenty-five patients were retrieved from nine European Intergroup for Childhood Non-Hodgkin's Lymphoma and/or international Berlin-Frankfurt-Münster Study Group members. Types of allografts included kidney (n = 11), liver (n = 4), heart (n = 5), bowel (n = 1) and haematopoietic stem cells (n = 4). Eighteen were male, 16 ≥ 10 years old, 21 had monomorphic disease and 24 solid intracranial tumour masses. Four-year event-free and overall survival rates were 50% ± 10% and 74% ± 9% respectively. This report represents the largest paediatric series of CNS PTLD reported to date, showing favourable survival odds following systemic and intrathecal chemotherapy and rituximab administration., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)

Despite poor survival, controversies remain in the treatment for refractory or relapsed pediatric non-Hodgkin lymphoma (r/r NHL). The current project aimed to collect international experience on the re-induction treatment of r/r NHL, hematopoietic stem cell transplantation (HSCT), risk factors associated with outcome, and to suggest treatment recommendations. Inclusion criteria were (i) refractory disease, disease progression or relapse of any NHL subtype except anaplastic large cell lymphoma, (ii) age < 18 years at initial diagnosis, (iii) diagnosis in/after January 2000. Data from 639 eligible patients were evaluable. The eight-year probability of overall survival was 34 ± 2% with highly significant differences according to NHL subtypes: 28 ± 3% for 254 Burkitt lymphoma/leukemia, 50 ± 6% for 98 diffuse large B-cell lymphomas, 57 ± 8% for 41 primary mediastinal large B-cell lymphomas, 27 ± 3% for 177 T-lymphoblastic lymphomas, 52 ± 10% for 34 precursor-B-cell lymphoblastic lymphomas and 30 ± 9% for 35 patients with rare NHL subtypes. Subtype-specific factors associated with survival and treatment recommendations are suggested. There were no survivors without HSCT, except in few very small subgroups. Conclusions: There is an urgent need to further improve survival in r/r NHL. The current study provides the largest real-world series, which underlines the role of HSCT and suggests treatment recommendations.

Data on the spectrum of second malignant neoplasms (SMNs) after primary childhood non-Hodgkin's lymphoma (NHL) are scarce. One-hundred-and-eighty-nine NHL patients diagnosed in a 30 years period of 1980-2010 developing an SMN were retrieved from 19 members of the European Intergroup for Childhood NHL and/or the international Berlin-Frankfurt-Münster Study Group. Five subgroups of SMNs were identified: (1) myeloid neoplasms (n = 43; 23%), (2) lymphoid neoplasms (n = 51; 27%), (3) carcinomas (n = 48; 25%), (4) central nervous system (CNS) tumors (n = 19; 10%), and (5) "other" SMNs (n = 28; 15%). In 37 patients (20%) preexisting disorders were reported with 90% having any kind of cancer predisposition syndrome (CPS). For the 189 primary NHL patients, 5-year overall survival (OS) after diagnosis of an SMN was 56 ± 4%, being worst for patients with preexisting disorders at 28 ± 8%. Five-year OS rates were 38 ± 8%, 59 ± 7%, 79 ± 8%, 34 ± 12%, and 62 ± 11%, respectively, for patients with myeloid and lymphoid neoplasms, carcinomas, CNS tumors, and "other" SMNs (p < 0.0001). Patients with SMNs after childhood NHL having a reported CPS, mostly mismatch repair disorders, carried a very poor prognosis. Moreover, although outcome was favorable in some subtypes of SMNs after childhood NHL (carcinomas, lymphoid neoplasms), other SMNs such as myeloid neoplasms and CNS tumors had a dismal prognosis.

Introduction: Zucker diabetic fatty (ZDF) rats are used widely as an animal model of metabolic syndrome and insulin resistance. Our study focused on the effects of high versus low dietary fat on the development of Type 2 diabetes in obese male ZDF rats (fa/fa), including biomarkers to detect early signs of hypercoagulability and vascular injury in the absence of overt thrombosis., Methods: In this study, male (5/group) 10-week-old CRL:ZDF370(obese) rats were fed low (LFD, 16.7% fat) or high fat (HFD, 60% fat) diet for 12 or 15 weeks. Cohorts of 5 rats within diet groups were scheduled for sample collection after weeks 12 and 15., Results: HFD-fed ZDF rats had oily coats, lower rates of food consumption, more accelerated weight gain and increased serum cholesterol (+15%) and triglyceride concentrations (+75%) vs. LFD-fed ZDF rats. Urinary ketones were observed only in HFD-fed ZDF rats and greater urine glucose and protein concentrations in HFD-fed ZDF vs. LFD-fed ZDF rats were seen. Hemostasis testing showed ~2-fold greater fibrinogen concentration, increased von Willebrand factor concentration, and high thrombin generation in HFD-fed ZDF vs LFD-fed ZDF rats. Increased mortality in the HFD-fed ZDF rat was attributed to exacerbations of altered carbohydrate metabolism as evidenced by ketonuria and nephropathy leading to renal failure., Discussion: This characterization shows that the ZDF rat at the age, sex and weight used in this study is highly sensitive to dietary fat content that can exacerbate prothrombotic, metabolic and renal disturbances and increase mortality., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Hepatocellular carcinoma (HCC) is a rare hepatic malignancy in children. Hepatitis B virus (HBV) infection is a key predisposing factor in endemic regions but its impact on outcome has not been studied. We aim to evaluate the prognostic implication of HBV seropositivity and role of cancer surveillance in children with HCC from East Asian populations with national HBV vaccination., Methods: Review of population-based databases for patients (< 18 years old) diagnosed with HCC from 1993 to 2017 in two Southeast Asian regions with universal HBV vaccination (instituted since 1988 and 1987 in Hong Kong and Singapore, respectively)., Results: Thirty-nine patients were identified (Hong Kong, 28; Singapore, 11). Thirty were male; median age at diagnosis was 10.8 years (range, 0.98-16.6). Abdominal pain was the commonest presentation while five patients were diagnosed through surveillance for underlying condition. Alpha-fetoprotein was raised in 36 patients (mean, 500,598 ng/ml). Nineteen had bilobar involvement, among the patients in whom pretreatment extent of disease (PRETEXT) staging could retrospectively be assigned, 3 had stage I, 13 had stage II, 4 had stage III, and 11 had stage IV disease. Seventeen had distant metastasis. HBsAg was positive in 19 of 38 patients. Two patients had fibrolamellar HCC. Upfront management involved tumor resection in 16 (liver transplantation, 2), systemic chemotherapy in 21, interventional procedures in 6 [transarterial chemoembolization (TACE), 5, radiofrequency ablation (RFA), 1], and radiotherapy in 4 (selective internal radiation, 3, external beam radiation, 1). Five-year event-free survival (EFS) and overall survival (OS) were 15.4 ± 6.0 and 26.1 ± 7.2%, respectively. Patient's HBsAg positivity, metastatic disease and inability to undergo definitive resection represent poor prognostic factors in univariate and multivariable analyses. Patients diagnosed by surveillance had significantly better outcome., Conclusion: Pediatric HCC has poor outcome. HBV status remains relevant in the era of universal HBV vaccination. HBV carrier has inferior outcome and use of surveillance may mitigate disease course., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Liu, Soh, Cheng, Pang, Luk, Li, Ho, Chan, Chan, Chung, Kimpo, Ahamed, Loh and Chiang.)

Oral appliance (OA) therapy is the leading alternative to continuous positive airway pressure (CPAP) for obstructive sleep apnea (OSA). It is well tolerated compared with CPAP. However, ≥50% of patients using OA therapy have incomplete resolution of their OSA. Combination therapy with CPAP and oral appliance (CPAP + OA) is a potential alternative for incomplete responders to OA therapy. This study aimed to determine the extent to which combination therapy reduces therapeutic CPAP requirements using gold-standard physiological methodology in those who have an incomplete response to OA therapy alone. Sixteen incomplete responders [residual apnea/hypopnea index (AHI) > 10 events/h] to a novel OA with a built-in oral airway were recruited (3 women:13 men, aged 31-65 yr, body mass index: 22-38 kg/m 2 , residual AHI range: 13-63 events/h). Participants were fitted with a nasal mask, pneumotachograph, epiglottic pressure catheter, and standard polysomnography equipment. CPAP titrations were performed during non-rapid eye movement (NREM) supine sleep in each participant during three conditions (order randomized): CPAP only, CPAP + OA (oral airway open), and CPAP + OA (oral airway closed). OSA was resolved at pressures of 4 ± 2 and 5 ± 2 cmH 2 O during CPAP + OA (oral airway open) and CPAP + OA (oral airway closed) conditions versus 8 ± 2 cmH 2 O during CPAP only ( P < 0.01). Negative epiglottic pressure swings in oral airway open and closed conditions were normalized to CPAP only levels [-2.5(-3.7, -2.6) vs. -2.3(-3.2, -2.4) vs. -2.1(-2.7, -2.3) cmH 2 O]. Combined CPAP and OA therapy reduces therapeutic CPAP requirements by 35%-45% and minimizes epiglottic pressure swings. This combination may be a therapeutic alternative for patients with incomplete responses to OA therapy alone and those who cannot tolerate high CPAP levels. NEW & NOTEWORTHY Combined CPAP and oral appliance therapy has been suggested as an alternative for incomplete responders to oral appliance therapy. We used a novel oral appliance incorporating an oral airway together with CPAP to show that pharyngeal pressure swings were normalized at reduced CPAP levels. Our findings demonstrate that using CPAP and oral appliance together may be a beneficial alternative for incomplete responders to oral appliance therapy and intolerant CPAP users due to high-pressure requirements.

Introduction: JUNIPER compared the efficacy and safety of abemaciclib, a selective cyclin-dependent kinase 4 and 6 inhibitor, with erlotinib in patients with non-small cell lung cancer (NSCLC) harboring a Kirsten rat sarcoma ( KRAS ) mutation., Methods: JUNIPER was a Phase III, multicenter, randomized, open-label trial of abemaciclib versus erlotinib in patients with stage IV NSCLC and a detectable mutation in codons 12 or 13 of the KRAS oncogene, who progressed after platinum-based chemotherapy and 1 additional therapy (could include immune checkpoint inhibitor therapy). Randomized patients (3:2) received either 200 mg abemaciclib twice daily or 150 mg erlotinib once daily with best supportive care until disease progression or unacceptable toxicity. The primary endpoint was overall survival (OS); secondary endpoints included overall response rate (ORR), progression-free survival (PFS), and safety., Results: Between December 2014 and April 2017, 453 patients were randomly assigned to receive abemaciclib (N = 270) or erlotinib (N = 183). Median OS was 7.4 months (95% confidence interval [CI]: 6.5, 8.8) with abemaciclib and 7.8 months (95% CI: 6.4, 9.5) with erlotinib (hazard ratio [HR] = 0.968 [95% CI: 0.768, 1.219]; p = .77). Median PFS was 3.6 months (95% CI: 2.8, 3.8) with abemaciclib and 1.9 months (95% CI: 1.9, 2.0) with erlotinib (HR = 0.583 [95% CI: 0.470, 0.723]; p <.000001). ORR was 8.9% and 2.7% (p = .010), and the disease control rate was 54.4% and 31.7% (p <.001) with abemaciclib and erlotinib, respectively. Safety results reflected the known safety profiles of abemaciclib and erlotinib., Conclusions: In this study, the primary endpoint of OS was not met; PFS and ORR were improved with manageable toxicity in the abemaciclib arm. The increases in response rates and PFS support further investigation of abemaciclib in other NSCLC subpopulations or in combination with other agents., Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT02152631., (Copyright © 2020 Goldman, Mazieres, Barlesi, Dragnev, Koczywas, Göskel, Cortot, Girard, Wesseler, Bischoff, Nadal, Park, Lu, Taus, Cobo, Estrem, Wijayawardana, Turner, Oakley, Hurt, Chiang, Hossain, John and Paz-Ares.)

Key Points: A decreased respiratory arousal threshold is one of the main contributors to obstructive sleep apnoea (OSA) pathogenesis. Several recent studies have sought to find a drug capable of increasing the respiratory arousal threshold without impairing pharyngeal muscle activity to reduce OSA severity, with variable success. Here we show that zolpidem increases the respiratory arousal threshold by ∼15%, an effect size which was insufficient to systematically decrease OSA severity as measured by the apnoea-hypopnoea index. Unlike recent physiological findings that showed paradoxical increases in pharyngeal muscle responsiveness during transient manipulations of airway pressure, zolpidem did not alter pharyngeal muscle responsiveness during natural sleep. It did, however, increase sleep efficiency without changing apnoea length, oxygen desaturation, next-day perceived sleepiness and alertness. These novel findings indicate that zolpidem was well tolerated and effective in promoting sleep in people with OSA, which may be therapeutically useful for people with OSA and comorbid insomnia., Abstract: A recent physiology study performed using continuous positive airway pressure (CPAP) manipulations indicated that the hypnotic zolpidem increases the arousal threshold and genioglossus responsiveness in people with and without obstructive sleep apnoea (OSA). Thus, zolpidem may stabilise breathing and reduce OSA severity without CPAP. Accordingly, we sought to determine the effects of zolpidem on OSA severity, upper airway physiology and next-day sleepiness and alertness. Nineteen people with OSA with low-to-moderate arousal threshold received 10 mg zolpidem or placebo according to a double-blind, randomised, cross-over design. Participants completed two overnight in-laboratory polysomnographies (1-week washout), with an epiglottic catheter, intramuscular genioglossus electromyography, nasal mask and pneumotachograph to measure OSA severity, arousal threshold and upper airway muscle responsiveness. Next-morning sleepiness and alertness were also assessed. Zolpidem did not change the apnoea-hypopnoea index versus placebo (40.6 ± 12.3 vs. 40.3 ± 16.4 events/h (means ± SD), p = 0.938) or nadir oxyhaemoglobin saturation (79.6 ± 6.6 vs. 79.7 ± 7.4%, p = 0.932), but was well tolerated. Zolpidem increased sleep efficiency by 9 ± 14% (83 ± 11 vs. 73 ± 17%, p = 0.010). Arousal threshold increased by 15 ± 5% with zolpidem throughout all sleep stages (p = 0.010), whereas genioglossus muscle responsiveness did not change. Next-morning sleepiness and alertness were not different between nights. In summary, a single night of 10 mg zolpidem is well tolerated and does not cause next-day impairment in alertness or sleepiness, or overnight hypoxaemia in OSA. However, despite increases in arousal threshold without any change in pharyngeal muscle responsiveness, zolpidem does not alter OSA severity. It does, however, increase sleep efficiency by ∼10%, which may be beneficial in people with OSA and insomnia., (© 2020 The Authors. The Journal of Physiology © 2020 The Physiological Society.)

Epstein-Barr virus (EBV) lytic induction therapy is an emerging virus-targeted therapeutic approach that exploits the presence of EBV in tumor cells to confer specific killing effects against EBV-associated malignancies. Efforts have been made in the past years to uncover the mechanisms of EBV latent-lytic switch and discover different classes of chemical compounds that can reactivate the EBV lytic cycle. Despite the growing list of compounds showing potential to be used in the lytic induction therapy, only a few are being tested in clinical trials, with varying degrees of success. This review will summarize the current knowledge on EBV lytic reactivation, the major hurdles of translating the lytic induction therapy into clinical settings, and highlight some potential strategies in the future development of this therapy for EBV-related lymphoid and epithelial malignancies.

Introduction: Temporomandibular disorder is a common musculoskeletal pain condition with development of chronic symptoms in 49% of patients. Although a number of biological factors have shown an association with chronic temporomandibular disorder in cross-sectional and case control studies, there are currently no biomarkers that can predict the development of chronic symptoms. The PREDICT study aims to undertake analytical validation of a novel peak alpha frequency (PAF) and corticomotor excitability (CME) biomarker signature using a human model of the transition to sustained myofascial temporomandibular pain (masseter intramuscular injection of nerve growth factor [NGF]). This article describes, a priori, the methods and analysis plan., Methods: This study uses a multisite longitudinal, experimental study to follow individuals for a period of 30 days as they progressively develop and experience complete resolution of NGF-induced muscle pain. One hundred fifty healthy participants will be recruited. Participants will complete twice daily electronic pain diaries from day 0 to day 30 and undergo assessment of pressure pain thresholds, and recording of PAF and CME on days 0, 2, and 5. Intramuscular injection of NGF will be given into the right masseter muscle on days 0 and 2. The primary outcome is pain sensitivity., Perspective: PREDICT is the first study to undertake analytical validation of a PAF and CME biomarker signature. The study will determine the sensitivity, specificity, and accuracy of the biomarker signature to predict an individual's sensitivity to pain., Registration Details: ClinicalTrials.gov: NCT04241562 (prospective)., Competing Interests: D.A. Seminowicz and A.J. Furman have a patent pending for “A Simple and Portable Biomarker for Pain Sensitivity”. The authors have no other conflicts of interest to declare.Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.)

HIV and EBV are human pathogens that cause a considerable burden to worldwide health. In combination, these viruses are linked to AIDS-associated lymphomas. We found that EBV, which transforms B cells, renders them susceptible to HIV-1 infection in a CXCR4 and CD4-dependent manner in vitro and that CXCR4-tropic HIV-1 integrates into the genome of these B cells with the same molecular profile as in autologous CD4 + T cells. In addition, we established a humanized mouse model to investigate the in vivo interactions of EBV and HIV-1 upon coinfection. The respective mice that reconstitute human immune system components upon transplantation with CD34 + human hematopoietic progenitor cells could recapitulate aspects of EBV and HIV immunobiology observed in dual-infected patients. Upon coinfection of humanized mice, EBV/HIV dual-infected B cells could be detected, but were susceptible to CD8 + T-cell-mediated immune control., (© 2020 McHugh et al.)

Post-transplant lymphoproliferative disorder (PTLD) is a rare but potentially life-threatening complication, frequently associated with Epstein-Barr virus (EBV), which develops after solid organ or stem cell transplantation. Immunosuppression received by transplant recipients has a significant impact on the development of PTLD by suppressing the function of T cells. The preferential proliferation of NKG2A-positive natural killer (NK) cells during primary symptomatic EBV infection known as infectious mononucleosis (IM) and their reactivity toward EBV-infected B cells point to a role of NK cell in the immune control of EBV. However, NK cell-mediated immune response to EBV in immunosuppressed transplant recipients who develop PTLD remains unclear. In this study, we longitudinally analyzed the phenotype and function of different NK cell subsets in a cohort of pediatric liver transplant patients who develop PTLD and compared them to those of children with IM. We found persistently elevated plasma EBV DNA levels in the PTLD patients indicating suboptimal anti-viral immune control. PTLD patients had markedly decreased frequency of CD56 dim NKG2A + Killer Immunoglobulin-like receptor (KIR) - NK cells from the time of diagnosis through remission compared to those of IM patients. Whilst the proliferation of CD56 dim NKG2A + KIR - NK cells was diminished in PTLD patients, this NK cell subset maintained its ability to potently degranulate against EBV-infected B cells. Compared to cytomegalovirus (CMV)-seropositive and -negative IM patients, PTLD patients co-infected with CMV and EBV had significantly higher levels of a CMV-associated CD56 dim NKG2C hi CD57 + NKG2A - KIR + NK cell subset accumulating at the expense of NKG2A + KIR - NK cells. Taken together, our data indicate that co-infection of CMV and EBV diminishes the frequency of CD56 dim NKG2A + KIR - NK cells and contributes to suboptimal control of EBV in immunosuppressed children with PTLD., (Copyright © 2020 Lam, Azzi, Hui, Wong, McHugh, Caduff, Chan, Münz and Chiang.)

Background: Rituximab added to chemotherapy prolongs survival among adults with B-cell cancer. Data on its efficacy and safety in children with high-grade, mature B-cell non-Hodgkin's lymphoma are limited., Methods: We conducted an open-label, international, randomized, phase 3 trial involving patients younger than 18 years of age with high-risk, mature B-cell non-Hodgkin's lymphoma (stage III with an elevated lactate dehydrogenase level or stage IV) or acute leukemia to compare the addition of six doses of rituximab to standard lymphomes malins B (LMB) chemotherapy with standard LMB chemotherapy alone. The primary end point was event-free survival. Overall survival and toxic effects were also assessed., Results: Analyses were based on 328 patients who underwent randomization (164 patients per group); 85.7% of the patients had Burkitt's lymphoma. The median follow-up was 39.9 months. Events were observed in 10 patients in the rituximab-chemotherapy group and in 28 in the chemotherapy group. Event-free survival at 3 years was 93.9% (95% confidence interval [CI], 89.1 to 96.7) in the rituximab-chemotherapy group and 82.3% (95% CI, 75.7 to 87.5) in the chemotherapy group (hazard ratio for primary refractory disease or first occurrence of progression, relapse after response, death from any cause, or second cancer, 0.32; 95% CI, 0.15 to 0.66; one-sided P = 0.00096, which reached the significance level required for this analysis). Eight patients in the rituximab-chemotherapy group died (4 deaths were disease-related, 3 were treatment-related, and 1 was from a second cancer), as did 20 in the chemotherapy group (17 deaths were disease-related, and 3 were treatment-related) (hazard ratio, 0.36; 95% CI, 0.16 to 0.82). The incidence of acute adverse events of grade 4 or higher after prephase treatment was 33.3% in the rituximab-chemotherapy group and 24.2% in the chemotherapy group (P = 0.07); events were related mainly to febrile neutropenia and infection. Approximately twice as many patients in the rituximab-chemotherapy group as in the chemotherapy group had a low IgG level 1 year after trial inclusion., Conclusions: Rituximab added to standard LMB chemotherapy markedly prolonged event-free survival and overall survival among children and adolescents with high-grade, high-risk, mature B-cell non-Hodgkin's lymphoma and was associated with a higher incidence of hypogammaglobulinemia and, potentially, more episodes of infection. (Funded by the Clinical Research Hospital Program of the French Ministry of Health and others; ClinicalTrials.gov number, NCT01516580.)., (Copyright © 2020 Massachusetts Medical Society.)

Detection of test article-related effects and the determination of the adversity of those changes are the primary goals of nonclinical safety assessment studies for drugs and chemicals in development. During these studies, variables that are not of primary interest to investigators may change and influence data interpretation. These variables, often referred to as "nuisance factors," may influence other groups of data and result in "block or batch effects" that complicate data interpretation. Definitions of the terms "nuisance factors," "block effects," and "batch effects," as they apply to nonclinical safety assessment studies, are reviewed. Multiple case examples of block and batch effects in safety assessment studies are provided, and the challenges these bring to pathology data interpretation are discussed. Methods to mitigate the occurrence of block and batch effects in safety assessment studies, including statistical blocking and utilization of study designs that minimize potential confounding variables, incorporation of adequate randomization, and use of an appropriate number of animals or repeated measurement of specific parameters for increased precision, are reviewed. [Box: see text].

Study Objectives: High nasal resistance is associated with oral appliance treatment failure in obstructive sleep apnea (OSA). A novel oral appliance with a built-in oral airway has been shown to reduce pharyngeal pressure swings during sleep and may be efficacious in those with high nasal resistance. The role of posture and mandibular advancement on nasal resistance in OSA remains unclear. This study aimed to determine (1) the effects of posture and mandibular advancement on nasal resistance in OSA and (2) the efficacy of a new oral appliance device including in patients with high nasal resistance., Methods: A total of 39 people with OSA (7 females, apnea-hypopnea index (AHI) (mean ± standard deviation) = 29 ± 21 events/h) completed split-night polysomnography with and without oral appliance (order randomized). Prior to sleep, participants were instrumented with a nasal mask, pneumotachograph, and a choanal pressure catheter for gold standard nasal resistance quantification seated, supine and lateral (with and without oral appliance, order randomized)., Results: Awake nasal resistance increased from seated, to supine, to lateral posture (median [interquartile range] = 1.8 [1.4, 2.7], 2.7 [1.7, 3.5], 3.4 [1.9, 4.6] cm H₂O/L/s, P < .001). Corresponding measures of nasal resistance did not change with mandibular advancement (2.3 [1.4, 3.5], 2.5 [1.8, 3.6], 3.5 [1.9, 4.8] cm H₂O/L/s, P = .388). The median AHI reduced by 47% with oral appliance therapy (29 ± 21 versus 18 ± 15 events/h, P = .002). Participants with high nasal resistance (> 3 cm H₂O/L/s) had similar reductions in AHI versus those with normal nasal resistance (61 [-8, 82] versus 40 [-5, 62] %, P = .244)., Conclusions: Nasal resistance changes with posture in people with OSA. A novel oral appliance with a built-in oral airway reduces OSA severity in people with OSA, including in those with high nasal resistance., Clinical Trial Registration: Registry: ANZCTR; Title: Combination therapy for obstructive sleep apnoea; Identifier: ACTRN12617000492358; URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=372279., (© 2020 American Academy of Sleep Medicine.)

Post-transplant lymphoproliferative disorder (PTLD) is a potentially fatal complication after organ transplantation frequently associated with the Epstein-Barr virus (EBV). Immunosuppressive treatment is thought to allow the expansion of EBV-infected B cells, which often express all eight oncogenic EBV latent proteins. Here, we assessed whether HLA-A2 transgenic humanized NSG mice treated with the immunosuppressant FK506 could be used to model EBV-PTLD. We found that FK506 treatment of EBV-infected mice led to an elevated viral burden, more frequent tumor formation and diminished EBV-induced T cell responses, indicative of reduced EBV-specific immune control. EBV latency III and lymphoproliferation-associated cellular transcripts were up-regulated in B cells from immunosuppressed animals, akin to the viral and host gene expression pattern found in EBV-PTLD. Utilizing an unbiased gene expression profiling approach, we identified genes differentially expressed in B cells of EBV-infected animals with and without FK506 treatment. Upon investigating the most promising candidates, we validated sCD30 as a marker of uncontrolled EBV proliferation in both humanized mice and in pediatric patients with EBV-PTLD. High levels of sCD30 have been previously associated with EBV-PTLD in patients. As such, we believe that humanized mice can indeed model aspects of EBV-PTLD development and may prove useful for the safety assessment of immunomodulatory therapies., Competing Interests: The authors have declared that no competing interests exist.