Early-phase clinical trial eligibility and response evaluation criteria for refractory, relapsed, or progressive neuroblastoma: A consensus statement from the National Cancer Institute Clinical Trials Planning Meeting

Consensus criteria; Early phase; NeuroblastomaCriteris de consens; Fase inicial; NeuroblastomaCriterios de consenso; Fase inicial; NeuroblastomaBackground International standardized criteria for eligibility, evaluable disease sites, and disease response assessment in patients with refractory, progressive, or relapsed high-risk neuroblastoma enrolled in early-phase clinical trials are lacking. Methods A National Cancer Institute–sponsored Clinical Trials Planning Meeting was convened to develop an international consensus to refine the tumor site eligibility criteria and evaluation of disease response for early-phase clinical trials in children with high-risk neuroblastoma. Results Standardized data collection of patient and disease characteristics (including specified genomic data), eligibility criteria, a definition of evaluable disease, and response evaluations for primary and metastatic sites of disease were developed. Eligibility included two distinct patient groups: progressive disease and refractory disease. The refractory disease group was subdivided into responding persistent disease and stable persistent disease to better capture the clinical heterogeneity of refractory neuroblastoma. Requirements for defining disease evaluable for a response assessment were provided; they included requirements for biopsy to confirm viable neuroblastoma and/or ganglioneuroblastoma in those patients with soft tissue or bone disease not avid for iodine-123 meta-iodobenzylguanidine. Standardized evaluations for response components and time intervals for response evaluations were established. Conclusions The use of international consensus eligibility, evaluability, and response criteria for early-phase clinical studies will facilitate the collection of comparable data across international trials and promote more rapid identification of effective treatment regimens for high-risk neuroblastoma.National Cancer Institute Pediatric and Adolescent Solid Tumor Steering Committee; Alex's Lemonade Stand Foundation for Childhood Cancer; Ben Towne Foundation; EVAN Foundation; Cancer Research UK Institute of Cancer Research, Grant/Award Number C347/A15403; National Institute for Health Research Research Methods Programme/Institute of Cancer Research Biomedical Research Centre

ERβ Binds N-CoR in the Presence of Estrogens via an LXXLL-like Motif in the N-CoR C-terminus

Nuclear receptors (NRs) usually bind the corepressors N-CoR and SMRT in the absence of ligand or in the presence of antagonists. Agonist binding leads to corepressor release and recruitment of coactivators. Here, we report that estrogen receptor β (ERβ) binds N-CoR and SMRT in the presence of agonists, but not antagonists, in vitro and in vivo. This ligand preference differs from that of ERα interactions with corepressors, which are inhibited by estradiol, and resembles that of ERβ interactions with coactivators. ERβ /N-CoR interactions involve ERβ AF-2, which also mediates coactivator recognition. Moreover, ERβ recognizes a sequence (PLTIRML) in the N-CoR C-terminus that resembles coactivator LXXLL motifs. Inhibition of histone deacetylase activity specifically potentiates ERβ LBD activity, suggesting that corepressors restrict the activity of AF-2. We conclude that the ER isoforms show completely distinct modes of interaction with a physiologically important corepressor and discuss our results in terms of ER isoform specificity in vivo

Skeletal muscle metastases in neuroblastoma share common progenitors with primary tumor and biologically resemble stage MS disease

IntroductionWhile subcutaneous metastases are often observed with stage MS neuroblastoma, an entity that usually resolves spontaneously, skeletal muscle metastases (SMM) have been rarely described. The purpose of this retrospective study was to investigate the significance of SMM in neuroblastoma.Patients and methodsSeventeen patients with neuroblastoma SMM were diagnosed at a median age of 4.3 (0.1-15.6) months. All had SMM at diagnosis and metastases at other sites. Fifteen (88%) had ≥ 2 SMM in disparate muscle groups. One, 14, and 2 patients had low, intermediate, and high-risk disease respectively. Fifteen tumors had favorable histology without MYCN amplification, and 2 were MYCN-amplified. Most SMM (80%; n=12/15 evaluated) were MIBG-avid.ResultsOnly 1 patient (with MYCN-non-amplified neuroblastoma) had disease progression. All survive at median follow-up of 47.9 (16.9-318.9) months post-diagnosis. Biological markers (histology, chromosomal and genetic aberrations) were not prognostic. Whole genome sequencing of 3 matched primary and SMM lesions suggested that both primary and metastatic tumors arose from the same progenitor. SMM completely resolved in 10 patients by 12 months post-diagnosis. Of 4 patients managed with watchful observation alone without any cytotoxic therapy, 3 maintain complete remission with SMM resolving by 5, 13, and 21 months post-diagnosis respectively.ConclusionsChildren with neuroblastoma SMM have an excellent prognosis, with a clinical course suggestive of stage MS disease. Based on these results, the initial management of infants with non-MYCN-amplified NB with SMM could be watchful observation, which could eliminate or reduce exposure to genotoxic therapy

Topical Application of a Mucoadhesive Freeze-Dried Black Raspberry Gel Induces Clinical and Histologic Regression and Reduces Loss of Heterozygosity Events in Premalignant Oral Intraepithelial Lesions: Results from a Multicentered, Placebo-Controlled Clinical Trial

Approximately 30%higher-grade premalignant oral intraepithelial neoplasia (OIN) lesions will progress to oral cancer. While surgery is the OIN treatment mainstay, many OIN lesions recur which is highly problematic for both surgeons and patients. This clinical trial assessed the chemopreventive efficacy of a natural-product based bioadhesive gel on OIN lesions

Specific gene expression profiles and chromosomal abnormalities are associated with infant disseminated neuroblastoma

Background: Neuroblastoma (NB) tumours have the highest incidence of spontaneous remission, especially among the stage 4s NB subgroup affecting infants. Clinical distinction of stage 4s from lethal stage 4 can be difficult, but critical for therapeutic decisions. The aim of this study was to investigate chromosomal alterations and differential gene expression amongst infant disseminated NB subgroups. Methods: Thirty-five NB tumours from patients diagnosed at < 18 months (25 stage 4 and 10 stage 4s), were evaluated by allelic and gene expression analyses. Results: All stage 4s patients underwent spontaneous remission, only 48% stage 4 patients survived despite combined modality therapy. Stage 4 tumours were 90% near-diploid/tetraploid, 44% MYCN amplified, 77% had 1p LOH (50% 1p36), 23% 11q and/or 14q LOH (27%) and 47% had 17q gain. Stage 4s were 90% near-triploid, none MYCN amplified and LOH was restricted to 11q. Initial comparison analyses between stage 4s and 4 < 12 months tumours revealed distinct gene expression profiles. A significant portion of genes mapped to chromosome 1 (P < 0.0001), 90% with higher expression in stage 4s, and chromosome 11 (P = 0.0054), 91% with higher expression in stage 4. Less definite expression profiles were observed between stage 4s and 4 < 18m, yet, association with chromosomes 1 (P < 0.0001) and 11 (P = 0.005) was maintained. Distinct gene expression profiles but no significant association with specific chromosomal region localization was observed between stage 4s and stage 4 < 18 months without MYCN amplification. Conclusion: Specific chromosomal aberrations are associated with distinct gene expression profiles which characterize spontaneously regressing or aggressive infant NB, providing the biological basis for the distinct clinical behaviour

Human total, basal and activity energy expenditures are independent of ambient environmental temperature

Acknowledgments The DLW database, which can be found at https://www.dlwdatabase.org, is hosted by the International Atomic Energy Agency (IAEA) and generously supported by Taiyo Nippon Sanso and SERCON . We are grateful to the IAEA and these companies for their support. XYZ was supported by the Chinese Academy of Sciences (grant CAS 153E11KYSB20190045 to J.R.S.), and the database was also supported by the US National Science Foundation (grant BCS-1824466 to H.P.). The funders played no role in the content of this manuscript.Peer reviewedPublisher PD

Total Daily Energy Expenditure Has Declined over the Past Three Decades Due to Declining Basal Expenditure, Not Reduced Activity Expenditure

Obesity is caused by prolonged positive energy balance1,2. Whether reduced energy expenditure stemming from reduced activity levels contributes, is debated3,4. Here we used the IAEA DLW database on energy expenditure of adults in the USA and Europe (n = 4799) to explore patterns in total (TEE: n=4799), basal (BEE: n = 1432) and physical activity energy expenditure (AEE: n = 1432) over time. In both sexes total energy expenditure (TEE) adjusted for body composition and age declined with time, while adjusted AEE increased over time. In males adjusted BEE decreased significantly, but in females this didn’t reach significance. A larger dataset of basal metabolic rate (BMR equivalent to BEE) measurements of 9912 adults across 163 studies spanning 100 years replicated the decline in BEE in both sexes. Increasing obesity in the USA/Europe has probably not been fueled by reduced physical activity leading to lowered TEE. We identify here decline in adjusted BEE, as a previously unrecognized novel factor

Variability in energy expenditure is much greater in males than females

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Variability in energy expenditure is much greater in males than females

In mammals, trait variation is often reported to be greater among males than females. However, to date, mainly only morphological traits have been studied. Energy expenditure represents the metabolic costs of multiple physical, physiological, and behavioral traits. Energy expenditure could exhibit particularly high greater male variation through a cumulative effect if those traits mostly exhibit greater male variation, or a lack of greater male variation if many of them do not. Sex differences in energy expenditure variation have been little explored. We analyzed a large database on energy expenditure in adult humans (1494 males and 3108 females) to investigate whether humans have evolved sex differences in the degree of interindividual variation in energy expenditure. We found that, even when statistically comparing males and females of the same age, height, and body composition, there is much more variation in total, activity, and basal energy expenditure among males. However, with aging, variation in total energy expenditure decreases, and because this happens more rapidly in males, the magnitude of greater male variation, though still large, is attenuated in older age groups. Considerably greater male variation in both total and activity energy expenditure could be explained by greater male variation in levels of daily activity. The considerably greater male variation in basal energy expenditure is remarkable and may be explained, at least in part, by greater male variation in the size of energy-demanding organs. If energy expenditure is a trait that is of indirect interest to females when choosing a sexual partner, this would suggest that energy expenditure is under sexual selection. However, we present a novel energetics model demonstrating that it is also possible that females have been under stabilizing selection pressure for an intermediate basal energy expenditure to maximize energy available for reproduction. (C) 2022 The Author(s). Published by Elsevier Ltd.Peer reviewe