Treatment at Relapse for Synovial Sarcoma of Children, Adolescents and Young Adults:From the State of Art to Future Clinical Perspectives

While the overall prognosis is generally quite satisfactory in children, adolescents and young adults with localised synovial sarcoma at first diagnosis, the outcome remains poor for patients after relapse. Conversely to the front-line standardised treatment options, patients with relapse generally have an individualised approach and to date, there is still a lack of consensus regarding standard treatment approaches. Studies on relapsed synovial sarcoma were able to identify some prognostic variables that influence post-relapse survival, in order to plan risk-adapted salvage protocols. Treatment proposals must consider previous first-line treatments, potential toxicities, and the possibility of achieving an adequate local treatment by new surgery and/or re-irradiation. Effective second-line drug therapies are urgently needed. Notably, experimental treatments such as adoptive engineered TCR-T cell immunotherapy seem promising in adults and are currently under validation also in paediatric patients.</p

Pediatric Non-Rhabdomyosarcoma Soft Tissue Sarcomas:Standard of Care and Treatment Recommendations from the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG)

This paper describes the standard of care for patients with non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) and the therapeutic recommendations developed by the European paediatric Soft tissue sarcoma Study Group (EpSSG). NRSTS form a very mixed group of mesenchymal extraskeletal malignancies. Their rarity, heterogeneity, and aggressiveness make the management of children and adolescents with these tumors complex and challenging. The overall cure rate for patients with NRSTS is around 70%, but survival depends on several prognostic variables, such as histotype and tumor grade, extent of disease and stage, tumor size, and tumor site. While surgery remains the mainstay of treatment for most of these tumors, a multimodal therapeutic approach including radiotherapy and chemotherapy is required in many cases. The EpSSG NRSTS 2005 study was the first prospective protocol tailored specifically to NRSTS. Together with the ARST0332 study developed by the North-American Soft Tissue Sarcoma Committee of the Children’s Oncology Group (COG), the EpSSG NRSTS 2005 study currently represents the benchmark for these tumors, establishing risk-adapted standards of care. The EpSSG has developed common treatment recommendations for the large group of adult-type NRSTS (including synovial sarcoma), and specific treatment recommendations for other particular adult-type histologies (ie, alveolar soft-part sarcoma, clear cell sarcoma and dermatofibrosarcoma protuberans); other highly malignant tumors with a biology and clinical behavior differing from those of adult-type NRSTS (ie, rhabdoid tumors and desmoplastic small round cell tumor); and soft tissue tumors of intermediate malignancy (ie desmoid-type fibromatosis, inflammatory myofibroblastic tumors, and infantile fibrosarcoma). New effective drugs are needed for patients whose NRSTS carries the worst prognosis, ie, those with unresectable tumors, metastases at diagnosis, or relapsing disease. Progress in this area relies on our ability to develop international integrated prospective collaborations, both within existing pediatric oncology networks and, importantly, between the communities of specialists treating pediatric and adult sarcoma.</p

Depot-Specific Adipose Tissue Metabolite Profiles and Corresponding Changes Following Aerobic Exercise

Objectives: Total, visceral, and abdominal subcutaneous adipose tissue (AT) depots have distinct associations with cardiometabolic health; however, the metabolite profiles that characterize each AT depot and its reduction following exercise are poorly understood. Our objectives were to (1) assess the independent associations between identified metabolites and total, visceral and abdominal subcutaneous AT; and (2) examine whether changes in metabolite concentrations and AT mass following aerobic exercise are associated.Methods: A secondary analysis was performed in 103 middle-aged abdominally obese men and women {[mean (SD)], 52.4 (8.0) years} randomized into one of four groups varying in exercise amount and intensity for 6 months duration: high amount high intensity, high amount low intensity, low amount low intensity, and control. One hundred and forty seven metabolites were profiled by liquid chromatography-tandem mass spectrometry. AT mass was measured by magnetic resonance imaging (MRI).Results: Individual metabolite associations with AT depots confirmed several established cross-sectional relationships between the obesity phenotype and metabolic pathways. Collapsed across exercise groups, reduction in visceral AT predicted increases in pyroglutamic acid (B = −0.41) and TCA cycle intermediates [succinic (B = −0.41) and fumaric acid (B = −0.20)], independent of change in total AT. Changes in UDP-GlcNAc (B = 0.43), pyroglutamic acid (B = −0.35), histidine (B = 0.20), citric acid/isocitric acid (B = −0.20), and creatine (B = 0.27) were significantly associated with changes in total AT (false discovery rate = 0.1).Conclusions: Our findings point to potential biomarkers of depot-specific AT reduction that may play a direct role in mediating cardiometabolic improvements

The Cross-Species Mycobacterial Growth Inhibition Assay (MGIA) Project, 2010-2014.

The development of a functional biomarker assay in the tuberculosis (TB) field would be widely recognized as a major advance in efforts to develop and to test novel TB vaccine candidates efficiently. We present preliminary studies using mycobacterial growth inhibition assays (MGIAs) to detect Mycobacterium bovis BCG vaccine responses across species, and we extend this work to determine whether a standardized MGIA can be applied in characterizing new TB vaccines. The comparative MGIA studies reviewed here aimed to evaluate robustness, reproducibility, and ability to reflect in vivo responses. In doing so, they have laid the foundation for the development of a MGIA that can be standardized and potentially qualified. A major challenge ahead lies in better understanding the relationships between in vivo protection, in vitro growth inhibition, and the immune mechanisms involved. The final outcome would be a MGIA that could be used with confidence in TB vaccine trials. We summarize data arising from this project, present a strategy to meet the goals of developing a functional assay for TB vaccine testing, and describe some of the challenges encountered in performing and transferring such assays

Varespladib and cardiovascular events in patients with an acute coronary syndrome: the VISTA-16 randomized clinical trial

IMPORTANCE: Secretory phospholipase A2(sPLA2) generates bioactive phospholipid products implicated in atherosclerosis. The sPLA2inhibitor varespladib has favorable effects on lipid and inflammatory markers; however, its effect on cardiovascular outcomes is unknown. OBJECTIVE: To determine the effects of sPLA2inhibition with varespladib on cardiovascular outcomes. DESIGN, SETTING, AND PARTICIPANTS: A double-blind, randomized, multicenter trial at 362 academic and community hospitals in Europe, Australia, New Zealand, India, and North America of 5145 patients randomized within 96 hours of presentation of an acute coronary syndrome (ACS) to either varespladib (n = 2572) or placebo (n = 2573) with enrollment between June 1, 2010, and March 7, 2012 (study termination on March 9, 2012). INTERVENTIONS: Participants were randomized to receive varespladib (500 mg) or placebo daily for 16 weeks, in addition to atorvastatin and other established therapies. MAIN OUTCOMES AND MEASURES: The primary efficacy measurewas a composite of cardiovascular mortality, nonfatal myocardial infarction (MI), nonfatal stroke, or unstable angina with evidence of ischemia requiring hospitalization at 16 weeks. Six-month survival status was also evaluated. RESULTS: At a prespecified interim analysis, including 212 primary end point events, the independent data and safety monitoring board recommended termination of the trial for futility and possible harm. The primary end point occurred in 136 patients (6.1%) treated with varespladib compared with 109 patients (5.1%) treated with placebo (hazard ratio [HR], 1.25; 95%CI, 0.97-1.61; log-rank P = .08). Varespladib was associated with a greater risk of MI (78 [3.4%] vs 47 [2.2%]; HR, 1.66; 95%CI, 1.16-2.39; log-rank P = .005). The composite secondary end point of cardiovascular mortality, MI, and stroke was observed in 107 patients (4.6%) in the varespladib group and 79 patients (3.8%) in the placebo group (HR, 1.36; 95% CI, 1.02-1.82; P = .04). CONCLUSIONS AND RELEVANCE: In patients with recent ACS, varespladib did not reduce the risk of recurrent cardiovascular events and significantly increased the risk of MI. The sPLA2inhibition with varespladib may be harmful and is not a useful strategy to reduce adverse cardiovascular outcomes after ACS. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01130246. Copyright 2014 American Medical Association. All rights reserved

Dementia as a disability: Implications for ethics, policy and practice. A Discussion Paper.

noPeople experience dementia in different ways, not just in terms of the type and severity of symptoms, but also in terms of how they react to and manage living with dementia. Increasingly, people with dementia are expressing a desire to get on with their everyday lives. They want to avoid being defined solely in relation to dementia and to continue to be considered as valued members of society. This is particularly important as the term dementia often has negative connotations. It is widely considered as a stigma. Neurological impairment may interfere with people’s ability to get on with their lives, as may differences in coping skills, financial resources, the emotional and psychological impact of dementia, and access to timely and good quality support. Reactions of relatives, friends and fellow citizens are also important, as well as society’s response to dementia. This was highlighted by Kitwood in the 1990s when he outlined what came to be known as the biopsychosocial model of dementia . There are also differences at the level of society, reflected in practices, attitudes and structures. These may, on the surface, seem fair or neutral (i.e. “that’s just the way it is”). In many cases, however, they reflect a lack of consideration and failure to act in a responsible, ethical and even legal way towards people with dementia... In this report, we focus on the possible implications for ethics, policy and practice of raising awareness about the potential of framing dementia as a potential disability

School-based relationship and sexuality education intervention engaging adolescent boys for the reductions of teenage pregnancy: the JACK cluster RCT

BACKGROUND: The need to engage boys in gender-transformative relationships and sexuality education (RSE) to reduce adolescent pregnancy is endorsed by the World Health Organization and the United Nations Educational, Scientific and Cultural Organization. OBJECTIVES: To evaluate the effects of If I Were Jack on the avoidance of unprotected sex and other sexual health outcomes. DESIGN: A cluster randomised trial, incorporating health economics and process evaluations. SETTING: Sixty-six schools across the four nations of the UK. PARTICIPANTS: Students aged 13-14 years. INTERVENTION: A school-based, teacher-delivered, gender-transformative RSE intervention (If I Were Jack) versus standard RSE. MAIN OUTCOME MEASURES: Self-reported avoidance of unprotected sex (sexual abstinence or reliable contraceptive use at last sex) after 12-14 months. Secondary outcomes included knowledge, attitudes, skills, intentions and sexual behaviours. RESULTS: The analysis population comprised 6556 students: 86.6% of students in the intervention group avoided unprotected sex, compared with 86.4% in the control group {adjusted odds ratio 0.85 [95% confidence interval (CI) 0.58 to 1.26], p = 0.42}. An exploratory post hoc analysis showed no difference for sexual abstinence [78.30% intervention group vs. 78.25% control group; adjusted odds ratio 0.85 (95% CI 0.58 to 1.24), p = 0.39], but more intervention group students than control group students used reliable contraception at last sex [39.62% vs. 26.36%; adjusted odds ratio 0.52 (95% CI 0.29 to 0.920), p = 0.025]. Students in schools allocated to receive the intervention had significantly higher scores on knowledge [adjusted mean difference 0.18 (95% CI 0.024 to 0.34), p = 0.02], gender-equitable attitudes and intentions to avoid unintended pregnancy [adjusted mean difference 0.61 (95% CI 0.16 to 1.07), p = 0.01] than students in schools allocated to receive the control. There were positive but non-significant differences in sexual self-efficacy and communication skills. The total mean incremental cost of the intervention compared with standard RSE was £2.83 (95% CI -£2.64 to £8.29) per student. Over a 20-year time horizon, the intervention is likely to be cost-effective owing to its impact on unprotected sex because it would result in 379 (95% CI 231 to 477) fewer unintended pregnancies, 680 (95% CI 189 to 1467) fewer sexually transmitted infections and a gain of 10 (95% CI 5 to 16) quality-adjusted life-years per 100,000 students for a cost saving of £9.89 (95% CI -£15.60 to -£3.83). LIMITATIONS: The trial is underpowered to detect some effects because four schools withdrew and the intraclass correlation coefficient (0.12) was larger than that in sample size calculation (0.01). CONCLUSIONS: We present, to our knowledge, the first evidence from a randomised trial that a school-based, male engagement gender-transformative RSE intervention, although not effective in increasing avoidance of unprotected sex (defined as sexual abstinence or use of reliable contraception at last sex) among all students, did increase the use of reliable contraception at last sex among students who were, or became, sexually active by 12-14 months after the intervention. The trial demonstrated that engaging all adolescents early through RSE is important so that, as they become sexually active, rates of unprotected sex are reduced, and that doing so is likely to be cost-effective. FUTURE WORK: Future studies should consider the longer-term effects of gender-transformative RSE as students become sexually active. Gender-transformative RSE could be adapted to address broader sexual health and other settings. TRIAL REGISTRATION: This trial is registered as ISRCTN10751359. FUNDING: This project was funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme (PHR 15/181/01) and will be published in full in Public Health Research; Vol. 11, No. 8. See the NIHR Journals Library website for further project information

Eight common genetic variants associated with serum dheas levels suggest a key role in ageing mechanisms

Dehydroepiandrosterone sulphate (DHEAS) is the most abundant circulating steroid secreted by adrenal glands-yet its function is unknown. Its serum concentration declines significantly with increasing age, which has led to speculation that a relative DHEAS deficiency may contribute to the development of common age-related diseases or diminished longevity. We conducted a meta-analysis of genome-wide association data with 14,846 individuals and identified eight independent common SNPs associated with serum DHEAS concentrations. Genes at or near the identified loci include ZKSCAN5 (rs11761528; p = 3.15×10-36), SULT2A1 (rs2637125; p = 2.61×10-19), ARPC1A (rs740160; p = 1.56×10-16), TRIM4 (rs17277546; p = 4.50×10-11), BMF (rs7181230; p = 5.44×10-11), HHEX (rs2497306; p = 4.64×10-9), BCL2L11 (rs6738028; p = 1.72×10-8), and CYP2C9 (rs2185570; p = 2.29×10-8). These genes are associated with type 2 diabetes, lymphoma, actin filament assembly, drug and xenobiotic metabolism, and zinc finger proteins. Several SNPs were associated with changes in gene expression levels, and the related genes are connected to biological pathways linking DHEAS with ageing. This study provides much needed insight into the function of DHEAS

Consensus guidelines for sarcopenia prevention, diagnosis and management in Australia and New Zealand

Background: Sarcopenia is an age-associated skeletal muscle condition characterized by low muscle mass, strength, and physical performance. There is no international consensus on a sarcopenia definition and no contemporaneous clinical and research guidelines specific to Australia and New Zealand. The Australian and New Zealand Society for Sarcopenia and Frailty Research (ANZSSFR) Sarcopenia Diagnosis and Management Task Force aimed to develop consensus guidelines for sarcopenia prevention, assessment, management and research, informed by evidence, consumer opinion, and expert consensus, for use by health professionals and researchers in Australia and New Zealand. Methods: A four-phase modified Delphi process involving topic experts and informed by consumers, was undertaken between July 2020 and August 2021. Phase 1 involved a structured meeting of 29 Task Force members and a systematic literature search from which the Phase 2 online survey was developed (Qualtrics). Topic experts responded to 18 statements, using 11-point Likert scales with agreement threshold set a priori at >80%, and five multiple-choice questions. Statements with moderate agreement (70%–80%) were revised and re-introduced in Phase 3, and statements with low agreement (80%) were confirmed by the Task Force in Phase 4. Conclusions: The ANZSSFR Task Force present 17 sarcopenia management and research recommendations for use by health professionals and researchers which includes the recommendation to adopt the EWGSOP2 sarcopenia definition in Australia and New Zealand. This rigorous Delphi process that combined evidence, consumer expert opinion and topic expert consensus can inform similar initiatives in countries/regions lacking consensus on sarcopenia