Molecular Classification of the PORTEC-3 Trial for High-Risk Endometrial Cancer:Impact on Prognosis and Benefit From Adjuvant Therapy

PURPOSE The randomized Adjuvant Chemoradiotherapy Versus Radiotherapy Alone in Women With High-Risk Endometrial Cancer (PORTEC-3) trial investigated the benefit of combined adjuvant chemotherapy and radiotherapy (CTRT) versus radiotherapy alone (RT) for women with high-risk endometrial cancer (EC). Because The Cancer Genome Atlas defined an EC molecular classification with strong prognostic value, we investigated prognosis and impact of chemotherapy for each molecular subgroup using tissue samples from PORTEC-3 trial participants. METHODS Paraffin-embedded tissues of 423 consenting patients were collected. Immunohistochemistry for p53 and mismatch repair (MMR) proteins, and DNA sequencing for POLE exonuclease domain were done to classify tumors as p53 abnormal (p53abn), POLE-ultramutated (POLEmut), MMR-deficient (MMRd), or no specific molecular profile (NSMP). The primary end point was recurrence-free survival (RFS). Kaplan-Meier method, log-rank test, and Cox model were used for analysis. RESULTS Molecular analysis was successful in 410 high-risk EC (97%), identifying the 4 subgroups: P53abn EC (n = 93; 23%), POLEmut (n = 51; 12%), MMRd (n = 137; 33%), and NSMP (n = 129; 32%). Five-year RFS was 48% for patients with p53abn EC, 98% for POLEmut EC, 72% for MMRd EC, and 74% for NSMP EC (P <001). The 5-year RFS with CTRT versus RT for p53abn EC was 59% versus 36% (P =019); 100% versus 97% for patients with POLEmut EC (P =637); 68% versus 76% (P =428) for MMRd EC; and 80% versus 68% (P =243) for NSMP EC. CONCLUSION Molecular classification has strong prognostic value in high-risk EC, with significantly improved RFS with adjuvant CTRT for p53abn tumors, regardless of histologic type. Patients with POLEmut EC had an excellent RFS in both trial arms. EC molecular classification should be incorporated in the risk stratification of these patients as well as in future trials to target specific subgroups of patients

Surveillance towards preventing paediatric incidence of respiratory syncytial virus attributable respiratory tract infection in primary and secondary/tertiary healthcare settings in Merseyside, Cheshire and Bristol, UK

Respiratory syncytial virus (RSV) is a common respiratory virus, particularly affecting children, and can cause respiratory infections such as croup and bronchiolitis. The latter is a leading cause of paediatric hospitalisation within the UK. Children <3 years of age and/or with underlying health conditions are more vulnerable to severe RSV infection.There are currently limited data on the incidence of laboratory-confirmed RSV, particularly within primary care settings and outside the typical 'RSV season', which in the Northern hemisphere tends to coincide with winter months. There is also a lack of data on the health economic impact of RSV infection on families and healthcare systems.This observational surveillance study aims to collect data on the incidence of laboratory-confirmed RSV-attributable respiratory tract infection (RTI) in children aged <3 years presenting to primary, secondary or tertiary care; it also aims to estimate the health economic and quality of life impact of RSV-attributable infection in this cohort. Such data will contribute to informing public health strategies to prevent RSV-associated infection, including use of preventative medications. Parents/carers of children <3 years of age with RTI symptoms will consent for a respiratory sample (nasal swab) to be taken. Laboratory PCR testing will assess for the presence of RSV and/or other pathogens. Data will be obtained from medical records on demographics, comorbidities, severity of infection and hospitalisation outcomes. Parents will complete questionnaires on the impact of ongoing infection symptoms at day 14 and 28 following enrolment. The primary outcome is incidence of laboratory-confirmed RSV in children <3 years presenting to primary, secondary or tertiary care with RTI symptoms leading to health-seeking behaviours. Recruitment will be carried out from December 2021 to March 2023, encompassing two UK winter seasons and intervening months. Ethical approval has been granted (21/WS/0142), and study findings will be published as per International Committee of Medical Journal Editors' guidelines

Effect of priming interval on reactogenicity, peak immunological response, and waning after homologous and heterologous COVID-19 vaccine schedules: exploratory analyses of Com-COV, a randomised control trial

BackgroundPriming COVID-19 vaccine schedules have been deployed at variable intervals globally, which might influence immune persistence and the relative importance of third-dose booster programmes. Here, we report exploratory analyses from the Com-COV trial, assessing the effect of 4-week versus 12-week priming intervals on reactogenicity and the persistence of immune response up to 6 months after homologous and heterologous priming schedules using the vaccines BNT162b2 (tozinameran, Pfizer/BioNTech) and ChAdOx1 nCoV-19 (AstraZeneca).MethodsCom-COV was a participant-masked, randomised immunogenicity trial. For these exploratory analyses, we used the trial's general cohort, in which adults aged 50 years or older were randomly assigned to four homologous and four heterologous vaccine schedules using BNT162b2 and ChAdOx1 nCoV-19 with 4-week or 12-week priming intervals (eight groups in total). Immunogenicity analyses were done on the intention-to-treat (ITT) population, comprising participants with no evidence of SARS-CoV-2 infection at baseline or for the trial duration, to assess the effect of priming interval on humoral and cellular immune response 28 days and 6 months post-second dose, in addition to the effects on reactogenicity and safety. The Com-COV trial is registered with the ISRCTN registry, 69254139 (EudraCT 2020–005085–33).FindingsBetween Feb 11 and 26, 2021, 730 participants were randomly assigned in the general cohort, with 77–89 per group in the ITT analysis. At 28 days and 6 months post-second dose, the geometric mean concentration of anti-SARS-CoV-2 spike IgG was significantly higher in the 12-week interval groups than in the 4-week groups for homologous schedules. In heterologous schedule groups, we observed a significant difference between intervals only for the BNT162b2–ChAdOx1 nCoV-19 group at 28 days. Pseudotyped virus neutralisation titres were significantly higher in all 12-week interval groups versus 4-week groups, 28 days post-second dose, with geometric mean ratios of 1·4 (95% CI 1·1–1·8) for homologous BNT162b2, 1·5 (1·2–1·9) for ChAdOx1 nCoV-19–BNT162b2, 1·6 (1·3–2·1) for BNT162b2–ChAdOx1 nCoV-19, and 2·4 (1·7–3·2) for homologous ChAdOx1 nCoV-19. At 6 months post-second dose, anti-spike IgG geometric mean concentrations fell to 0·17–0·24 of the 28-day post-second dose value across all eight study groups, with only homologous BNT162b2 showing a slightly slower decay for the 12-week versus 4-week interval in the adjusted analysis. The rank order of schedules by humoral response was unaffected by interval, with homologous BNT162b2 remaining the most immunogenic by antibody response. T-cell responses were reduced in all 12-week priming intervals compared with their 4-week counterparts. 12-week schedules for homologous BNT162b2 and ChAdOx1 nCoV-19–BNT162b2 were up to 80% less reactogenic than 4-week schedules.InterpretationThese data support flexibility in priming interval in all studied COVID-19 vaccine schedules. Longer priming intervals might result in lower reactogenicity in schedules with BNT162b2 as a second dose and higher humoral immunogenicity in homologous schedules, but overall lower T-cell responses across all schedules. Future vaccines using these novel platforms might benefit from schedules with long intervals

Nitrogen cycling in high elevation reclaimed mine spoil in southeastern British Columbia

The research that has been carried out on N at Westar has been essential to determine the ability of the reclaimed sites to survive once management practices are terminated. It has been established that N is not accumulating in the litter on the soil surface but substantial amounts are being recycled by decomposition processes. A large proportion of the plant N is present in the plant roots; where it should be for a stable, self-sustaining plant system to develop. The labelled fertilizer study has shown that in the older reclaimed sites, only a small portion of the N in the plant comes from the fertilizer and most of it comes from supplies accumulated in the soil. This suggests that present management practices at Westar are successfully creating plant/soil systems on their high elevation reclaimed sites which recycle sufficient nutrients to meet the needs of plant growth.Non UBCUnreviewedOthe

Calcium inhibits GTP-binding proteins in squid photoreceptors

A NATO Advanced study Institute on "Receptors, Membrane Trans­ port and Signal Transduction", was held on the Island of Spet­ sai, Greece, from August 16-27, 1988, in order to consider re­ cent developments in membrane receptor research, membrane trans­ port and signal transduction mechanisms. These topics were put in the larger context of current knowledge on the structure and function of membranes; connections between different fields of research were established by in-depth dis­ cussions of energy transduction and transport mechanisms. The general principles of regulation by signal transduction and protein phosphorylation/dephosphorylation were presented in the context of specific cellular processes. Discussions included al­ so the role of protein tyrosine kinases which are structurally related to oncogene products and, therefore, implicated in va­ rious aspects of cell development and transformation. This book presents the content of the major lectures and a se­ lection of the most relevant posters presented during the course of the Institute. The book is intended to make the proceedings of the Institute accessible to a larger audience and to offer a comprehensive account of those topics on receptors, membrane transport and signal transduction that were discussed extensive­ ly during the course of the Institute

Effects of calcium on light-activated GTP-binding proteins in squid photoreceptor membranes

1. At least two distinct G-proteins are activated by light in squid photoreceptor membranes, a 45,000 mol. wt cholera toxin substrate and a 40,000 mol. wt pertussis toxin substrate. 2. The light-stimulated GTPase activity is partially inhibited by pretreatment with either toxin and abolished by treatment with both toxins. 3. At 24 degrees C, a free calcium ion concentration of 1 microM inhibits GTPase activity of both toxin substrates and ADP ribosylation by pertussis toxin. 4. This calcium sensitivity of squid G-proteins may be important in interpretation of experimental results on the phosphoinositide or other signalling pathways in squid visual transduction

Interregional Differences in Agricultural Development across Circumpolar Canada

In response to the circumpolar region’s high levels of food insecurity, many Canadian communities have identified the development of local agriculture as a means to resolve the issue. Agricultural development is varied across the circumpolar region, an area which includes Yukon, the Northwest Territories, Nunavut, Nunavik (Quebec), and Nunatsiavut (Newfoundland and Labrador). This review explores the interregional differences in circumpolar agriculture, their historical development, and their relationship to prevailing biophysical, socioeconomic, and political conditions. Drawing upon local food strategies and literature pertaining to current agricultural initiatives, we discuss the future direction of circumpolar agriculture in Canada. Yukon and the Northwest Territories are the most agriculturally developed subregions of circumpolar Canada, and their territorial governments support the development of commercial agriculture. In Nunavut, Nunavik, and Nunatsiavut, relatively few agricultural initiatives are underway although local efforts have been made to establish community gardens or greenhouses and improve access to fresh commodities through subsidization of imported goods. Because of variability in biophysical, social, institutional, and political environments, strategies for food production would be most effective if tailored to each subregion. The continued development of agriculturally favorable policies and certified processing facilities in Yukon and the Northwest Territories could improve market access, both locally and out-of-territory. The eastern subregions (Nunavut, Nunavik, and Nunatsiavut) seem more inclined towards small, community-driven projects; these initiatives could be promoted to encourage community involvement for their long-term sustainability. Most studies on circumpolar agriculture have focused on the biophysical and social challenges; the region would benefit from additional research into the institutional and political barriers to agricultural development. En réponse aux degrés d’insécurité alimentaire élevés dans la région circumpolaire, de nombreuses communautés canadiennes estiment que le développement de l’agriculture locale constitue un moyen de surmonter cet enjeu. Le développement agricole prend plusieurs formes dans la région circumpolaire, région qui comprend le Yukon, les Territoires du Nord-Ouest, le Nunavut, le Nunavik (Québec) et le Nunatsiavut (Terre-Neuve-et-Labrador). Dans cet article, nous explorons les différences interrégionales en matière d’agriculture circumpolaire, leur développement historique et leur lien avec les conditions biophysiques, socioéconomiques et politiques qui ont cours dans les diverses régions. Nous nous appuyons sur les stratégies alimentaires locales et sur la documentation concernant les initiatives agricoles actuelles pour discuter de l’orientation future de l’agriculture circumpolaire au Canada. Du point de vue agricole, le Yukon et les Territoires du Nord-Ouest sont les sous-régions les plus développées de la région circumpolaire du Canada, et les gouvernements de ces territoires soutiennent le développement de l’agriculture commerciale. Au Nunavut, au Nunavik et au Nunatsiavut, relativement peu d’initiatives agricoles sont en cours, bien que des efforts aient été déployés à l’échelle locale pour établir des jardins ou des serres communautaires et pour améliorer l’accès aux produits frais grâce à la subvention de produits importés. En raison de la variabilité des environnements biophysiques, sociaux, institutionnels et politiques, les stratégies de production alimentaire donneraient de meilleurs résultats si elles étaient adaptées à chaque sous-région. Le développement continu de politiques agricoles favorables et d’installations de transformation homologuées au Yukon et dans les Territoires du Nord-Ouest pourrait améliorer l’accès aux marchés, tant à l’échelle locale qu’à l’extérieur des territoires. Les sous-régions de l’est (Nunavut, Nunavik et Nunatsiavut) ont davantage tendance à préconiser de petits projets communautaires. Les initiatives de ce genre pourraient être facilitées pour inciter les communautés à jouer un rôle dans leur durabilité à long terme. La plupart des études sur l’agriculture circumpolaire portent sur les défis biophysiques et sociaux. La région pourrait bénéficier de recherches plus approfondies au sujet des obstacles institutionnels et politiques du développement agricole.

Comprehensive review of safety in Experimental Human Pneumococcal Challenge.

IntroductionExperimental Human Pneumococcal Challenge (EHPC) involves the controlled exposure of adults to a specific antibiotic-sensitive Streptococcus pneumoniae serotype, to induce nasopharyngeal colonisation for the purpose of vaccine research. The aims are to review comprehensively the safety profile of EHPC, explore the association between pneumococcal colonisation and frequency of safety review and describe the medical intervention required to undertake such studies.MethodsA single-centre review of all EHPC studies performed 2011-2021. All recorded serious adverse events (SAE) in eligible studies are reported. An unblinded meta-analysis of collated anonymised individual patient data from eligible EHPC studies was undertaken to assess the association between experimental pneumococcal colonisation and the frequency of safety events following inoculation.ResultsIn 1416 individuals (median age 21, IQR 20-25), 1663 experimental pneumococcal inoculations were performed. No pneumococcal-related SAE have occurred. 214 safety review events were identified with 182 (12.85%) participants presenting with symptoms potentially in keeping with pneumococcal infection, predominantly in pneumococcal colonised individuals (colonised = 96/658, non-colonised = 86/1005, OR 1.81 (95% CI 1.28-2.56, P = DiscussionNo SAEs were identified directly relating to pneumococcal inoculation. Safety review for symptoms was infrequent but occurred more in experimentally colonised participants. Most symptoms were mild and resolved with conservative management. A small minority required antibiotics, notably those serotype 3 inoculated.ConclusionOutpatient human pneumococcal challenge can be conducted safely with appropriate levels of safety monitoring procedures in place

Prognostic refinement of NSMP high-risk endometrial cancers using oestrogen receptor immunohistochemistry

Background: Risk-assessment of endometrial cancer (EC) is based on clinicopathological factors and molecular subgroup. It is unclear whether adding hormone receptor expression, L1CAM expression or CTNNB1 status yields prognostic refinement.Methods: Paraffin-embedded tumour samples of women with high-risk EC (HR-EC) from the PORTEC-3 trial (n = 424), and a Dutch prospective clinical cohort called MST (n = 256), were used. All cases were molecularly classified. Expression of L1CAM, ER and PR were analysed by whole-slide immunohistochemistry and CTNNB1 mutations were assessed with a next-generation sequencing. Kaplan–Meier method, log-rank tests and Cox’s proportional hazard models were used for survival analysis.Results: In total, 648 HR-EC were included. No independent prognostic value of ER, PR, L1CAM, and CTNNB1 was found, while age, stage, and adjuvant chemotherapy had an independent impact on risk of recurrence. Subgroup-analysis showed that only in NSMP HR-EC, ER-positivity was independently associated with a reduced risk of recurrence (HR 0.33, 95%CI 0.15–0.75).Conclusions: We confirmed the prognostic impact of the molecular classification, age, stage, and adjuvant CTRT in a large cohort of high-risk EC. ER-positivity is a strong favourable prognostic factor in NSMP HR-EC and identifies a homogeneous subgroup of NSMP tumours. Assessment of ER status in high-risk NSMP EC is feasible in clinical practice and could improve risk stratification and treatment.</p