Immune activation by DNA damage predicts response to chemotherapy and survival in oesophageal adenocarcinoma.

OBJECTIVE: Current strategies to guide selection of neoadjuvant therapy in oesophageal adenocarcinoma (OAC) are inadequate. We assessed the ability of a DNA damage immune response (DDIR) assay to predict response following neoadjuvant chemotherapy in OAC. DESIGN: Transcriptional profiling of 273 formalin-fixed paraffin-embedded prechemotherapy endoscopic OAC biopsies was performed. All patients were treated with platinum-based neoadjuvant chemotherapy and resection between 2003 and 2014 at four centres in the Oesophageal Cancer Clinical and Molecular Stratification consortium. CD8 and programmed death ligand 1 (PD-L1) immunohistochemical staining was assessed in matched resection specimens from 126 cases. Kaplan-Meier and Cox proportional hazards regression analysis were applied according to DDIR status for recurrence-free survival (RFS) and overall survival (OS). RESULTS: A total of 66 OAC samples (24%) were DDIR positive with the remaining 207 samples (76%) being DDIR negative. DDIR assay positivity was associated with improved RFS (HR: 0.61; 95% CI 0.38 to 0.98; p=0.042) and OS (HR: 0.52; 95% CI 0.31 to 0.88; p=0.015) following multivariate analysis. DDIR-positive patients had a higher pathological response rate (p=0.033), lower nodal burden (p=0.026) and reduced circumferential margin involvement (p=0.007). No difference in OS was observed according to DDIR status in an independent surgery-alone dataset.DDIR-positive OAC tumours were also associated with the presence of CD8+ lymphocytes (intratumoural: p<0.001; stromal: p=0.026) as well as PD-L1 expression (intratumoural: p=0.047; stromal: p=0.025). CONCLUSION: The DDIR assay is strongly predictive of benefit from DNA-damaging neoadjuvant chemotherapy followed by surgical resection and is associated with a proinflammatory microenvironment in OAC.This work was supported by the Gastrointestinal Cancer Research Charitable Fund administered by the Belfast Health and Social Care Trust, the Cancer Research UK Experimental Cancer Medicine Centre Initiative, Invest Northern Ireland and Almac Diagnostics. Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) was funded by a programme grant from Cancer Research UK (RG66287). We would like to thank the Human Research Tissue Bank, which is supported by the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre from Addenbrooke’s Hospital. Additional infrastructure support was provided from the CRUK funded Experimental Cancer Medicine Centre. RF has programmatic funding from the Medical Research Council and infrastructure support from the NIHR Biomedical Research Centre and the Cambridge Experimental Medicine Centre. Tissue samples used in this research were received from the Northern Ireland Biobank, which is funded by HSC Research and Development Division of the Public Health Agency in Northern Ireland and Cancer Research UK through the Belfast Cancer Research UK Centre and the Northern Ireland Experimental Cancer Medicine Centre; additional support was received from the Friends of the Cancer Centre. The Northern Ireland Molecular Pathology Laboratory has received funding from Cancer Research UK, the Friends of the Cancer Centre and the Sean Crummey Foundation. This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement no 721906. The OCCAMS Study Group is a multicentre UK collaboration

Determining the accurate placement of a posterior portal in shoulder arthroscopy with the use of computerized tomography images

Background: Portal placement is an important factor in performing a successful shoulder arthroscopy. Recent cadaveric studies have found variance in the anatomy of the glenohumeral joint. Our aim was to determine if computerized tomography (CT) images could be used to map the trajectory of the posterior portal objectively and then measure the distance between this trajectory and palpable landmarks to apply this knowledge to clinical practice. Methods: Two-dimensional multiplanar reformatted CT images were generated using OsiriX (Pixmeo, Switzerland) from CT images performed in a tertiary hospital over a 1-month period. The center of the glenoid was identified and a trajectory through it radiologically mapped. Horizontal and lateral measurements were taken from this trajectory to both the posterolateral edge of the acromion and tip of the coracoid. Results: Following application of inclusion and exclusion criteria, 226 shoulders were analyzed. Fifty scans were selected at random and re-reviewed by the primary examiner to assess intra-rater reliability which showed strong correlation and no significant differences between first and second measurements (P 0.6). The mean distance from acromion to portal trajectory was 1.39 cm inferiorly (95% confidence interval [CI] 1.31-1.48, standard deviation [SD] 0.65 cm) and 1.44 cm medially (95% CI 1.35-1.53, SD 0.71 cm). The mean distance from the coracoid to the trajectory was 1.71 cm inferiorly (95% CI 1.64-1.78, SD 0.55 cm) and 1.26 cm medially (95% CI 1-2-1.31, SD 0.45 cm). Paired t-test analysis between right and left shoulders within the same subject, where these data were available (n = 81), showed no significant difference (P > .05) between sides. Subset analysis was also performed between males and females, but only showed a significant difference between the vertical distance from the coracoid process to the center of the glenohumeral joint. This distance was shorter in females compared to males (1.56 cm in females compared to 1.84 cm in males, P < .001). Conclusions: Knowledge of shoulder anatomy is vital to the placement of arthroscopic portals, yet research on this topic has been based primarily on surface anatomy, small sample sized cadaveric studies or expert opinion alone. Our study shows that posterior portal placement in shoulder arthroscopy can be measured objectively using CT scanning

Covid-19 estimating the burden of symptomatic disease in the community and the impact of public health measures on physical, mental and social wellbeing: a study protocol.

: Covid-19 was declared a pandemic in March 2020. Since then, governments have implemented unprecedented public health measures to contain the virus. This study will provide evidence to inform responses to the pandemic by: i) estimating population prevalence and trends of self-reported symptoms of Covid-19 and the proportions of symptomatic individuals and household contacts testing positive for Covid-19; ii) describing acceptance and compliance with physical-distancing measures, explore effects of public health measures on physical, mental and social wellbeing; iii) developing a mathematical network model to inform decisions on the optimal levels of physical distancing measures. : Two cross-sectional nationally-representative telephone surveys will be conducted in Ireland using random digit-dialling, with response rates estimates based on proportion of non-operational and non-answering numbers. The first survey with four waves in May and June will address adherence to social distancing measures and whether the respondent or other household members are or have been unwell during the preceding two weeks with one or more symptoms of Covid-19. The second survey with three waves in June, July and September will address knowledge, attitudes, and compliance towards physical-distancing measures and physical, mental and social wellbeing. The mathematical network model will be developed for all-Ireland (on various levels of spatial granularity including the scale of counties and electoral divisions) based on outputs from both cross-sectional surveys and relevant publicly available data to inform decisions on optimal levels and duration of physical distancing measures. : This study will contribute to our understanding of the impact and sustainability of public health measures of the Covid-19 pandemic. Findings will have long-lasting benefits, informing decision-making on the best levels, and duration of physical-distancing measures, balancing a range of factors including capacity of the health service with the effects on individuals' wellbeing and economic disruption. Findings will be shared with key policy-makers

Immune activation by DNA damage predicts response to chemotherapy and survival in oesophageal adenocarcinoma.

OBJECTIVE: Current strategies to guide selection of neoadjuvant therapy in oesophageal adenocarcinoma (OAC) are inadequate. We assessed the ability of a DNA damage immune response (DDIR) assay to predict response following neoadjuvant chemotherapy in OAC. DESIGN: Transcriptional profiling of 273 formalin-fixed paraffin-embedded prechemotherapy endoscopic OAC biopsies was performed. All patients were treated with platinum-based neoadjuvant chemotherapy and resection between 2003 and 2014 at four centres in the Oesophageal Cancer Clinical and Molecular Stratification consortium. CD8 and programmed death ligand 1 (PD-L1) immunohistochemical staining was assessed in matched resection specimens from 126 cases. Kaplan-Meier and Cox proportional hazards regression analysis were applied according to DDIR status for recurrence-free survival (RFS) and overall survival (OS). RESULTS: A total of 66 OAC samples (24%) were DDIR positive with the remaining 207 samples (76%) being DDIR negative. DDIR assay positivity was associated with improved RFS (HR: 0.61; 95% CI 0.38 to 0.98; p=0.042) and OS (HR: 0.52; 95% CI 0.31 to 0.88; p=0.015) following multivariate analysis. DDIR-positive patients had a higher pathological response rate (p=0.033), lower nodal burden (p=0.026) and reduced circumferential margin involvement (p=0.007). No difference in OS was observed according to DDIR status in an independent surgery-alone dataset.DDIR-positive OAC tumours were also associated with the presence of CD8+ lymphocytes (intratumoural: p<0.001; stromal: p=0.026) as well as PD-L1 expression (intratumoural: p=0.047; stromal: p=0.025). CONCLUSION: The DDIR assay is strongly predictive of benefit from DNA-damaging neoadjuvant chemotherapy followed by surgical resection and is associated with a proinflammatory microenvironment in OAC.This work was supported by the Gastrointestinal Cancer Research Charitable Fund administered by the Belfast Health and Social Care Trust, the Cancer Research UK Experimental Cancer Medicine Centre Initiative, Invest Northern Ireland and Almac Diagnostics. Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) was funded by a programme grant from Cancer Research UK (RG66287). We would like to thank the Human Research Tissue Bank, which is supported by the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre from Addenbrooke’s Hospital. Additional infrastructure support was provided from the CRUK funded Experimental Cancer Medicine Centre. RF has programmatic funding from the Medical Research Council and infrastructure support from the NIHR Biomedical Research Centre and the Cambridge Experimental Medicine Centre. Tissue samples used in this research were received from the Northern Ireland Biobank, which is funded by HSC Research and Development Division of the Public Health Agency in Northern Ireland and Cancer Research UK through the Belfast Cancer Research UK Centre and the Northern Ireland Experimental Cancer Medicine Centre; additional support was received from the Friends of the Cancer Centre. The Northern Ireland Molecular Pathology Laboratory has received funding from Cancer Research UK, the Friends of the Cancer Centre and the Sean Crummey Foundation. This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement no 721906. The OCCAMS Study Group is a multicentre UK collaboration

Immune activation by DNA damage predicts response to chemotherapy and survival in oesophageal adenocarcinoma

Objective Current strategies to guide selection of neoadjuvant therapy in oesophageal adenocarcinoma (OAC) are inadequate. We assessed the ability of a DNA damage immune response (DDIR) assay to predict response following neoadjuvant chemotherapy in OAC. Design Transcriptional profiling of 273 formalin-fixed paraffin-embedded prechemotherapy endoscopic OAC biopsies was performed. All patients were treated with platinum-based neoadjuvant chemotherapy and resection between 2003 and 2014 at four centres in the Oesophageal Cancer Clinical and Molecular Stratification consortium. CD8 and programmed death ligand 1 (PD-L1) immunohistochemical staining was assessed in matched resection specimens from 126 cases. Kaplan-Meier and Cox proportional hazards regression analysis were applied according to DDIR status for recurrence-free survival (RFS) and overall survival (OS). Results A total of 66 OAC samples (24%) were DDIR positive with the remaining 207 samples (76%) being DDIR negative. DDIR assay positivity was associated with improved RFS (HR: 0.61; 95% CI 0.38 to 0.98; p=0.042) and OS (HR: 0.52; 95% CI 0.31 to 0.88; p=0.015) following multivariate analysis. DDIR-positive patients had a higher pathological response rate (p=0.033), lower nodal burden (p=0.026) and reduced circumferential margin involvement (p=0.007). No difference in OS was observed according to DDIR status in an independent surgery-alone dataset. DDIR-positive OAC tumours were also associated with the presence of CD8+ lymphocytes (intratumoural: p&lt;0.001; stromal: p=0.026) as well as PD-L1 expression (intratumoural: p=0.047; stromal: p=0.025). Conclusion The DDIR assay is strongly predictive of benefit from DNA-damaging neoadjuvant chemotherapy followed by surgical resection and is associated with a proinflammatory microenvironment in OAC