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

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

[American flag at half staff outside Parkland Hospital]

Original black and white photographic negative taken by Dallas Times Herald staff photographer Eamon Kennedy. This image shows the United States flag flying at half staff outside Parkland Hospital on November 22, 1963

[Man and children reacting to news of President Kennedy's death]

Original black and white photographic negative taken by Dallas Times Herald staff photographer Eamon Kennedy. This image shows a man and two children outside of Parkland Hospital reacting to news of President Kennedy's death

[Woman outside Parkland Hospital the day of the assassination]

Original black and white photographic negative taken by Dallas Times Herald staff photographer Eamon Kennedy. This image shows Wilda Atkinson standing next to her daughter Kathey Atkinson (far right, head bowed in prayer) outside of Parkland Hospital the day of the assassination

[Priest in the parking lot of Parkland Hospital]

Original black and white photographic negative taken by Dallas Times Herald staff photographer Eamon Kennedy. This image shows an unidentified Catholic priest in the parking lot of Parkland Hospital on November 22, 1963

[People outside of Parkland Hospital]

Original black and white photographic negative taken by Dallas Times Herald staff photographer Eamon Kennedy. This image shows several groups of people in the parking lot outside of Parkland Hospital on November 22, 1963. Police officers, nurses and orderlies can be seen in the image

[Crowd outside Parkland Hospital awaiting news]

Original black and white photographic negative taken by Dallas Times Herald staff photographer Eamon Kennedy. This image shows a crowd outside Parkland Hospital awaiting news

[Women reacting to news of John F. Kennedy's Death]

Original black and white photographic negative taken by Dallas Times Herald staff photographer Eamon Kennedy. This image shows two unidentified women outside of Parkland Hospital reacting to news of President Kennedy's death