Venous thromboembolism risk in amyotrophic lateral sclerosis: a hospital record-linkage study.

BACKGROUND: Venous thromboembolism (VTE) can occur in amyotrophic lateral sclerosis (ALS) and pulmonary embolism causes death in a minority of cases. The benefits of preventing VTE must be weighed against the risks. An accurate estimate of the incidence of VTE in ALS is crucial to assessing this balance. METHODS: This retrospective record-linkage cohort study derived data from the Hospital Episode Statistics database, covering admissions to England's hospitals from 1 April 2003 to 31 December 2019 and included 21 163 patients with ALS and 17 425 337 controls. Follow-up began at index admission and ended at VTE admission, death or 2 years (whichever came sooner). Adjusted HRs (aHRs) for VTE were calculated, controlling for confounders. RESULTS: The incidence of VTE in the ALS cohort was 18.8/1000 person-years. The relative risk of VTE in ALS was significantly greater than in controls (aHR 2.7, 95% CI 2.4 to 3.0). The relative risk of VTE in patients with ALS under 65 years was five times higher than controls (aHR 5.34, 95% CI 4.6 to 6.2), and higher than that of patients over 65 years compared with controls (aHR 1.86, 95% CI 1.62 to 2.12). CONCLUSIONS: Patients with ALS are at a higher risk of developing VTE, but this is similar in magnitude to that reported in other chronic neurological conditions associated with immobility, such as multiple sclerosis, which do not routinely receive VTE prophylaxis. Those with ALS below the median age of symptom onset have a notably higher relative risk. A reappraisal of the case for routine antithrombotic therapy in those diagnosed with ALS now requires a randomised controlled trial.

Age-related differences in cancer relative survival in the United States: A SEER-18 analysis.

Cancer survival has improved since the 1990s, but to different extents across age groups, with a disadvantage for older adults. We aimed to quantify age-related differences in relative survival (RS-1-year and 1-year conditioning on surviving 1 year) for 10 common cancer types by stage at diagnosis. We used data from 18 United States Surveillance Epidemiology and End Results cancer registries and included cancers diagnosed in 2012 to 2016 followed until December 31, 2017. We estimated absolute differences in RS between the 50 to 64 age group and the 75 to 84 age group. The smallest differences were observed for prostate and breast cancers (1.8%-points [95% confidence interval (CI): 1.5-2.1] and 1.9%-points [95% CI: 1.5-2.3], respectively). The largest was for ovarian cancer (27%-points, 95% CI: 24-29). For other cancers, differences ranged between 7 (95% CI: 5-9, esophagus) and 18%-points (95% CI: 17-19, pancreas). Except for pancreatic cancer, cancer type and stage combinations with very high (>95%) or very low (<40%) 1-year RS tended to have smaller age-related differences in survival than those with mid-range prognoses. Age-related differences in 1-year survival conditioning on having survived 1-year were small for most cancer and stage combinations. The broad variation in survival differences by age across cancer types and stages, especially in the first year, age-related differences in survival are likely influenced by amenability to treatment. Future work to measure the extent of age-related differences that are avoidable, and identify how to narrow the survival gap, may have most benefit by prioritizing cancers with relatively large age-related differences in survival (eg, stomach, esophagus, liver and pancreas).

Immortal-time bias in older vs younger age groups: a simulation study with application to a population-based cohort of patients with colon cancer.

BACKGROUND: In observational studies, the risk of immortal-time bias (ITB) increases with the likelihood of early death, itself increasing with age. We investigated how age impacts the magnitude of ITB when estimating the effect of surgery on 1-year overall survival (OS) in patients with Stage IV colon cancer aged 50-74 and 75-84 in England. METHODS: Using simulations, we compared estimates from a time-fixed exposure model to three statistical methods addressing ITB: time-varying exposure, delayed entry and landmark methods. We then estimated the effect of surgery on OS using a population-based cohort of patients from the CORECT-R resource and conducted the analysis using the emulated target trial framework. RESULTS: In simulations, the magnitude of ITB was larger among older patients when their probability of early death increased or treatment was delayed. The bias was corrected using the methods addressing ITB. When applied to CORECT-R data, these methods yielded a smaller effect of surgery than the time-fixed exposure approach but effects were similar in both age groups. CONCLUSION: ITB must be addressed in all longitudinal studies, particularly, when investigating the effect of exposure on an outcome in different groups of people (e.g., age groups) with different distributions of exposure and outcomes.

Consultations for clinical features of possible cancer and associated urgent referrals before and during the COVID-19 pandemic: an observational cohort study from English primary care.

BACKGROUND: It remains unclear to what extent reductions in urgent referrals for suspected cancer during the COVID-19 pandemic were the result of fewer patients attending primary care compared to GPs referring fewer patients. METHODS: Cohort study including electronic health records data from 8,192,069 patients from 663 English practices. Weekly consultation rates, cumulative consultations and referrals were calculated for 28 clinical features from the NICE suspected cancer guidelines. Clinical feature consultation rate ratios (CRR) and urgent referral rate ratios (RRR) compared time periods in 2020 with 2019. FINDINGS: Consultations for cancer clinical features decreased by 24.19% (95% CI: 24.04-24.34%) between 2019 and 2020, particularly in the 6-12 weeks following the first national lockdown. Urgent referrals for clinical features decreased by 10.47% (95% CI: 9.82-11.12%) between 2019 and 2020. Overall, once patients consulted with primary care, GPs urgently referred a similar or greater proportion of patients compared to previous years. CONCLUSION: Due to the significant fall in patients consulting with clinical features of cancer there was a lower than expected number of urgent referrals in 2020. Sustained efforts should be made throughout the pandemic to encourage the public to consult their GP with cancer clinical features.

Inflammatory Bowel Disease-Associated Colorectal Cancer Epidemiology and Outcomes: An English Population-Based Study.

INTRODUCTION: Patients with inflammatory bowel diseases (IBDs) of the colon are at an increased risk of colorectal cancer (CRC). This study investigates the epidemiology of IBD-CRC and its outcomes. METHODS: Using population data from the English National Health Service held in the CRC data repository, all CRCs with and without prior diagnosis of IBD (Crohn's, ulcerative colitis, IBD unclassified, and IBD with cholangitis) between 2005 and 2018 were identified. Descriptive analyses and logistic regression models were used to compare the characteristics of the 2 groups and their outcomes up to 2 years. RESULTS: Three hundred ninety thousand six hundred fourteen patients diagnosed with CRC were included, of whom 5,141 (1.3%) also had a previous diagnosis of IBD. IBD-CRC cases were younger (median age at CRC diagnosis [interquartile range] 66 [54-76] vs 72 [63-79] years [ P < 0.01]), more likely to be diagnosed with CRC as an emergency (25.1% vs 16.7% [ P < 0.01]), and more likely to have a right-sided colonic tumor (37.4% vs 31.5% [ P < 0.01]). Total colectomy was performed in 36.3% of those with IBD (15.4% of Crohn's, 44.1% of ulcerative colitis, 44.5% of IBD unclassified, and 67.7% of IBD with cholangitis). Synchronous (3.2% vs 1.6% P < 0.01) and metachronous tumors (1.7% vs 0.9% P < 0.01) occurred twice as frequently in patients with IBD compared with those without IBD. Stage-specific survival up to 2 years was worse for IBD-associated cancers. DISCUSSION: IBD-associated CRCs occur in younger patients and have worse outcomes than sporadic CRCs. There is an urgent need to find reasons for these differences to inform screening, surveillance, and treatment strategies for CRC and its precursors in this high-risk group.

Addressing the variation in adjuvant chemotherapy treatment for colorectal cancer: Can a regional intervention promote national change?

Analysis of routine population-based data has previously shown that patterns of surgical treatment for colorectal cancer can vary widely, but there is limited evidence available to determine if such variation is also seen in the use of chemotherapy. This study quantified variation in adjuvant chemotherapy across both England using cancer registry data and in more detail across the representative Yorkshire and Humber regions. Individuals with Stages II and III colorectal cancer who underwent major resection from 2014 to 2015 were identified. Rates of chemotherapy were calculated from the Systemic Anticancer Treatment database using multilevel logistic regression. Additionally, questionnaires addressing different clinical scenarios were sent to regional oncologists to investigate the treatment preferences of clinicians. The national adjusted chemotherapy treatment rate ranged from 2% to 46% (Stage II cancers), 19% to 81% (Stage III cancers), 24% to 75% (patients aged <70 years) and 5% to 46% (patients aged ≥70 years). Regionally, the rates of treatment and the proportions of treated patients receiving combination chemotherapy varied by stage (Stage II 4%-26% and 0%-55%, Stage III 48%-71% and 40%-84%) and by age (<70 years 35%-68% and 49%-91%; ≥70 years 15%-39% and 6%-75%). Questionnaire responses showed significant variations in opinions for high-risk Stage II patients with both deficient and proficient mismatch repair tumours and Stage IIIB patients aged ≥70 years. Following a review of the evidence, open discussion in our region has enabled a consensus agreement on an algorithm for colorectal cancer that is intended to reduce variation in practice.

COVID-19 pandemic and admission rates for and management of acute coronary syndromes in England.

BACKGROUND: Several countries affected by the COVID-19 pandemic have reported a substantial drop in the number of patients attending the emergency department with acute coronary syndromes and a reduced number of cardiac procedures. We aimed to understand the scale, nature, and duration of changes to admissions for different types of acute coronary syndrome in England and to evaluate whether in-hospital management of patients has been affected as a result of the COVID-19 pandemic. METHODS: We analysed data on hospital admissions in England for types of acute coronary syndrome from Jan 1, 2019, to May 24, 2020, that were recorded in the Secondary Uses Service Admitted Patient Care database. Admissions were classified as ST-elevation myocardial infarction (STEMI), non-STEMI (NSTEMI), myocardial infarction of unknown type, or other acute coronary syndromes (including unstable angina). We identified revascularisation procedures undertaken during these admissions (ie, coronary angiography without percutaneous coronary intervention [PCI], PCI, and coronary artery bypass graft surgery). We calculated the numbers of weekly admissions and procedures undertaken; percentage reductions in weekly admissions and across subgroups were also calculated, with 95% CIs. FINDINGS: Hospital admissions for acute coronary syndrome declined from mid-February, 2020, falling from a 2019 baseline rate of 3017 admissions per week to 1813 per week by the end of March, 2020, a reduction of 40% (95% CI 37-43). This decline was partly reversed during April and May, 2020, such that by the last week of May, 2020, there were 2522 admissions, representing a 16% (95% CI 13-20) reduction from baseline. During the period of declining admissions, there were reductions in the numbers of admissions for all types of acute coronary syndrome, including both STEMI and NSTEMI, but relative and absolute reductions were larger for NSTEMI, with 1267 admissions per week in 2019 and 733 per week by the end of March, 2020, a percent reduction of 42% (95% CI 38-46). In parallel, reductions were recorded in the number of PCI procedures for patients with both STEMI (438 PCI procedures per week in 2019 vs 346 by the end of March, 2020; percent reduction 21%, 95% CI 12-29) and NSTEMI (383 PCI procedures per week in 2019 vs 240 by the end of March, 2020; percent reduction 37%, 29-45). The median length of stay among patients with acute coronary syndrome fell from 4 days (IQR 2-9) in 2019 to 3 days (1-5) by the end of March, 2020. INTERPRETATION: Compared with the weekly average in 2019, there was a substantial reduction in the weekly numbers of patients with acute coronary syndrome who were admitted to hospital in England by the end of March, 2020, which had been partly reversed by the end of May, 2020. The reduced number of admissions during this period is likely to have resulted in increases in out-of-hospital deaths and long-term complications of myocardial infarction and missed opportunities to offer secondary prevention treatment for patients with coronary heart disease. The full extent of the effect of COVID-19 on the management of patients with acute coronary syndrome will continue to be assessed by updating these analyses. FUNDING: UK Medical Research Council, British Heart Foundation, Public Health England, Health Data Research UK, and the National Institute for Health Research Oxford Biomedical Research Centre.

National variation in pulmonary metastasectomy for colorectal cancer.

AIM: Evidence on patterns of use of pulmonary metastasectomy in colorectal cancer patients is limited. This population-based study aims to investigate the use of pulmonary metastasectomy in the colorectal cancer population across the English National Health Service (NHS) and quantify the extent of any variations in practice and outcome. METHODS: All adults who underwent a major resection for colorectal cancer in an NHS hospital between 2005 and 2013 were identified in the COloRECTal cancer data Repository (CORECT-R). All inpatient episodes corresponding to pulmonary metastasectomy, occurring within 3 years of the initial colorectal resection, were identified. Multi-level logistic regression was used to determine patient and organizational factors associated with the use of pulmonary metastasectomy for colorectal cancer, and Kaplan-Meier and Cox models were used to assess survival following pulmonary metastasectomy. RESULTS: In all, 173 354 individuals had a major colorectal resection over the study period, with 3434 (2.0%) undergoing pulmonary resection within 3 years. The frequency of pulmonary metastasectomy increased from 1.2% of patients undergoing major colorectal resection in 2005 to 2.3% in 2013. Significant variation was observed across hospital providers in the risk-adjusted rates of pulmonary metastasectomy (0.0%-6.8% of patients). Overall 5-year survival following pulmonary resection was 50.8%, with 30-day and 90-day mortality of 0.6% and 1.2% respectively. CONCLUSIONS: This study shows significant variation in the rates of pulmonary metastasectomy for colorectal cancer across the English NHS.

Influence of age on surgical treatment and postoperative outcomes of patients with colorectal cancer in Denmark and Yorkshire, England.

AIM: Denmark and Yorkshire are demographically similar and both have undergone changes in their management of colorectal cancer to improve outcomes. The differential provision of surgical treatment, especially in the older age groups, may contribute to the magnitude of improved survival rates. This study aimed to identify differences in the management of colorectal cancer surgery and postoperative outcomes according to patient age between Denmark and Yorkshire. METHOD: This was a retrospective population-based study of colorectal cancer patients diagnosed in Denmark and Yorkshire between 2005 and 2016. Proportions of patients undergoing major surgical resection, postoperative mortality and relative survival were compared between Denmark and Yorkshire across several age groups (18-59, 60-69, 70-79 and ≥80 years) and over time. RESULTS: The use of major surgical resection was higher in Denmark than in Yorkshire, especially for patients aged ≥80 years (70.5% versus 50.5% for colon cancer, 49.3% versus 38.1% for rectal cancer). Thirty-day postoperative mortality for Danish patients aged ≥80 years was significantly higher than that for Yorkshire patients with colonic cancer [OR (95% CI) = 1.22 (1.07, 1.38)] but not for rectal cancer or for 1-year postoperative mortality. Relative survival significantly increased in all patients aged ≥80 years except for Yorkshire patients with colonic cancer. CONCLUSION: This study suggests that there are major differences between the management of elderly patients with colorectal cancer between the two populations. Improved selection for surgery and better peri- and postoperative care in these patients appears to improve long-term outcomes, but may come at the cost of a higher 30-day mortality.

Health economic studies of colorectal cancer and the contribution of administrative data: A systematic review.

INTRODUCTION: Several forces are contributing to an increase in the number of people living with and surviving colorectal cancer (CRC). However, due to the lack of available data, little is known about the implications of these forces. In recent years, the use of administrative records to inform research has been increasing. The aim of this paper is to investigate the potential contribution that administrative data could have on the health economic research of CRC. METHODS: To achieve this aim, we conducted a systematic review of the health economic CRC literature published in the United Kingdom and Europe within the last decade (2009-2019). RESULTS: Thirty-seven relevant studies were identified and divided into economic evaluations, cost of illness studies and cost consequence analyses. CONCLUSIONS: The use of administrative data, including cancer registry, screening and hospital records, within the health economic research of CRC is commonplace. However, we found that this data often come from regional databases, which reduces the generalisability of results. Further, administrative data appear less able to contribute towards understanding the wider and indirect costs associated with the disease. We explore several ways in which various sources of administrative data could enhance future research in this area.

Variation in the Use of Resection for Colorectal Cancer Liver Metastases.

OBJECTIVE: The aim of this study was to investigate variation in the frequency of resections for colorectal cancer liver metastases across the English NHS. BACKGROUND: Previous research has shown significant variation in access to liver resection surgery across the English NHS. This study uses more recent data to identify whether inequalities in access to liver resection still persist. METHODS: All adults who underwent a major resection for colorectal cancer in an NHS hospital between 2005 and 2012 were identified in the COloRECTal cancer data Repository (CORECT-R). All episodes of care, occurring within 3 years of the initial bowel operation, corresponding to liver resection were identified. RESULT: During the study period 157,383 patients were identified as undergoing major resection for a colorectal tumor, of whom 7423 (4.7%) underwent ≥1 liver resections. The resection rate increased from 4.1% in 2005, reaching a plateau around 5% by 2012. There was significant variation in the rate of liver resection across hospitals (2.1%-12.2%). Patients with synchronous metastases who have their primary colorectal resection in a hospital with an onsite specialist hepatobiliary team were more likely to receive a liver resection (odds ratio 1.22; 95% confidence interval, 1.10-1.35) than those treated in one without. This effect was absent in resection for metachronous metastases. CONCLUSIONS: This study presents the largest reported population-based analysis of liver resection rates in colorectal cancer patients. Significant variation has been observed in patient and hospital characteristics and the likelihood of patients receiving a liver resection, with the data showing that proximity to a liver resection service is as important a factor as deprivation.

Investigation of the international comparability of population-based routine hospital data set derived comorbidity scores for patients with lung cancer.

INTRODUCTION: The International Cancer Benchmarking Partnership (ICBP) identified significant international differences in lung cancer survival. Differing levels of comorbid disease across ICBP countries has been suggested as a potential explanation of this variation but, to date, no studies have quantified its impact. This study investigated whether comparable, robust comorbidity scores can be derived from the different routine population-based cancer data sets available in the ICBP jurisdictions and, if so, use them to quantify international variation in comorbidity and determine its influence on outcome. METHODS: Linked population-based lung cancer registry and hospital discharge data sets were acquired from nine ICBP jurisdictions in Australia, Canada, Norway and the UK providing a study population of 233 981 individuals. For each person in this cohort Charlson, Elixhauser and inpatient bed day Comorbidity Scores were derived relating to the 4-36 months prior to their lung cancer diagnosis. The scores were then compared to assess their validity and feasibility of use in international survival comparisons. RESULTS: It was feasible to generate the three comorbidity scores for each jurisdiction, which were found to have good content, face and concurrent validity. Predictive validity was limited and there was evidence that the reliability was questionable. CONCLUSION: The results presented here indicate that interjurisdictional comparability of recorded comorbidity was limited due to probable differences in coding and hospital admission practices in each area. Before the contribution of comorbidity on international differences in cancer survival can be investigated an internationally harmonised comorbidity index is required.

Post-colonoscopy colorectal cancer (PCCRC) rates vary considerably depending on the method used to calculate them: a retrospective observational population-based study of PCCRC in the English National Health Service.

OBJECTIVE: Post-colonoscopy colorectal cancer (PCCRC) is a key quality indicator of colonoscopy. This study compares methods for defining PCCRC rates, proposes a new method of calculating them and quantifies them across the English National Health Service (NHS). DESIGN: This retrospective observational population-based study involved all individuals with a first primary diagnosis of colorectal cancer made between 2001 and 2010 and treated in the English NHS. Previously published methods for deriving PCCRC rates were applied to the linked routine health data for this population to investigate the effect on the rate. A new method, based on the year of the colonoscopy rather than colorectal cancer diagnosis, was then used to calculate PCCRC rates. RESULTS: Of 297,956 individuals diagnosed with colorectal cancer, a total of 94,648 underwent a colonoscopy in the 3 years prior to their diagnosis. The application of the published methods and exclusion criteria to the dataset produced significantly different PCCRC rates from 2.5% to 7.7%. The new method demonstrates that PCCRC rates within 3 years of colonoscopy (without exclusions) decreased in the English NHS over 8 years, falling from 10.6% to 7.3% for colonoscopies performed in 2001 and 2007 respectively. CONCLUSIONS: The method used to determine PCCRC rates significantly affects findings with potential to substantially underestimate rates. To enable international benchmarking there needs to be a standardised method for defining PCCRC. This study proposes a new methodology using colonoscopy as a denominator and between 2001 and 2007 this method indicated an 8.6% PCCRC rate across the English NHS. It also demonstrated PCCRC rates have fallen over time.

Trends in incidence of pneumothorax in England before, during and after the COVID-19 pandemic (2017-2023): a population-based observational study.

Background: COVID-19 is a risk factor for pneumothorax. The pandemic may have influenced healthcare-seeking behaviour for pneumothorax. This study aimed to investigate recent trends in the incidence of pneumothorax in England. Methods: A population-based epidemiological study was conducted using an English national dataset of hospital admissions (Hospital Episode Statistics) from 2017 to 2023. Record-linkage was used to identify multiple admissions per person and co-morbidity. Pneumothoraces co-occurring with COVID-19 were identified by concurrent COVID-19 diagnostic coding. The pre-pandemic (January 2017-February 2020), pandemic (March-2020-February-2021) and post-pandemic periods (March 2021-March 2023) were compared. Findings: From 2017 to 2023, there were 72,275 hospital admissions for spontaneous pneumothorax among 59,130 patients. Admissions showed marked variability, peaking in January 2021 when the rate of admissions was about two-thirds higher than that of the pre-pandemic level (Incidence rate ratio [IRR] 1.65, 95% CI: 1.48-1.84). However, when excluding patients with a concurrent COVID-19 diagnosis, the overall trend shifted to a reduction during the pandemic period. Post-pandemic rates were not significantly different from pre-pandemic levels (IRR = 0.96, 95% CI: 0.89-1.04). The incidence of spontaneous pneumothorax was significantly higher in males (rate ratio compared to females: 2.29, 95% CI: 2.19-2.39). However, the trends were consistent in both males and females. Interpretation: This study highlights a significant peak in COVID-19 related cases but a corresponding trough in non-COVID-related cases (end 2020, early 2021). Despite a previous report of increasing incidence of (non-COVID-related) hospitalised spontaneous pneumothorax over the long-term between 1968 and 2016, we did not observe any continued increase throughout this study period, prompting further investigation into the impact of recent guidelines. Funding: Authors are supported by the NIHR Oxford BRC, Li Ka Shing and Robertson Foundations, MRC, and HDR UK.

Minimally Invasive Surgery for Colorectal Cancer: Benchmarking Uptake for a Regional Improvement Programme.

BACKGROUND: The uptake of minimally invasive surgery (MIS) for patients with colorectal cancer has progressed at differing rates, both across countries, and within countries. This study aimed to investigate uptake for a regional colorectal cancer improvement programme in England. METHOD: We calculated the proportion of patients receiving elective laparoscopic and robot-assisted surgery amongst those diagnosed with colorectal cancer over 3 time periods (2007-2011, 2012-2016 and 2017-2021) in hospitals participating in the Yorkshire Cancer Research Bowel Cancer Improvement Programme (YCR BCIP). These were benchmarked against national rates. Regression analysis and funnel plots were used to develop a data driven approach for analysing trends in the use of MIS at hospitals in the programme. RESULTS: In England, resections performed by MIS increased from 34.9% to 72.9% for colon cancer and from 28.8% to 72.5% for rectal cancer. Robot-assisted surgery increased from 0.1% to 2.7% for colon cancer and from 0.2% to 7.9% for rectal cancer. Wide variation in the uptake of MIS was observed at a hospital level. Detailed analysis of the YCR BCIP region identified a decreasing number of surgical departments, since the start of the programme, as potential outliers for MIS when compared to the English national average. CONCLUSION: Wide variation in use of MIS for colorectal cancer exists within the English National Health Service and a data-driven approach can help identify outlying hospitals. Addressing some of the challenges behind the uptake of MIS, such as ensuring adequate provision of surgical training and equipment, could help increase its use.

The comprehensive English National Lynch Syndrome Registry: development and description of a new genomics data resource.

Background: Lynch Syndrome (LS) is a cancer predisposition syndrome caused by constitutional pathogenic variants in the mismatch repair (MMR) genes. To date, fragmentation of clinical and genomic data has restricted understanding of national LS ascertainment and outcomes, and precluded evaluation of NICE guidance on testing and management. To address this, via collaboration between researchers, the National Disease Registration Service (NDRS), NHS Genomic Medicine Service Alliances (GMSAs), and NHS Regional Clinical Genetics Services, a comprehensive registry of LS carriers in England has been established. Methods: For comprehensive ascertainment of retrospectively identified MMR pathogenic variant (PV) carriers (diagnosed prior to January 1, 2023), information was retrieved from all clinical genetics services across England, then restructured, amalgamated, and validated via a team of trained experts in NDRS. An online submission portal was established for prospective ascertainment from January 1, 2023. The resulting data, stored in a secure database in NDRS, were used to investigate the demographic and genetic characteristics of the cohort, censored at July 25, 2023. Cancer outcomes were investigated via linkage to the National Cancer Registration Dataset (NCRD). Findings: A total of 11,722 retrospective and 570 prospective data submissions were received, resulting in a comprehensive English National Lynch Syndrome Registry (ENLSR) comprising 9030 unique individuals. The most frequently identified pathogenic MMR genes were MSH2 and MLH1 at 37.2% (n = 3362) and 29.1% (n = 2624), respectively. 35.9% (n = 3239) of the ENLSR cohort received their LS diagnosis before their first cancer diagnosis (presumptive predictive germline test). Of these, 6.3% (n = 204) developed colorectal cancer, at a median age of initial diagnosis of 51 (IQR 40-62), compared to 73 years (IQR 64-80) in the general population (p < 0.0001). Interpretation: The ENLSR represents the first comprehensive national registry of PV carriers in England and one of the largest cohorts of MMR PV carriers worldwide. The establishment of a secure, centralised infrastructure and mechanism for routine registration of newly identified carriers ensures sustainability of the data resource. Funding: This work was funded by the Wellcome Trust, Cancer Research UK and Bowel Cancer UK. The funder of this study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

Clinical trial results in context: comparison of baseline characteristics and outcomes of 38,510 RECOVERY trial participants versus a reference population of 346,271 people hospitalised with COVID-19 in England.

BACKGROUND: Randomised trials are essential to reliably assess medical interventions. Nevertheless, interpretation of such studies, particularly when considering absolute effects, is enhanced by understanding how the trial population may differ from the populations it aims to represent. METHODS: We compared baseline characteristics and mortality of RECOVERY participants recruited in England (n = 38,510) with a reference population hospitalised with COVID-19 in England (n = 346,271) from March 2020 to November 2021. We used linked hospitalisation and mortality data for both cohorts to extract demographics, comorbidity/frailty scores, and crude and age- and sex-adjusted 28-day all-cause mortality. RESULTS: Demographics of RECOVERY participants were broadly similar to the reference population, but RECOVERY participants were younger (mean age [standard deviation]: RECOVERY 62.6 [15.3] vs reference 65.7 [18.5] years) and less frequently female (37% vs 45%). Comorbidity and frailty scores were lower in RECOVERY, but differences were attenuated after age stratification. Age- and sex-adjusted 28-day mortality declined over time but was similar between cohorts across the study period (RECOVERY 23.7% [95% confidence interval: 23.3-24.1%]; vs reference 24.8% [24.6-25.0%]), except during the first pandemic wave in the UK (March-May 2020) when adjusted mortality was lower in RECOVERY. CONCLUSIONS: Adjusted 28-day mortality in RECOVERY was similar to a nationwide reference population of patients admitted with COVID-19 in England during the same period but varied substantially over time in both cohorts. Therefore, the absolute effect estimates from RECOVERY were broadly applicable to the target population at the time but should be interpreted in the light of current mortality estimates. TRIAL REGISTRATION: ISRCTN50189673- Feb. 04, 2020, NCT04381936- May 11, 2020.

Risks of second primary cancers among 584,965 female and male breast cancer survivors in England: a 25-year retrospective cohort study.

Background: Second primary cancers (SPCs) after breast cancer (BC) present an increasing public health burden, with little existing research on socio-demographic, tumour, and treatment effects. We addressed this in the largest BC survivor cohort to date, using a novel linkage of National Disease Registration Service datasets. Methods: The cohort included 581,403 female and 3562 male BC survivors diagnosed between 1995 and 2019. We estimated standardized incidence ratios (SIRs) for combined and site-specific SPCs using incidences for England, overall and by age at BC and socioeconomic status. We estimated incidences and Kaplan-Meier cumulative risks stratified by age at BC, and assessed risk variation by socio-demographic, tumour, and treatment characteristics using Cox regression. Findings: Both genders were at elevated contralateral breast (SIR: 2.02 (95% CI: 1.99-2.06) females; 55.4 (35.5-82.4) males) and non-breast (1.10 (1.09-1.11) females, 1.10 (1.00-1.20) males) SPC risks. Non-breast SPC risks were higher for females younger at BC diagnosis (SIR: 1.34 (1.31-1.38) <50 y, 1.07 (1.06-1.09) ≥50 y) and more socioeconomically deprived (SIR: 1.00 (0.98-1.02) least deprived quintile, 1.34 (1.30-1.37) most). Interpretation: Enhanced SPC surveillance may benefit BC survivors, although specific recommendations require more detailed multifactorial risk and cost-benefit analyses. The associations between deprivation and SPC risks could provide clinical management insights. Funding: CRUK Catalyst Award CanGene-CanVar (C61296/A27223). Cancer Research UK grant: PPRPGM-Nov 20∖100,002. This work was supported by core funding from the NIHR Cambridge Biomedical Research Centre (NIHR203312)]. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.

Age-related differences in colon and rectal cancer survival by stage, histology, and tumour site: An analysis of United States SEER-18 data.

Age-related differences in colon and rectal cancer survival have been observed, even after accounting for differences in background mortality. To determine how stage, tumour site, and histology contribute to these differences, we extracted age-specific one-year relative survival ratio (RS) stratified by these factors. We used colon and rectal cancer cases diagnosed between 2012 and 2016 from 18 United States Surveillance Epidemiology and End Results cancer registries. For colon cancer, 1-year RS ranged from 87.8 % [95 % Confidence Interval: 87.5-88.2] in the 50-64-year-olds to 62.3 % [61.3-63.3] in 85-99-year-olds and for rectal cancer ranged from 92.3 % [91.8-92.7] to 65.0 % [62.3-67.5]. With respect to stage, absolute differences in RS between 50-64-year-olds and 75-84-year-olds increased with increasing stage (from 6 [5-7] %-points in localised disease to 27 [25-29] %-points in distant disease) and were the highest for cancers of unknown stage (> 28 %-points). Age-related differences in survival were smallest for persons with tumours in the right-sided colon (8 [7-9] %-points) and largest for tumours of the colon without tumour site further specified (25 [21-29] %-points). With respect to histology, differences ranged from 7.4 % to 10.6 %-points for cancers with one of the three primary histologies (adenocarcinoma, mucinous adenocarcinoma, signet ring cell carcinoma) and were several-fold higher (42 %-points) for those with unknown/other histology (< 6 % of cases). Because age-related differences in survival were observed for all histologies and tumour sites, RS differences are unlikely to be driven by differences in the distribution of these factors by age. Differences in stage distribution by age are likely to contribute toward age-related differences in survival. Within stage groups, age differences in survival could be explained by frailty and/or therapy. Future studies incorporating data on treatment and geriatric conditions including frailty and comorbidity would support further understanding of the age gap in colon and rectal cancer survival.