The diagnostic odyssey in children and adolescents with X-linked hypophosphataemia: population-based, case-control study.

CONTEXT: X-linked hypophosphataemia (XLH) is a rare genetic disorder causing renal phosphate wasting, which predicates musculoskeletal manifestations such as rickets. Diagnosis is often delayed. OBJECTIVE: To explore the recording of clinical features, and the diagnostic odyssey of children and adolescents with XLH in primary care electronic healthcare records (EHR) in the United Kingdom. METHODS: Using the Optimum Patient Care Research Database, individuals aged 20 years or younger after 1st Jan 2000 at date of recorded XLH diagnosis were identified using SNOMED/Read codes, and age-matched to 100 controls. Recording of XLH-related clinical features was summarised, then compared between cases and controls using Chi-squared or Fisher's exact tests. RESULTS: 261 XLH cases were identified; 99 met inclusion criteria. Of these, 84/99 had at least 1 XLH-related clinical feature recorded in their primary care EHR. Clinical codes for rickets, genu varum and low phosphate were recorded prior to XLH diagnosis in under 20% of cases (median of 1, 1, and 3 years prior, respectively). Rickets, genu varum, low phosphate, nephrocalcinosis and growth delay were significantly more likely to be recorded in cases. CONCLUSION: This characterisation of the EHR phenotypes of children and adolescents with XLH may inform future case-finding approaches to expedite diagnosis in primary care.

Long-Term Outcomes of Liver Transplantation for the Management of Neuroendocrine Neoplasms: A Systematic Review.

Liver transplantation is an uncommonly used, controversially debated therapeutic approach for highly selected individuals with neuroendocrine liver metastases. Synthesising evidence regarding outcomes from this approach is crucial to understand its position within the broad neuroendocrine liver metastases armamentarium. In this narrative systematic review of studies published in PubMed, Scopus and OVID until 1 July 2021, we summarise and critically appraise the existing literature regarding this modality, with a special focus on long-term outcomes data where possible. Fourteen studies were identified that reported outcomes from the use of liver transplantation for metastatic neuroendocrine neoplasms. No randomised trials were identified. Generally, indications and selection criteria were poorly articulated, with the notable exception of studies using the Milan criteria. The median 5-year overall survival was 65% (ranging from 36% to 97.2%, 11 studies), and the median 10-year overall survival was 50% (ranging from 46.1% to 88.8%, 3 studies). One additional study focussed on treatments and outcomes following post-transplant recurrence. No studies reported outcomes past 10 years. Further follow-up of the largest series with explicit selection criteria will deepen our understanding of the role that transplantation has to play in this setting.

Management of Small Bowel Neuroendocrine Tumours: 10 Years' Experience at a Tertiary Referral Centre.

BACKGROUND: Neuroendocrine tumours (NET) arising from the small bowel are clinically challenging and are often diagnosed at advanced stages. Disease control with surgery alone can be demanding. Multimodal treatment concepts integrating surgery and non-surgical modalities could be of benefit. METHOD: Retrospective review of consecutive adult patients with SB NET treated at Imperial College Healthcare NHS Trust between 1 January 2010 and 31 December 2019. Data regarding clinicopathological characteristics, treatments, and disease trajectory were extracted and summarised. Overall and progression/recurrence-free survival were estimated at 5 and 10 years. RESULTS: 154 patients were identified, with a median age of 64 years (range 33-87); 135/154 (87.7%) had stage III/IV disease at diagnosis. Surgery was used in 125 individuals (81.2%), typically with either segmental small bowel resection (60.8%) or right hemicolectomy (33.6%) and mesenteric lymphadenectomy for the primary tumour. Systemic and/or liver-directed therapies were used in 126 (81.8%); 60 (47.6%) had more than one line of non-surgical treatment. Median follow-up was 67.2 months (range 3.1-310.4); overall survival at 5 and 10 years was 91.0% (95% CI: 84.9-94.7%) and 82.5% (95% CI: 72.9-88.9%), respectively. Imaging-based median progression-free survival was 42.7 months (95% CI: 24.7 to 72.4); 5-year progression-free survival was 63.4% (95% CI: 55.0-70.6%); 10-year progression-free survival was 18.7% (95% CI: 12.4-26.1). Nineteen patients (12.3%) reached 10 years follow-up without disease recurrence and therefore were considered cured. CONCLUSIONS: Most patients with SB NET present in a metastasised stage. Multimodal treatment concepts may be associated with excellent clinical outcomes. Future work should explore optimal approaches to treatment sequencing and patient selection.

Developments in interventional management of hepatic metastases from neuroendocrine tumours.

Neuroendocrine tumours commonly metastasise to the liver, particularly those arising from the intestinal tract and pancreas. Whilst surgery offers the only approach with intent to cure, the vast majority of patients with neuroendocrine liver metastases are ineligible. Liver-directed interventional therapies seek to exploit the patho-anatomy of the blood supply of hepatic metastases to deliver therapy to liver deposits. This may involve percutaneous ablation, bland embolization, or the selective infusion of chemotherapeutics, targeted agents or radiolabelled embolic material. Retrospective case series evidence has characterised objective response rates, disease control rates, and longer-term outcomes associated with each approach. Recent advances in this field include ongoing comparative trials of different techniques, but more importantly, combinations of interventional liver-directed therapies and other systemic therapy in multimodal treatment concepts.

Transplantation for metastatic liver disease.

The liver is a common site of metastases from many cancers, particularly those originating in the gastrointestinal tract. Liver transplantation is an uncommonly used but promising and at times controversial treatment option for neuroendocrine and colorectal liver metastases. Transplantation with meticulous patient selection has been associated with excellent long-term outcomes in individuals with neuroendocrine liver metastases, but questions remain regarding the role of transplantation in those who could also be eligible for hepatectomy, the role of neoadjuvant/adjuvant treatments in minimising recurrence, and the optimal timing of the procedure. A prospective pilot study of liver transplantation for unresectable colorectal liver metastases that reported a 5-year overall survival rate of 60% reinvigorated interest in this area following initially dismal outcomes. This has been followed by larger studies, and prospective trials are ongoing to quantify the potential benefits of liver transplantation over palliative chemotherapy. This review provides a critical summary of currently available knowledge on liver transplantation for neuroendocrine and colorectal liver metastases, and highlights avenues for further study to address gaps in the evidence base.

Factors influencing influenza, pneumococcal and shingles vaccine uptake and refusal in older adults: a population-based cross-sectional study in England.

OBJECTIVES: Uptake of influenza, pneumococcal and shingles vaccines in older adults vary across regions and socioeconomic backgrounds. In this study, we study the coverage and factors associated with vaccination uptake, as well as refusal in the unvaccinated population and their associations with ethnicity, deprivation, household size and health conditions. DESIGN, SETTING AND PARTICIPANTS: This is a cross-sectional study of adults aged 65 years or older in England, using a large primary care database. Associations of vaccine uptake and refusal in the unvaccinated with ethnicity, deprivation, household size and health conditions were modelled using multivariable logistic regression. OUTCOME MEASURE: Influenza, pneumococcal and shingles vaccine uptake and refusal (in the unvaccinated). RESULTS: This study included 2 054 463 patients from 1318 general practices. 1 711 465 (83.3%) received at least one influenza vaccine, 1 391 228 (67.7%) pneumococcal vaccine and 690 783 (53.4%) shingles vaccine. Compared with White ethnicity, influenza vaccine uptake was lower in Chinese (OR 0.49; 95% CI 0.45 to 0.53), 'Other ethnic' groups (0.63; 95% CI 0.60 to 0.65), black Caribbean (0.68; 95% CI 0.64 to 0.71) and black African (0.72; 95% CI 0.68 to 0.77). There was generally lower vaccination uptake among more deprived individuals, people living in larger household sizes (three or more persons) and those with fewer health conditions. Among those who were unvaccinated, higher odds of refusal were associated with the black Caribbean ethnic group and marginally with increased deprivation, but not associated with higher refusal in those living in large households or those with lesser health conditions. CONCLUSION: Certain ethnic minority groups, deprived populations, large households and 'healthier' individuals were less likely to receive a vaccine, although higher refusal was only associated with ethnicity and deprivation but not larger households nor healthier individuals. Understanding these may inform tailored public health messaging to different communities for equitable implementation of vaccination programmes.

Hemicolectomy versus appendectomy for patients with appendiceal neuroendocrine tumours 1-2 cm in size: a retrospective, Europe-wide, pooled cohort study.

BACKGROUND: Awareness of the potential global overtreatment of patients with appendiceal neuroendocrine tumours (NETs) of 1-2 cm in size by performing oncological resections is increasing, but the rarity of this tumour has impeded clear recommendations to date. We aimed to assess the malignant potential of appendiceal NETs of 1-2 cm in size in patients with or without right-sided hemicolectomy. METHODS: In this retrospective cohort study, we pooled data from 40 hospitals in 15 European countries for patients of any age and Eastern Cooperative Oncology Group performance status with a histopathologically confirmed appendiceal NET of 1-2 cm in size who had a complete resection of the primary tumour between Jan 1, 2000, and Dec 31, 2010. Patients either had an appendectomy only or an appendectomy with oncological right-sided hemicolectomy or ileocecal resection. Predefined primary outcomes were the frequency of distant metastases and tumour-related mortality. Secondary outcomes included the frequency of regional lymph node metastases, the association between regional lymph node metastases and histopathological risk factors, and overall survival with or without right-sided hemicolectomy. Cox proportional hazards regression was used to estimate the relative all-cause mortality hazard associated with right-sided hemicolectomy compared with appendectomy alone. This study is registered with ClinicalTrials.gov, NCT03852693. FINDINGS: 282 patients with suspected appendiceal tumours were identified, of whom 278 with an appendiceal NET of 1-2 cm in size were included. 163 (59%) had an appendectomy and 115 (41%) had a right-sided hemicolectomy, 110 (40%) were men, 168 (60%) were women, and mean age at initial surgery was 36·0 years (SD 18·2). Median follow-up was 13·0 years (IQR 11·0-15·6). After centralised histopathological review, appendiceal NETs were classified as a possible or probable primary tumour in two (1%) of 278 patients with distant peritoneal metastases and in two (1%) 278 patients with distant metastases in the liver. All metastases were diagnosed synchronously with no tumour-related deaths during follow-up. Regional lymph node metastases were found in 22 (20%) of 112 patients with right-sided hemicolectomy with available data. On the basis of histopathological risk factors, we estimated that 12·8% (95% CI 6·5 -21·1) of patients undergoing appendectomy probably had residual regional lymph node metastases. Overall survival was similar between patients with appendectomy and right-sided hemicolectomy (adjusted hazard ratio 0·88 [95% CI 0·36-2·17]; p=0·71). INTERPRETATION: This study provides evidence that right-sided hemicolectomy is not indicated after complete resection of an appendiceal NET of 1-2 cm in size by appendectomy, that regional lymph node metastases of appendiceal NETs are clinically irrelevant, and that an additional postoperative exclusion of metastases and histopathological evaluation of risk factors is not supported by the presented results. These findings should inform consensus best practice guidelines for this patient cohort. FUNDING: Swiss Cancer Research foundation.

Temporality of body mass index, blood tests, comorbidities and medication use as early markers for pancreatic ductal adenocarcinoma (PDAC): a nested case-control study.

OBJECTIVE: Prior studies identified clinical factors associated with increased risk of pancreatic ductal adenocarcinoma (PDAC). However, little is known regarding their time-varying nature, which could inform earlier diagnosis. This study assessed temporality of body mass index (BMI), blood-based markers, comorbidities and medication use with PDAC risk . DESIGN: We performed a population-based nested case-control study of 28 137 PDAC cases and 261 219 matched-controls in England. We described the associations of biomarkers with risk of PDAC using fractional polynomials and 5-year time trends using joinpoint regression. Associations with comorbidities and medication use were evaluated using conditional logistic regression. RESULTS: Risk of PDAC increased with raised HbA1c, liver markers, white blood cell and platelets, while following a U-shaped relationship for BMI and haemoglobin. Five-year trends showed biphasic BMI decrease and HbA1c increase prior to PDAC; early-gradual changes 2-3 years prior, followed by late-rapid changes 1-2 years prior. Liver markers and blood counts (white blood cell, platelets) showed monophasic rapid-increase approximately 1 year prior. Recent diagnosis of pancreatic cyst, pancreatitis, type 2 diabetes and initiation of certain glucose-lowering and acid-regulating therapies were associated with highest risk of PDAC. CONCLUSION: Risk of PDAC increased with raised HbA1c, liver markers, white blood cell and platelets, while followed a U-shaped relationship for BMI and haemoglobin. BMI and HbA1c derange biphasically approximately 3 years prior while liver markers and blood counts (white blood cell, platelets) derange monophasically approximately 1 year prior to PDAC. Profiling these in combination with their temporality could inform earlier PDAC diagnosis.

Neuropsychiatric Ramifications of Severe COVID-19 and Other Severe Acute Respiratory Infections.

Importance: Individuals surviving severe COVID-19 may be at increased risk of neuropsychiatric sequelae. Robust assessment of these risks may help improve clinical understanding of the post-COVID syndrome, aid clinical care during the ongoing pandemic, and inform postpandemic planning. Objective: To quantify the risks of new-onset neuropsychiatric conditions and new neuropsychiatric medication prescriptions after discharge from a COVID-19-related hospitalization, and to compare these with risks after discharge from hospitalization for other severe acute respiratory infections (SARI) during the COVID-19 pandemic. Design, Setting, and Participants: In this cohort study, adults (≥18 years of age) were identified from QResearch primary care and linked electronic health record databases, including national SARS-CoV-2 testing, hospital episode statistics, intensive care admissions data, and mortality registers in England, from January 24, 2020, to July 7, 2021. Exposures: COVID-19-related or SARI-related hospital admission (including intensive care admission). Main Outcomes and Measures: New-onset diagnoses of neuropsychiatric conditions (anxiety, dementia, psychosis, depression, bipolar disorder) or first prescription for relevant medications (antidepressants, hypnotics/anxiolytics, antipsychotics) during 12 months of follow-up from hospital discharge. Maximally adjusted hazard ratios (HR) with 95% CIs were estimated using flexible parametric survival models. Results: In this cohort study of data from 8.38 million adults (4.18 million women, 4.20 million men; mean [SD] age 49.18 [18.45] years); 16 679 (0.02%) survived a hospital admission for SARI, and 32 525 (0.03%) survived a hospital admission for COVID-19. Compared with the remaining population, survivors of SARI and COVID-19 hospitalization had higher risks of subsequent neuropsychiatric diagnoses. For example, the HR for anxiety in survivors of SARI was 1.86 (95% CI, 1.56-2.21) and for survivors of COVID-19 infection was 2.36 (95% CI, 2.03-2.74); the HR for dementia for survivors of SARI was 2.55 (95% CI, 2.17-3.00) and for survivors of COVID-19 infection was 2.63 (95% CI, 2.21-3.14). Similar findings were observed for all medications analyzed; for example, the HR for first prescriptions of antidepressants in survivors of SARI was 2.55 (95% CI, 2.24-2.90) and for survivors of COVID-19 infection was 3.24 (95% CI, 2.91-3.61). There were no significant differences observed when directly comparing the COVID-19 group with the SARI group apart from a lower risk of antipsychotic prescriptions in the former (HR, 0.80; 95% CI, 0.69-0.92). Conclusions and Relevance: In this cohort study, the neuropsychiatric sequelae of severe COVID-19 infection were found to be similar to those for other SARI. This finding may inform postdischarge support for people surviving SARI.

Development and validation of clinical prediction models for breast cancer incidence and mortality: a protocol for a dual cohort study.

INTRODUCTION: Breast cancer is the most common cancer and the leading cause of cancer-related death in women worldwide. Risk prediction models may be useful to guide risk-reducing interventions (such as pharmacological agents) in women at increased risk or inform screening strategies for early detection methods such as screening. METHODS AND ANALYSIS: The study will use data for women aged 20-90 years between 2000 and 2020 from QResearch linked at the individual level to hospital episodes, cancer registry and death registry data. It will evaluate a set of modelling approaches to predict the risk of developing breast cancer within the next 10 years, the 'combined' risk of developing a breast cancer and then dying from it within 10 years, and the risk of breast cancer mortality within 10 years of diagnosis. Cox proportional hazards, competing risks, random survival forest, deep learning and XGBoost models will be explored. Models will be developed on the entire dataset, with 'apparent' performance reported, and internal-external cross-validation used to assess performance and geographical and temporal transportability (two 10-year time periods). Random effects meta-analysis will pool discrimination and calibration metric estimates from individual geographical units obtained from internal-external cross-validation. We will then externally validate the models in an independent dataset. Evaluation of performance heterogeneity will be conducted throughout, such as exploring performance across ethnic groups. ETHICS AND DISSEMINATION: Ethics approval was granted by the QResearch scientific committee (reference number REC 18/EM/0400: OX129). The results will be written up for submission to peer-reviewed journals.

Association between smoking, e-cigarette use and severe COVID-19: a cohort study.

BACKGROUND: Smoking is a risk factor for most respiratory infections, but it may protect against SARS-CoV-2 infection. The objective was to assess whether smoking and e-cigarette use were associated with severe COVID-19. METHODS: This cohort ran from 24 January 2020 until 30 April 2020 at the height of the first wave of the SARS-CoV-2 epidemic in England. It comprised 7 869 534 people representative of the population of England with smoking status, demographic factors and diseases recorded by general practitioners in the medical records, which were linked to hospital and death data. The outcomes were COVID-19-associated hospitalization, intensive care unit (ICU) admission and death. The associations between smoking and the outcomes were assessed with Cox proportional hazards models, with sequential adjustment for confounding variables and indirect causal factors (body mass index and smoking-related disease). RESULTS: Compared with never smokers, people currently smoking were at lower risk of COVID-19 hospitalization, adjusted hazard ratios (HRs) were 0.64 (95% confidence intervals 0.60 to 0.69) for <10 cigarettes/day, 0.49 (0.41 to 0.59) for 10-19 cigarettes/day, and 0.61 (0.49 to 0.74) for ≥20 cigarettes/day. For ICU admission, the corresponding HRs were 0.31 (0.24 to 0.40), 0.15 (0.06 to 0.36), and 0.35 (0.17 to 0.74) and death were: 0.79 (0.70 to 0.89), 0.66 (0.48 to 0.90), and 0.77 (0.54 to 1.09) respectively. Former smokers were at higher risk of severe COVID-19: HRs: 1.07 (1.03 to 1.11) for hospitalization, 1.17 (1.04 to 1.31) for ICU admission, and 1.17 (1.10 to 1.24) for death. All-cause mortality was higher for current smoking than never smoking, HR 1.42 (1.36 to 1.48). Among e-cigarette users, the adjusted HR for e-cigarette use and hospitalization with COVID-19 was 1.06 (0.88 to 1.28), for ICU admission was 1.04 (0.57 to 1.89, and for death was 1.12 (0.81 to 1.55). CONCLUSIONS: Current smoking was associated with a reduced risk of severe COVID-19 but the association with e-cigarette use was unclear. All-cause mortality remained higher despite this possible reduction in death from COVID-19 during an epidemic of SARS-CoV-2. Findings support investigating possible protective mechanisms of smoking for SARS-CoV-2 infection, including the ongoing trials of nicotine to treat COVID-19.

Smoking and COVID-19 outcomes: an observational and Mendelian randomisation study using the UK Biobank cohort.

BACKGROUND: Conflicting evidence has emerged regarding the relevance of smoking on risk of COVID-19 and its severity. METHODS: We undertook large-scale observational and Mendelian randomisation (MR) analyses using UK Biobank. Most recent smoking status was determined from primary care records (70.8%) and UK Biobank questionnaire data (29.2%). COVID-19 outcomes were derived from Public Health England SARS-CoV-2 testing data, hospital admissions data, and death certificates (until 18 August 2020). Logistic regression was used to estimate associations between smoking status and confirmed SARS-CoV-2 infection, COVID-19-related hospitalisation, and COVID-19-related death. Inverse variance-weighted MR analyses using established genetic instruments for smoking initiation and smoking heaviness were undertaken (reported per SD increase). RESULTS: There were 421 469 eligible participants, 1649 confirmed infections, 968 COVID-19-related hospitalisations and 444 COVID-19-related deaths. Compared with never-smokers, current smokers had higher risks of hospitalisation (OR 1.80, 95% CI 1.26 to 2.29) and mortality (smoking 1-9/day: OR 2.14, 95% CI 0.87 to 5.24; 10-19/day: OR 5.91, 95% CI 3.66 to 9.54; 20+/day: OR 6.11, 95% CI 3.59 to 10.42). In MR analyses of 281 105 White British participants, genetically predicted propensity to initiate smoking was associated with higher risks of infection (OR 1.45, 95% CI 1.10 to 1.91) and hospitalisation (OR 1.60, 95% CI 1.13 to 2.27). Genetically predicted higher number of cigarettes smoked per day was associated with higher risks of all outcomes (infection OR 2.51, 95% CI 1.20 to 5.24; hospitalisation OR 5.08, 95% CI 2.04 to 12.66; and death OR 10.02, 95% CI 2.53 to 39.72). INTERPRETATION: Congruent results from two analytical approaches support a causal effect of smoking on risk of severe COVID-19.

Identifying symptoms associated with diagnosis of pancreatic exocrine and neuroendocrine neoplasms: a nested case-control study of the UK primary care population.

BACKGROUND: Pancreatic cancer has the worst survival rate among all cancers. Almost 70% of patients in the UK were diagnosed at Stage IV. AIM: This study aimed to investigate the symptoms associated with the diagnoses of pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine neoplasms (PNEN), and comparatively characterise the symptomatology between the two tumour types to inform earlier diagnosis. DESIGN AND SETTING: A nested case-control study in primary care was conducted using data from the QResearch® database. Patients aged ≥25 years and diagnosed with PDAC or PNEN during 2000 to 2019 were included as cases. Up to 10 controls from the same general practice were matched with each case by age, sex, and calendar year using incidence density sampling. METHOD: Conditional logistic regression was used to investigate the association between the 42 shortlisted symptoms and the diagnoses of PDAC and (or) PNEN in different timeframes relative to the index date, adjusting for patients' sociodemographic characteristics, lifestyle, and relevant comorbidities. RESULTS: A total of 23 640 patients were identified as diagnosed with PDAC and 596 with PNEN. Of the symptoms identified, 23 were significantly associated with PDAC, and nine symptoms with PNEN. The two alarm symptoms for both tumours were jaundice and gastrointestinal bleeding. The two newly identified symptoms for PDAC were thirst and dark urine. The risk of unintentional weight loss may be longer than 2 years before the diagnosis of PNEN. CONCLUSION: PDAC and PNEN have overlapping symptom profiles. The QCancer® (pancreas) risk prediction model could be updated by including the newly identified symptoms and comorbidities, which could help GPs identify high-risk patients for timely investigation in primary care.

Hormone replacement therapy and cancer survival: a longitudinal cohort study: protocol paper.

INTRODUCTION: Hormone replacement therapy (HRT) can help women experiencing menopausal symptoms, but usage has declined due to uncertainty around risks of cancer and some cardiovascular diseases (CVD). Moreover, improved cancer survival rates mean that more women who survive cancer go on to experience menopausal symptoms. Understanding these relationships is important so that women and their clinicians can make informed decisions around the risks and benefits of HRT. This study's primary aim is to determine the association between HRT use after cancer diagnosis and the risk of cancer-specific mortality. The secondary aims are to investigate the risks of HRT on subsequent cancer, all-cause mortality and CVD. METHODS AND ANALYSIS: We will conduct a population-based longitudinal cohort study of 18-79 year-old women diagnosed with cancer between 1998 and 2020, using the QResearch database. The main exposure is HRT use, categorised based on compound, dose and route of administration, and modelled as a time-varying covariate. Analysis of HRT use precancer and postcancer diagnosis will be conducted separately. The primary outcome is cancer-specific mortality, which will be stratified by cancer site. Secondary outcomes include subsequent cancer diagnosis, CVD (including venous thrombo-embolism) and all-cause mortality. Adjustment will be made for key confounders such as age, body mass index, ethnicity, deprivation index, comorbidities, and cancer grade, stage and treatment. Statistical analysis will include descriptive statistics and Cox proportional hazards models to calculate HRs and 95% CIs. ETHICS AND DISSEMINATION: Ethical approval for this project was obtained from the QResearch Scientific Committee (Ref: OX24, project title 'Use of hormone replacement therapy and survival from cancer'). This project has been, and will continue to be, supported by patient and public involvement panels. We intend to the submit the findings for peer-reviewed publication in an academic journal and disseminate them to the public through Cancer Research UK.

Multifocal neuroendocrine tumour of the small bowel presenting as an incarcerated incisional hernia: a surgical challenge in a high-risk patient.

Neuroendocrine tumours (NET) of the small bowel present significant clinical challenges, such as their rate of metastasis at initial presentation, common multifocality and understaging even with gold standard imaging. Here, we present a case of a high-risk surgical patient with a complex medical history initially presenting as an acute abdomen due to an incarcerated incisional hernia. He was found at emergency laparotomy to have three small NET deposits in a 30-cm segment of incarcerated ileum which was resected. Postoperative morphological and functional imaging and biochemical markers were unremarkable, but due to clinical suspicion for undetected residual tumour bulk given the non-systematic palpation of the entire small bowel at initial operation, underwent re-operation where a further 70 cm of ileum was found to harbour multiple tumour deposits (n = 25) and was resected. There was no surgical morbidity and the patient remains tumour-free at 9-month follow-up.

A combination of surgery, theranostics, and liquid biopsy - a personalised oncologic approach to treatment of patients with advanced metastatic neuroendocrine neoplasms.

Rationale: Neuroendocrine neoplasia (NEN) of small bowel (SBNEN) frequently present with metastatic disease. Theranostics (molecular imaging followed by targeting therapy) allow for personalised medicine. Liquid biopsies enable precise identification of residual disease and real-time monitoring of therapeutic response. Our aim was to determine the clinical utility of a combination of surgery, theranostics, and a multigene blood measurement in metastasised SBNEN. Methods: Inclusion criteria were SBNEN, G1/G2 NEN, initial tumour diagnosis, stage IV NEN, positivity on 68Ga somatostatin analogue PET/CT, eligible for surgery, and 177Lu peptide receptor radionuclide therapy (PRRT). Blood samples for NETest were collected longitudinally. Progression-free survival (PFS) and overall survival (OS) were calculated. NETest results were assessed prior to surgery and during clinical follow-up. Results: A surgical cohort of 39 SBNEN patients met eligibility criteria. Thirty-two patients underwent ileal resection and 7 right hemicolectomy. The mean number of 177Lu PRRT cycles was 4. Mortality was nil. Surgical morbidity was 10.3%. Transient grade 1/2 toxicity occurred in 41% (PRRT). NETest scores (n=9 patients) decreased in 100% following treatment and correlated with diminished tumour volume and disease stabilization following surgery and PRRT. Median follow-up: 78 months. Median PFS and OS: 42.7 and 110 months, respectively. Progression-free survival at 1-, 3-, and 5-years was 79.4%, 57.1% and 40.5%, respectively. Overall survival at 1-, 3-, and 5-years was 97.4%, 97.4%, and 94.1%, respectively. Conclusions: Surgery combined with 177Lu PRRT is safe and provides favourable PFS and OS in selected patients with advanced SBNEN. Liquid biopsy (NETest) has the potential to accurately delineate disease status.

Association between pre-existing respiratory disease and its treatment, and severe COVID-19: a population cohort study.

BACKGROUND: Previous studies suggested that the prevalence of chronic respiratory disease in patients hospitalised with COVID-19 was lower than its prevalence in the general population. The aim of this study was to assess whether chronic lung disease or use of inhaled corticosteroids (ICS) affects the risk of contracting severe COVID-19. METHODS: In this population cohort study, records from 1205 general practices in England that contribute to the QResearch database were linked to Public Health England's database of SARS-CoV-2 testing and English hospital admissions, intensive care unit (ICU) admissions, and deaths for COVID-19. All patients aged 20 years and older who were registered with one of the 1205 general practices on Jan 24, 2020, were included in this study. With Cox regression, we examined the risks of COVID-19-related hospitalisation, admission to ICU, and death in relation to respiratory disease and use of ICS, adjusting for demographic and socioeconomic status and comorbidities associated with severe COVID-19. FINDINGS: Between Jan 24 and April 30, 2020, 8 256 161 people were included in the cohort and observed, of whom 14 479 (0·2%) were admitted to hospital with COVID-19, 1542 (<0·1%) were admitted to ICU, and 5956 (0·1%) died. People with some respiratory diseases were at an increased risk of hospitalisation (chronic obstructive pulmonary disease [COPD] hazard ratio [HR] 1·54 [95% CI 1·45-1·63], asthma 1·18 [1·13-1·24], severe asthma 1·29 [1·22-1·37; people on three or more current asthma medications], bronchiectasis 1·34 [1·20-1·50], sarcoidosis 1·36 [1·10-1·68], extrinsic allergic alveolitis 1·35 [0·82-2·21], idiopathic pulmonary fibrosis 1·59 [1·30-1·95], other interstitial lung disease 1·66 [1·30-2·12], and lung cancer 2·24 [1·89-2·65]) and death (COPD 1·54 [1·42-1·67], asthma 0·99 [0·91-1·07], severe asthma 1·08 [0·98-1·19], bronchiectasis 1·12 [0·94-1·33], sarcoidosis 1·41 [0·99-1·99), extrinsic allergic alveolitis 1·56 [0·78-3·13], idiopathic pulmonary fibrosis 1·47 [1·12-1·92], other interstitial lung disease 2·05 [1·49-2·81], and lung cancer 1·77 [1·37-2·29]) due to COVID-19 compared with those without these diseases. Admission to ICU was rare, but the HR for people with asthma was 1·08 (0·93-1·25) and severe asthma was 1·30 (1·08-1·58). In a post-hoc analysis, relative risks of severe COVID-19 in people with respiratory disease were similar before and after shielding was introduced on March 23, 2020. In another post-hoc analysis, people with two or more prescriptions for ICS in the 150 days before study start were at a slightly higher risk of severe COVID-19 compared with all other individuals (ie, no or one ICS prescription): HR 1·13 (1·03-1·23) for hospitalisation, 1·63 (1·18-2·24) for ICU admission, and 1·15 (1·01-1·31) for death. INTERPRETATION: The risk of severe COVID-19 in people with asthma is relatively small. People with COPD and interstitial lung disease appear to have a modestly increased risk of severe disease, but their risk of death from COVID-19 at the height of the epidemic was mostly far lower than the ordinary risk of death from any cause. Use of inhaled steroids might be associated with a modestly increased risk of severe COVID-19. FUNDING: National Institute for Health Research Oxford Biomedical Research Centre and the Wellcome Trust.

Quantifying the association between ethnicity and COVID-19 mortality: a national cohort study protocol.

INTRODUCTION: Recent evidence suggests that ethnic minority groups are disproportionately at increased risk of hospitalisation and death from SARS-CoV-2 infection. Population-based evidence on potential explanatory factors across minority groups and within subgroups is lacking. This study aims to quantify the association between ethnicity and the risk of hospitalisation and mortality due to COVID-19. METHODS AND ANALYSIS: This is a retrospective cohort study of adults registered across a representative and anonymised national primary care database (QResearch) that includes data on 10 million people in England. Sociodemographic, deprivation, clinical and domicile characteristics will be summarised and compared across ethnic subgroups (categorised as per 2011 census). Cox models will be used to calculate HR for hospitalisation and COVID-19 mortality associated with ethnic group. Potential confounding and explanatory factors (such as demographic, socioeconomic and clinical) will be adjusted for within regression models. The percentage contribution of distinct risk factor classes to the excess risks seen in ethnic groups/subgroups will be calculated. ETHICS AND DISSEMINATION: The study has undergone ethics review in accordance with the QResearch agreement (reference OX102). Findings will be disseminated through peer-reviewed manuscripts, presentations at scientific meetings and conferences with national and international stakeholders.

Liver-Directed Therapies for Neuroendocrine Neoplasms.

PURPOSE OF REVIEW: To comprehensively synthesise and appraise the available evidence regarding therapies for metastatic neuroendocrine neoplasms that exploit the hepatic vasculature to deliver therapy to liver metastases. RECENT FINDINGS: Various techniques including transarterial embolisation/chemoembolisation (TAE/TACE) and selective internal radiotherapy (SIRT, also termed radioembolisation [RE]) have been examined in patents with neuroendocrine liver metastases. Variations in the radioactive agents for selective internal radiotherapy (SIRT) have been explored, such as the use of Holmium-166, in addition to more established agents such as Yttrium-90. Recent trials have examined the safety and efficacy of combining liver-targeted therapy with systemic treatments, such as peptide receptor radionuclide therapy. More retrospective case series of liver-directed modalities will not provide additional knowledge. Randomised clinical trials have begun to compare the efficacy of different forms of liver-directed therapies, and also their combination with systemic treatment. Their results are expected to guide optimal treatment sequencing within multimodal concepts.