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.

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.

Circulating MicroRNAs in Small-bowel Neuroendocrine Tumors: A Potential Tool for Diagnosis and Assessment of Effectiveness of Surgical Resection.

OBJECTIVE: To discover serum-based microRNA (miRNA) biomarkers for small-bowel neuroendocrine tumors (SBNET) to help guide clinical decisions. BACKGROUND: MiRNAs are small noncoding RNA molecules implicated in the initiation and progression of many cancers. MiRNAs are remarkably stable in bodily fluids, and can potentially be translated into clinically useful biomarkers. Novel biomarkers are needed in SBNET to determine disease aggressiveness, select patients for treatment, detect early recurrence, and monitor response. METHODS: This study was performed in 3 stages (discovery, validation, and a prospective, longitudinal assessment). Discovery comprised of global profiling of 376 miRNA in sera from SBNET patients (n = 11) versus healthy controls (HCs; n = 3). Up-regulated miRNAs were subsequently validated in additional SBNET (n = 33) and HC sera (n = 14); and then longitudinally after SBNET resection (n = 12), with serial serum sampling (preoperatively day 0; postoperatively at 1 week, 1 month, and 12 months). RESULTS: Four serum miRNAs (miR-125b-5p, -362-5p, -425-5p and -500a-5p) were significantly up-regulated in SBNET (P < 0.05; fold-change >2) based on multiple normalization strategies, and were validated by RT-qPCR. This combination was able to differentiate SBNET from HC with an area under the curve of 0.951. Longitudinal assessment revealed that miR-125b-5p returned towards HC levels at 1 month postoperatively in patients without disease, whereas remaining up-regulated in those with residual disease (RSD). This was also true at 12 months postoperatively. In addition, miR-362-5p appeared up-regulated at 12 months in RSD and recurrent disease (RCD). CONCLUSIONS: Our study represents the largest global profiling of serum miRNAs in SBNET patients, and the first to evaluate ongoing serum miRNA expression changes after surgical resection. Serum miR-125b-5p and miR-362-5p have potential to be used to detect RSD/RCD.

The Use of Primary Care Big Data in Understanding the Pharmacoepidemiology of COVID-19: A Consensus Statement From the COVID-19 Primary Care Database Consortium.

The use of big data containing millions of primary care medical records provides an opportunity for rapid research to help inform patient care and policy decisions during the first and subsequent waves of the coronavirus disease 2019 (COVID-19) pandemic. Routinely collected primary care data have previously been used for national pandemic surveillance, quantifying associations between exposures and outcomes, identifying high risk populations, and examining the effects of interventions at scale, but there is no consensus on how to effectively conduct or report these data for COVID-19 research. A COVID-19 primary care database consortium was established in April 2020 and its researchers have ongoing COVID-19 projects in overlapping data sets with over 40 million primary care records in the United Kingdom that are variously linked to public health, secondary care, and vital status records. This consensus agreement is aimed at facilitating transparency and rigor in methodological approaches, and consistency in defining and reporting cases, exposures, confounders, stratification variables, and outcomes in relation to the pharmacoepidemiology of COVID-19. This will facilitate comparison, validation, and meta-analyses of research during and after the pandemic.

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.

ALPPS in neuroendocrine liver metastases not amenable for conventional resection - lessons learned from an interim analysis of the International ALPPS Registry.

BACKGROUND: Surgery is the most effective treatment option for neuroendocrine liver metastases (NELM). This study investigated the role of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) as a novel strategy in treatment of NELM. METHODS: The International ALPPS Registry was reviewed to study patients who underwent ALPPS for NELM. RESULTS: From 2010 to 2017, 954 ALPPS procedures from 135 international centers were recorded in the International ALPPS Registry. Of them, 24 (2.5%) were performed for NELM. Twenty-one patients entered the final analysis. Overall grade ≥3b morbidity was 9% after stage 1 and 27% after stage 2. Ninety-day mortality was 5%. R0 resection was achieved in 19 cases (90%) at stage 2. Median follow-up was 28 (19-48) months. Median disease free survival (DFS) was 17.3 (95% CI: 7.1-27.4) months, 1-year and 2-year DFS was 73.2% and 41.8%, respectively. Median overall survival (OS) was not reached. One-year and 2-year OS was 95.2% and 95.2%, respectively. CONCLUSIONS: ALPPS appears to be a suitable strategy for inclusion in the multimodal armamentarium of well-selected patients with neuroendocrine liver metastases. In light of the morbidity in this initial series and a high rate of disease-recurrence, the procedure should be taken with caution.

Radioembolisation with 90Y microspheres for neuroendocrine liver metastases: an institutional case series, systematic review and meta-analysis.

BACKGROUND: Neuroendocrine liver metastases are clinically challenging due to their frequent disseminated distribution. This study aims to present a British experience with an emerging modality, radioembolisation with yttrium-90 labelled microspheres, and embed this within a meta-analysis of response and survival outcomes. METHODS: A retrospective case series of patients treated with SIR-Spheres (radiolabelled resin microspheres) was performed. Results were included in a systematic review and meta-analysis of published results with glass or resin microspheres. Objective response rate (ORR) was defined as complete or partial response. Disease control rate (DCR) was defined as complete/partial response or stable disease. RESULTS: Twenty-four patients were identified. ORR and DCR in the institutional series was 14/24 and 21/24 at 3 months. Overall survival and progression-free survival at 3-years was 77.6% and 50.4%, respectively. There were no grade 3/4 toxicities post-procedure. A fixed-effects pooled estimate of ORR of 51% (95% CI: 47%-54%) was identified from meta-analysis of 27 studies. The fixed-effects weighted average DCR was 88% (95% CI: 85%-90%, 27 studies). CONCLUSION: Current data demonstrate evidence of the clinical effectiveness and safety of radioembolisation for neuroendocrine liver metastases. Prospective randomised studies to compare radioembolisation with other liver directed treatment modalities are needed.

Morphological and Functional Imaging for Detecting and Assessing the Resectability of Neuroendocrine Liver Metastases.

This review evaluates the diagnostic efficacy of different morphological and functional imaging modalities (ultrasound [US], computed tomography [CT], magnetic resonance [MR] imaging, scintigraphy, and positron emission tomography [PET]) in detecting neuroendocrine liver metastases (NELM), assessing vascular and biliary involvement, and the presence of extrahepatic disease. MR imaging is superior for depicting NELM compared to US, CT, and somatostatin receptor scintigraphy. Diffusion-weighted MR imaging is more sensitive for detecting NELM than both T2-weighted and dynamic gadolinium-enhanced MR sequences, and should be systematically performed. Similarly, gadoxetic acid-enhanced MR imaging is more sensitive for detecting liver metastases than conventional extracellular gadolinium chelate-enhanced MR sequences. Its role in detecting NELM remains investigational but appears promising. Somatostatin receptor-targeted PET/CT is a highly effective approach in assessing the resectability of well-differentiated NELM due to very high specificity (and high sensitivity) and its ability to detect small volume extrahepatic disease; this molecular imaging modality is becoming increasingly available in and outside Europe after the recent approval of 6868-DOTATATE in the US. In addition, the information from multiphase, contrast-enhanced CT with 3D reconstruction - obtained concurrently with the information on somatostatin receptor expression of the metastases - is very helpful in planning the extent and type of resection of NELM.

Surgical Management of Patients with Neuroendocrine Neoplasms of the Appendix: Appendectomy or More.

BACKGROUND: Appendiceal neuroendocrine neoplasms (ANEN) are mostly indolent tumours treated effectively with simple appendectomy. However, controversy exists regarding the necessity of oncologic right hemicolectomy (RH) in patients with histologic features suggestive of more aggressive disease. We assess the effects of current guidelines in selecting the surgical strategy (appendectomy or RH) for the management of ANEN. Methods/Aims: This is a retrospective review of all ANEN cases treated over a 14-year period at 3 referral centres and their management according to consensus guidelines of the European and the North American Neuroendocrine Tumor Societies (ENETS and NANETS, respectively). The operation performed, the tumour stage and grade, the extent of residual disease, and the follow-up outcomes were evaluated. RESULTS: Of 14,850 patients who had appendectomies, 215 (1.45%) had histologically confirmed ANEN. Four patients had synchronous non-ANEN malignancies. One hundred and ninety-three patients had index appendectomy. Seventeen patients (7.9%) had lymph node metastases within the mesoappendix. Forty-nine patients underwent RH after appendectomy. The percentages of 30-day morbidity and mortality after RH were 2 and 0%, respectively. Twelve patients (24.5%) receiving completion RH were found to have lymph node metastases. Two patients had liver metastases, both of them synchronous. The median follow-up was 38.5 months (range 1-143). No patient developed disease recurrence. Five- and 10-year overall survival for all patients with ANEN as the only malignancy was both 99.05%. CONCLUSIONS: The current guidelines appear effective in identifying ANEN patients at risk of harbouring nodal disease, but they question the oncological relevance of ANEN lymph node metastases. RH might present an overtreatment for a number of patients with ANEN.

Therapeutic strategies for neuroendocrine liver metastases.

Patients who have neuroendocrine tumors frequently present with liver metastases. A wide panel of treatment options exists for these patients. Liver resection with curative intent achieves the best long-term results. Highly selected patients may be considered for liver transplantation. Substantial recurrence rates reported after surgical approaches call for neoadjuvant and adjuvant concepts. Liver-directed, locally ablative procedures are recommended for patients with limited, nonresectable tumor burden. Angiographic liver-directed techniques, such as transarterial embolization, transarterial chemoembolization, and selective internal radiotherapy, offer excellent palliation for patients with liver-predominant disease. Peptide receptor radionuclide therapy is a promising palliative procedure for patients with hepatic and/or extrahepatic metastases. The efficacy of these treatment options needs to be evaluated in randomized trials. Somatostatin analogues have demonstrated effectiveness not only for symptomatic relief in patients with secreting tumors but also for the control of proliferation in small intestinal neuroendocrine tumors and most recently also in those originating from the pancreas. Chemotherapy is an option mainly for those with pancreatic neuroendocrine tumors and high-grade tumors irrespective of the origin. Novel drugs targeting specific pathways within the tumor cell have produced improved progression-free survival compared with placebo in patients with pancreatic neuroendocrine tumors. Despite such a diverse armamentarium, there is uncertainty with regard to the optimal treatment regimens. Newly introduced molecular-based markers, along with the conduction of clinical trials comparing the efficacy of treatment modalities, offer a chance to move the treatment of neuroendocrine tumor disease toward personalized patient care. In this report, the authors review the approaches for treatment of neuroendocrine liver metastases, identify shortcomings, and anticipate future perspectives. Furthermore, clinical practice recommendations are provided for currently available treatment options. Although multiple modalities are available for the treatment of neuroendocrine liver metastases, optimal management is unclear. The current knowledge pertaining to these treatment options is analyzed.

Incidence of Second Primary Malignancies in Patients with Neuroendocrine Tumours.

BACKGROUND: An association between neuroendocrine tumours (NET) and increased risk of developing second primary malignancies (SPM) has been recognised. METHODS: This was a retrospective review of our institutional prospectively maintained database of NET patients. We identified patients who had been diagnosed with both neuroendocrine and any additional malignancies via examination of patient notes. RESULTS: Clinical data for 169 patients were analysed. After exclusion of patients known to have hereditary tumour predisposition syndromes, 29 SPM were identified in 26 patients (15.38%), the commonest being colorectal (n = 6), breast and renal carcinomas (both n = 5). SPM were classified as previous, synchronous or subsequent relative to NET diagnosis. Rates of SPM in pancreatic and small-bowel NET patients were comparable (15.7 vs. 19.6%, p = 0.78). A person-year methodology was used to compare observed numbers of SPM against expected values generated from age- and sex-specific incidence tables, with standardised incidence ratios (SIR) and 95% confidence intervals (CI) calculated. SPM incidence was significantly elevated in the synchronous subset (SIR 2.732, CI 1.177-5.382) whilst significantly fewer NET patients had a cancer history compared to the general population (SIR 0.4, CI 0.241-0.624). No overall differences were evident between observed and expected incidences of subsequent SPM (SIR 0.36, CI 0.044-1.051). The incidence of synchronous colorectal cancers was markedly elevated (SIR 13.079, CI 4.238-30.474). CONCLUSIONS: Our data support the use of colonoscopy in the diagnostic work-up of NET patients in anticipation of a colorectal SPM. The mechanistic underpinnings of this clinical phenomenon require further genetic investigation, and consideration of this knowledge in patient management pathways is warranted.

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.

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.

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.

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.

Neuroendocrine Neoplasms: Identification of Novel Metabolic Circuits of Potential Diagnostic Utility.

The incidence of neuroendocrine neoplasms (NEN) is increasing, but established biomarkers have poor diagnostic and prognostic accuracy. Here, we aim to define the systemic metabolic consequences of NEN and to establish the diagnostic utility of proton nuclear magnetic resonance spectroscopy (1H-NMR) for NEN in a prospective cohort of patients through a single-centre, prospective controlled observational study. Urine samples of 34 treatment-naïve NEN patients (median age: 59.3 years, range: 36-85): 18 had pancreatic (Pan) NEN, of which seven were functioning; 16 had small bowel (SB) NEN; 20 age- and sex-matched healthy control individuals were analysed using a 600 MHz Bruker 1H-NMR spectrometer. Orthogonal partial-least-squares-discriminant analysis models were able to discriminate both PanNEN and SBNEN patients from healthy control (Healthy vs. PanNEN: AUC = 0.90, Healthy vs. SBNEN: AUC = 0.90). Secondary metabolites of tryptophan, such as trigonelline and a niacin-related metabolite were also identified to be universally decreased in NEN patients, while upstream metabolites, such as kynurenine, were elevated in SBNEN. Hippurate, a gut-derived metabolite, was reduced in all patients, whereas other gut microbial co-metabolites, trimethylamine-N-oxide, 4-hydroxyphenylacetate and phenylacetylglutamine, were elevated in those with SBNEN. These findings suggest the existence of a new systems-based neuroendocrine circuit, regulated in part by cancer metabolism, neuroendocrine signalling molecules and gut microbial co-metabolism. Metabonomic profiling of NEN has diagnostic potential and could be used for discovering biomarkers for these tumours. These preliminary data require confirmation in a larger cohort.

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.

Development and Validation of Risk Scores for All-Cause Mortality for a Smartphone-Based "General Health Score" App: Prospective Cohort Study Using the UK Biobank.

BACKGROUND: Given the established links between an individual's behaviors and lifestyle factors and potentially adverse health outcomes, univariate or simple multivariate health metrics and scores have been developed to quantify general health at a given point in time and estimate risk of negative future outcomes. However, these health metrics may be challenging for widespread use and are unlikely to be successful at capturing the broader determinants of health in the general population. Hence, there is a need for a multidimensional yet widely employable and accessible way to obtain a comprehensive health metric. OBJECTIVE: The objective of the study was to develop and validate a novel, easily interpretable, points-based health score ("C-Score") derived from metrics measurable using smartphone components and iterations thereof that utilize statistical modeling and machine learning (ML) approaches. METHODS: A literature review was conducted to identify relevant predictor variables for inclusion in the first iteration of a points-based model. This was followed by a prospective cohort study in a UK Biobank population for the purposes of validating the C-Score and developing and comparatively validating variations of the score using statistical and ML models to assess the balance between expediency and ease of interpretability and model complexity. Primary and secondary outcome measures were discrimination of a points-based score for all-cause mortality within 10 years (Harrell c-statistic) and discrimination and calibration of Cox proportional hazards models and ML models that incorporate C-Score values (or raw data inputs) and other predictors to predict the risk of all-cause mortality within 10 years. RESULTS: The study cohort comprised 420,560 individuals. During a cohort follow-up of 4,526,452 person-years, there were 16,188 deaths from any cause (3.85%). The points-based model had good discrimination (c-statistic=0.66). There was a 31% relative reduction in risk of all-cause mortality per decile of increasing C-Score (hazard ratio of 0.69, 95% CI 0.663-0.675). A Cox model integrating age and C-Score had improved discrimination (8 percentage points; c-statistic=0.74) and good calibration. ML approaches did not offer improved discrimination over statistical modeling. CONCLUSIONS: The novel health metric ("C-Score") has good predictive capabilities for all-cause mortality within 10 years. Embedding the C-Score within a smartphone app may represent a useful tool for democratized, individualized health risk prediction. A simple Cox model using C-Score and age balances parsimony and accuracy of risk predictions and could be used to produce absolute risk estimations for app users.

Using genetics to inform the pharmacological targeting of neuroendocrine neoplasms.

Neuroendocrine neoplasms (NEN) are a class of tumours heterogeneous in terms of their anatomical sites of origin and clinical behaviour. Outdated perspectives of indolence have been superseded by appreciation for their myriad clinical challenges, such as the high rates of regional and distant metastases at initial diagnosis, lack of clarity on optimal treatment strategies/sequencing, and incompletely elucidated genetic/other pathophysiological drivers. The first randomised controlled trials in this arena were published approximately a decade ago - since then, increased understanding of the genetic drivers and signalling pathway perturbations in these tumours have suggested promise for precision therapy influenced by an individual tumour's molecular sub-type, but this is yet to be realised for manifold reasons. In this article, the authors review the genetic landscapes as currently understood for selected forms of NEN and discuss the current and developing evidence to support the use of genetic information to influence therapy. They provide a critical assessment of the potential limitations of using such approaches and also posit avenues for future developments in this arena.