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.

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.

Neuroendocrine Neoplasms of the Small Bowel and Pancreas.

The traditionally promulgated perspectives of neuroendocrine neoplasms (NEN) as rare, indolent tumours are blunt and have been outdated for the last 2 decades. Clear increments in their incidence over the past decades render them increasingly clinically relevant, and at initial diagnosis many present with nodal and/or distant metastases (notably hepatic). The molecular pathogenesis of these tumours is increasingly yet incompletely understood. Those arising from the small bowel (SB) or pancreas typically occur sporadically; the latter may occur within the context of hereditary tumour predisposition syndromes. NENs can also be associated with endocrinopathy of hormonal hypersecretion. Tangible advances in the development of novel biomarkers, functional imaging modalities and therapy are especially applicable to this sub-set of tumours. The management of SB and pancreatic neuroendocrine tumours (NET) may be challenging, and often comprises a multidisciplinary approach wherein surgical, medical, interventional radiological and radiotherapeutic modalities are implemented. This review provides a comprehensive overview of the epidemiology, pathophysiology, diagnosis and treatment of SB and pancreatic NETs. Moreover, we provide an outlook of the future in these tumour types which will include the development of precision oncology frameworks for individualised therapy, multi-analyte predictive biomarkers, artificial intelligence-derived clinical decision support tools and elucidation of the role of the microbiome in NEN development and clinical behaviour.

Functional imaging in liver tumours.

Functional imaging encompasses techniques capable of assessing physiological parameters of tissues, and offers useful clinical information in addition to that obtained from morphological imaging. Such techniques may include magnetic resonance imaging with diffusion-weighted sequences or hepatobiliary contrast agents, perfusion imaging, or molecular imaging with radiolabelled tracers. The liver is of major importance in oncological practice; not only is hepatocellular carcinoma one of the malignancies with steadily rising incidence worldwide, but hepatic metastases are regularly observed with a range of solid neoplasms. Within the realm of hepatic oncology, different functional imaging modalities may occupy pivotal roles in lesion characterisation, treatment selection and follow-up, depending on tumour size and type. In this review, we characterise the major forms of functional imaging, discuss their current application to the management of patients with common primary and secondary liver tumours, and anticipate future developments within this field.

The Diagnostic Odyssey in Children and Adolescents With X-linked Hypophosphatemia: Population-Based, Case-Control Study.

CONTEXT: X-linked hypophosphatemia (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 (EHRs) in the United Kingdom. METHODS: Using the Optimum Patient Care Research Database, individuals aged 20 years or younger after January 1, 2000, at date of recorded XLH diagnosis were identified using Systematized Nomenclature of Medicine Clinical Terms (SNOMED)/Read codes and age-matched to 100 controls. Recording of XLH-related clinical features was summarized then compared between cases and controls using chi-squared or Fisher's exact test. RESULTS: In total, 261 XLH cases were identified; 99 met the 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 characterization of the EHR phenotypes of children and adolescents with XLH may inform future case-finding approaches to expedite diagnosis in primary care.

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.

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.

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.

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.

Prostate-specific antigen testing and opportunistic prostate cancer screening: a cohort study in England, 1998-2017.

BACKGROUND: Prostate cancer is a leading cause of cancer- related death. Interpreting the results from trials of screening with prostate-specific antigen (PSA) is complex in terms of defining optimal prostate cancer screening policy. AIM: To assess the rates of, and factors associated with, the uptake of PSA testing and opportunistic screening (that is, a PSA test in the absence of any symptoms) in England between 1998 and 2017, and to estimate the likely rates of pre-randomisation screening and contamination (that is, unscheduled screening in the 'control' arm) of the UK-based Cluster Randomised Trial of PSA Testing for Prostate Cancer (CAP). DESIGN AND SETTING: Open cohort study of men in England aged 40-75 years at cohort entry (1998-2017), undertaken using the QResearch database. METHOD: Eligible men were followed for up to 19 years. Rates of PSA testing and opportunistic PSA screening were calculated; Cox regression was used to estimate associations. RESULTS: The cohort comprised 2 808 477 men, of whom 631 426 had a total of 1 720 855 PSA tests. The authors identified that 410 724 men had opportunistic PSA screening. Cumulative proportions of uptake of opportunistic screening in the cohort were 9.96% at 5 years', 22.71% at 10 years', and 44.13% at 19 years' follow-up. The potential rate of contamination in the CAP control arm was estimated at 24.50%. CONCLUSION: A substantial number of men in England opt in to opportunistic prostate cancer screening, despite uncertainty regarding its efficacy and harms. The rate of opportunistic prostate cancer screening in the population is likely to have contaminated the CAP trial, making it difficult to interpret the results.

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.

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.

Liver transplantation and multivisceral transplantation in the management of patients with advanced neuroendocrine tumours.

Orthotopic liver transplantation (OLT) represents a generally accepted albeit somewhat controversially discussed therapeutic strategy in highly selected patients with non-resectable hepatic metastases from neuroendocrine tumours (NET). Whilst there are some exclusion criteria, these are not universally followed, and the optimal set of inclusion parameters for deeming patients eligible has not yet been elucidated. This is due to heterogeneity in the study populations, as well differing approaches employed and also divergences in selection criteria between centres. Recent data have suggested that OLT may represent the most efficacious approach in terms of overall and disease-free survival to the management of NET metastatic to the liver when conducted in accordance with the modified Milan criteria. Therefore, a consensus set of selection criteria requires definition to facilitate stringent and fair allocation of deceased-donor organs, as well as consideration for living-donor organs. In the context of classically non-resectable metastatic tumour bulk, multivisceral transplantation with or without the liver may also be indicated, yet experience is very limited. In this review, we discuss the diagnostic work-up of patients in whom the aforementioned transplantation approaches are being considered, critically analyse the published experience and also anticipate future developments in this field, including a discussion of immediate and longer-term research priorities.

Surgical Approaches to the Management of Neuroendocrine Liver Metastases.

Surgical approaches to hepatic metastases occupy an important role in the management of patients with neuroendocrine neoplasms and may have curative or palliative intentions. Resection of hepatic disease with curative intent is the only modality offering potential cure for patients with liver metastases; however, only a minority of patients are eligible. Regardless of resection margin, disease recurrence almost invariably occurs and novel adjuvant/neoadjuvant therapies are mandated to be included within multimodal treatment concepts. Liver transplantation in meticulously selected patients may be associated with excellent outcomes, but unfortunately demands on donated organs limit the wider utilization of this approach.

Role of Staging in Patients with Small Intestinal Neuroendocrine Tumours.

Small bowel neuroendocrine tumours are the commonest malignancy arising in the small intestine and have substantially increased in incidence in recent decades. Patients with small bowel neuroendocrine tumours commonly develop lymph node and/or distant metastases. Here, we examine the role of staging in 84 surgically treated patients with small bowel neuroendocrine tumours, comparing diagnostic information yielded from morphological, functional and endoscopic modalities. Furthermore, we correlate pre-operative staging with intra-operative findings in a sub-cohort of 20 patients. The vast majority of patients had been histologically confirmed to have low-grade (Ki-67 <2%) disease; however, lymph node and distant metastases were observed in 74 (88.1%) and 51 (60.7%) of patients at presentation, respectively. Liver metastases were evident in 48 (57.1%) patients, with solely peritoneal and bone metastases observed in 2 (2.4%) and 1 (1.2%) patients, respectively. Forty patients (47.6%) received multimodal treatment. In our sub-cohort analysis, pre-operative imaging understaged disease in 14/20 (70%) when compared with intra-operative findings. In patients with multifocal primary tumours and miliary liver metastases, no imaging modality was able to detect entire disease spread. Overall, presently available imaging modalities heavily underestimate disease stage, with meticulous intra-operative abdominal examination being superior to any imaging technology. Multimodal treatment has an important role in prolonging survival.