Years of life lost due to cancer in the United Kingdom from 1988 to 2017.

BACKGROUND: We investigated the application of years of life lost (YLL) in routine cancer statistics using cancer mortality data from 1988 to 2017. METHODS: Cancer mortality data for 17 cancers and all cancers in the UK from 1988 to 2017 were provided by the UK Association of Cancer Registries by sex, 5-year age group, and year. YLL, age-standardised YLL rate (ASYR) and age-standardised mortality rate (ASMR) were estimated. RESULTS: The annual average YLL due to cancer, in the time periods 1988-1992 and 2013-2017, were about 2.2 and 2.3 million years, corresponding to 4510 and 3823 ASYR per 100,000 years, respectively. During 2013-2017, the largest number of YLL occurred in lung, bowel and breast cancer. YLL by age groups for all cancers showed a peak between 60-64 and 75-79. The relative contributions to incidence, mortality, and YLL differ between cancers. For instance, pancreas (in women and men) made up a smaller proportion of incidence (3%) but bigger proportion of mortality (6 and 5%) and YLL (5 and 6%), whereas prostate cancer (26% of incidence) contributed 13% mortality and 9% YLL. CONCLUSION: YLL is a useful measure of the impact different cancers have on society and puts a higher weight on cancer deaths in younger individuals.

Protocol for the YORKSURe prospective multistage study testing the feasibility for early detection of bladder cancer in populations with high disease-specific mortality risk.

INTRODUCTION: Around 25% of patients with bladder cancer (BCa) present with invasive disease. Non-randomised studies of population-based screening have suggested reductions in BCa-specific mortality are possible through earlier detection. The low prevalence of lethal disease in the general population means screening is not cost-effective and there is no consensus on the best strategy. Yorkshire has some of the highest mortality rates from BCa in England. We aim to test whether population screening in a region of high mortality risk will lead to a downward stage-migration of aggressive BCa, improved survival and is cost-effective. METHODS AND ANALYSIS: YORKSURe is a tiered, randomised, multicohort study to test the feasibility of a large BCa screening randomised controlled trial. In three parallel cohorts, participants will self-test urine (at home) up to six times. Results are submitted via a mobile app or freephone. Those with a positive result will be invited for further investigation at community-based early detection clinics or within usual National Health Service (NHS) pathways. In Cohort 1, we will post self-testing kits to research engaged participants (n=2000) embedded within the Yorkshire Lung Screening Trial. In Cohort 2, we will post self-testing kits to 3000 invitees. Cohort 2 participants will be randomised between haematuria and glycosuria testing using a reveal/conceal design. In Cohort 3, we will post self-testing kits to 500 patients within the NHS pathway for investigation of haematuria. Our primary outcomes are rates of recruitment and randomisation, rates of positive test and acceptability of the design. The study is currently recruiting and scheduled to finish in June 2023. ETHICS AND DISSEMINATION: The study has received the following approvals: London Riverside Research Ethics Committee (22/LO/0018) and Health Research Authority Confidentiality Advisory Group (20/CAG/0009). Results will be made available to providers and researchers via publicly accessible scientific journals. TRIAL REGISTRATION NUMBER: ISRCTN34273159.

Exploring the utility and acceptability of Faecal immunochemical testing (FIT) as a novel intervention for the improvement of colorectal Cancer (CRC) surveillance in individuals with lynch syndrome (FIT for lynch study): a single-arm, prospective, multi-centre, non-randomised study.

BACKGROUND: Lynch Syndrome (LS) is an inherited cancer predisposition syndrome defined by pathogenic variants in the mismatch repair (MMR) or EPCAM genes. In the United Kingdom, people with LS are advised to undergo biennial colonoscopy from as early as 25 until 75 years of age to mitigate a high lifetime colorectal cancer (CRC) risk, though the consideration of additional surveillance intervention(s) through the application of non-invasive diagnostic devices has yet to be longitudinally observed in LS patients. In this study, we will examine the role of annual faecal immunochemical testing (FIT) alongside biennial colonoscopy for CRC surveillance in people with LS. METHODS/DESIGN: In this single-arm, prospective, non-randomised study, 400 LS patients will be recruited across 11 National Health Service (NHS) Trusts throughout the United Kingdom. Study inclusion requires a LS diagnosis, between 25 and 73 years old, and a routine surveillance colonoscopy scheduled during the recruitment period. Eligible patients will receive a baseline OC-Sensor™ FIT kit ahead of their colonoscopy, and annually for 3 years thereafter. A pre-paid envelope addressed to the central lab will be included within all patient mailings for the return of FIT kits and relevant study documents. A questionnaire assessing attitudes and perception of FIT will also be included at baseline. All study samples received by the central lab will be assayed on an OC-Sensor™ PLEDIA Analyser. Patients with FIT results of ≥6 µg of Haemoglobin per gram of faeces (f-Hb) at Years 1 and/or 3 will be referred for colonoscopy via an urgent colonoscopy triage pathway. 16S rRNA gene V4 amplicon sequencing will be carried out on residual faecal DNA of eligible archived FIT samples to characterise the faecal microbiome. DISCUSSION: FIT may have clinical utility alongside colonoscopic surveillance in people with LS. We have designed a longitudinal study to examine the efficacy of FIT as a non-invasive modality. Potential limitations of this method will be assessed, including false negative or false positive FIT results related to specific morphological features of LS neoplasia or the presence of post-resection anastomotic inflammation. The potential for additional colonoscopies in a subset of participants may also impact on colonoscopic resources and patient acceptability. TRIAL REGISTRATION: Trial Registration: ISRCTN, ISRCTN15740250 . Registered 13 July 2021.

Boosting of Waned Humoral and Cellular Responses to SARS-CoV-2 Variants of Concern Among Patients with Cancer.

This study offers longitudinal insight into the impact of three SARS-CoV-2 vaccinations on humoral and cellular immunity in patients with solid cancers, patients with hematologic malignancies, and persons without cancer. For all cohorts, virus-neutralizing immunity was significantly depleted over a period of up to 9 months following the second vaccine dose, the one striking exception being IL2 production by SARS-CoV-2 antigen-specific T cells. Immunity was restored by the third vaccine dose, except in a substantial number of patients with hematologic malignancy, for whom both cancer type and treatment schedule were associated with nonresponse. Thus, whereas most patients with myelodysplastic syndrome were conspicuously good responders, some patients with other hematologic malignancies receiving cancer therapies within 2 weeks of vaccination showed no seroconversion despite three vaccine doses. Moreover, SARS-CoV-2 exposure during the course of the study neither prevented immunity waning, even in healthy controls, nor guaranteed vaccine responsiveness. These data offer real-world human immunologic insights that can inform health policy for patients with cancer.

Safety and immunogenicity of one versus two doses of the COVID-19 vaccine BNT162b2 for patients with cancer: interim analysis of a prospective observational study.

BACKGROUND: The efficacy and safety profiles of vaccines against SARS-CoV-2 in patients with cancer is unknown. We aimed to assess the safety and immunogenicity of the BNT162b2 (Pfizer-BioNTech) vaccine in patients with cancer. METHODS: For this prospective observational study, we recruited patients with cancer and healthy controls (mostly health-care workers) from three London hospitals between Dec 8, 2020, and Feb 18, 2021. Participants who were vaccinated between Dec 8 and Dec 29, 2020, received two 30 µg doses of BNT162b2 administered intramuscularly 21 days apart; patients vaccinated after this date received only one 30 µg dose with a planned follow-up boost at 12 weeks. Blood samples were taken before vaccination and at 3 weeks and 5 weeks after the first vaccination. Where possible, serial nasopharyngeal real-time RT-PCR (rRT-PCR) swab tests were done every 10 days or in cases of symptomatic COVID-19. The coprimary endpoints were seroconversion to SARS-CoV-2 spike (S) protein in patients with cancer following the first vaccination with the BNT162b2 vaccine and the effect of vaccine boosting after 21 days on seroconversion. All participants with available data were included in the safety and immunogenicity analyses. Ongoing follow-up is underway for further blood sampling after the delayed (12-week) vaccine boost. This study is registered with the NHS Health Research Authority and Health and Care Research Wales (REC ID 20/HRA/2031). FINDINGS: 151 patients with cancer (95 patients with solid cancer and 56 patients with haematological cancer) and 54 healthy controls were enrolled. For this interim data analysis of the safety and immunogenicity of vaccinated patients with cancer, samples and data obtained up to March 19, 2021, were analysed. After exclusion of 17 patients who had been exposed to SARS-CoV-2 (detected by either antibody seroconversion or a positive rRT-PCR COVID-19 swab test) from the immunogenicity analysis, the proportion of positive anti-S IgG titres at approximately 21 days following a single vaccine inoculum across the three cohorts were 32 (94%; 95% CI 81-98) of 34 healthy controls; 21 (38%; 26-51) of 56 patients with solid cancer, and eight (18%; 10-32) of 44 patients with haematological cancer. 16 healthy controls, 25 patients with solid cancer, and six patients with haematological cancer received a second dose on day 21. Of the patients with available blood samples 2 weeks following a 21-day vaccine boost, and excluding 17 participants with evidence of previous natural SARS-CoV-2 exposure, 18 (95%; 95% CI 75-99) of 19 patients with solid cancer, 12 (100%; 76-100) of 12 healthy controls, and three (60%; 23-88) of five patients with haematological cancers were seropositive, compared with ten (30%; 17-47) of 33, 18 (86%; 65-95) of 21, and four (11%; 4-25) of 36, respectively, who did not receive a boost. The vaccine was well tolerated; no toxicities were reported in 75 (54%) of 140 patients with cancer following the first dose of BNT162b2, and in 22 (71%) of 31 patients with cancer following the second dose. Similarly, no toxicities were reported in 15 (38%) of 40 healthy controls after the first dose and in five (31%) of 16 after the second dose. Injection-site pain within 7 days following the first dose was the most commonly reported local reaction (23 [35%] of 65 patients with cancer; 12 [48%] of 25 healthy controls). No vaccine-related deaths were reported. INTERPRETATION: In patients with cancer, one dose of the BNT162b2 vaccine yields poor efficacy. Immunogenicity increased significantly in patients with solid cancer within 2 weeks of a vaccine boost at day 21 after the first dose. These data support prioritisation of patients with cancer for an early (day 21) second dose of the BNT162b2 vaccine. FUNDING: King's College London, Cancer Research UK, Wellcome Trust, Rosetrees Trust, and Francis Crick Institute.

The Transcriptomic Landscape of Prostate Cancer Development and Progression: An Integrative Analysis.

Next-generation sequencing of primary tumors is now standard for transcriptomic studies, but microarray-based data still constitute the majority of available information on other clinically valuable samples, including archive material. Using prostate cancer (PC) as a model, we developed a robust analytical framework to integrate data across different technical platforms and disease subtypes to connect distinct disease stages and reveal potentially relevant genes not identifiable from single studies alone. We reconstructed the molecular profile of PC to yield the first comprehensive insight into its development, by tracking changes in mRNA levels from normal prostate to high-grade prostatic intraepithelial neoplasia, and metastatic disease. A total of nine previously unreported stage-specific candidate genes with prognostic significance were also found. Here, we integrate gene expression data from disparate sample types, disease stages and technical platforms into one coherent whole, to give a global view of the expression changes associated with the development and progression of PC from normal tissue through to metastatic disease. Summary and individual data are available online at the Prostate Integrative Expression Database (PIXdb), a user-friendly interface designed for clinicians and laboratory researchers to facilitate translational research.

Predicting shockwave lithotripsy outcome for urolithiasis using clinical and stone computed tomography texture analysis variables.

We aimed to develop and evaluate a statistical model, which included known pre-treatment factors and new computed tomography texture analysis (CTTA) variables, for its ability to predict the likelihood of a successful outcome after extracorporeal shockwave lithotripsy (SWL) treatment for renal and ureteric stones. Up to half of patients undergoing SWL may fail treatment. Better prediction of which cases will likely succeed SWL will help patients to make an informed decision on the most effective treatment modality for their stone. 19 pre-treatment factors for SWL success, including 6 CTTA variables, were collected from 459 SWL cases at a single centre. Univariate and multivariable analyses were performed by independent statisticians to predict the probability of a stone free (both with and without residual fragments) outcome after SWL. A multivariable model had an overall accuracy of 66% on Receiver Operator Curve (ROC) analysis to predict for successful SWL outcome. The variables most frequently chosen for the model were those which represented stone size. Although previous studies have suggested SWL can be reliably predicted using pre-treatment factors and that analysis of CT stone images may improve outcome prediction, the results from this study have not produced a useful model for SWL outcome prediction.

Biomarkers of collagen synthesis predict progression in the PROFILE idiopathic pulmonary fibrosis cohort.

Idiopathic pulmonary fibrosis (IPF) is characterised by excessive extracellular matrix (ECM) deposition and remodelling. Measuring this activity provides an opportunity to develop tools capable of identifying individuals at-risk of progression. Longitudinal change in markers of ECM synthesis was assessed in 145 newly-diagnosed individuals with IPF.Serum levels of collagen synthesis neoepitopes, PRO-C3 and PRO-C6 (collagen type 3 and 6), were elevated in IPF compared with controls at baseline, and progressive disease versus stable disease during follow up, (PRO-C3 p < 0.001; PRO-C6 p = 0.029). Assessment of rate of change in neoepitope levels from baseline to 3 months (defined as 'slope to month 3': HIGH slope, slope > 0 vs. LOW slope, slope < =0) demonstrated no relationship with mortality for these markers (PRO-C3 (HR 1.62, p = 0.080); PINP (HR 0.76, p = 0.309); PRO-C6 (HR 1.14, p = 0.628)). As previously reported, rising concentrations of collagen degradation markers C1M, C3M, C6M and CRPM were associated with an increased risk of overall mortality (HR = 1.84, CI 1.03-3.27, p = 0.038, HR = 2.44, CI 1.39-4.31, p = 0.002; HR = 2.19, CI 1.25-3.82, p = 0.006; HR = 2.13 CI 1.21-3.75, p = 0.009 respectively).Elevated levels of PRO-C3 and PRO-C6 associate with IPF disease progression. Collagen synthesis and degradation biomarkers have the potential to enhance clinical trials in IPF and may inform prognostic assessment and therapeutic decision making in the clinic.

A new pragmatic design for dose escalation in phase 1 clinical trials using an adaptive continual reassessment method.

BACKGROUND: A key challenge in phase I trials is maintaining rapid escalation in order to avoid exposing too many patients to sub-therapeutic doses, while preserving safety by limiting the frequency of toxic events. Traditional rule-based designs require temporarily stopping recruitment whilst waiting to see whether enrolled patients develop toxicity. This can be both inefficient and introduces logistic challenges to recruitment in the clinic. We describe a novel two-stage dose assignment procedure designed for a phase I clinical trial (STARPAC), where a good estimation of prior was possible. METHODS: The STARPAC design uses rule-based design until the first patient has a dose limiting toxicity (DLT) and then switches to a modified CRM, with rules to handle patient recruitment during follow-up of earlier patients. STARPAC design is compared via simulations with the TITE-CRM and 3 + 3 methods in various toxicity estimate (T1-5), rate of recruitment (R1-2), and DLT events timing (DT1-4), scenarios using several metrics: accuracy of maximum tolerated dose (MTD), numbers of DLTs, number of patients enrolled and those missed; duration of trial; and proportion of patients treated at the therapeutic dose or MTD. RESULTS: The simulations suggest that STARPAC design performed well in MTD estimation and in treating patients at the highest possible therapeutic levels. STARPAC and TITE-CRM were comparable in the number of patients required and DLTs incurred. The 3 + 3 design often had fewer patients and DLTs although this is due to its low escalation rate leading to poor MTD estimation. For the numbers of declined patients and MTD estimation 3 + 3 is uniformly worse, with STARPAC being better in those metrics for high toxicity scenarios and TITE-CRM better with low toxicity. In situations including doses with toxicities both above and below 30%, the STARPAC design outperformed TITE-CRM with respect to every metric. CONCLUSION: When considering doses with toxicities both above and below the target of 30% toxicities, the two-stage STARPAC dose escalation design provides a more efficient phase I trial design than either the traditional 3 + 3 or the TITE-CRM design. Trialists should model various designs via simulation to adopt the most efficient design for their clinical scenario. TRIAL REGISTRATION: Clinical Trials NCT03307148 (11 October 2017).

Should reporting of peri-neural invasion and extra prostatic extension be mandatory in prostate cancer biopsies? correlation with outcome in biopsy cases treated conservatively.

The identification of perineural invasion (PNI) and extraprostatic extension (ECE) in prostate cancer (PC) biopsies is time consuming and can be difficult. Although this is required information in many datasets, there is little evidence on their effect on outcome in patients treated conservatively. Cases of PC were identified from three cancer registries in the UK from men with clinically localized prostate cancer diagnosed by needle biopsy from 1990-2003. The endpoint was prostate cancer death (DOD). Patients treated radically within 6 months, those with objective evidence of metastases or who had prior hormone therapy were excluded. Follow-up was through cancer registries up until 2012. Deaths were divided into those from PC and those from other causes, according to WHO criteria. 988 biopsy cases (6522 biopsy cores) were centrally reviewed by three uropathologists and assigned a Gleason score and Grade Group (GG). The presence of both PNI and ECE was recorded. Of 988 patients, PNI was present in 288 (DOD = 75) and ECE in 23 (DOD = 5). On univariable analysis PNI was highly significantly associated with DOD (hazard ratio [HR] 2.28, 95% CI: 1.68, 3.1, log-rank test p-value = 4.8 × 10-8), but ECE was not (log-rank test p-value = 0.334). On multivariable analysis with GG, serum PSA (per 10%), clinical stage and extent of disease (per 10%), PNI lost significance (HR 1.16, 95% CI: 0.83, 1.63, likelihood ratio test p-value = 0.371). The utility of routinely examining prostate biopsies for ECE and PNI is doubtful as it is not independently associated with higher grade, stage or prognosis.

Identification of FBXL4 as a Metastasis Associated Gene in Prostate Cancer.

Prostate cancer is the most common cancer among western men, with a significant mortality and morbidity reported for advanced metastatic disease. Current understanding of metastatic disease is limited due to difficulty of sampling as prostate cancer mainly metastasizes to bone. By analysing prostate cancer bone metastases using high density microarrays, we found a common genomic copy number loss at 6q16.1-16.2, containing the FBXL4 gene, which was confirmed in larger series of bone metastases by fluorescence in situ hybridisation (FISH). Loss of FBXL4 was also detected in primary tumours and it was highly associated with prognostic factors including high Gleason score, clinical stage, prostate-specific antigen (PSA) and extent of disease, as well as poor patient survival, suggesting that FBXL4 loss contributes to prostate cancer progression. We also demonstrated that FBXL4 deletion is detectable in circulating tumour cells (CTCs), making it a potential prognostic biomarker by 'liquid biopsy'. In vitro analysis showed that FBXL4 plays a role in regulating the migration and invasion of prostate cancer cells. FBXL4 potentially controls cancer metastasis through regulation of ERLEC1 levels. Therefore, FBXL4 could be a potential novel prostate cancer suppressor gene, which may prevent cancer progression and metastasis through controlling cell invasion.

Validation of a contemporary prostate cancer grading system using prostate cancer death as outcome.

BACKGROUND: Gleason scoring (GS) has major deficiencies and a novel system of five grade groups (GS⩽6; 3+4; 4+3; 8; ⩾9) has been recently agreed and included in the WHO 2016 classification. Although verified in radical prostatectomies using PSA relapse for outcome, it has not been validated using prostate cancer death as an outcome in biopsy series. There is debate whether an 'overall' or 'worst' GS in biopsies series should be used. METHODS: Nine hundred and eighty-eight prostate cancer biopsy cases were identified between 1990 and 2003, and treated conservatively. Diagnosis and grade was assigned to each core as well as an overall grade. Follow-up for prostate cancer death was until 31 December 2012. A log-rank test assessed univariable differences between the five grade groups based on overall and worst grade seen, and using univariable and multivariable Cox proportional hazards. Regression was used to quantify differences in outcome. RESULTS: Using both 'worst' and 'overall' GS yielded highly significant results on univariate and multivariate analysis with overall GS slightly but insignificantly outperforming worst GS. There was a strong correlation with the five grade groups and prostate cancer death. CONCLUSIONS: This is the largest conservatively treated prostate cancer cohort with long-term follow-up and contemporary assessment of grade. It validates the formation of five grade groups and suggests that the 'worst' grade is a valid prognostic measure.

Evaluation of a minimally invasive cell sampling device coupled with assessment of trefoil factor 3 expression for diagnosing Barrett's esophagus: a multi-center case-control study.

BACKGROUND: Barrett's esophagus (BE) is a commonly undiagnosed condition that predisposes to esophageal adenocarcinoma. Routine endoscopic screening for BE is not recommended because of the burden this would impose on the health care system. The objective of this study was to determine whether a novel approach using a minimally invasive cell sampling device, the Cytosponge, coupled with immunohistochemical staining for the biomarker Trefoil Factor 3 (TFF3), could be used to identify patients who warrant endoscopy to diagnose BE. METHODS AND FINDINGS: A case-control study was performed across 11 UK hospitals between July 2011 and December 2013. In total, 1,110 individuals comprising 463 controls with dyspepsia and reflux symptoms and 647 BE cases swallowed a Cytosponge prior to endoscopy. The primary outcome measures were to evaluate the safety, acceptability, and accuracy of the Cytosponge-TFF3 test compared with endoscopy and biopsy. In all, 1,042 (93.9%) patients successfully swallowed the Cytosponge, and no serious adverse events were attributed to the device. The Cytosponge was rated favorably, using a visual analogue scale, compared with endoscopy (p < 0.001), and patients who were not sedated for endoscopy were more likely to rate the Cytosponge higher than endoscopy (Mann-Whitney test, p < 0.001). The overall sensitivity of the test was 79.9% (95% CI 76.4%-83.0%), increasing to 87.2% (95% CI 83.0%-90.6%) for patients with ≥3 cm of circumferential BE, known to confer a higher cancer risk. The sensitivity increased to 89.7% (95% CI 82.3%-94.8%) in 107 patients who swallowed the device twice during the study course. There was no loss of sensitivity in patients with dysplasia. The specificity for diagnosing BE was 92.4% (95% CI 89.5%-94.7%). The case-control design of the study means that the results are not generalizable to a primary care population. Another limitation is that the acceptability data were limited to a single measure. CONCLUSIONS: The Cytosponge-TFF3 test is safe and acceptable, and has accuracy comparable to other screening tests. This test may be a simple and inexpensive approach to identify patients with reflux symptoms who warrant endoscopy to diagnose BE.

Dialysate cytokine levels do not predict encapsulating peritoneal sclerosis.

BACKGROUND: Encapsulating peritoneal sclerosis (EPS) is a rare but devastating complication of long-term peritoneal dialysis (PD). There is no well-validated method for predicting which patients will develop the condition, although known risk factors include long duration of PD, high glucose exposure and lack of residual renal function. We have investigated whether dialysate cytokines (MCP-1 (monocyte chemotactic protein-1), CCL18 (pulmonary and activation-regulated cytokine, PARC), IL-6 (interleukin-6), CCL15 (leukotactin) and angiogenin) could be used to predict the onset of EPS more effectively than known clinical risk factors. METHODS: Samples of dialysate and clinical data were prospectively collected from 151 patients at the West London Renal center between 2003 and 2010. Dialysate cytokine levels were measured using the enzyme-linked immunoabsorbant assay (ELISA) technique. Encapsulating peritoneal sclerosis subsequently developed in 17 patients during a follow-up period of 27 - 113 months. Cytokines found at higher levels in dialysate of pre-EPS patients were investigated as candidate predictors of EPS using logistic regression analysis. RESULTS: Dialysate IL-6, MCP-1 and CCL15 were significantly higher in patients who subsequently developed EPS; however, a logistic regression model using dialysate cytokines to predict EPS was no better than a model using well-recognized clinical markers (length of time on PD and membrane transport status). CONCLUSIONS: Although MCP-1, IL-6 and CCL15 were found at higher levels in the dialysate of patients who subsequently developed EPS, dialysate levels of these cytokines do not improve prediction of future EPS above a model using known clinical risk factors.

Validation of the isovolumetric relaxation time for the estimation of pulmonary systolic arterial blood pressure in chronic pulmonary hypertension.

AIMS: Transthoracic echocardiography is a useful technique for non-invasive detection of pulmonary arterial systolic pressure (PASP). Isovolumic relaxation time (IVRT) measured by Doppler tissue imaging (DTI) is a sensitive measurement of changes in pulmonary vasculature. Our aim was to validate IVRT in the echocardiographic assessment of pulmonary hypertension (PH) patients. METHODS AND RESULTS: We studied 196 PH patients (67% women, mean age 51.8 ± 16.6 years, mean PASP: 81 ± 24 mmHg) and 37 consecutive age- and sex-matched controls (58% women, mean age 44.7 ± 16.4 years, mean PASP 27.7 ± 5.5 mmHg). The estimation of PASP was derived from tricuspid regurgitation velocity according to the Bernoulli equation. The measurement of IVRT was calculated using pulsed tissue Doppler. In the PH group and in the healthy volunteers group (P < 0.0001), the average IVRT was 113.4 ± 28.5 ms [95% confidence interval (CI): 109-117] and 41 ± 12.5 ms (95% CI: 37-45), respectively. We found a strong correlation between IVRT and systolic pulmonary pressure in the PH group (r = 0.52, P < 0.0001) and a cut-off of 75 ms showed a sensitivity and specificity of 94% and 97%, respectively, for the prediction of elevated PASP. CONCLUSION: The determination of IVRT by DTI is a simple and reproducible method that correlates well with PASP. It is, therefore, a parameter to consider in the echocardiographic assessment of patients with PH, and may be particularly important when the tricuspid Doppler signal is poor.

Relationship between price paid for off-trade alcohol, alcohol consumption and income in England: a cross-sectional survey.

AIMS: In order to examine the potential impact of an increase in the minimum price per unit of alcohol to 50 pence ($0.78), we examined drinking patterns and household incomes of people who purchase alcohol in England at above and below this price. METHODS: Cross-sectional survey of 515 members of the public in seven towns and cities in the south of England. The primary outcome was whether the participant had purchased alcohol at <50 p/unit. The main exposures were annual household income and alcohol consumption, measured using the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C). RESULTS: The median price paid per unit of alcohol was 53.1 pence (range 16.4-297.0 pence). Those buying alcohol at <50 p/unit had a mean AUDIT-C score of 6.2 compared with 5.5 among those buying alcohol at above this price. The odds ratio (OR) of a person on low income with high-risk drinking purchasing alcohol at <50 p/unit was 1.29 [95% confidence interval (CI) = 0.82-1.79] compared with all other study participants. The OR of a person on low income with low-risk drinking purchasing alcohol below this price was 0.51 (95% CI = 0.30-0.87) compared with all other participants. CONCLUSIONS: These data suggest that an increase in the minimum price of alcohol to 50 pence price per unit is only likely to disproportionately affect people on low incomes if their alcohol consumption is excessive.

A novel and validated prognostic index in hepatocellular carcinoma: the inflammation based index (IBI).

BACKGROUND & AIMS: Outcome prediction is uniquely different in hepatocellular carcinoma (HCC) as the progressive functional impairment of the liver impacts patient survival independently of tumour stage. As chronic inflammation is associated with the pathogenesis of HCC, we explored the prognostic impact of a panel of inflammatory based scores, including the modified Glasgow Prognostic Score (mGPS), neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR), in independent cohorts. METHODS: Inflammatory markers, Barcelona Clinic Liver Cancer (BCLC) and Cancer of the Liver Italian Program (CLIP) scores were studied in a training set of 112 patients with predominantly unresectable HCC (75%). Independent predictors of survival identified in multivariate analysis were validated in an independent cohort of 466 patients with an overall lower tumour burden (BCLC-A, 56%). RESULTS: In both training and validation sets, mGPS and CLIP scores emerged as independent predictors of overall survival. The predictive accuracy of the combined mGPS and CLIP score (c score 0.7, 95% CI 0.6-0.8) appeared superior to that of the CLIP score alone (c score 0.6, 95% CI 0.5-0.7). CONCLUSIONS: Systemic inflammation as measured by the mGPS, independently predicts overall survival in HCC. We have validated a novel, easy to use inflammatory score that can be used to stratify individuals. These data enable formulation of a new prognostic system, the inflammation based index in HCC (IBI). Further validation of the IBI considering treatment allocation and survival is warranted in an independent patient cohort.