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Objective There is evidence that colorectal cancer screening using faecal haemoglobin is less effective in women than men. The faecal haemoglobin concentrations were therefore examined in women and men with screen-detected colorectal cancer. Setting Scottish Bowel Screening Programme, following the introduction of a faecal immunochemical test from November 2017, to March 2020. Methods Data were collated on faecal haemoglobin concentrations, pathological stage and anatomical site of the main lesion in participants who had colorectal cancer detected. The data in women and men were compared. Results For the faecal haemoglobin concentrations studied (>80 µg Hb/g faeces), the distributions indicated lower concentrations in women. Marked differences were found between women and men diagnosed with colorectal cancer. The median faecal haemoglobin concentration for women ( n = 720) was 408 µg Hb/g faeces compared to 473 µg Hb/g faeces for men ( n = 959) ( p = 0.004) and 50.6% of the results were >400 µg Hb/g faeces in women; in men, this was 57.8%. The difference in faecal haemoglobin concentrations in women and men became less statistically significant as stage advanced from stages I–IV. For right-sided, left-sided and rectal colorectal cancer, a similar gender difference persisted in all sites. Differences in faecal haemoglobin between the genders were significant for left-sided cancers and stage I and approached significance for rectal cancers and stage II, but all sites and stages showed lower median faecal haemoglobin concentrations for women. Conclusions To minimise gender inequalities, faecal immunochemical test-based colorectal cancer screening programmes should evaluate a strategy of using different faecal haemoglobin concentration thresholds in women and men.

Background Carbon monoxide is a common environmental toxin, and some patients present with features of cardiac injury in addition to the noxious effects of carbon monoxide poisoning. A very small fraction of those have a transient left ventricular apical ballooning syndrome or Takotsubo cardiomyopathy, both terms are used to define a syndrome that affects the systolic function of the heart. It usually presents with elevated troponin levels with or without electrocardiographic changes. Cardiac angiograms generally illustrate coronary arteries without significant obstruction. Case Report Here we report the curious case of a 37-year-old Hispanic man brought in for carbon monoxide poisoning, but found to have significantly elevated troponin levels. Echocardiogram demonstrated decreased ejection fraction of 35%. Left heart catheterization 2 days after admission revealed patent coronary arteries, improved ejection fraction to 45%, and wall motion abnormalities plus apical ballooning compatible with Takotsubo cardiomyopathy. The case is unusual because our patient differs from the classically defined elderly, postmenopausal female demographic, and did not experience an emotional crisis that could have provoked this series of events. It is also noteworthy for the fact that the only identifiable trigger was exposure to carbon monoxide. Why Should an Emergency Physician Be Aware of This? Carbon monoxide poisoning is a common occurrence resulting in a multitude of annual emergency department visits. Given the known toxic effects of carbon monoxide poisoning on the heart, prompt cardiac workup is important to prevent overlooking a major, although rare, manifestation of carbon monoxide exposure.

Background Faecal haemoglobin concentration (f-Hb), estimated using a faecal immunochemical test, can be safely implemented in primary care to assess risk of colorectal cancer (CRC). Clinical outcomes of patients presenting with symptoms of lower gastrointestinal disease were examined using an extensive range of f-Hb thresholds to decide on reassurance or referral for further investigation. Methods All patients who attended primary care and submitted a single faecal specimen faecal immunochemical test in the first year of the routine service had f-Hb estimated using HM-JACKarc: f-Hb thresholds from Results Low f-Hb thresholds of 400 µg/g, ≥200 µg/g and ≥100 µg/g. However, patients with a f-Hb concentration of Conclusions In primary care, f-Hb, in conjunction with clinical assessment, can safely and objectively determine individual risk of CRC and decide on simple reassurance or urgent, or routine referral.

AimsThe presence of detectable faecal haemoglobin (f-Hb) has been shown to be associated with all-cause mortality and with death from a number of chronic diseases not known to cause gastrointestinal blood loss. This effect is independent of taking medicines that increase the risk of bleeding. To further investigate the association of f-Hb with chronic disease, the relationship between f-Hb and prescription of medicines for a variety of conditions was studied.MethodsAll subjects (134 192) who participated in guaiac faecal occult blood test (gFOBT) screening in Tayside, Scotland, between March 2000 and March 2016, were studied in a cross-sectional manner by linking their gFOBT result (abnormal or normal) with prescribing data at the time of the test.ResultsThe screening participants with an abnormal gFOBT result were more likely to have been being prescribed medicines for heart disease, hypertension, diabetes and depression than those with a normal test result. This association persisted after adjustment for sex, age and deprivation (OR 1.35 (95%CI 1.23 to 1.48), 1.39 (1.27 to 1.52), 1.35 (1.15 to 1.58), 1.36 (1.16 to 1.59), all pConclusionsThe results of this study confer further substantial weight to the concept that detectable f-Hb is associated with a range of common chronic conditions that have a systemic inflammatory component; we speculate that f-Hb might have potential in identifying individuals who are high risk of developing chronic conditions or are at an early stage of disease.

Background Quantitative faecal immunochemical tests measure faecal haemoglobin concentration (f-Hb), which increases in the presence of colorectal neoplasia. Objective We examined the diagnostic accuracy of faecal immunochemical test (FIT)in patients at increased risk of colorectal cancer (CRC) attending for surveillance colonoscopy as per national guidelines. Methods A total of 1103 consecutive patients were prospectively invited to complete a FIT before their scheduled colonoscopy in two university hospitals in 2014– 2016. F-Hb was analysed on an OC-Sensor io automated analyser (Eiken Chemical Co., Ltd, Tokyo, Japan) with a limit of detection of 2 µg Hb/g faeces. The diagnostic accuracy of f-Hb for CRC and higher-risk adenoma was examined. Results A total of 643 patients returned a faecal test. After excluding 4 patients with known inflammatory bowel disease, 639 (57.9%) remained in the study: age range: 25–90 years (median: 64 years, interquartile range (IQR): 55–71): 54.6% male. Of 593 patients who also completed colonoscopy, 41 (6.9%) had advanced neoplasia (4 CRC, 37 higher-risk adenoma). Of the 238 patients (40.1%) who had detectable f-Hb, 31 (13.0%) had advanced neoplasia (2 CRC, 29 higher-risk adenoma) compared with 10 (2.8%) in those with undetectable f-Hb (2 CRC, 8 higher-risk adenoma). Detectable f-Hb gave negative predictive values of 99.4% for CRC and 97.2% for CRC plus higher-risk adenoma. Conclusion In patients at increased risk of CRC under colonoscopy surveillance, a test measuring faecal haemoglobin can provide an objective estimate of the risk of advanced neoplasia, and could enable tailored scheduling of colonoscopy.

Objectives Faecal immunochemical tests for haemoglobin (FIT) are becoming widely used in colorectal cancer (CRC) screening and assessment of symptomatic patients. Faecal haemoglobin concentration (f-Hb) thresholds are used to guide subsequent investigation. We established the distributions of f-Hb in a large screening population by sex, age, deprivation and geography. Methods Single estimates of f-Hb were documented for all individuals participating in the first 18 months of the Scottish Bowel Screening Programme (SBoSP). The distributions of f-Hb were generated for all participants, all men and women, and men and women by age quintile and deprivation quintile. Distributions were also generated by geographical region for all participants, men and women, and by deprivation. Comparisons of f-Hb distributions with those found in a pilot evaluation of FIT and three other countries were performed. Results f-Hb was documented for 887,248 screening participants, 422,385 men and 464,863 women. f-Hb varied by sex, age, deprivation quintile and geographical region. The f-Hb distributions by sex and age differed between the SBoSP and the pilot evaluation and the three other countries. Conclusions f-Hb is higher in men than in women and increases with age and deprivation in both sexes. f-Hb also varies by geographical region, independently of deprivation, and by country. The f-Hb distribution estimated by pilot evaluation may not represent the population distribution. Decision limits have advantages over reference intervals. Use of partitioned f-Hb thresholds for further investigation, based on the data generated, has advantages and disadvantages, as do risk scores based on a spectrum of influencing variables.

Background Current guidelines document persistent rectal bleeding as an alarm symptom in patients presenting to primary care. We studied whether a faecal immunochemical test could assist in their assessment. Methods From December 2015, faecal immunochemical tests were routinely available to primary care when assessing patients with new-onset bowel symptoms: general practitioners were encouraged to include faecal haemoglobin concentration (f-Hb) within any referral to secondary care. Results with f-Hb ≥10 μg Hb/g faeces were defined as positive. The incidence of significant bowel disease (SBD: colorectal cancer [CRC], higher-risk adenoma [HRA: any ≥1 cm, or three or more] and inflammatory bowel disease [IBD]) at subsequent colonoscopy, referred symptoms and f-Hb were recorded. Results Of 1447 patients with a faecal immunochemical test result and colonoscopy outcome, SBD was diagnosed in 296 patients (20.5%; 95 with CRC, 133 with HRA, and 68 with IBD). Four hundred and sixty-two patients (31.9%) reported rectal bleeding: 294 had f-Hb ≥10 μg Hb/g faeces. At colonoscopy, 105/294 had SBD versus 14/168 with rectal bleeding and f-Hb Conclusion Patients with rectal bleeding and f-Hb

Objectives Flexible sigmoidoscopy screening at around age 60 can reduce colorectal cancer incidence. Insufficient evidence exists on flexible sigmoidoscopy at age 60 in a population being offered biennial faecal occult blood test screening from age 50. This randomized controlled trial assessed if flexible sigmoidoscopy would be an effective adjunct to faecal occult blood test. Methods In the Scottish Bowel Screening Programme between June 2014 and December 2015, 51,769 individuals were randomized to be offered flexible sigmoidoscopy instead of faecal occult blood test at age 60 or to continue faecal occult blood test. Those not accepting flexible sigmoidoscopy and those with normal flexible sigmoidoscopy were offered faecal occult blood test. All with flexible sigmoidoscopy-detected neoplasia or a positive faecal occult blood test result were offered colonoscopy. Results Overall flexible sigmoidoscopy uptake was 17.8%, higher in men than women, and decreased with increasing deprivation (25.7% in the least to 9.2% in the most deprived quintile). In those who underwent flexible sigmoidoscopy, detection rate for colorectal cancer was 0.13%, for adenoma 7.27%, and for total neoplasia 7.40%. In those who underwent colonoscopy after a positive flexible sigmoidoscopy, detection rate for colorectal cancer was 0.28%, adenoma 8.66%, and total neoplasia 8.83%. On an intention to screen basis, there was no difference in colorectal cancer detection rate between the study and control groups. Adenoma and total neoplasia detection rate were significantly higher in the study group, with odds ratios of 5.95 (95%CI: 4.69–7.56) and 5.10 (95%CI: 4.09–6.35), respectively. Conclusions In a single screening round at age 60, there was low uptake and neoplasia detection rate. Flexible sigmoidoscopy detected significantly more neoplasia than faecal occult blood test alone.

Screening is a well-established tool to advance earlier cancer diagnosis. We used Davison’s concept of ‘candidacy’ to explore how individuals draw on collectively constructed images of ‘typical’ colorectal cancer (CRC) sufferers, or ‘candidates’, in order to evaluate their own risk and to ascertain the impact of candidacy on screening participation in CRC. We interviewed 61 individuals who were invited to participate in the Scottish Bowel Screening Programme. Of these, 37 were screeners (17 men and 20 women) and 24 non-screeners (13 men and 11 women). To analyse these data we used a coding frame that drew on: symptoms, risk factors, and retrospective and prospective candidacy. Few participants could identify a definite bowel cancer candidate and notions of candidacy were largely predicated on luck in the sense that anyone could be a candidate for CRC and there was little evidence to support a linear relationship between feelings of risk and screening decisions. Often participants described screening as part of a wider portfolio of being healthy and referred to feeling obliged to look after themselves. Our study suggests that rather than candidates for bowel cancer, screeners viewed themselves as candidates for screening by which screening decisions pointed towards the acceptance and normalisation of the rhetoric of personal responsibility for health. These findings have related theoretical and practical implications; the moral structure that underpins the new public health can be witnessed practically in the narratives by which those who see themselves as candidates for screening embrace wider positive health practices.

BACKGROUND AND AIMS HCV often causes chronic infection in liver, cirrhosis, and, in some instances, HCC. HCV encodes several factors' those impair host genes for establishment of chronic infection. The long noncoding RNAs (lncRNAs) display diverse effects on biological regulations. However, their role in virus replication and underlying diseases is poorly understood. In this study, we have shown that HCV exploits lncRNA long intergenic nonprotein-coding RNA, p53 induced transcript (Linc-Pint) in hepatocytes for enhancement of lipogenesis. APPROACH AND RESULTS We identified a lncRNA, Linc-Pint, which is significantly down-regulated in HCV-replicating hepatocytes and liver specimens from HCV infected patients. Using RNA pull-down proteomics, we identified serine/arginine protein specific kinase 2 (SRPK2) as an interacting partner of Linc-Pint. A subsequent study demonstrated that overexpression of Linc-Pint inhibits the expression of lipogenesis-related genes, such as fatty acid synthase and ATP-citrate lyase. We also observed that Linc-Pint significantly inhibits HCV replication. Furthermore, HCV-mediated enhanced lipogenesis can be controlled by exogenous Linc-Pint expression. Together, our results suggested that HCV-mediated down-regulation of Linc-Pint enhances lipogenesis favoring virus replication and liver disease progression. CONCLUSIONS We have shown that SRPK2 is a direct target of Linc-Pint and that depletion of SRPK2 inhibits lipogenesis. Our study contributes to the mechanistic understanding of the role of Linc-Pint in HCV-associated liver pathogenesis.

SARS-CoV-2 infection causes cytokine storm and overshoot immunity in humans; however, it remains to be determined whether genetic material of SARS-CoV-2 and/or virus induced soluble mediators from lung epithelial cells as natural host are carried out by macrophages or other vehicles at distant organs causing tissue damage. We speculated that exosomes as extracellular vesicles are secreted from SARS-CoV-2 infected cells may transport messages to other cells of distant organs leading to pathogenic consequences. For this, we took an unbiased proteomic approach for analyses of exosomes isolated from plasma of healthy volunteers and SARS-CoV-2 infected patients. Our results revealed that tenascin-C (TNC) and fibrinogen-β (FGB) are highly abundant in exosomes from SARS-CoV-2 infected patient’s plasma as compared to that of healthy normal controls. Since TNC and FGB stimulate pro-inflammatory cytokines via NF-κB pathway, we examined the status of TNF-α, IL-6 and CCL5 expression upon exposure of hepatocytes to exosomes from COVID-19 patients and observed significant increase when compared with that from healthy subjects. Together, our results demonstrated that soluble mediators, like TNC and FGB, are transported through plasma exosomes in SARS-CoV-2 infected patients and trigger pro-inflammatory cytokine expression in cells of distant organs in COVID-19 patients.ImportanceExosomes play an important role in intercellular communication by inducing physiological changes in recipient cells by transferring bioactive proteins. Little is known about exosomes from SARS-CoV-2 infected cells and their role in pathogenesis. Here, we have carefully examined and analyzed this aspect of SARS-CoV-2 infection. Our results uncovered the potential mechanisms by which SARS-CoV-2 communicates with other cells of distant organs and promotes pathogenesis. We expect to detect whether other factors are modulated in the presence of COVID-19 exosomes. Our exosomes related proteomic experiments prioritize after initial verification to further examine their role in SARS-CoV-2 associated other pathogenic mechanisms to target for therapeutic modalities.

Aim Lung cancer screening reduces mortality. We aim to validate the performance of Lung EpiCheck, a six-marker panel methylation-based plasma test, in the detection of lung cancer in European and Chinese samples. Methods A case–control European training set (n=102 lung cancer cases, n=265 controls) was used to define the panel and algorithm. Two cut-offs were selected, low cut-off (LCO) for high sensitivity and high cut-off (HCO) for high specificity. The performance was validated in case–control European and Chinese validation sets (cases/controls 179/137 and 30/15, respectively). Results The European and Chinese validation sets achieved AUCs of 0.882 and 0.899, respectively. The sensitivities/specificities with LCO were 87.2%/64.2% and 76.7%/93.3%, and with HCO they were 74.3%/90.5% and 56.7%/100.0%, respectively. Stage I nonsmall cell lung cancer (NSCLC) sensitivity in European and Chinese samples with LCO was 78.4% and 70.0% and with HCO was 62.2% and 30.0%, respectively. Small cell lung cancer (SCLC) was represented only in the European set and sensitivities with LCO and HCO were 100.0% and 93.3%, respectively. In multivariable analyses of the European validation set, the assay's ability to predict lung cancer was independent of established risk factors (age, smoking, COPD), and overall AUC was 0.942. Conclusions Lung EpiCheck demonstrated strong performance in lung cancer prediction in case–control European and Chinese samples, detecting high proportions of early-stage NSCLC and SCLC and significantly improving predictive accuracy when added to established risk factors. Prospective studies are required to confirm these findings. Utilising such a simple and inexpensive blood test has the potential to improve compliance and broaden access to screening for at-risk populations., Lung EpiCheck, a simple blood test, detected 85% of early-stage lung cancers with specificity of 64% in high-risk population, reaching AUC of 0.942 when combined with risk factors. This could improve efficiency of implementing lung cancer screening. https://bit.ly/3jWhLOn

Oral squamous cell carcinoma (OSCC) is the sixth most common cancer with a 5-year overall survival rate of 50%. Thus, there is a critical need to understand the disease process, and to identify improved therapeutic strategies. Previously, we found the long non-coding RNA (lncRNA) EGFR long non-coding downstream RNA (ELDR) induced in a mouse tongue cancer model; however, its functional role in human oral cancer remained unknown. Here, we show that ELDR is highly expressed in OSCC patient samples and in cell lines. Overexpression of ELDR in normal non-tumorigenic oral keratinocytes induces cell proliferation, colony formation, and PCNA expression. We also show that ELDR depletion reduces OSCC cell proliferation and PCNA expression. Proteomics data identifies the RNA binding protein ILF3 as an interacting partner of ELDR. We further show that the ELDR-ILF3 axis regulates Cyclin E1 expression and phosphorylation of the retinoblastoma (RB) protein. Intratumoral injection of ELDR-specific siRNA reduces OSCC and PDX tumor growth in mice. These findings provide molecular insight into the role of ELDR in oral cancer and demonstrate that targeting ELDR has promising therapeutic potential.

Background There is currently no existing evidence on the effects of personalised risk information on uptake of colonoscopy following first line screening for colorectal cancer. This study aimed to measure the impact of providing risk information based on faecal haemoglobin concentration to allow a fully informed choice around whether or not to undergo colonoscopy. Methods Two thousand seven hundred sixty-seven participants from the Scottish Bowel Screening Programme (SBoSP) database, who had not recently been invited for screening, were randomised to receive one of three types of hypothetical risk information materials: (1) numerical risk information (risk categories of one in 40, one in 1600 and one in 3500), (2) categorical risk information (highest, moderate and lowest risk), or (3) positive screening result letter (control group). The primary outcome was the impact of the risk materials on intention to undergo colonoscopy, to allow comparison with the current colonoscopy uptake of 77% for those with a positive screening result in the SBoSP. Secondary outcomes were knowledge, attitudes and emotional responses to the materials. Results Four hundred thirty-four (15.7%) agreed to participate with 100 from the numerical risk group (69.0%), 104 from the categorical risk group (72.2%) and 104 from the control group (71.7%) returning completed materials. Intention to undergo colonoscopy was highest in the highest risk groups for the numerical and categorical study arms (96.8% and 95.3%, respectively), but even in the lowest risk groups was > 50% (58.1% and 60.7%, respectively). Adequate knowledge of colorectal screening and the risks and benefits of colonoscopy was found in ≥ 98% of participants in all three arms. All participants reported that they found the information easy-to-understand. 19.1%, 24.0% and 29.6% of those in the numerical, categorical and control group, respectively, reported that they found the information distressing (p > 0.05). Conclusions Applying the risk categories to existing SBoSP data shows that if all participants were offered an informed choice to have colonoscopy, over two thirds of participants would intend to have the test. Equating to an increase in the number of screening colonoscopies from approx. 14,000 to 400,000 per annum, this would place an unmanageable demand on colonoscopy services, with a very small proportion of cancers and pre-cancers detected. However, the response to the materials were very positive, suggesting that providing risk information to those in lowest and moderate risk groups along with advice that colonoscopy is not currently recommended may be an option. Future research would be required to examine actual uptake. Trial registration Date applied 1 December 2017 ISRCTN number 14254582.

Objective Colorectal cancer (CRC) is the fourth most common cancer in the UK. It is estimated that around 50% of the disease burden is caused by lifestyle factors. This paper evaluates the impact of a training programme for Specialist Screening Practitioners (SSPs) on knowledge of CRC risk reduction and subsequent health promotion activities. Method Attendees (n = 21) were invited to participate in semi‐structured qualitative telephone interviews developed in conjunction with programme organisers. An independent researcher undertook the interviews on the perceived impact of the training on knowledge about risk reduction, communicating health promotion messages and working practices. Results Ten interviews were conducted. The programme was perceived to be successful in increasing knowledge about CRC risk and methods to promote behavioural change. Participants questioned the suitability of the endoscopy setting to communicate health promotion messages given patient anxiety pre‐investigation and post‐investigation elation after negative results. Key barriers to health promotion activities were time, hesitancy over raising issues that could not be easily discussed and scepticism about the ability of older adults to change their lifestyle. Conclusions Training on CRC risk reduction increased knowledge and behaviour change skills among SSPs. Further work is needed to explore opportunities to optimise the screening environment for health promotion activities.

Background Patients with rectal cancer who present with sarcopenia (low muscle mass) are at significantly greater risk of postoperative complications and reduction in disease-free survival. We performed a subanalysis of a randomised controlled study [the REx trial; www.isrctn.com; 62859294] to assess the potential of prehabilitation to modify muscle mass in patients having neoadjuvant chemoradiotherapy (NACRT). Methods Patients scheduled for NACRT, then potentially curative surgery (August 2014–March 2016) had baseline physical assessment and psoas muscle mass measurement (total psoas index using computed tomography-based measurements). Participants were randomised to either the intervention (13–17-week telephone-guided graduated walking programme) or control group (standard care). Follow-up testing was performed 1–2 weeks before surgery. Results The 44 patients had a mean age of 66.8 years (SD 9.6) and were male (64%); white (98%); American Society of Anesthesiologists class 2 (66%); co-morbid (58%); overweight (72%) (body mass index ≥ 25 kg/m2). At baseline, 14% were sarcopenic. At follow-up, 13 (65%) of patients in the prehabilitation group had increased muscle mass versus 7 (35%) that experienced a decrease. Conversely, 16 (67%) controls experienced a decrease in muscle mass and 8 (33%) showed an increase. An adjusted linear regression model estimated a mean treatment difference in Total Psoas Index of 40.2mm2/m2 (95% CI − 3.4 to 83.7) between groups in change from baseline (p = 0.07). Conclusions Prehabilitation improved muscle mass in patients with rectal cancer who had NACRT. These results need to be explored in a larger trial to determine if the poorer short- and long-term patient outcomes associated with low muscle mass can be minimised by prehabilitation.

AIM: Lower gastrointestinal (GI) symptoms are poor predictors of colorectal cancer (CRC). The aim of this study was to examine the diagnostic yield of colonoscopy by faecal haemoglobin (f-Hb) concentration in symptomatic patients assessed in primary care by faecal immunochemical testing (FIT). METHOD: In three Scottish NHS Boards, FIT kits (HM-JACKarc, Hitachi Chemical Diagnostics Systems Co., Ltd, Tokyo, Japan) were used by general practitioners to guide referrals for patients with lower GI symptoms (laboratory data studied for 12 months from December 2015 onwards in Tayside, 18 months from June 2018 onwards in Fife and 5 months from September 2018 onwards in Greater Glasgow and Clyde). Cases of CRC diagnosed at colonoscopy were ascertained from colonoscopy and pathology records. RESULTS: Four thousand eight hundred and forty one symptomatic patients who underwent colonoscopy after FIT submission were included. Of the 2166 patients (44.7%) with f-Hb

ObjectivesIn developed countries, the incidence of colorectal cancer (CRC) has declined in the over 50 years age group but increased in younger people. We studied CRC incidence by age and the influence of screening uptake.DesignAge-standardised and sex-standardised incidences for CRC from 1997 to 2017 were obtained from the Scottish Cancer Registry (SCR). In addition, linkage between the Scottish Bowel Screening Database and the SCR allowed investigation of any association between screening participation and CRC incidence.SettingScotland and the Scottish Bowel Screening Programme, in which guaiac faecal occult blood test screening was piloted from March 2000 and fully rolled by December 2009.ParticipantsFrom the introduction of screening in 2000 through to 2017, 2 395 172 were invited to participate, of whom 1 487 999 participated at least once.Main outcome measuresIncidence of CRC.ResultsIn the screening age range (50–74 years), CRC incidence peaked at 156.5 cases per 100 000 in 2010 after full roll-out of screening across Scotland but fell to 123.9 per 100 000 in 2017. However, under 50 years, there was a rise from 5.3 cases per 100 000 in 2000 to 6.8 per 100 000 in 2017. When CRC incidence was examined in those who had been offered screening, incidence fell in the participant group more than in the non-participant group after roll-out of screening was complete. Analysis of cumulative incidence demonstrated that CRC incidence in the participant group remained consistently below that of the non-participant from around 7 years of follow-up.ConclusionsThe incidence of CRC in Scotland has declined in the over 50 years age group but increased in younger people. It is likely that population screening has contributed to the reduction in CRC incidence in the over 50 years age group.

Background and aims Chronic hepatitis C virus (HCV) infection is one of the major causal factors for hepatocellular carcinoma (HCC). The treatment options for HCC are limited for lack of a convenient animal model for study in HCV infection and liver pathogenesis. This study aimed to develop a patient-derived xenograft (PDX) tumor in mice by using a tumor from a patient with HCV-associated HCC and evaluating this model's therapeutic potential. Approach and results After resection of the primary tumor from the patient liver, excess viable tumor was implanted into highly immunodeficient mice. A mouse xenograft tumor line was developed, and the tumor was successfully passaged for at least three rounds in immunodeficient mice. The patient's primary tumor and the mouse xenografts were histologically similar. Genetic profiling by short-tandem-repeat analysis verified that the HCC-PDX model was derived from the HCC clinical specimen. HCV RNA present in the patient liver specimen was undetectable after passage as xenograft tumors in mice. Human albumin, α1 -antitrypsin, glypican-3, α-smooth muscle actin, and collagen type 1A2 markers were detected in human original tumor tissues and xenograft tumors. Both the patient primary tumor and the xenograft tumors had a significantly higher level of receptor tyrosine kinase (c-Kit) mRNA. Treatment of HCC-PDX xenograft tumor-bearing mice with the c-Kit inhibitor imatinib significantly reduced tumor growth and phospho-Akt and cyclin D1 expression, as compared with untreated control tumors. Conclusions Our results demonstrated establishment of an HCV-associated HCC-PDX model as a powerful tool for evaluating candidate drugs. Information on molecular changes in cancer-specific gene expression facilitates efficient targeted therapies and treatment strategies.

Background Colorectal cancer (CRC) is an illness strongly influenced by sex and gender, with mortality rates in males significantly higher than females. There is still a dearth of understanding on where sex differences exist along the pathway from presentation to survival. The aim of this review is to identify where actions are needed to improve outcomes for both sexes, and to narrow the gap for CRC. Methods A cross-sectional review of national data was undertaken to identify sex differences in incidence, screening uptake, route to diagnosis, cancer stage at diagnosis and survival, and their influence in the sex differences in mortality. Results Overall incidence is higher in men, with an earlier age distribution, however, important sex differences exist in anatomical site. There were relatively small differences in screening uptake, route to diagnosis, cancer staging at diagnosis and survival. Screening uptake is higher in women under 69 years. Women are more likely to present as emergency cases, with more men diagnosed through screening and two-week-wait. No sex differences are seen in diagnosis for more advanced disease. Overall, age-standardised 5-year survival is similar between the sexes. Conclusions As there are minimal sex differences in the data from routes to diagnosis to survival, the higher mortality of colorectal cancer in men appears to be a result of exogenous and/or endogenous factors pre-diagnosis that lead to higher incidence rates. There are however, sex and gender differences that suggest more targeted interventions may facilitate prevention and earlier diagnosis in both men and women.

Aim The delivery of the Scottish Bowel Screening Programme (SBoSP) is rooted in the provision of a high quality, effective and participant-centred service. Safe and effective colonoscopy forms an integral part of the process. Additional accreditation as part of a multi-faceted programme for participating colonoscopists, as in England, does not exist in Scotland. This study aimed to describe the quality of colonoscopy in the SBoSP and compare this to the English national screening standards. Methods Data were collected from the SBoSP between 2007 and 2014. End-points for analysis were caecal intubation, cancer, polyp and adenoma detection, and complications. Overall results were compared with 2012 published English national standards for screening and outcomes from 2006 to 2009. Results During the study period 53 332 participants attended for colonoscopy. The colonoscopy completion rate was 95.6% overall. The mean cancer detection rate was 7.1%, the polyp detection rate was 45.7% and the adenoma detection rate was 35.5%. The overall complication rate was 0.47%. Conclusion Colonoscopy quality in the SBoSP has exceeded the standard set for screening colonoscopy in England, despite not adopting a multi-faceted programme for screening colonoscopy. However, the overall adenoma detection rate in Scotland was 9.1% lower than that in England which has implications for colonoscopy quality and may have an impact on cancer prevention rates, a key aim of the SBoSP.

Background Uptake of population-based screening for colorectal cancer in Scotland is around 55 per cent. Abdominal aortic aneurysm (AAA) screening has recently been introduced for men aged 65 years and the reported uptake is 78 per cent. The aim was to determine the impact of a brief intervention on bowel screening in men who attended AAA screening, but previously failed to complete bowel screening. Methods Men invited for AAA screening between September 2015 and March 2016 within NHS Tayside were included. Attendees who had not responded to their latest bowel screening invitation were seen by a colorectal cancer clinical nurse specialist. Reasons for not completing the faecal occult blood test (FOBT) were recorded; brief information on colorectal cancer screening was communicated, and participants were offered a further invitation to complete a FOBT. Those who responded positively were sent a further FOBT from the Scottish Bowel Screening Centre. Subsequent return of a completed FOBT within 6 months was recorded. Results A total of 556 men were invited for AAA screening, of whom 38·1 per cent had not completed a recent FOBT. The primary reason stated for not participating was the time taken to complete the test or forgetting it (35·1 per cent). Other reasons included: lack of motivation (23·4 per cent), confusion regarding the aim of screening (16·2 per cent), disgust (19·8 per cent), fear (6·3 per cent) and other health problems (9·9 per cent). Following discussion, 81·1 per cent agreed to complete the FOBT and 49 per cent subsequently returned the test. Conclusion A substantial proportion of previous bowel screening non-responders subsequently returned a completed FOBT following a brief intervention with a nurse specialist. Attendance at non-bowel screening appointments may provide a valuable opportunity to improve bowel screening uptake.

Aim: Colorectal surgeons regularly make the decision to anastomose, defunction or form an end colostomy when performing rectal surgery. This study aimed to define personality traits of colorectal surgeons and explore any influence of such traits on the decision to perform a rectal anastomosis. Method: Fifty attendees of The Association of Coloproctology of Great Britain and Ireland 2016 Conference participated. After written consent, all underwent personality testing: alexithymia (inability to understand emotions), type of thinking process (intuitive versus rational) and personality traits (extraversion, agreeableness, openness, emotional stability, conscientiousness). Questions were answered regarding anastomotic decisions in various clinical scenarios and results analysed to reveal any influence of the surgeon's personality on anastomotic decision. Results: Participants were: male (86%), consultants (84%) and based in England (68%). Alexithymia was low (4%) with 81% displaying intuitive thinking (reflex, fast). Participants scored higher in emotional stability (ability to remain calm) and conscientiousness (organized, methodical) compared with population norms. Personality traits influenced the next anastomotic decision if: surgeons had recently received criticism at a departmental audit meeting; were operating with an anaesthetist that was not their regular one; or there had been no anastomotic leaks in their patients for over 1 year. Conclusion: Colorectal surgeons have speciality relevant personalities that potentially influence the important decision to anastomose and could explain the variation in surgical practice across the UK. Future work should explore these findings in other countries and any link of personality traits to patient-related outcomes.

Breast cancer is a major public health problem worldwide in women and current therapeutic strategies are not adequately effective for this deadly disease. We have previously shown the anti-proliferative activity of bitter melon extract (BME) in breast cancer cells. In this study, we observed that BME treatment induces autophagosome-bound Long chain 3 (LC3)-B and accumulates protein p62/SQSTM1 (p62) in breast cancer cells. Additionally, we observed that BME treatment in breast cancer cells increases phospho-AMPK expression and inhibits the mTOR/Akt signaling pathway. Subsequently, we demonstrated that BME feeding effectively inhibited breast cancer growth in syngeneic and xenograft mouse models. Further, we observed the increased p62 accumulation, induction of autophagy and apoptotic cell death in tumors from BME-fed animals. Taken together, our results demonstrate that BME treatment inhibits breast tumor growth, and this anti-tumor activity in breast cancer is, in part, mediated by induction of autophagy and modulation of the AMPK/mTOR pathway. The antitumor activity of BME by oral feeding in breast cancer models suggested the high potential for a clinical application.

Hepatitis C virus (HCV)-mediated chronic liver disease is a serious health problem around the world and often causes fibrosis/cirrhosis and hepatocellular carcinoma. The mechanism of liver disease progression during HCV infection is still unclear, although inflammation is believed to be an important player in disease pathogenesis. We previously reported that macrophages including Kupffer cells exposed to HCV induce proinflammatory cytokines. These secreted cytokines may activate hepatic stellate cells (HSCs) toward fibrosis. In this study, we examined crosstalk between macrophages and HSCs following HCV infection. Primary human HSCs and immortalized HSCs (LX2 cells) were incubated with conditioned medium derived from HCV-exposed human macrophages. Expression of inflammasome and fibrosis-related genes in these cells was examined, with increased expression of inflammatory (NLR family pyrin domain containing 3, interleukins 1β and 6, and cysteine-cysteine chemokine ligand 5 [CCL5]) and profibrogenic (transforming growth factor β1, collagen type 4 alpha 1, matrix metalloproteinase 2, and alpha-smooth muscle actin) markers. Further investigation suggested that CCL5, secreted from HCV-exposed macrophages, activates inflammasome and fibrosis markers in HSCs and that neutralizing antibody to CCL5 inhibited activation. Conclusion Together, our results demonstrate that human macrophages exposed to HCV induce CCL5 secretion, which plays a significant role in hepatic inflammation and fibrosis. (Hepatology 2017;66:746-757).

Natural killer (NK) cells are one of the major components of innate immunity, with the ability to mediate antitumor activity. Understanding the role of NK-cell–mediated tumor killing in controlling of solid tumor growth is still in the developmental stage. We have shown recently that bitter melon extract (BME) modulates the regulatory T cell (Treg) population in head and neck squamous cell carcinoma (HNSCC). However, the role of BME in NK-cell modulation against HNSCC remains unknown. In this study, we investigated whether BME can enhance the NK-cell killing activity against HNSCC cells. Our results indicated that treatment of human NK-cell line (NK3.3) with BME enhances ability to kill HNSCC cells. BME increases granzyme B accumulation and translocation/accumulation of CD107a/LAMP1 in NK3.3 cells exposed to BME. Furthermore, an increase in cell surface expression of CD16 and NKp30 in BME-treated NK3.3 cells was observed when cocultured with HNSCC cells. Collectively, our results demonstrated for the first time that BME augments NK-cell–mediated HNSCC killing activity, implicating an immunomodulatory role of BME. Cancer Prev Res; 10(6); 337–44. ©2017 AACR.

Objective Age, sex, and deprivation are known factors influencing colorectal (bowel) cancer screening uptake. We investigated the influence of these factors on uptake over time. Methods Data from the Scottish Bowel Screening Programme (SBoSP) were collected between 2007 and 2014. End-points for analysis were uptake, faecal occult blood test positivity, and disease detection, adjusted for age, sex, deprivation, and year of screening. Results From 5,308,336 individual screening episodes documented, uptake gradually increased with increasing age up to 65–69 and was lower in men than women (52.4% vs. 58.7%, respectively). Deprivation had a significant effect on uptake by men and women of all age groups, with the most deprived least likely to complete a screening test. Uptake has increased with time in both sexes and across the deprivation gradient. The number needed to screen to detect significant neoplasia was significantly lower in men than women overall (170 vs. 365), and this held over all age and deprivation groups. The number needed to screen was also lower in the more deprived population. Conclusions Although lower age, male sex, and increased deprivation are associated with lower bowel cancer screening uptake in Scotland, uptake has increased since SBoSP introduction in all age groups, both sexes, and across the deprivation gradient. Despite a lower uptake, the number needed to screen to find significant disease was lower in men and in those with higher levels of deprivation.

Prediction models for colorectal cancer (CRC) detection in symptomatic patients, based on easily obtainable variables such as fecal haemoglobin concentration (f-Hb), age and sex, may simplify CRC diagnosis. We developed, and then externally validated, a multivariable prediction model, the FAST Score, with data from five diagnostic test accuracy studies that evaluated quantitative fecal immunochemical tests in symptomatic patients referred for colonoscopy. The diagnostic accuracy of the Score in derivation and validation cohorts was compared statistically with the area under the curve (AUC) and the Chi-square test. 1,572 and 3,976 patients were examined in these cohorts, respectively. For CRC, the odds ratio (OR) of the variables included in the Score were: age (years): 1.03 (95% confidence intervals (CI): 1.02–1.05), male sex: 1.6 (95% CI: 1.1–2.3) and f-Hb (0–

BackgroundIn Scotland, the uptake of clinic-based breast (72%) and cervical (77%) screening is higher than home-based colorectal screening (~60%). To inform new approaches to increase uptake of colorectal screening, we compared the perceptions of colorectal screening among women with different screening histories.MethodsWe purposively sampled women with different screening histories to invite to semistructured interviews: (1) participated in all; (2) participated in breast and cervical but not colorectal (‘colorectal-specific non-participants’); (3) participated in none. To identify the sample we linked the data for all women eligible for all three screening programmes in Glasgow, Scotland (aged 51–64 years; n=68 324). Interviews covered perceptions of cancer, screening and screening decisions. Framework method was used for analysis.ResultsOf the 2924 women invited, 86 expressed an interest, and 59 were interviewed. The three groups’ perceptions differed, with the colorectal-specific non-participants expressing that: (1) treatment for colorectal cancer is more severe than for breast or cervical cancer; (2) colorectal symptoms are easier to self-detect than breast or cervical symptoms; (3) they worried about completing the test incorrectly; and (4) the colorectal test could be more easily delayed or forgotten than breast or cervical screening.ConclusionOur comparative approach suggested targets for future interventions to increase colorectal screening uptake including: (1) reducing fear of colorectal cancer treatments; (2) increasing awareness that screening is for the asymptomatic; (3) increasing confidence to self-complete the test; and (4) providing a suggested deadline and/or additional reminders.

ObjectiveFaecal immunochemical tests (FIT) are replacing guaiac faecal occult blood tests (FOBT) in colorectal cancer (CRC) screening. Data from the first year of FIT screening were compared with those from FOBT screening and assumptions based on a pilot evaluation of FIT.DesignData on uptake, positivity, positive predictive value (PPV) for CRC and higher-risk adenoma from participants in the first year of the FIT-based Scottish Bowel Screening Programme (n=919 665), with a threshold of 80 µg Hb/g faeces, were compared with those from the penultimate year of the FOBT-based programme (n=862 165) and those from the FIT evaluation (n=66 225).ResultsOverall, uptake of FIT was 63.9% compared with 56.4% for FOBT. Positivity was 3.1% and 2.2% with FIT and FOBT; increases were seen in both sexes, and across age range and deprivation. More CRC and adenomas were detected by FIT, but the PPV for CRC was less (5.2% with FIT and 6.4% with FOBT). However, for higher-risk adenoma, PPV was greater with FIT (24.3% with FIT and 19.3% with FOBT). In the previous FIT evaluation, uptake was 58.5% with FIT compared with 54.0% with FOBT; positivity was 2.5% with FIT and 2.0% with FOBT.ConclusionTransition to FIT from FOBT produced higher uptake and positivity with lower PPV for CRC and higher PPV for adenoma. The FIT pilot evaluation underestimated uptake and positivity. Introducing FIT at the same threshold as the evaluation caused a 67.2% increase in colonoscopy demand instead of a predicted 10%.

Objectives Changes in the prevalence of faecal occult blood test positivity over time have not been previously reported, but could have important implications. This study examined the positivity of the initial guaiac faecal occult blood test, a surrogate marker for colorectal bleeding, in participants aged 50 in a national bowel screening programme. Methods Data from the Scottish Bowel Screening Programme were used to study the initial positivity of the guaiac faecal occult blood test between 2007 and 2017. Positive predictive values of the testing process for colorectal cancer and adenoma were assessed over the same time period. Results Across Scotland, the initial guaiac faecal occult blood test positivity increased from 4.1 to 10.8%. In NHS Grampian and NHS Fife, two of the three NHS Boards which began roll-out of screening in 2007, it increased from 4.0 to 10.9%. In the Scottish Bowel Screening Programme, the positive predictive value declined from 11.0 to 6.6% for colorectal cancer and increased from 31.6 to 39.8% for adenoma. Conclusions In the Scottish programme over a decade, initial guaiac faecal occult blood test positivity increased in participants aged 50. This may be associated with changes in lifestyle and might have implications for screening clinical outcomes, including positive predictive value.

ObjectiveTo determine whether a faecal immunochemical test (FIT) for faecal haemoglobin concentration (f-Hb) can be safely implemented in primary care as a rule-out test for significant bowel disease (SBD) (colorectal cancer (CRC), higher risk adenoma (HRA) and inflammatory bowel disease (IBD)) when used as an adjunct to the clinical assessment of new bowel symptoms.DesignSingle-centre prospective cohort study of all patients who attended primary care and submitted a FIT in the first calendar year of the service beginning December 2015. f-Hb was estimated using HM-JACKarc (Kyowa Medex) with a clinical cut-off of ≥10 µg Hb/g faeces. Incident cases of CRC were verified via anonymised record linkage to the Scottish Cancer Registry.Results5422 patients submitted 5660 FIT specimens, of which 5372 were analysed (positivity: 21.9%). 2848 patients were referred immediately to secondary care and three with f-Hb ConclusionIn primary care, measurement of f-Hb, in conjunction with clinical assessment, can safely and objectively determine a patient’s risk of SBD.

Background The present study aimed to assess modifiable risk factors in patients at high risk for colorectal cancer (CRC) and their experience of lifestyle advice. Methods A questionnaire study was conducted in high-risk CRC patients attending for surveillance colonoscopy. Current lifestyle behaviours [smoking, alcohol, diet (fruit and vegetables, wholegrains, red meat, processed meat), physical activity and bodyweight] related to CRC were ascertained, and experience on receiving, seeking and desire for advice was queried. Results In total, 385 study invitations were sent and 208 (54%) questionnaires were returned. The majority of participants (72%) were estimated to have a body mass index beyond the healthy range, 89% achieved a fibre score indicative of a low plant-based diet and 91% reported eating processed meat. Overall, 36% were achieving at least four recommendations and 2% were adhering to all recommendations examined. The main area in which participants reported receiving advice on was body weight (33%) and 31% reported that they had personally sought information on this topic, although the data suggest that 72% of people may benefit from such guidance. Fewer participants reported receiving (18-26%) and seeking (15-17%) dietary advice on fruits, vegetables and wholegrains. Many participants said they would find lifestyle information useful, notably in relation to body fatness (43%) and physical activity (38%). Conclusions The development of a process for supporting lifestyle change in this patient group, comprising individuals who are already engaging in positive health practices (regular colonoscopy surveillance), could usefully be identified and tested.

Aim Rectal cancer patients undergoing neoadjuvant chemoradiotherapy (NACRT) experience physical deterioration and reductions in their quality of life. This feasibility study assessed prehabilitation (a walking intervention) before, during and after NACRT to inform a definitive multi-centred randomized clinical trial (REx trial). Methods Patients planned for NACRT followed by potentially curative surgery were approached (August 2014-March 2016) (www.isrctn.com; 62859294). Prior to NACRT, baseline physical and psycho-social data were recorded using validated tools. Participants were randomized to either the intervention group (exercise counselling session followed by a 13-17 week telephone-guided walking programme) or a control group (standard care). Follow-up testing was undertaken 1-2 weeks before surgery. Results Of the 296 screened patients, 78 (26%) were eligible and 48 (61%) were recruited. N = 31 (65%) were men with a mean age of 65.9 years (range 33.7-82.6). Mean intervention duration was 14 weeks with 75% adherence. n = 40 (83%) completed follow-up testing. Both groups recorded reductions in daily walking but the reduction was less in the intervention group although not statistically significant. Participants reported high satisfaction and fidelity to trial procedures. Conclusion This study demonstrates that prehabilitation is feasible in rectal cancer patients undergoing NACRT. Good recruitment, adherence, retention and patient satisfaction rates support the development of a fully powered trial. The effects of the intervention on physical outcomes were promising.

Background Head and neck squamous cell carcinoma (HNSCC) represents one of the most common malignancies worldwide with a high mortality rate mainly due to lack of early detection markers, frequent association with metastasis and aggressive phenotype. Recently, long non-coding RNAs (lncRNAs) have been shown to have important regulatory roles in human cancers. The lncRNA prostate cancer-associated transcript 1 (PCAT-1) showed potential oncogenic roles in different cancers, however its role in HNSCC is not known. In this study, we evaluated the role of the PCAT-1 in HNSCC. Methods The expression of PCAT-1 was measured by quantitative real-time PCR in 23 paired human HNSCC tissues and adjacent non-tumor tissue specimens. Cell proliferation after depleting PCAT-1 was determined. Effect of PCAT-1 depletion in HNSCC cell lines was determined by qRT-PCR and Western blot analyses. Finally, JHU029 HNSCC cells was implanted subcutaneously into athymic nude mice and therapeutic potential of PCAT-1 was investigated. Results Up-regulation of PCAT-1 in TCGA dataset of HNSCC was noted. We also observed increased expression of PCAT-1 in archived HNSCC patient samples as compared to adjacent non-tumor tissues. Knockdown of PCAT-1 significantly reduced cell proliferation in HNSCC cell lines. Mechanistic study revealed significant down regulation of c-Myc and AKT1 gene in both RNA and protein levels upon knockdown of PCAT-1. We observed that c-Myc and AKT1 positively correlate with PCAT-1 expression in HNSCC. Further, we observed activation of p38 MAPK and apoptosis signal-regulating kinase 1 upon knockdown of PCAT-1 which induces Caspase 9 and PARP mediated apoptosis. Targeted inhibition of PCAT-1 regresses tumor growth in nude mice. Conclusion Together our data demonstrated an important role of the PCAT-1 in HNSCC and might serve as a target for HNSCC therapy.

In general, in-hospital mortality of elective patients is low, as such admissions do not correspond to an emergency or urgent admission, but rather are doctor scheduled admissions and so the death of a patient would not in general be expected. Nevertheless, there are still some cases of in-hospital death for elective admissions. In this work we have developed all-health condition, machine learning-based models to predict death for the case of elective admissions, applicable at the time of scheduling the admission, drawing upon a large cross-provider, state-wide dataset of discharge records. The best performing of the developed models demonstrated an AUC of 0.924, showing high discriminative performance. Based on a review of the literature there appears to be no equivalent previously published all-condition predictive model to predict in-hospital mortality of elective admission patients. This makes the work an important novel contribution to the field, and such models can potentially contribute to life-saving decisions for elective patients.

Background In Scotland a new, easier to complete bowel screening test, the Faecal Immunochemical Test (FIT), has been introduced. This test gives more accurate information about an individual’s risk of having colorectal cancer (CRC), based on their age and gender, and could lead to fewer missed cancers compared to the current screening test. However, there is no evidence of the effect on colonoscopy uptake of providing individuals with personalised risk information following a positive FIT test. The objectives of the study are:1)To develop novel methods of presenting personalised risk information in an easy-to-understand format using infographics with involvement of members of the public2)To assess the impact of different presentations of risk information on informed choice and intention to take up an offer of colonoscopy after FIT3)To assess participants’ responses to receiving personal risk information (knowledge, attitudes to screening/risk, emotional responses including anxiety). Methods Adults (age range 50–74) registered on the Scottish Bowel Screening database will be invited by letter to take part. Consenting participants will be randomised to one of three groups to receive hypothetical information about their risk of cancer, based on age, gender and faecal haemoglobin concentration: 1) personalised risk information in numeric form (e.g. 1 in 100) with use of infographics, 2) personalised information described as ‘highest’, ‘moderate’ or ‘lowest’ risk with use of infographics, and 3) as a ‘positive’ test result, as is current practice. Groups will be compared on informed choice, intention to have a colonoscopy, and satisfaction with their decision. Follow-up semi-structured qualitative interviews will be conducted, by telephone, with a small number of consenting participants (n = 10 per group) to explore the acceptability/readability and any potential negative impact of the risk information, participants’ understanding of risk factors, attitudes to the different scenarios, and reasons for reported intentions. Discussion Proving personalised risk information and allowing patient choice could lead to improved detection of CRC and increase patient satisfaction by facilitating informed choice over when/whether to undergo further invasive screening. However, we need to determine whether/how informed choice can be achieved and assess the potential impact on the colonoscopy service. Trial registration The trial is registered on www.isrctn.com on 08/12/2017. Registration no: ISRCTN14254582.

Emergency admissions involve unplanned admissions for which admission must occur at the earliest possible point of time. Being able to predict in-hospital mortality at the point of admission has significant clinical importance. In this work we have drawn from a large state-wide dataset to train predictive models for in-hospital mortality of emergency admissions, that can be applicable at time of admission. A number of models demonstrate high predictive performance, with AUC scores of up to 0.861. The approach taken represents an alternative to models based upon rich clinical data and may offer a number of comparative advantages in terms of very early point-in-time applicability and broad generalizability.

In the current qualitative research study, we focused on understanding the ecological systems, contexts, behaviors, and strategies of parents (N = 435) advocating for their children with an intellectual and developmental disability diagnosis, specifically Down syndrome (DS). Based on the data analysis, parents of children with DS advocate for their children frequently, in a variety of settings, with different actions, attitudes, motivations, and outcomes. The most common settings where advocacy occurred were primarily school and healthcare systems. The goals of parents often included inclusiveness, equality, and acceptance, whereas a few parents reported advocating due to discrimination and judgment. Implications for further research and professional practice also are described.

Purpose\ud \ud There are no internationally agreed upon clinical guidelines as to which women with gynecological cancer would benefit from Lynch syndrome screening or how best to manage the risk of gynecological cancer in women with Lynch syndrome. The Manchester International Consensus Group was convened in April 2017 to address this unmet need. The aim of the Group was to develop clear and comprehensive clinical guidance regarding the management of the gynecological sequelae of Lynch syndrome based on existing evidence and expert opinion from medical professionals and patients.\ud \ud Methods\ud \ud Stakeholders from Europe and North America worked together over a two-day workshop to achieve consensus on best practice.\ud \ud Results\ud \ud Guidance was developed in four key areas: (1) whether women with gynecological cancer should be screened for Lynch syndrome and (2) how this should be done, (3) whether there was a role for gynecological surveillance in women at risk of Lynch syndrome, and (4) what preventive measures should be recommended for women with Lynch syndrome to reduce their risk of gynecological cancer.\ud \ud Conclusion\ud \ud This document provides comprehensive clinical guidance that can be referenced by both patients and clinicians so that women with Lynch syndrome can expect and receive appropriate standards of care.

The all-condition prediction of patient mortality at the time of hospital admission has significant clinical value and broader implications for patient care and clinical decision support capabilities. In this study we have applied machine learning models to predict inpatient mortality, that is whether a patient will die during the hospital stay, as predicted from a time near to admission. We have utilized an Agency for Healthcare Research and Quality-provided large dataset of hospital discharges, to develop and evaluate a number of machine learning models. We report on the performance of the best performing of these models, with the best performing model having an AUC score of 0.802. We also evaluate the generalizability of the models via evaluating these on a separate large dataset corresponding to a different time period. We describe the results and provide an analysis and discussion of their significance.

Background Many patients present in primary care with lower bowel symptoms, but significant bowel disease (SBD), comprising colorectal cancer (CRC), advanced adenoma (AA), or inflammatory bowel disease (IBD), is uncommon. Quantitative faecal immunochemical tests for haemoglobin (FIT), which examine faecal haemoglobin concentrations (f-Hb), assist in deciding who would benefit from colonoscopy. Incorporation of additional variables in an individual risk-score might improve this approach. We investigated if the published f-Hb, age and sex test score (FAST score) added value. Methods Data from the first year of routine use of FIT in primary care in one NHS Board in Scotland were examined: f-Hb was estimated using one HM-JACKarc FIT system (Kyowa Medex Co., Ltd., Tokyo, Japan) with a cut-off for positivity ≥10 μg Hb/g faeces. 5660 specimens were received for analysis in the first year. 4072 patients were referred to secondary care: 2881 (70.6%) of these had returned a FIT specimen. Of those referred, 1447 had colonoscopy data as well as the f-Hb result (group A): 2521 patients, also with f-Hb, were not immediately referred (group B). The FAST score was assessed in both groups. Results 1196 (41.7%) of patients who returned a specimen for FIT analysis had f-Hb ≥10 μg Hb/g faeces. In group A, 252 of 296 (85.1%) with SBD had f-Hb > 10 μg Hb/g faeces, as did 528 of 1151 (45.8%) without SBD. Using a FAST score > 2.12, which gives high clinical sensitivity for CRC, only 1143 would have been referred for colonoscopy (21.0% reduction in demand): 286 of 296 (96.6%) with SBD had a positive FAST score, as did 857 of 1151 (74.5%) without SBD. However, one CRC, five AA and four IBD would have been missed. In group B, although 95.2% had f-Hb > 2.12 was found in 13 of 15 (86.7%) with SBD. Conclusions The performance characteristics of the FAST score did not seem to enhance the utility of f-Hb alone. Locally-derived formulae might confer desired benefits.

Simple Summary The incidence of head and neck cancer (HNC), one of the most aggressive cancers, is increasing rapidly globally. Conventional and targeted therapies show limited success with several undesirable side effects. Thus, there is a critical clinical need to identify additional alternative therapeutic strategies for successfully managing the disease. Preclinical and clinical studies indicate the crucial roles of dietary phytochemicals to manage different cancers. We and others previously showed the potential anticancer effect of bitter melon extract (BME) to prevent various cancers, including HNC. In this study, we identified momordicine-I (M-I) as a bioactive component in the BME. Subsequent mechanistic study showed that M-I inhibited HNC cell (JHU022, JHU029, Cal27) proliferation involving c-Met and downstream signaling. In pre-clinical mouse models, M-I showed similar effectiveness to prevent HNC tumor growth in mice with no apparent toxic side effect, suggesting an additional option for HNC therapy. Abstract Head and neck cancer (HNC) is one of the most aggressive cancers, and treatments are quite challenging due to the difficulty in early diagnosis, lack of effective chemotherapeutic drugs, adverse side effects and therapy resistance. We identified momordicine-I (M-I), a bioactive secondary metabolite in bitter melon (Momordica charantia), by performing liquid chromatography-high resolution electrospray ionization mass spectrometry (LC-HRESIMS) analysis. M-I inhibited human HNC cell (JHU022, JHU029, Cal27) viability in a dose-dependent manner without an apparent toxic effect on normal oral keratinocytes. Mechanistic studies showed that M-I inhibited c-Met and its downstream signaling molecules c-Myc, survivin, and cyclin D1 through the inactivation of STAT3 in HNC cells. We further observed that M-I was non-toxic and stable in mouse (male C57Bl/6) blood, and a favorable pharmacokinetics profile was observed after IP administration. M-I treatment reduced HNC xenograft tumor growth in nude mice and inhibited c-Met and downstream signaling. Thus, M-I has potential therapeutic implications against HNC.

Objectives Quantitative faecal immunochemical tests (FIT) for faecal haemoglobin (f-Hb) in colorectal cancer (CRC) screening pose challenges when colonoscopy is limited. For low positivity rates, high f-Hb concentration cut-offs are required, but little is known about interval cancer (IC) proportions using FIT. We assessed IC proportions using an 80 µg Hb/g cut-off. Methods In two NHS Boards in the Scottish Bowel Screening Programme, f-Hb was estimated for 30,893 participants aged 50–75, of whom 753 participants with f-Hb ≥ 80 µg Hb/g were referred for colonoscopy. ICs, defined as CRC within two years of a negative result, were identified from the Scottish Cancer Registry. Results There were 31 ICs and 30 screen-detected (SD) CRCs, an IC proportion of 50.8% (48.4% for men, 53.3% for women). CRC site distribution was similar between ICs and SD, but ICs were later stage (46.7% and 33.3%, Dukes’ stages C and D, respectively). Of 31 ICs, 23 had f-Hb Conclusions The IC proportion was similar to that seen with guaiac-based FOBT. The later stage distribution of ICs highlights the benefits of lower f-Hb cut-offs, but with 19.4% of ICs having undetectable f-Hb, some cancers would have been missed, even with drastic reduction in the f-Hb cut-off.

Objective To examine associations between faecal haemoglobin concentrations below the cut-off used in colorectal cancer screening and outcomes in the next screening round. Methods In the Scottish Bowel Screening Programme, faecal haemoglobin concentrations and diagnostic outcomes were investigated for participants with a negative result (faecal haemoglobin concentrations Results Of 37,780 participants with negative results, at the next screening round, 556 (1.5%) screened positive and 30,293 (80.2%) negative. Initial median faecal haemoglobin concentrations (2.1 µg Hb/g faeces, IQR: 0.0–13.2) were higher in those with subsequent positive results than those with subsequent negative results (0.0 µg Hb/g faeces, IQR: 0.0–1.4; p Conclusions A higher proportion of participants with faecal haemoglobin concentrations of ≥ 20 µg Hb/g faeces had advanced neoplasia detected at the next round than participants with lower faecal haemoglobin concentrations. Although most relevant when using high faecal haemoglobin concentrations cut-offs, studies of faecal haemoglobin concentrations and outcomes over screening rounds may provide strategies to direct available colonoscopy towards those at highest risk.

On 7 December 2015, the British Society of Gastroenterology and the Royal College of Physicians held a joint conference: GI cancer in the UK: can we do better? The meeting was timely as, although outcomes for patients with most gastrointestinal cancers in the UK have steadily improved in the past 10 years, survival figures remain substantially worse than in many other comparable nations. After defining the scale of the problem, the issues around early diagnosis were discussed. Screening as prevention has huge potential where there are defined premalignant conditions. Uptake into the Bowel Cancer Screening Programme (BCSP) is variable but in some areas remains low. It is hoped that with the National Screening Committee recommendation to replace the guaiac faecal occult blood test (gFOBT) with the faecal immunochemical test (FIT), the planned age extension and the continued roll-out of bowel scope screening by the National Health Service (NHS) will extend the value of the programme further. The view from primary care suggested that many factors affect the decision to make a referral for suspected cancer. Lack of direct access to testing was highlighted as a concern, as was the compounding issue of the many patients who delay seeking care. The Independent Cancer Force is the latest of several bodies calling for general practitioners (GPs) to be able to refer ‘direct to test’. However, a particular concern from secondary care relates to further stretching of diagnostic resources already under pressure—and how that can be addressed in times of austerity. Waiting times for endoscopy have begun to rise, yet capacity to expand is limited. Training, recruitment and retention of clinical staff were all highlighted as key issues limiting the availability of these procedures. Various practical ways to improve detection with endoscopy were proposed, as were possible ways to support and retain staff. While …

// Sourav Bhattacharya 1 , Naoshad Muhammad 1 , Robert Steele 1 , Guangyong Peng 2 , Ratna B. Ray 1, 2 1 Department of Pathology, Saint Louis University, Saint Louis, Missouri, USA 2 Department of Internal Medicine, Saint Louis University, Saint Louis, Missouri, USA Correspondence to: Ratna B. Ray email: rayrb@slu.edu Keywords: bitter melon, TME, HNSCC Abbreviation: BME, bitter melon extract; HNSCC, head and neck squamous cell carcinoma; TIL, tumor infiltrating lymphocytes Received: February 20, 2016 Accepted: April 10, 2016 Published: April 21, 2016 ABSTRACT Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer and leading cause of cancer related mortality worldwide. Despite the advancement in treatment procedures the overall survival rate of patients has not considerably enhanced in the past few decades. Therefore, new strategies to achieve a favorable response for the improvement in the prognosis of HNSCC are urgently needed. In this study, we examined the role of bitter melon extract (BME) in HNSCC tumor microenvironment. Mouse head and neck cancer (SCCVII) cells were subcutaneously injected into the flanks of syngeneic mice. We observed that oral gavage of BME significantly inhibits the tumor growth in mice as compared to control group. Further study suggested that BME inhibits cell proliferation as evident from low expression of proliferating cell nuclear antigen (PCNA) and c-Myc in the tumors of BME fed mice as compared to that of control group. We next investigated the role of BME as an immunomodulator in HNSCC model. Forkhead box protein P3 + (FoxP3 + ) T cells suppress tumor immunity. Our data suggested that BME treatment decreases the infiltrating regulatory T (Treg) cells by inhibiting FoxP3 + populations in the tumors and in spleens. Additionally, BME treatment reduces Th17 cell population in the tumor. However, BME treatment did not alter Th1 and Th2 cell populations. Together, our findings offer a new insight into how bitter melon extract inhibits head and neck tumor growth by modulating cell proliferation and Treg populations, with implications for how to control tumor-infiltrating lymphocytes and tumor progression.