One-year mortality of colorectal cancer patients: development and validation of a prediction model using linked national electronic data.

BACKGROUND: The existing literature does not provide a prediction model for mortality of all colorectal cancer patients using contemporary national hospital data. We developed and validated such a model to predict colorectal cancer death within 90, 180 and 365 days after diagnosis. METHODS: Cohort study using linked national cancer and death records. The development population included 27,480 patients diagnosed in England in 2015. The test populations were diagnosed in England in 2016 (n = 26,411) and Wales in 2015-2016 (n = 3814). Predictors were age, gender, socioeconomic status, referral source, performance status, tumour site, TNM stage and treatment intent. Cox regression models were assessed using Brier scores, c-indices and calibration plots. RESULTS: In the development population, 7.4, 11.7 and 17.9% of patients died from colorectal cancer within 90, 180 and 365 days after diagnosis. T4 versus T1 tumour stage had the largest adjusted association with the outcome (HR 4.67; 95% CI: 3.59-6.09). C-indices were 0.873-0.890 (England) and 0.856-0.873 (Wales) in the test populations, indicating excellent separation of predicted risks by outcome status. Models were generally well calibrated. CONCLUSIONS: The model was valid for predicting short-term colorectal cancer mortality. It can provide personalised information to support clinical practice and research.

The importance of the feasibility study: Lessons from a study of the hand-held fan used to relieve dyspnea in people who are breathless at rest.

BACKGROUND: The dyspnea accompanying advanced cardiorespiratory disease is often refractory to palliation. It is disabling, distressing and associated with the diseases most common everywhere in the world. The hand-held fan, used to generate a draught across the face, is a simple, cost-effective, safe, and universally applicable palliative breathlessness intervention, consistently described as valuable in qualitative research. A previous crossover trial confirmed its benefit in patients breathless at rest, but the washout period was uncertain. AIM: To determine the washout period after use of the hand-held fan to inform accurate randomized controlled trial design. DESIGN: An observational methodological study. Breathlessness intensity was measured using 100 mm visual analog scale and numerical rating scale, and "relief of breathlessness" was measured on a 5-point scale. Those benefitting from the fan provided visual analog scale/numerical rating scale scores until (1) scores returned to baseline values or (2) until response had plateaued. The primary outcome measure was the time (in minutes) to reach either component of the primary study endpoint. SETTINGS/PARTICIPANTS: Four in-/out-patient hospice/hospital units; participants had chronic refractory breathlessness using the fan. RESULTS: Overall, 31 patients participated (mean age: 74.8 years; range: 49-98 years, standard deviation = 11.5 years); 64% were males. Approximately, half of the sample experienced benefit of moderate effect size. The relative reduction in breathlessness relative to the mean baseline score for the sample was 27% for the visual analog scale and 19% for the numerical rating scale. CONCLUSION: Feasibility work is essential, even for simple widely employed interventions.

Eating and drinking interventions for people at risk of lacking decision-making capacity: who decides and how?

BACKGROUND: Some people with progressive neurological diseases find they need additional support with eating and drinking at mealtimes, and may require artificial nutrition and hydration. Decisions concerning artificial nutrition and hydration at the end of life are ethically complex, particularly if the individual lacks decision-making capacity. Decisions may concern issues of life and death: weighing the potential for increasing morbidity and prolonging suffering, with potentially shortening life. When individuals lack decision-making capacity, the standard processes of obtaining informed consent for medical interventions are disrupted. Increasingly multi-professional groups are being utilised to make difficult ethical decisions within healthcare. This paper reports upon a service evaluation which examined decision-making within a UK hospital Feeding Issues Multi-Professional Team. METHODS: A three month observation of a hospital-based multi-professional team concerning feeding issues, and a one year examination of their records. The key research questions are: a) How are decisions made concerning artificial nutrition for individuals at risk of lacking decision-making capacity? b) What are the key decision-making factors that are balanced? c) Who is involved in the decision-making process? RESULTS: Decision-making was not a singular decision, but rather involved many different steps. Discussions involving relatives and other clinicians, often took place outside of meetings. Topics of discussion varied but the outcome relied upon balancing the information along four interdependent axes: (1) Risks, burdens and benefits; (2) Treatment goals; (3) Normative ethical values; (4) Interested parties. CONCLUSIONS: Decision-making was a dynamic ongoing process with many people involved. The multiple points of decision-making, and the number of people involved with the decision-making process, mean the question of 'who decides' cannot be fully answered. There is a potential for anonymity of multiple decision-makers to arise. Decisions in real world clinical practice may not fit precisely into a model of decision-making. The findings from this service evaluation illustrate that within multi-professional team decision-making; decisions may contain elements of both substituted and supported decision-making, and may be better represented as existing upon a continuum.

Evidence for aldosterone-dependent growth of renal cell carcinoma.

The aim if this study was to investigate the hypothesis that K-RAS 4A is upregulated in a mineralocorticoid-dependent manner in renal cell carcinoma and that this supports the proliferation and survival of some renal cancers. Expression of the K-RAS in renal tumour tissues and cell lines was examined by real-time PCR and Western blot and mineralocorticoid receptor, and its gatekeeper enzyme 11ß-hydroxysteroid dehydrogenase-2 was examined by immunocytochemistry on a tissue microarray of 27 cases of renal cell carcinoma. Renal cancer cells lines 04A018 (RCC4 plus VHL) and 04A019 (RCC4 plus vector alone) were examined for the expression of K-RAS4A and for the effect on K-RAS expression of spironolactone blockade of the mineralocorticoid receptor. K-RAS4A was suppressed by siRNA, and the effect on cell survival, proliferation and activation of the Akt and Raf signalling pathways was investigated in vitro. K-RAS4A was expressed in RCC tissue and in the renal cancer cell lines but K-RAS was downregulated by spironolactone and upregulated by aldosterone. Spironolactone treatment and K-RAS suppression both led to a reduction in cell number in vitro. Both Akt and Raf pathways showed activation which was dependent on K-RAS expression. K-RAS expression in renal cell carcinoma is at least partially induced by aldosterone. Aldosterone supports the survival and proliferation of RCC cells by upregulation of K-RAS acting through the Akt and Raf pathways.

Should they have a percutaneous endoscopic gastrostomy? the importance of assessing decision-making capacity and the central role of a multidisciplinary team.

Decisions about percutaneous endoscopic gastrostomy (PEG) can be clinically and ethically challenging, particularly when patients lack decision-making capacity. As the age of the UK population rises, with the associated increase in prevalence of dementias and neurodegenerative diseases, it is becoming an increasingly important issue for clinicians. The recent review and subsequent withdrawal of the Liverpool Care Pathway highlighted feeding as a particular area of concern. The authors undertook a 1-year retrospective review of individuals referred to the feeding issues multidisciplinary team (FIMDT) at Addenbrooke's Hospital, Cambridge, UK, in 2011. The majority of patients referred (n = 158) had a primary diagnosis of cancer (44%). The second largest group was those who had had a stroke or brain haemorrhage (13%). Twenty-eight per cent of patients had no, or uncertain, decision-making capacity on at least one occasion during decision-making. There are reflections on the role of a multidisciplinary team in the process of decision-making for these complex patients.

Non-oxime inhibitors of B-Raf(V600E) kinase.

The development of inhibitors of B-Raf(V600E) serine-threonine kinase is described. Various head-groups were examined to optimize inhibitor activity and ADME properties. Several of the head-groups explored, including naphthol, phenol and hydroxyamidine, possessed good activity but had poor pharmacokinetic exposure in mice. Exposure was improved by incorporating more metabolically stable groups such as indazole and tricyclic pyrazole, while indazole could also be optimized for good cellular activity.

Non-oxime pyrazole based inhibitors of B-Raf kinase.

The synthesis and biological evaluation of non-oxime pyrazole based B-Raf inhibitors is reported. Several oxime replacements have been prepared and have shown excellent enzyme activity. Further optimization of fused pyrazole 2a led to compound 38, a selective and potent B-Raf inhibitor.

Implementation of a care bundle improves the management of patients with non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is common and is associated with liver-related and cardiovascular-related morbidity. Our aims were: (1) to review the current management of patients with NAFLD attending hospital clinics in North East England (NEE) and assess the variability in care; (2) develop a NAFLD 'care bundle' to standardise care; (3) to assess the impact of implementation of the NAFLD care bundle. METHODS: A retrospective review was conducted to determine baseline management of patients with NAFLD attending seven hospitals in NEE. A care bundle for the management of NAFLD was developed including important recommendations from international guidelines. Impact of implementation of the bundle was evaluated prospectively in a single centre. RESULTS: Baseline management was assessed in 147 patients attending gastroenterology, hepatology and a specialist NAFLD clinic. Overall, there was significant variability in the lifestyle advice given and management of metabolic risk factors, with patients attending an NAFLD clinic significantly more likely to achieve >10% body weight loss and have metabolic risk factors addressed. Following introduction of the NAFLD bundle 50 patients were evaluated. Use of the bundle was associated with significantly better documentation and implementation of most aspects of patient management including management of metabolic risk factors, documented lifestyle advice and provision of NAFLD-specific patient advice booklets. CONCLUSION: The introduction of an outpatient 'care bundle' led to significant improvements in the assessment and management of patients with NAFLD in the NEE and could help improve and standardise care if used more widely.

Genomic evidence supports a clonal diaspora model for metastases of esophageal adenocarcinoma.

The poor outcomes in esophageal adenocarcinoma (EAC) prompted us to interrogate the pattern and timing of metastatic spread. Whole-genome sequencing and phylogenetic analysis of 388 samples across 18 individuals with EAC showed, in 90% of patients, that multiple subclones from the primary tumor spread very rapidly from the primary site to form multiple metastases, including lymph nodes and distant tissues-a mode of dissemination that we term 'clonal diaspora'. Metastatic subclones at autopsy were present in tissue and blood samples from earlier time points. These findings have implications for our understanding and clinical evaluation of EAC.

PDGF C is a selective alpha platelet-derived growth factor receptor agonist that is highly expressed in platelet alpha granules and vascular smooth muscle.

OBJECTIVE: The platelet-derived growth factor (PDGF) family consists of four members, PDGF A, PDGF B, and 2 new members, PDGF C and PDGF D, which signal through the alpha and beta PDGF receptor (PDGFR) tyrosine kinases. This study was performed to determine the receptor specificity and cellular expression profile of PDGF C. METHODS AND RESULTS: PDGF C growth factor domain (GFD) was shown to preferentially bind and activate alpha PDGFR and activate beta PDGFR when it is co-expressed with alpha PDGFR through heterodimer formation. An investigation of PDGF C mRNA and protein expression revealed that during mouse fetal development, PDGF C was expressed in the mesonephric mesenchyme, prefusion skeletal muscle, cardiac myoblasts, and in visceral and vascular smooth muscle, whereas in adult human tissues expression was largely restricted to smooth muscle. Microarray analysis of various cell types showed PDGF C expression in vascular smooth muscle cells, renal mesangial cells, and platelets. PDGF C mRNA expression in platelets was confirmed by real-time polymerase chain reaction, and PDGF C protein was localized in alpha granules by immuno-gold electron microscopy. Western blot analysis of platelets identified 55-kDa and 80-kDa PDGF C isoforms that were secreted on platelet activation. CONCLUSIONS: Taken together, our results demonstrated for the first time to our knowledge that like PDGF A and B, PDGF C is likely to play a role in platelet biology.

The World Health Organization's Framework Convention on Tobacco Control: implications for global epidemics of food-related deaths and disease.

This paper reviews the major elements of the WHO Framework Convention on Tobacco Control and considers those that can be applied to diet and nutrition. Tobacco and food policy have important differences: the two commodities have distinctly different health impacts, and food companies may be more responsive to public concerns than the tobacco industry. Nevertheless, both food and tobacco policy address public health issues surrounding legal products. Both require comprehensive and multi-sector approaches at global and national levels. The degree of flexibility possible in interacting and partnering with the private sector and food and related industries and the related implications for regulations and laws are reasons for a more nuanced approach to diet and physical activity policy.

Nonpharmacological interventions for breathlessness.

PURPOSE OF REVIEW: Breathlessness is difficult to palliate and nonpharmacological interventions are effective management strategies currently available for mobile patients. These are a diverse group of interventions, currently poorly defined and inconsistently used. This review concentrates on identifying and recommending the most effective nonpharmacological strategies for breathlessness, to aid clinical practice. RECENT FINDINGS: Much of the evidence presented is based on a Cochrane Review, which demonstrated that facial cooling, by handheld fan, mobility aids (e.g. rollators) and neuromuscular electrical stimulation all had evidence to support their use in breathlessness. Breathing exercises, pacing and positioning are frequently used to manage breathlessness, but need definition and further research. Anxiety reduction techniques and carer support are used in chronic disease management and applicable for breathlessness, but act indirectly. Exercise is a long established management strategy in both respiratory and other chronic diseases to maintain fitness (which reduces breathlessness) and increase psychological well being. SUMMARY: All patients with breathlessness should learn appropriate nonpharmacological interventions. Some can be taught by clinicians without specialist training, but others require specialist skills and high levels of engagement by cognitively intact and highly motivated people. Specialist breathlessness services may be more effective in delivering complex nonpharmacological interventions, but more research is needed.

Utility of frozen cell lines in medium throughput electrophysiology screening of hERG and NaV1.5 blockade.

INTRODUCTION: The development of drug candidates must take into account that many compounds have off-target activity against voltage-gated ion channels (VGIC) which may prevent their progression to market. Of particular concern are hERG and hNa(V)1.5. Screening against these ion channels is necessary but expensive, partially due to maintenance of constantly cultured cell lines. Here, we show that frozen HEK-293 cells can be maintained indefinitely, reducing variability in cell performance, time and expense of cell culture. METHODS: Cells, constantly cultured or frozen, were assayed on the PatchXpress 7000A using tool compounds. RESULTS: Amitriptyline, quinidine, compound A, fluoxetine and imipramine inhibited hERG with IC(50)s (paired values denote constantly cultured and frozen, respectively) of 4.8±0.4 and 5.1±0.4, 1.4±0.1 and 1.1±0.1, 24.4±2.4 and 21.9±1.8, 2.1±0.4 and 2.1±0.1, 5.2±0.4 and 4.0±0.2µM. Quinidine, flecainide, mexiletine and amitriptyline inhibited hNa(V)1.5 with IC(50)s of 46.6±4.3 and 28.0±2.3, 7.6±0.7 and 6.2±0.5, 153.5±13.0 and 106.0±4.7, 5.5±0.5 and 4.8±0.2µM. Voltage dependences of activation (V(1/2)) for hERG were statistically identical, 0.4±0.8mV and 2.5±0.5mV. In hNa(V)1.5, the V(1/2) of inactivation and activation were statistically identical, -82.7±0.1mV versus -84.9±0.3mV, -47.5±0.3mV versus -45.0±0.6mV. Current density in both conditions in hERG experiments was similar, 47.0±4.1pA versus 42.3±6.0pA/pF. DISCUSSION: hERG and hNa(V)1.5 screens run using frozen cells have statistically identical IC(50)s, voltage dependence of activation, IV relationships and current density to screens using continuously cultured cells. Frozen cells have more constant performance and allow rapid switching between experiments on several cell lines without sacrificing data quality.

Discovery and characterization of a cell-permeable, small-molecule c-Abl kinase activator that binds to the myristoyl binding site.

c-Abl kinase activity is regulated by a unique mechanism involving the formation of an autoinhibited conformation in which the N-terminal myristoyl group binds intramolecularly to the myristoyl binding site on the kinase domain and induces the bending of the αI helix that creates a docking surface for the SH2 domain. Here, we report a small-molecule c-Abl activator, DPH, that displays potent enzymatic and cellular activity in stimulating c-Abl activation. Structural analyses indicate that DPH binds to the myristoyl binding site and prevents the formation of the bent conformation of the αI helix through steric hindrance, a mode of action distinct from the previously identified allosteric c-Abl inhibitor, GNF-2, that also binds to the myristoyl binding site. DPH represents the first cell-permeable, small-molecule tool compound for c-Abl activation.

Does the use of a handheld fan improve chronic dyspnea? A randomized, controlled, crossover trial.

CONTEXT: Dyspnea is a disabling distressing symptom that is common in advanced disease affecting millions of people worldwide. Current palliative strategies are partially effective in managing this symptom; facial cooling has been shown to reduce the sensation of breathlessness when induced in volunteers but has not been formally investigated in dyspnea associated with disease. OBJECTIVE: The objective of this study was to investigate whether a handheld fan reduces the sensation of breathlessness in such patients, enhancing palliative approaches. METHODS: The effectiveness of a handheld fan (blowing air across the nose and mouth) in reducing the sensation of breathlessness was assessed in patients with advanced disease. Fifty participants were randomized to use a handheld fan for five minutes directed to their face or leg first and then crossed over to the other treatment. The primary outcome measure was a decrease of greater than 1cm in breathlessness recorded on a 10 cm visual analog scale (VAS). RESULTS: There was a significant difference in the VAS scores between the two treatments, with a reduction in breathlessness when the fan was directed to the face (P=0.003). CONCLUSION: This study supports the hypothesis that a handheld fan directed to the face reduces the sensation of breathlessness. The fan was acceptable to participants: it is inexpensive, portable, enhances self-efficacy, and available internationally. It should be recommended as part of a palliative management strategy for reducing breathlessness associated with advanced disease.

A global response to a global problem: the epidemic of overnutrition.

It is estimated that by 2020 two-thirds of the global burden of disease will be attributable to chronic noncommunicable diseases, most of them strongly associated with diet. The nutrition transition towards refined foods, foods of animal origin, and increased fats plays a major role in the current global epidemics of obesity, diabetes and cardiovascular diseases, among other noncommunicable conditions. Sedentary lifestyles and the use of tobacco are also significant risk factors. The epidemics cannot be ended simply by encouraging people to reduce their risk factors and adopt healthier lifestyles, although such encouragement is undoubtedly beneficial if the targeted people can respond. Unfortunately, increasingly obesogenic environments, reinforced by many of the cultural changes associated with globalization, make even the adoption of healthy lifestyles, especially by children and adolescents, more and more difficult. The present paper examines some possible mechanisms for, and WHO's role in, the development of a coordinated global strategy on diet, physical activity and health. The situation presents many countries with unmanageable costs. At the same time there are often continuing problems of undernutrition. A concerted multisectoral approach, involving the use of policy, education and trade mechanisms, is necessary to address these matters.