Severity of Dementia and Survival in Patients Diagnosed with Colorectal Cancer: A National Cohort Study in England and Wales.

AIMS: There is little evidence about the survival of patients with colorectal cancer (CRC) also diagnosed with dementia. We quantified dementia severity and estimated how it is associated with 2-year overall survival. MATERIALS AND METHODS: Records of patients aged 65 years or older diagnosed with CRC in England and Wales were identified. A novel proxy for dementia severity combined dementia diagnosis in administrative hospital data with Eastern Cooperative Oncology Group performance status. Cox regression was used to estimate hazard ratios with and without risk adjustment. RESULTS: In total, 4033 of 105 250 CRC patients (3.8%) had dementia recorded. Two-year survival decreased with increasing dementia severity from 65.4% without dementia, 53.5% with mild dementia, 33.0% with moderate dementia to 16.5% with severe dementia (hazard ratio comparing severe with no dementia: 2.97; 95% confidence interval 2.79, 3.16). Risk adjustment for comorbidity and cancer stage reduced this association slightly (hazard ratio 2.52; 95% confidence interval 2.37, 2.68) and additional adjustment for treatment factors reduced it further (hazard ratio 1.60; 95% confidence interval 1.50, 1.70). CONCLUSIONS: Survival of CRC patients varied strongly according to dementia severity, suggesting that a 'one-size-fits-all' policy for the care of CRC patients with dementia is not appropriate. Comprehensive assessment of cancer patients with dementia that considers dementia severity is essential in a shared decision-making process that ensures patients receive the most appropriate treatment for their individual needs and preferences.

Determinants of Variation in the Use of Adjuvant Chemotherapy for Stage III Colon Cancer in England.

AIMS: Adjuvant chemotherapy (ACT) for stage III colon cancer is well-established. This study aimed to explore the determinants of ACT use and between-hospital variation within the English National Health Service (NHS). MATERIALS AND METHODS: In total, 11 932 patients (diagnosed 2014-2017) with pathological stage III colon cancer in the English NHS were identified from the National Bowel Cancer Audit. Records were linked to Systemic Anti-Cancer Therapy and Hospital Episode Statistics databases. Multi-level logistic regression analyses were carried out to estimate independent factors for ACT use, including age, sex, deprivation, comorbidities, performance status, American Society of Anaesthesiologists (ASA) grade, surgical urgency, surgical access, TNM staging, readmission and hospital-level factors (university teaching hospital, on-site chemotherapy and high-volume centre). A random intercept was modelled for each English NHS hospital (n = 142). Between-hospital variation was explored using funnel plot methodology. Fully adjusted random-intercept models were fitted separately in young (<70 years) and elderly (≥70 years) patients and intra-class correlation coefficients estimated. RESULTS: 60.7% of patients received ACT. Age was the strongest determinant. Compared with patients aged <60 years, those aged 60-64 (adjusted odds ratio [aOR] 0.76, 95% confidence interval 0.63-0.93), 65-69 (aOR 0.63, 95% confidence interval 0.54-0.74), 70-74 (aOR 0.53, 95% confidence interval 0.44-0.62), 75-79 (aOR 0.23, 95% confidence interval 0.19-0.27) and ≥80 years (aOR 0.05, 95% confidence interval 0.04-0.06) were significantly less likely to receive ACT. With adjustment for other factors, ACT use was more likely in patients with higher socioeconomic status, fewer comorbidities, better performance status, lower ASA grade, advanced disease, elective resections, laparoscopic procedures and no unplanned readmissions. Hospital-level factors were non-significant. The observed proportions of ACT administration in the young and elderly were 46-100% (80% of hospitals 74-90%) and 10-81% (80% of hospitals 33-65%), respectively. Risk adjustment did not reduce between-hospital variation. Despite adjustment, age accounted for 9.9% (7.2-13.4%) of between-hospital variation in the elderly compared with 2.7% (1.2-5.7%) in the young. CONCLUSIONS: There is significant between-hospital variation in ACT use for stage III colon cancer, especially for older patients. Advanced age alone seems to be a greater barrier to ACT use in some hospitals.

Modified de Gramont with oxaliplatin in the first-line treatment of advanced colorectal cancer.

We previously reported high activity for oxaliplatin and a modified de Gramont regimen (OxMdG) in a single centre study of patients with metastatic colorectal cancer. We now report results with a further 56 patients treated at 14 centres. Low rates of grade 3 and 4 toxicity were seen, with no toxic deaths. Objective response rates were CR/PR=53%; NC=34.7%; PD=12.2%. Median time to progression was 8.3 months and overall survival was 14.5 months. This regimen is more convenient than those based around the conventional de Gramont regimen but is highly active and well tolerated; it forms part of a current UK MRC phase 3 trial.

Prostacyclin rather than nitric oxide lowers human umbilical artery tone in vitro.

This study was designed to determine vasodilator activities of two endothelium-derived relaxing factors: prostacyclin (PGI2) and nitric oxide (NO) in human umbilical arteries. Isolated vessel segments were contracted by submaximal concentrations of serotonin and bradykinin. These contractions were enhanced after inhibition of prostaglandin formation by the cyclooxygenase inhibitor indomethacin and after removal of the endothelium, both resulting in a pronounced decrease in PGI2 formation. Contractions remained unchanged after treatment of the vessels with nitro-L-arginine, a selective inhibitor of endogenous NO biosynthesis. The efficacy of inhibition of NO biosynthesis was established by a more than 60% reduction in cyclic GMP accumulation. Even inhibition of stimulated NO formation by histamine did not change vascular tone. These data suggest that PGI2 rather than NO is an endothelium-derived relaxing factor in human umbilical arteries.

Actions of n-alcohols on nicotinic acetylcholine receptor channels in cultured rat myotubes.

1. The actions of the n-alcohols from pentanol to dodecanol on nicotinic acetylcholine receptor (nAChR) channels were investigated by recording single ACh-activated channel activity from inside-out membrane patches isolated from cultured rat myotubes. Alcohols were applied to the cytoplasmic side of the membrane; aqueous concentrations ranged from 11.7 mM-pentanol to 0.02 mM-dodecanol. 2. The intermediate-chain alcohols (pentanol to octanol) caused channel currents to fluctuate between the fully open and closed state level so that openings occurred in bursts interrupted by brief gaps. Closed time distributions were fitted well with two exponential components, the fast component representing the closures within a burst. The number of gaps within a burst was dependent on alcohol concentration whereas gap duration was independent of concentration but increased with increasing chain length of the alcohol up to octanol. 3. Nonanol and decanol reduced the mean duration of bursts of openings but did not cause an increase in the number of short closed intervals within a burst. Beyond decanol there was a decline in the ability of the n-alcohols to affect channel function. A saturated solution of undecanol (0.07 mM) reduced the mean open time by 33 +/- 17%, whereas a saturated solution of dodecanol had no significant effect. 4. The current integral per burst was reduced by all the n-alcohols between pentanol and undecanol. The IC50S were as follows: hexanol, 0.53 +/- 0.14 mM; heptanol, 0.097 +/- 0.02 mM; octanol, 0.04 mM and nonanol, 0.16 +/- 0.035 mM. 5. The results were analysed in terms of an open channel block model with a long-lived closed-blocked state beyond the blocked state. Over the range of concentrations tested this describes the effects of all the n-alcohols (C5 to C12) on channel gating reasonably well. 6. Blocking rate constants (k+B) for pentanol through to nonanol were calculated to be between 2.8 and 5.7 X 10(6) M-1 S-1. These values are based on the assumption that the concentration of the alcohols at their site(s) of action was equal to the aqueous concentration applied to the membrane. 7. Equilibrium dissociation constants (KD), calculated from the blocking and unblocking rate constants (KD = k-B/k+B), decreased with increasing chain length from 8 mM for pentanol to 0.15 mM for octanol. The standard free energy per methylene group for adsorption to the site of action was calculated to be about -3.3 kJ mol-1.(ABSTRACT TRUNCATED AT 400 WORDS)

The effects of short-chain phospholipids on the acetylcholine-activated ion channel.

The effects of a homologous series of short-chain phospholipids, the phosphatidylcholines from dihexanoylglycerophosphocholine (Hxo2GroPCho) to didecanoylglycerophosphocholine, on the nicotinic acetylcholine-activated ion channel in cultured rat muscle cells were investigated. Standard patch-clamp techniques were used to measure single-channel currents in excised patches. All phospholipids investigated markedly reduced the frequency of channel opening in a concentration-dependent manner. Other parameters, such as the mean open time, the duration and frequency of brief closures within an opening, and channel amplitude, were not significantly affected. This effect was independent of the side of the membrane to which the phospholipid was added. Dose/response curves were obtained for Hxo2-, diheptanoyl(Hpo2)- and dinonanoyl(Nno2)GroPCho. The concentration leading to 50% reduction in channel activity decreased upon ascending the homologous series from 16.69 microM Hxo2GroPCho to 4.52 microM and 0.043 microM for Hpo2- and Nno2GroPCho, respectively. The more hydrophobic the molecule the more effective it was, and hence the higher its affinity to the binding site. Calculation of the standard free-energy change of adsorption into the site led to a value of -3.1 kJ/mol, which indicates a very hydrophobic binding site. In conclusion, the phospholipids interact in a non-specific way with the lipid membrane thereby disturbing proper channel function.