Patient consent in the post-Montgomery era: A national multi-speciality prospective study.

BACKGROUND: The Montgomery ruling has had a wide-ranging impact on the consent process and has been the subject of new guidelines by bodies, including the Royal College of Surgeons (RCSEng). This is the first study to examine the current standard of consent for surgical procedures at a national level. METHOD: A national collaborative research model was used, with prospective data collection performed across hospitals in Scotland. Variables associated with the consent process were audited across three surgical specialities (general surgery, urology and orthopaedics) and measured against standards set by RCSEng, the Scottish Public Services Ombudsman and medical defence organisations. RESULTS: A total of 289 cases were identified from 12 hospitals. The majority of patients were reviewed by a consultant surgeon in clinic (79.9%) or on the day of surgery (55.4%). The clinic consent rate was 27.0%, while a copy of the documented discussion was only provided to 4.2% of patients. On the day of surgery, the benefits, risks and alternatives to the planned procedure were discussed in less than half of cases. This rate was similar across different clinician grades, while marked variation was seen across hospitals. CONCLUSION: In this prospective multi-centre study we have demonstrated wide variation in the consent processes in many surgical specialities across Scotland. Following the Montgomery ruling, we have demonstrated the current consent process in elective surgery is likely to be substandard, and may require additional steps to be taken by clinicians to ensure patients are fully informed to make decisions regarding their treatment.

Urinary diagnostic proteomic markers for dynapenia in cancer patients.

Dynapenia is defined as the age-related loss of muscle strength, and plays a significant role in the loss of physical function and increased risk of disability among older individuals. The need for an early diagnosis supports the search for a biomarker that reflects muscle 'weakening'. This has previously proven difficult due to patient heterogeneity at presentation and lack of understanding of the underlying molecular mechanisms. The aim of the present study was to identify potential urinary biomarkers of dynapenia in patients undergoing potentially curative surgery for upper gastrointestinal cancer. Maximum isometric knee extensor strength (strain gauge) and maximum leg extensor power (Nottingham power rig) measurements were taken. Cut-off values for dynapenia were based on the Allied Dunbar national fitness survey. Values below the 5th percentile for the population matched for age and sex on the Allied Dunbar national fitness survey were used to stratify the cohort into dynapenic or normal. Urine samples taken at induction of anaesthesia were analysed by SELDI-TOF mass spectrometry using CM10 and IMAC30 chip-types to establish statistically significant m/z peak fingerprint patterns, followed by in-gel LC-MS/MS to identify molecular constituents. Statistical analysis of decision-tree calculations using Biomarker Pattern software resulted in models with sensitivities of 86 and 96%, specificities of 81 and 89%, and overall correctness of 84 and 93%, when applied to the entire cohort for power and strength measurement-based stratifications using the IMAC30 chip-type and the CM10 chip-type, respectively. The molecular identities of 10 peaks of interest were further investigated. After subtraction of potentially unrelated proteins, they were identified as fragments of Annexin A1, collagen α-1 (XV), perlecan and myotrophin. These results demonstrate that urinary screening can be used to define cancer-associated muscle weakness, and the identification of potential biomarkers could be invaluable in establishing a rapid test to measure and assess dynapenia in the clinical setting.

Proteomic identification of potential markers of myosteatosis in human urine.

Myosteatosis, the infiltration of fat in skeletal muscle, is associated with lower skeletal muscle density (SMD) as detected by computed tomography (CT). It increases with aging and obesity and is thought to play a role in the aetiology of insulin resistance and type II diabetes. The clinical significance of myosteatosis in cancer cachexia, however, remains to be determined. Along with demonstrable subcutaneous and visceral lipolysis, myosteatosis may also be a key component of the syndrome. We aimed to investigate the use of human urine as a non-invasive way to screen for molecular biomarkers of myosteatosis/reduced SMD using SELDI-TOF mass spectrometry. Pre-operative CT scans of patients undergoing surgery for upper gastrointestinal or hepatopancreaticobiliary cancer were analysed at the level of the third lumbar vertebrae. Myosteatosis was inferred as the presence of reduced SMD, which was defined as Hounsfield units for skeletal muscle <39.5 (two standard deviations below a normal healthy cohort). Urine was analysed by mass spectrometry using CM10 and IMAC30 SELDI-chips. Peaks observed in the CM10 and IMAC30 chip types, showed marked expressional differences between control and myosteatosis, were further investigated by mascot SELDI matrix matching. A total of 55 patients was recruited; 31 patients were found to be myosteatotic on CT scan. Application of the IMAC30-derived model to the entire cohort showed a sensitivity of 97%, specificity of 71% and an overall correctness of 85%. Application of the CM10 chipset-based model to the entire cohort, showed a 77% sensitivity, 67% specificity and 73% overall correctness. Analysis of the peaks of interest resulted in the identification of significant fragments of cathepsin C, argin, arylsulfatase A and glial fibrillary acidic protein. We identified several potential urinary molecular biomarkers associated with reduced SMD in cancer. Such markers are potentially useful in deriving a clinical screening test for myosteatosis.

The abundance of large, piscivorous Ferox Trout (Salmo trutta) in Loch Rannoch, Scotland.

BACKGROUND: Ferox Trout are large, long-lived piscivorous Brown Trout (Salmo trutta). Due to their exceptionally large size, Ferox Trout are highly sought after by anglers while their life-history strategy, which includes delayed maturation, multiphasic growth and extended longevity, is of interest to ecological and evolutionary modelers. However, despite their recreational and theoretical importance, little is known about the typical abundance of Ferox Trout. METHODS: To rectify this situation a 16 year angling-based mark-recapture study was conducted on Loch Rannoch, which at 19 km2 is one of the largest lakes in the United Kingdom. RESULTS: A hierarchical Bayesian Jolly-Seber analysis of the data suggest that if individual differences in catchability are negligible the population of Ferox Trout in Loch Rannoch in 2009 was approximately 71 fish. The results also suggest that a single, often unaccompanied, highly-experienced angler was able to catch roughly 8% of the available fish on an annual basis. DISCUSSION: It is recommended that anglers adopt a precautionary approach and release all trout with a fork length ≥400 mm caught by trolling in Loch Rannoch. There is an urgent need to assess the status of Ferox Trout in other lakes.

Habitual Myofibrillar Protein Synthesis Is Normal in Patients with Upper GI Cancer Cachexia.

PURPOSE: Skeletal muscle wasting and weight loss are characteristic features of cancer cachexia and contribute to impaired function, increased morbidity, and poor tolerance of chemotherapy. This study used a novel technique to measure habitual myofibrillar protein synthesis in patients with cancer compared with healthy controls. EXPERIMENTAL DESIGN: An oral heavy water (87.5 g deuterium oxide) tracer was administered as a single dose. Serum samples were taken over the subsequent week followed by a quadriceps muscle biopsy. Deuterium enrichment was measured in body water, serum alanine, and alanine in the myofibrillar component of muscle using gas chromatography-pyrolysis-isotope ratio mass spectrometry and the protein synthesis rate calculated from the rate of tracer incorporation. Net change in muscle mass over the preceding 3 months was calculated from serial CT scans and allowed estimation of protein breakdown. RESULTS: Seven healthy volunteers, 6 weight-stable, and 7 weight-losing (≥5% weight loss) patients undergoing surgery for upper gastrointestinal cancer were recruited. Serial CT scans were available in 10 patients, who lost skeletal muscle mass preoperatively at a rate of 5.6%/100 days. Myofibrillar protein fractional synthetic rate was 0.058%, 0.061%, and 0.073%/hour in controls, weight-stable, and weight-losing patients, respectively. Weight-losing patients had higher synthetic rates than controls (P = 0.03). CONCLUSION: Contrary to previous studies, there was no evidence of suppression of myofibrillar protein synthesis in patients with cancer cachexia. Our finding implies a small increase in muscle breakdown may account for muscle wasting.

Suppression of skeletal muscle turnover in cancer cachexia: evidence from the transcriptome in sequential human muscle biopsies.

PURPOSE: The mechanisms underlying muscle wasting in patients with cancer remain poorly understood, and consequently there remains an unmet clinical need for new biomarkers and treatment strategies. EXPERIMENTAL DESIGN: Microarrays were used to examine the transcriptome in single biopsies from healthy controls (n = 6) and in paired biopsies [pre-resection baseline (weight-loss 7%) and 8 month post-resection follow-up (disease-free/weight-stable for previous 2 months)] from quadriceps muscle of patients with upper gastrointestinal cancer (UGIC; n = 12). RESULTS: Before surgery, 1,868 genes were regulated compared with follow-up (false discovery rate, 6%). Ontology analysis showed that regulated genes belonged to both anabolic and catabolic biologic processes with overwhelming downregulation in baseline samples. No literature-derived genes from preclinical cancer cachexia models showed higher expression in baseline muscle. Comparison with healthy control muscle (n = 6) revealed that despite differences in the transcriptome at baseline (941 genes regulated), the muscle of patients at follow-up was similar to control muscle (2 genes regulated). Physical activity (step count per day) did not differ between the baseline and follow-up periods (P = 0.9), indicating that gene expression differences reflected the removal of the cancer rather than altered physical activity levels. Comparative gene expression analysis using exercise training signatures supported this interpretation. CONCLUSIONS: Metabolic and protein turnover-related pathways are suppressed in weight-losing patients with UGIC whereas removal of the cancer appears to facilitate a return to a healthy state, independent of changes in the level of physical activity.

Sexual dimorphism modulates the impact of cancer cachexia on lower limb muscle mass and function.

BACKGROUND & AIMS: There is a sparsity of data on the impact of cachexia on human muscle function. This study examined the relationship between cachexia, quality of life and the mass/function/mechanical quality of lower limb skeletal muscle in gastrointestinal cancer patients. METHODS: Quadriceps strength and lower limb power were measured in 54 patients with gastrointestinal cancer (n = 24 ≥ 10% weight-loss) and 18 healthy controls. Quadriceps cross-sectional area was measured in 33/54 patients and in all controls using MRI. Muscle mechanical quality was defined as quadriceps strength/unit quadriceps cross-sectional area. Quality of life was assessed using the EORTC QLQ-C30. Patients with weight-loss ≥ 10% were classified as cachectic. RESULTS: In male cachectic patients, quadriceps strength (p = 0.003), lower limb power (p = 0.026), quadriceps cross-sectional area (p = 0.019) and muscle quality (p = 0.008) were reduced compared with controls. In female cachectic patients, quadriceps strength (p = 0.001) and muscle quality (p = 0.001) were reduced compared with controls. Physical function (p = 0.013) and fatigue (p = 0.004) quality of life scores were reduced in male cachectic compared with non-cachectic patients, but not in females. CONCLUSIONS: Muscle quality is reduced in cancer patients. The degree of impairment of lower limb muscle mass, quality and function and the impact on quality of life varies with weight-loss and sex.

The advantages and limitations of cross-sectional body composition analysis.

PURPOSE OF REVIEW: Cross-sectional (C-S) imaging is now commonly used to measure body composition in clinical studies. This review highlights the advantages, limitations and suggested future directions for this technique. RECENT FINDINGS: Current understanding of C-S imaging reproducibility, tissue identification and segmentation methods, comparison between imaging techniques and estimates of whole body composition using a single image are described. SUMMARY: C-S imaging can reliably measure muscle and fat distribution and uniquely discriminate between intra-abdominal organ and muscle component of fat-free mass. It precisely tracks changes within an individual, but is less able to distinguish true differences in whole body estimates between individuals.

Intramyocellular lipid droplets increase with progression of cachexia in cancer patients.

BACKGROUND: Intramyocellular lipids are an important source of fuel for mitochondrial fat oxidation and play an important role in intramuscular lipid homeostasis. We hypothesised that due to the phenotype associated with cancer cachexia, there would exist an association between increasing weight loss and the number/size of intramyocellular lipid droplets. METHODS: Nineteen cancer patients and 6 controls undergoing surgery were recruited. A rectus abdominis biopsy was performed and processed for transmission electron microscopy (TEM). The number of intramyocellular lipid droplets and lipid droplet diameter were calculated from the TEM images. CT scans, performed as part of patients' routine care, were analysed to determine amount of adipose (intermuscular, visceral and subcutaneous) and muscle tissue. RESULTS: Compared with controls, cancer patients had increased numbers of lipid droplets (mean (SD) 1.8 (1.9) vs. 6.4 (9.1) per ×2,650 field, respectively, p = 0.036). Mean (SD) lipid droplet diameter was also higher in cancer patients compared with controls (0.42 (0.13) vs. 0.24 (0.21) µm, p = 0.015). Mean lipid droplet count correlated positively with the severity of weight loss (R = 0.51, p = 0.025) and negatively with CT-derived measures of intermuscular fat (R = -0.53, p = 0.022) and visceral fat (R = -0.51, p = 0.029). CONCLUSIONS: This study suggests that the number and size of intramyocellular lipid droplets is increased in the presence of cancer and increases further with weight loss/loss of adipose mass in other body compartments.

Proteomic analysis of urinary upper gastrointestinal cancer markers.

PURPOSE: We have investigated the use of human urine as a non-invasive medium to screen for molecular biomarkers of carcinomas of the upper gastrointestinal (uGI) tract using SELDI-TOF-MS. EXPERIMENTAL DESIGN: A total of 120 urine specimens from 60 control and 60 uGI cancer patients were analysed to establish a potential biomarker fingerprint for the weak cation exchanger CM10 chip surface, which was validated by blind testing using a further 59 samples from 33 control and 26 uGI cancer patients. RESULTS: Using Biomarker Pattern software, we established a model with a sensitivity of 98% and specificity of 95% for the learning sample set, and a sensitivity of 96% and specificity of 72% for the validation data set. Model variable importance included six peptides with m/z of 10,230, 10,436, 10,574, 10,311, 10,467, and 10,118 of which the 10, 230 molecular species was the main decider (sensitivity 86% and specificity 80%). Initial protein database searching identified 10,230 as S100-A6, 10,436 as S100-P, 10,467 as S100-A9, and 10,574 as S100-A12 of which S100-A6 and S100-A9 were confirmed by Western blotting. CONCLUSIONS AND CLINICAL RELEVANCE: We have demonstrated that SELDI-TOF-MS as a screening tool is a rapid and valid methodology in the search for urinary cancer biomarkers, and is potentially useful in defining and consolidating biomarker patterns for uGI cancer screening.

Sham feed or sham? A meta-analysis of randomized clinical trials assessing the effect of gum chewing on gut function after elective colorectal surgery.

PURPOSE: Enhanced recovery programs aim to expedite gut function after elective colorectal surgery. Early oral feeding simulates gut function but is not always feasible. Gum chewing, a form of sham feed, is an alternative. We assessed current evidence for gum chewing and gut function. STUDY DESIGN: All randomized controlled trials (RCTs) between 1990 and 2008 comparing gum chewing with controls/placebo were analyzed irrespective of language, blinding, or publication bias. The Jadad scale was used to assess study quality. Endpoints were time to flatus/feces, postoperative complications, and hospital stay. Random and fixed models were employed to aggregate study endpoints and assess heterogeneity. RESULTS: Six RCTs containing 256 patients were included. Significant heterogeneity was identified and random effects model was employed. Heterogeneity may be explained through variations in delivery of surgical care. Significant reductions in the time to flatus and time to feces were identified but no significant difference in hospital or in-hospital postoperative complications were found. CONCLUSIONS: Gum chewing significantly reduced time to flatus and feces; however, hospital stay and postoperative complications were not reduced. Significant study heterogeneity means that these results should be interpreted with caution.

Early versus delayed laparoscopic cholecystectomy for acute cholecystitis: a meta-analysis of randomized clinical trials.

BACKGROUND: The appropriate timing for laparoscopic cholecystectomy in the treatment of acute cholecystitis remains controversial. More recent evaluation indicates early laparoscopic surgery may be a safe option in acute cholecystitis, although conversion rates may be higher. No conclusive evidence establishing best practice in terms of clinical benefit exists. METHODS: All randomized clinical studies published between 1987 and 2006 comparing early versus delayed laparoscopic cholecystectomy for acute cholecystitis were analyzed, irrespective of language, blinding, or publication status. Exclusions were quasi-randomized trials, inadequate follow-up description, or allocation concealment. Endpoints included conversion rates, postoperative complications, total hospital stay, and operation time. Random and fixed-effect models were used to aggregate the study endpoints and assess heterogeneity. RESULTS: Four studies containing 375 patients were included. No significant study heterogeneity or publication bias was found. There was no significant difference in conversion rates (odds ratio = .915 [95% confidence interval (CI), .567-1.477], P = .718) and postoperative complications (odds ratio = 1.073 [95% CI, .599-1.477], P = .813) between both groups. Operation time was significantly reduced (weighted mean difference [WMD] = .412 [95% CI, .149-.675], P = .002) with delayed cholecystectomy. The total hospital stay was significantly reduced (WMD = .905 [95% CI, .630-1.179], P = .0005) with early cholecystectomy. The postoperative stay was significantly reduced in the delayed group (WMD = .393 [95% CI, .128-.659], P = .004). CONCLUSIONS: These meta-analysis data suggest that early laparoscopic cholecystectomy allows significantly shorter total hospital stay at the cost of a significantly longer operation time with no significant differences in conversion rates or complications.