Factors predictive of an advanced stage of colorectal cancer at presentation - a bi-national study.

AIM: Identifying elements associated with advanced colorectal cancer (CRC) stage may inform understanding of whether advanced disease is a corollary of access to healthcare or tumour biology and in turn allow the use of targeted screening and awareness programmes. The aim of this study was to identify factors that predict advanced stage of CRC at presentation in Australia and New Zealand. METHOD: This was a cross-sectional registry study sourced from the prospectively maintained Binational Colorectal Cancer Audit database of Australia and New Zealand. The primary outcome was stage as defined by the TNM system with associations drawn to demographic and perioperative variables. RESULTS: In total, 25 282 separate cancers were included. Univariate analysis found younger age, treatment at a public facility, increasing American Society of Anesthesiologists (ASA) grade, more distal tumours, and less recent year of surgery to all be associated with more advanced disease; sex and presentation at a rural vs urban hospital had no bearing on this outcome. Logistic regression identified younger age (< 60 years vs > 80 years: OR 1.96; 95% CI 1.80-2.14; P = 0.002), treatment at a public vs private hospital (OR 1.21; 95% CI 1.14-1.28; P < 0.001), increasing ASA grade (ASA4 vs ASA1: OR 1.37; 95% CI 1.17-1.59, P < 0.001) and more distal tumours (mid-low rectal vs right colon tumours: OR 1.52; 95% CI 1.41-1.64; P < 0.001) to be independent predictors of nodal or metastatic disease at presentation. CONCLUSION: Younger age, increasing ASA grade, more distal tumours, and treatment at a public rather than private facility are independently associated with the presence of nodal or distant CRC metastases at diagnosis.

Hyperactive cyclic motor activity in the distal colon after colonic surgery as defined by high-resolution colonic manometry.

BACKGROUND: Recovery after colonic surgery is invariably delayed by disturbed gut motility. It is commonly assumed that colonic motility becomes quiescent after surgery, but this hypothesis has not been evaluated rigorously. This study quantified colonic motility through the early postoperative period using high-resolution colonic manometry. METHODS: Fibre-optic colonic manometry was performed continuously before, during and after surgery in the left colon and rectum of patients undergoing right hemicolectomy, and in healthy controls. Motor events were characterized by pattern, frequency, direction, velocity, amplitude and distance propagated. RESULTS: Eight patients undergoing hemicolectomy and nine healthy controls were included in the study. Colonic motility became markedly hyperactive in all operated patients, consistently dominated by cyclic motor patterns. Onset of cyclic motor patterns began to a minor extent before operation, occurring with increasing intensity nearer the time of surgery; the mean(s.d.) active duration was 12(7) per cent over 3 h before operation and 43(17) per cent within 1 h before surgery (P = 0.024); in fasted controls it was 2(4) per cent (P < 0·001). After surgery, cyclic motor patterns increased markedly in extent and intensity, becoming nearly continuous (active duration 94(13) per cent; P < 0·001), with peak frequency 2-4 cycles per min in the sigmoid colon. This postoperative cyclic pattern was substantially more prominent than in non-operative controls, including in the fed state (active duration 27(20) per cent; P < 0·001), and also showed higher antegrade velocity (P < 0·001). CONCLUSION: Distal gut motility becomes markedly hyperactive with colonic surgery, dominated by cyclic motor patterns. This hyperactivity likely represents a novel pathophysiological aspect of the surgical stress response. Hyperactive motility may contribute to gut dysfunction after surgery, potentially offering a new therapeutic target to enhance recovery.

Intra-operative high-resolution mapping of slow wave propagation in the human jejunum: Feasibility and initial results.

BACKGROUND: Bioelectrical slow waves are a coordinating mechanism of small intestine motility, but extracellular human studies have been restricted to a limited number of sparse electrode recordings. High-resolution (HR) mapping has offered substantial insights into spatiotemporal intestinal slow wave dynamics, but has been limited to animal studies to date. This study aimed to translate intra-operative HR mapping to define pacemaking and conduction profiles in the human small intestine. METHODS: Immediately following laparotomy, flexible-printed-circuit arrays were applied around the serosa of the proximal jejunum (128-256 electrodes; 4-5.2 mm spacing; 28-59 cm2 ). Slow wave propagation patterns were mapped, and frequencies, amplitudes, downstroke widths, and velocities were calculated. Pacemaking and propagation patterns were defined. KEY RESULTS: Analysis comprised nine patients with mean recording duration of 7.6 ± 2.8 minutes. Slow waves occurred at a frequency of 9.8 ± 0.4 cpm, amplitude 0.3 ± 0.04 mV, downstroke width 0.5 ± 0.1 seconds, and with faster circumferential velocity than longitudinal (10.1 ± 0.8 vs 9.0 ± 0.7 mm/s; P = .001). Focal pacemakers were identified and mapped (n = 4; mean frequency 9.9 ± 0.2 cpm). Disordered slow wave propagation was observed, including wavefront collisions, conduction blocks, and breakout and entrainment of pacemakers. CONCLUSIONS & INFERENCES: This study introduces HR mapping of human intestinal slow waves, and provides first descriptions of intestinal pacemaker sites and velocity anisotropy. Future translation to other intestinal regions, disease states, and postsurgical dysmotility holds potential for improving the basic and clinical understanding of small intestine pathophysiology.

Restoration of normal colonic motor patterns and meal responses after distal colorectal resection.

BACKGROUND: Colorectal resections alter colonic motility, including disruption of control by neural or bioelectrical cell networks. The long-term impact of surgical resections and anastomoses on colonic motor patterns has, however, never been assessed accurately. Fibreoptic high-resolution colonic manometry was employed to define motility in patients who had undergone distal colorectal resection. METHODS: Recruited patients had undergone distal colorectal resections more than 12 months previously, and had normal bowel function. Manometry was performed in the distal colon (36 sensors; 1-cm intervals), with 2-h recordings taken before and after a meal, with comparison to controls. Analysis quantified all propagating events and frequencies (cyclical, short single, and long single motor patterns), including across anastomoses. RESULTS: Fifteen patients and 12 controls were recruited into the study. Coordinated propagating events directly traversed the healed anastomoses in nine of 12 patients with available data, including antegrade and retrograde cyclical, short single and long single patterns. Dominant frequencies in the distal colon were similar in patients and controls (2-3 cycles/min) (antegrade P = 0·482; retrograde P = 0·178). Compared with values before the meal, the mean(s.d.) number of dominant cyclical retrograde motor patterns increased in patients after the meal (2·1(2·7) versus 32·6(31·8) in 2 h respectively; P < 0·001), similar to controls (P = 0·178), although the extent of propagation was 41 per cent shorter in patients, by a mean of 3·4 cm (P = 0·003). Short and long single propagating motor patterns were comparable between groups in terms of frequency, velocity, extent and amplitude. CONCLUSION: Motility patterns and meal responses are restored after distal colorectal resection in patients with normal bowel function. Coordinated propagation across healed anastomoses may indicate regeneration of underlying cellular networks.

Isolation and characterisation of a novel trophoblast side-population from first trimester placentae.

The placenta is responsible for all nutrient and gas exchange between mother and baby during pregnancy. The differentiation of specialised placental epithelial cells called trophoblasts is essential for placental function, but we understand little about how these populations arise. Mouse trophoblast stem cells have allowed us to understand many of the factors that regulate murine trophoblast lineage development, but the human placenta is anatomically very different from the mouse, and it is imperative to isolate a human trophoblast stem cell to understand human placental development. Here we have developed a novel methodology to isolate a Hoechst side-population of trophoblasts from early gestation placentae and compared their transcriptome to differentiated trophoblast populations (cytotrophoblasts and extravillous trophoblasts) using microarray technology. Side-population trophoblasts clustered as a transcriptomically distinct population but were more closely related to cytotrophoblasts than extravillous trophoblasts. Side-population trophoblasts up-regulated a number of genes characteristic of trophectoderm and murine trophoblast stem cells in comparison to cytotrophoblasts or extravillous trophoblasts and could be distinguished from both of these more mature populations by a unique set of 22 up-regulated genes, which were enriched for morphogenesis and organ development and the regulation of growth functions. Cells expressing two of these genes (LAMA2 and COL6A3) were distributed throughout the cytotrophoblast layer at the trophoblast/mesenchymal interface. Comparisons to previously published trophoblast progenitor populations suggest that the side-population trophoblasts isolated in this work are a novel human trophoblast population. Future work will determine whether these cells exhibit functional progenitor/stem cell attributes.

Systemic levels of local anaesthetic after intra-peritoneal application--a systematic review.

There is a lack of cohesive reports on the systemic levels of local anaesthetic after intraperitoneal application. A comprehensive systematic review with no language restriction was conducted. Eighteen suitable articles were identified. Data were compiled and presented according to local anaesthetic agent. Intraperitoneal local anaesthetic has been studied in many different procedures, including open and laparoscopic surgery. A total of 415 patients were included for analysis. There were no cases of clinical toxicity. There were 11 (2.7%) cases with a systemic level above or close to a safe threshold (as determined by the report authors) in three trials utilising intraperitoneal local anaesthetic after laparoscopic cholecystectomy. Intraperitoneal lignocaine doses varied from 100 to 1000 mg, mean Cmax ranged from 1.01 to 4.32 microg/ml and mean Tmax ranged from 15 to 40 minutes. Intraperitoneal bupivacaine doses varied from 50 to 150 mg (weight based doses also reported), mean Cmax ranged from 0.29 to 1.14 microg/ml and mean Tmax ranged from 15 to 60 minutes. Intraperitoneal ropivacaine doses varied from 100 to 300 mg, mean Cmax ranged from 0.66 to 3.76 microg/ml and mean Tmax ranged from 15 to 35 minutes. The addition of adrenaline to intraperitoneal local anaesthetic almost halves systemic levels and prolongs Tmax. Intraperitoneal local anaesthetic results in detectable systemic levels in the perioperative setting. Despite a lack of clinical toxicity, careful attention to dose is still required to prevent potential systemic toxic levels. Clinicians should also consider the addition of adrenaline to intraperitoneal local anaesthetic solutions to further add to the systemic safety profile.

Ethnic disparity in colonic cancer outcomes in New Zealand--biology or an access issue?

BACKGROUND: There is an ethnic variation in outcomes for colonic cancer in New Zealand. Whether this disparity is caused by cancer biology or inequitable provision of treatment services after diagnosis has not been elucidated. METHOD: National cancer registry data from 1996 to 2003 were obtained. Incidence and mortality rates for the four major ethnic groups were age-adjusted to the new WHO world population. The impact of age, sex, AJCC stage and site of cancer at diagnosis was compared between ethnic groups using a Cox regression analysis. RESULTS: A total of 11 987 colonic cancer registrations were identified. The overall raw 5-year mortality was 53.7%. The age-adjusted incidence in Europeans was more than double that of the Maori, Asian and Pacific populations at 33.0 per 100,000 population/year. Europeans presented at a greater age, with more right sided cancers, and at an earlier stage of disease. The opposite was true for the Maori population. Pacific Islanders and Asians presented at a younger age, but with a similar site, stage and sex distribution to the rest of the population. There were no significant differences in 5 year mortality after diagnosis when age, sex, stage, and site at presentation were controlled for by cox regression analysis. CONCLUSION: These results suggest that age, sex, stage and site at presentation may be more important than inequality in treatment provision after diagnosis in explaining differences in outcomes between the ethnicities. Efforts need to be focused on identifying reasons for the increased risk of colonic neoplasia in Europeans and the later stage disease presentation in the Maori population.

Concentrations in beef and lamb of taurine, carnosine, coenzyme Q(10), and creatine.

Levels of taurine, carnosine, coenzyme Q(10), and creatine were measured in beef liver and several muscles of beef and lamb and in cooked and uncooked meat. The amino acid taurine has numerous biological functions, the dipeptide carnosine is a buffer as well as an antioxidant, coenzyme Q(10) is also an antioxidant present within mitochondria, and creatine along with creatine phosphate is involved with energy metabolism in muscle. Large differences were shown for all compounds between beef cheek muscle (predominantly red fibres) and beef semitendinosus muscle (mainly white fibres), with cheek muscle containing 9.9 times as much taurine, and 3.2 times as much coenzyme Q(10), but only 65% as much creatine and 9% as much carnosine. Levels in lamb relative to beef semitendinosus muscles were higher for taurine but slightly lower for carnosine, coenzyme Q(10) and creatine. Values for all the compounds varied significantly between eight lamb muscles, possibly due in part to differences in the proportion of muscle fibre types. Slow cooking (90 min at 70 °C) of lamb longissimus and semimembranosus muscles led to significant reductions in the content of taurine, carnosine, and creatine (P<0.001), but a slight increase in coenzyme Q(10). There was also a four-fold increase in creatinine, presumably due to its formation from creatine. It is concluded that biologically, and possibly nutritionally, significant levels of taurine, carnosine, coenzyme Q(10), and creatine are present in beef and lamb, but that these levels vary between muscles, between animals, and with cooking.

Cooking temperature effects on the forms of iron and levels of several other compounds in beef semitendinosus muscle.

The influence of final cooked temperature on the form of iron present and on the concentration of taurine, carnosine, coenzyme Q(10) and creatine was investigated in surface and inner parts of 30-mm thick steaks from beef semitendinosus muscle (n=6). The use of a fast, dry-heat cooking method with a Silex clam cooker (set at 200 °C) led to cooking times ranging from 5.6 to 8.6 min for final internal temperatures of 60 and 85 °C, respectively. The proportion of iron as soluble haem iron decreased from 65% in uncooked meat to 22% when cooked to 60 °C and then decreased more gradually with increases in final cooked temperature. The proportion of insoluble haem iron increased in a reciprocal manner, while changes in the proportions of soluble and insoluble non-haem iron were relatively small, but increases in the percentage of insoluble non-haem iron with increasing final temperature were significant (P<0.01). Changes in the forms of iron with cooking generally took place more rapidly in surface samples than inner samples. On a dry-matter basis, concentrations of taurine, carnosine, coenzyme Q(10), and creatine all decreased with cooking, but the decreases were greatest for taurine and creatine. Losses of creatine were at least partly due to conversion to creatinine, and, along with the other compounds, probably included some loss in cooking juices. It is concluded that despite these changes with cooking, beef semitendinosus muscle remains a good source of iron and a useful source of the potentially bioactive compounds taurine, carnosine, coenzyme Q(10) and creatine.