The Influence of Systemic Inflammation on Treatment Response and Survival in Anal Squamous Cell Cancer.

AIMS: The incidence of anal squamous cell cancer (SCCA) is rising. Although chemoradiotherapy (CRT) provides a chance of cure, a proportion of patients have an incomplete response or develop recurrence. This study assessed the value of inflammation-based prognostic indicators, including the modified Glasgow Prognostic Score (mGPS) and neutrophil:lymphocyte ratio (NLR), in patients with SCCA treated by CRT with curative intent. MATERIAL AND METHODS: Patients with histologically confirmed SCCA were identified from pathology records. Medical records were retrospectively reviewed and clinical, pathological and treatment characteristics were abstracted. The mGPS (0 = normal C-reactive protein [CRP] and albumin, 1 = CRP >10 mg/l and 2 = CRP >10 mg/l and albumin <35 mg/l) and NLR were calculated from routine blood tests obtained prior to CRT. RESULTS: In total, 118 patients underwent CRT for SCCA between December 2007 and February 2018. Of these, 99 patients had appropriate pretreatment blood results available. Systemic inflammation as indicated by NLR >3 and mGPS >0 was present in 41% and 39% of patients, respectively. Most patients had T2 or larger tumours (n = 85, 86%) without nodal involvement (n = 64, 65%). An elevated mGPS was associated with more advanced T-stage (56% versus 35%, P = 0.036). NLR >5 was associated with nodal positivity (56% versus 31%, P = 0.047). On multivariate analysis, more advanced T-stage (odds ratio 7.49, 95% confidence interval 1.51-37.20, P = 0.014) and a raised mGPS (odds ratio 5.13, 95% confidence interval 1.25-21.14, P = 0.024) were independently related to incomplete CRT response. An elevated mGPS was prognostic of inferior survival (hazard ratio 3.09, 95% confidence interval 1.47-6.50, P = 0.003) and cancer-specific survival (hazard ratio 4.32, 95% confidence interval 1.54-12.15, P = 0.006), independent of TNM stage. CONCLUSION: Systemic inflammation, as measured by the mGPS, is associated with an incomplete CRT response and is independently prognostic of inferior survival in patients with SCCA. The mGPS may offer a simple marker of inferior outcome that could be used to identify high-risk patients.

Eli Lilly and Company Insulins - A Century of Innovation.

Eli Lilly and Company has played a pivotal role in the development of insulin products since its discovery in 1921. Through their dedication to pharmaceutical innovation, Josiah K. Lilly Sr. and George HA Clowes, in close collaborations with the University of Toronto, made insulin commercially available in 1923. Other innovations include the development and commercialization of the first biosynthetic human insulin, a rapid-acting insulin analog and analog mixtures. Lilly has advanced the field of knowledge with significant efforts toward developing a hepatic preferential basal insulin. Other important insulin projects include the first concentrated rapid-acting insulin analog, clinical studies supporting the use of highly concentrated human insulin, and an advanced clinical development program for an ultra-rapid insulin analog. Lilly's commitment to people affected with diabetes remains strong and will continue into the future through collaborative research, innovative product development and investing in advanced technologies.

Karydakis flap for post-proctectomy perineal sinus: A case series and review.

INTRODUCTION: Persistent perineal sinus (PPS) may occur in up to 38% of patients undergoing proctectomy. The available therapeutic options range from simple but ineffective to relatively successful but complex. The Karydakis procedure is a straightforward day-case operation, commonly performed by general surgeons in the treatment of pilonidal disease, a not dissimilar pathology to PPS. This report is the first in the literature describing the use of Karydakis procedure in patients who developed PPS after proctectomy for Crohn's disease. PRESENTATION OF CASE: Two patients, both of whom suffered from Crohn's disease and a PPS, underwent a Karydakis procedure as first-line treatment for PPS. Case 1 had a relatively superficial PPS while Case 2 had a deeper, more complex and longstanding PPS. Both patients had no post-operative complications and were discharged on the same day. They achieved complete healing in eight weeks and eight months respectively. The follow up range was 8-16 months. DISCUSSION: Various techniques, including complex myocutaneous flap reconstruction, have been described in the literature to treat PPS. In contrast to these complex techniques, Karydakis operation is a simple day case procedure that was successful in treating PPS in our patients. While there is robust data regarding low recurrence rates following a Karydakis flap for pilonidal disease, there is no existing data for the indication outlined in this report. CONCLUSION: While it requires further assessment, the Karydakis operation has potential as a simple, safe and effective first-line treatment in selected patients with PPS while not precluding more complex operative options in the future.

Juvenile idiopathic arthritis and future risk for cardiovascular disease: a multicenter study.

OBJECTIVES: To evaluate the frequency of cardiovascular disease (CVD) and CVD risk factor development in adult patients previously diagnosed with juvenile idiopathic arthritis (JIA). METHOD: A cohort study was conducted utilizing patients at two academic institutions (cohorts 1 and 2). Each institution evaluated the common endpoint of CVD outcomes and CVD risk factor development in adults aged ≥ 30 years and at the 29-year follow-up from disease onset in cohorts 1 and 2, respectively, with comparison to control groups of similar age and sex. RESULTS: Cohort 1 included 41 patients with JIA and follow-up ≥ 30 years of age with comparison to 41 controls. Three patients (7%) had CVD, compared to one control (2%; p = 0.31). Cohort 2 included 170 patients with JIA and a median of 29 years of follow-up from disease onset with comparison to 91 controls. Two patients (2%) had CVD, compared to none of the controls (p = 0.29). The presence of CVD risk factors was found to be increased in the JIA group compared to the controls in three categories: family history of CVD (cohort 1), hypertension (cohort 2), and ever smokers (cohorts 2). CONCLUSIONS: There is no increase in CVD events in patients with JIA 29 years following disease onset when compared to the general population. As these cohorts age, it will be informative to evaluate whether this baseline risk remains present or a trend towards increasing CVD emerges. Continued longitudinal follow-up of these cohorts and larger population-based studies are needed to establish a definitive relationship between JIA and CVD.

Dose-finding results in an adaptive, seamless, randomized trial of once-weekly dulaglutide combined with metformin in type 2 diabetes patients (AWARD-5).

AIMS: AWARD-5 was an adaptive, seamless, double-blind study comparing dulaglutide, a once-weekly glucagon-like peptide-1 (GLP-1) receptor agonist, with placebo at 26 weeks and sitagliptin up to 104 weeks. The study also included a dose-finding portion whose results are presented here. METHODS: Type 2 diabetes (T2D) patients on metformin were randomized 3 : 1 : 1 to seven dulaglutide doses, sitagliptin (100 mg), or placebo. A Bayesian algorithm was used for randomization and dose selection. Patients were adaptively randomized to dulaglutide doses using available data on the basis of a clinical utility index (CUI) of glycosylated haemoglobin A1c (HbA1c) versus sitagliptin at 52 weeks and weight, pulse rate (PR) and diastolic blood pressure (DBP) versus placebo at 26 weeks. The algorithm randomly assigned patients until two doses were selected. RESULTS: Dulaglutide 1.5 mg was determined to be the optimal dose. Dulaglutide 0.75 mg met criteria for the second dose. Dulaglutide 1.5 mg showed the greatest Bayesian mean change from baseline (95% credible interval) in HbA1c versus sitagliptin at 52 weeks -0.63 (-0.98 to -0.20)%. Dulaglutide 2.0 mg showed the greatest placebo-adjusted mean change in weight [-1.99 (-2.88 to -1.20) kg] and in PR [0.78 (-2.10 to 3.80) bpm]. Dulaglutide 1.5 mg showed the greatest placebo-adjusted mean change in DBP [-0.62 (-3.40 to 2.30) mmHg]. CONCLUSIONS: The Bayesian algorithm allowed for an efficient exploration of a large number of doses and selected dulaglutide doses of 1.5 and 0.75 mg for further investigation in this trial.

The relationship between tumour site, clinicopathological characteristics and cancer-specific survival in patients undergoing surgery for colorectal cancer.

AIM: It is recognised that colorectal cancer may arise from different genomic instability pathways. There is evidence to suggest that colon and rectal cancers exhibit different clinicopathological features. We examined the relationship between tumour site, clinicopathological characteristics and cancer-specific survival in patients undergoing potentially curative resection for colorectal cancer. METHOD: Four hundred and eleven patients who underwent surgery. Clinicopathological data including components of the Peterson index, Klintrup scores, haemoglobin and the modified Glasgow Prognostic Score (mGPS) were studied. RESULTS: There were 134 (33%) right sided, 125 (30%) left sided and 152 (37%) rectal tumours. Emergency presentation (P < 0.001), anaemia (P < 0.001), higher mGPS (P < 0.001), advanced T stage (P < 0.001), poor differentiation (P < 0.001) and older age (P < 0.05) were more commonly observed in right sided cancer. The mean follow-up was 94 months (minimum 36 months) and 114 patients died of cancer. There was no difference between tumour site and survival (P = 0.427). On multivariate analysis older age (P = 0.015), lymph node ratio (P < 0.001), mGPS (P = 0.028), Peterson Index (P < 0.001) and Klintrup score (P = 0.008) were independently related to cancer-specific survival. Klintrup score was only associated with poor cancer-specific survival in rectal cancer (P = 0.009). CONCLUSION: The study suggests that colorectal cancer is a group of heterogeneous tumours with different clinicopathological features. Despite this, there was no difference between tumour site and survival. The prognostic role of clinicopathological factors in tumours arising from different genomic instability pathways requires further study.

Prognostic value of tumour necrosis and host inflammatory responses in colorectal cancer.

BACKGROUND: Tumour necrosis is a marker of poor prognosis in some tumours but the mechanism is unclear. This study examined the prognostic value of tumour necrosis and host inflammatory responses in colorectal cancer. METHODS: This was a retrospective study of patients undergoing potentially curative resection of colorectal cancer at a single surgical institution over a 10-year period. Patients who underwent preoperative radiotherapy were excluded. The systemic and local inflammatory responses were assessed using the modified Glasgow Prognostic Score and Klintrup-Makinen criteria respectively. Original tumour sections were retrieved and necrosis graded as absent, focal, moderate or extensive. Associations between necrosis and clinicopathological variables were examined, and multivariable survival analyses carried out. RESULTS: A total of 343 patients were included between 1997 and 2007. Tumour necrosis was graded as absent in 32 (9·3 per cent), focal in 166 (48·4 per cent), moderate in 101 (29·4 per cent) and extensive in 44 (12·8 per cent). There were significant associations between tumour necrosis and anaemia (P = 0·022), white cell count (P = 0·006), systemic inflammatory response (P < 0·001), local inflammatory cell infiltrate (P = 0·004), tumour node metastasis (TNM) stage (P = 0·015) and Petersen Index (P = 0·003). On univariable survival analysis, tumour necrosis was associated with cancer-specific survival (P < 0·001). On multivariable survival analysis, age (hazard ratio (HR) 1·29, 95 per cent confidence interval 1·00 to 1·66), systemic inflammatory response (HR 1·74, 1·27 to 2·39), low-grade local inflammatory cell infiltrate (HR 2·65, 1·52 to 4·63), TNM stage (HR 1·55, 1·02 to 2·35) and high-risk Petersen Index (HR 3·50, 2·21 to 5·55) were associated with reduced cancer-specific survival. CONCLUSION: The impact of tumour necrosis on colorectal cancer survival may be due to close associations with the host systemic and local inflammatory responses.

The effects of LY2189265, a long-acting glucagon-like peptide-1 analogue, in a randomized, placebo-controlled, double-blind study of overweight/obese patients with type 2 diabetes: the EGO study.

AIM: To evaluate the efficacy and tolerability of once-weekly LY2189265 (LY), a novel glucagon-like peptide-1 (GLP-1) IgG4-Fc fusion protein, in patients with type 2 diabetes failing oral antihyperglycaemic medications (OAMs). METHODS: Placebo-controlled, double-blind study in 262 patients (mean age 57 ± 12 years; BMI 33.9 ± 4.1 kg/m(2); and glycosylated haemoglobin A1c (A1c) 8.24 ± 0.93%) receiving two OAMs. Patients were randomized to once-weekly subcutaneous injections of placebo or LY 0.5 mg for 4 weeks, then 1.0 mg for 12 weeks (LY 0.5/1.0); 1.0 mg for 16 weeks (LY 1.0/1.0); or 1.0 mg for 4 weeks, then 2.0 mg for 12 weeks (LY 1.0/2.0). RESULTS: At week 16, A1c changes (least-squares mean ± standard error) were -0.24 ± 0.12, -1.38 ± 0.12, -1.32 ± 0.12 and -1.59 ± 0.12%, in the placebo, LY 0.5/1.0, LY 1.0/1.0 and LY 1.0/2.0 arms, respectively (all p < 0.001 vs. placebo). Both fasting (p < 0.001) and postprandial (p < 0.05) blood glucose decreased significantly compared to placebo at all LY doses. Weight loss was dose dependent and ranged from -1.34 ± 0.39 to -2.55 ± 0.40 kg at 16 weeks (all p < 0.05 vs. placebo). At the highest LY dosage, the most common adverse events were nausea (13.8%), diarrhoea (13.8%) and abdominal distension (13.8%). Hypoglycaemia was uncommon overall (≤0.8 episodes/patient/30 days) but more common with LY than placebo through the initial 4 weeks (p < 0.05). No differences in cardiovascular events or blood pressure were shown between treatments. CONCLUSIONS: LY2189265, given to overweight/obese patients with type 2 diabetes for 16 weeks in combination with OAMs, was relatively well tolerated and significantly reduced A1c, blood glucose and body weight.

The relationship between patient physiology, the systemic inflammatory response and survival in patients undergoing curative resection of colorectal cancer.

BACKGROUND: It is increasingly recognised that host-related factors may be important in determining cancer outcome. The aim was to examine the relationship between patient physiology, the systemic inflammatory response and survival after colorectal cancer resection. METHODS: Patients undergoing potentially curative resection of colorectal cancer were identified from a prospectively maintained database. Patient physiology was assessed using the physiological and operative severity score for the enumeration of mortality and morbidity (POSSUM) criteria. The systemic inflammatory response was assessed using the modified Glasgow Prognostic Score (mGPS). Multivariate 5-year survival analysis was carried out with calculation of hazard ratios (HR). RESULTS: A total of 320 patients were included. During follow-up (median 74 months), there were 136 deaths: 83 colorectal cancer related and 53 non-cancer related. Independent predictors of cancer-specific survival were age (HR: 1.46, P<0.01), Dukes stage (HR: 2.39, P<0.001), mGPS (HR: 1.78, P<0.001) and POSSUM physiology score (HR: 1.38, P=0.02). Predictors of overall survival were age (HR: 1.64, P<0.001), smoking (HR: 1.52, P=0.02), Dukes stage (HR: 1.64, P<0.001), mGPS (HR: 1.60, P<0.001) and POSSUM physiology score (HR: 1.27, P=0.03). A relationship between mGPS and POSSUM physiology score was also established (P<0.006). CONCLUSION: The POSSUM physiology score and the systemic inflammatory response are strongly associated and both are independent predictors of cancer specific and overall survival in patients undergoing potentially curative resection of colorectal cancer.

Selection on breeding date and body size in colonizing coho salmon, Oncorhynchus kisutch.

Selection during the colonization of new habitat is critical to the process of local adaptation, but has rarely been studied. We measured the form, direction, and strength of selection on body size and date of arrival to the breeding grounds over the first three cohorts (2003-2005) of a coho salmon (Oncorhynchus kisutch) population colonizing 33 km of habitat made accessible by modification of Landsburg Diversion Dam, on the Cedar River, Washington, USA. Salmon were sampled as they bypassed the dam, parentage was assigned based on genotypes from 10 microsatellite loci, and standardized selection gradients were calculated using the number of returning adult offspring as the fitness metric. Larger fish in both sexes produced more adult offspring, and the magnitude of the effect increased in subsequent years for males, suggesting that low densities attenuated traditional size-biased intrasexual competition. For both sexes, directional selection favoured early breeders in 2003, but stabilizing selection on breeding date was observed in 2004 and 2005. Adults that arrived, and presumably bred, early produced stream-rearing juvenile offspring that were larger at a common date than offspring from later parents, providing a possible mechanism linking breeding date to offspring viability. Comparison to studies employing similar methodology indicated selection during colonization was strong, particularly with respect to reproductive timing. Finally, female mean reproductive success exceeded that needed for replacement in all years so the population expanded in the first generation, demonstrating that salmon can proficiently exploit vacant habitat.

Preoperative systemic inflammation predicts postoperative infectious complications in patients undergoing curative resection for colorectal cancer.

The presence of systemic inflammation before surgery, as evidenced by the glasgow prognostic score (mGPS), predicts poor long-term survival in colorectal cancer. The aim was to examine the relationship between the preoperative mGPS and the development of postoperative complications in patients undergoing potentially curative resection for colorectal cancer. Patients (n=455) who underwent potentially curative resections between 2003 and 2007 were assessed consecutively, and details were recorded in a database. The majority of patients presented for elective surgery (85%) were over the age of 65 years (70%), were male (58%), were deprived (53%), and had TNM stage I/II disease (61%), had preoperative haemoglobin (56%), white cell count (87%) and mGPS 0 (58%) in the normal range. After surgery, 86 (19%) patients developed a postoperative complication; 70 (81%) of which were infectious complications. On multivariate analysis, peritoneal soiling (P<0.01), elevated preoperative white cell count (P<0.05) and mGPS (P<0.01) were independently associated with increased risk of developing a postoperative infection. In elective patients, only the mGPS (OR=1.75, 95% CI=1.17-2.63, P=0.007) was significantly associated with increased risk of developing a postoperative infection. Preoperative elevated mGPS predicts increased postoperative infectious complications in patients undergoing potentially curative resection for colorectal cancer.

Comparison of tumour-based (Petersen Index) and inflammation-based (Glasgow Prognostic Score) scoring systems in patients undergoing curative resection for colon cancer.

After resection, it is important to identify colon cancer patients, who are at a high risk of recurrence and who may benefit from adjuvant treatment. The Petersen Index (PI), a prognostic model based on pathological criteria is validated in Dukes' B and C disease. Similarly, the modified Glasgow Prognostic Score (mGPS) based on biochemical criteria has also been validated. This study compares both the scores in patients undergoing curative resection of colon cancer. A total of 244 patients underwent elective resection between 1997 and 2005. The PI was constructed from pathological reports; the mGPS was measured pre-operatively. The median follow-up was 67 months (minimum 36 months) during which 109 patients died; 68 of them from cancer. On multivariate analysis of age, Dukes' stage, PI and mGPS, age (hazard ratio, HR, 1.74, P=0.001), Dukes' stage (HR, 3.63, P<0.001), PI (HR, 2.05, P=0.010) and mGPS (HR, 2.34, P<0.001) were associated independently with cancer-specific survival. Three-year cancer-specific survival rates for Dukes' B patients with the low-risk PI were 98, 92 and 82% for the mGPS of 0, 1 and 2, respectively (P<0.05). The high-risk PI population is small, in particular for Dukes' B disease (9%). The mGPS further stratifies those patients classified as low risk by the PI. Combining both the scoring systems could identify patients who have undergone curative surgery but are at high-risk of cancer-related death, therefore guiding management and trial stratification.

Free radical activity and lipid soluble anti-oxidant vitamin status in patients with long-term ileal pouch-anal anastomosis.

OBJECTIVE: Ileal pouch-anal anastomosis (IPAA) is the operation of choice for patients with ulcerative colitis. Free radical activity and the status of lipid soluble antioxidant vitamins have not been previously assessed in patients with IPAA. The aim of the present study was to measure the plasma concentrations of lipophyllic antioxidants and free radical activity in IPAA patients and compare them with normal subjects. METHOD: Forty-eight IPAA patients and 50 healthy controls were studied. A dietary assessment of vitamin E (alpha-tocopherol) and carotene was undertaken and plasma antioxidant status was assessed. Plasma malondialdehyde (MDA) was measured to assess the extent of free radical damage. In IPAA patients, association between the degree of inflammation in the pouch mucosa and the plasma concentration of lipophyllic antioxidants and extent of free radical activity was investigated. RESULTS: The dietary intake of carotene was similar in both groups. Intake of vitamin E was significantly lower in patients than controls (P = 0.01). In the IPAA group plasma concentrations of alpha-carotene, beta-carotene and lycopene were significantly lower (P < 0.001) and alpha-tocopherol:cholesterol ratio significantly higher (P < 0.001). Free radical damage was significantly greater in patients than controls (P < 0.01). There were no significant correlations between the degree of inflammation in the pouch and plasma concentrations of MDA, carotenoids, alpha-tocopherol:cholesterol ratio or intake of vitamins. CONCLUSION: Compared with normal subjects, patients with IPAA have significantly lower plasma concentrations of lipophyllic antioxidants alpha-carotene, beta-carotene and lycopene and higher free radical activity suggesting increased oxidative stress. These differences do not appear to be related to diet and do not correlate with histological severity of pouch inflammation.

Comparison of the prognostic value of selected markers of the systemic inflammatory response in patients with colorectal cancer.

There is increasing evidence that the presence of a systemic inflammatory response plays an important role in predicting survival in patients with colorectal cancer. However, it is not clear what components of the systemic inflammatory response best predict survival. The aim of the present study was to compare the prognostic value of an inflammation-based prognostic score (modified Glasgow Prognostic Score (Mgps) 0=C-reactive protein <10 mg l(-1), 1=C-reactive protein >10 mg l(-1), and 2=C-reactive protein >10 mg l(-1) and albumin<35 g l(-1)) with that of components of the white cell count (neutrophils, lymphocytes, monocytes and platelets using standard thresholds) in patients with colorectal cancer. Two patient groups were studied: 149 patients who underwent potentially curative resection for colorectal cancer and 84 patients who had synchronous unresectable liver metastases. In those patients who underwent potentially curative resection the minimum follow-up was 36 months and 20 patients died of their cancer. On multivariate survival analysis only TNM stage (HR 3.75, 95% CI 1.54-9.17, P=0.004), monocyte count (HR 3.79, 95% CI 1.29-11.12, P=0.015) and mGPS (HR 2.21, 95% CI 1.11-4.41, P=0.024) were independently associated with cancer-specific survival. In patients with synchronous unresectable liver metastases the minimum follow-up was 6 months and 71 patients died of their cancer. On multivariate survival analysis only single liver metastasis >5 cm (HR 1.78, 95% CI 0.99-3.21, P=0.054), extra-hepatic disease (HR 2.09, 95% CI 1.05-4.17, P=0.036), chemotherapy treatment (HR 2.40, 95% CI 1.82-3.17, P<0.001) and mGPS (HR 1.44, 95% CI 1.01-2.04, P=0.043) were independently associated with cancer-specific survival. In summary, markers of the systemic inflammatory response are associated with poor outcome in patients with either primary operable or synchronous unresectable colorectal cancer. An acute-phase protein-based prognostic score, the mGPS, appears to be a superior predictor of survival compared with the cellular components of the systemic inflammatory response.

Vitamin B12 deficiency following restorative proctocolectomy.

OBJECTIVE: Restorative proctocolectomy (RP) involves terminal ileal resection and formation of a small bowel reservoir that predisposes to bacterial overgrowth. It was anticipated that these patients would be at risk of vitamin B12 deficiency. METHOD: Vitamin B12 levels were measured sequentially in 171 patients who underwent RP. Prospective results were obtained from all 20 patients undergoing pouch formation after the commencement of the study. Further results were obtained retrospectively from case notes and computerized laboratory records of the 151 patients who underwent RP prior to the commencement of the study and these were correlated with the results of follow-up samples taken prospectively from the same patients after the commencement of the study. The median age of the patients was 40 years (range: 13-67) and the median duration of follow up was 5.4 years (range: 1-12). Patients with an abnormally low serum B12 level underwent both a Schilling and a hydrogen breath test. Eight of these patients were then treated with oral vitamin B12. RESULTS: Abnormally low serum B12 levels were found in 25% of patients. Forty per cent of our patient group had three or more sequential B12 measurements and of these, 66% showed steadily declining B12 levels. Ninety-four per cent of patients with low B12 had a normal Schilling test and were negative for bacterial overgrowth. CONCLUSION: Subnormal vitamin B12 levels develop in almost one-quarter of patients after pouch surgery. The exact mechanism for B12 deficiency in these patients is uncertain. In the majority of patients undergoing RP, vitamin B12 levels fall on sequential measurement. Serum B12 levels should be measured during follow up and pouch patients with subnormal B12 levels, should see them successfully restored to a normal value after treatment with oral B12 replacement therapy.

Long-term cancer risk of the anorectal cuff following restorative proctocolectomy assessed by p53 expression and cuff dysplasia.

OBJECTIVE: Restorative proctocolectomy (RP) for ulcerative colitis (UC) retains a 'cuff' of columnar rectal epithelium that has unknown risk of malignant change. Markers of malignant potential in UC include aberrant p53 expression and dysplasia. We undertook a prospective study comprising serial surveillance biopsy and assessed the occurrence of aberrant p53 expression, epithelial dysplasia and carcinoma in the retained anorectal cuff following stapled RP. METHOD: A total of 110 patients who underwent stapled RP for UC between 1988 and 1998 were followed up by cuff surveillance biopsies under general anaesthesia. Histological samples were analysed by a specialist colorectal pathologist for the presence of rectal mucosa, dysplasia and carcinoma. Immunohistochemistry for p53 expression was performed for each most recent cuff biopsy. Median follow-up was 56 months (12-145) and median time since diagnosis of UC was 8.8 years (2-32). RESULTS: Rectal mucosa was obtained from the cuff in 65% of biopsies. No overt carcinomas developed during the follow-up period and there was no dysplasia or carcinoma in any cuff biopsy. The p53 overexpression was identified in 38 specimens (50.6%), but was also identified in controls (3/3 colitis, 3/3 ileal pouch and 6/6 stapled haemorrhoidectomy donuts). CONCLUSION: The lack of carcinoma and dysplasia in the columnar cuff epithelium specimens is reassuring. The lack of stabilized p53 and absence of a relationship between p53 stabilization and dysplasia up to 12 years after pouch formation suggests neoplastic transformation is a rare event. Furthermore, p53 expression was not useful in surveillance of cuff biopsies from patients who have undergone RP for UC and the search should continue for alternative predysplastic markers. These data suggest that in patients who do not have high-grade dysplasia or colorectal cancer at the time of RP, cuff surveillance in the first decade after pouch formation is unnecessary. However, we consider regular cuff surveillance biopsies should continue for patients with high-grade dysplasia, whether or not there was a carcinoma in the original colectomy specimen.

Preoperative but not postoperative systemic inflammatory response correlates with survival in colorectal cancer.

BACKGROUND: The aim of the present study was to evaluate the relationship between the preoperative and postoperative systemic inflammatory response and survival in patients undergoing potentially curative resection for colorectal cancer. METHODS: One hundred and eighty patients with colorectal cancer were studied. Circulating concentrations of C-reactive protein (CRP) were measured before surgery and in the immediate postoperative period. RESULTS: The peak in CRP concentration occurred on day 2 (P < 0.001). During the course of the study 59 patients died, 30 from cancer and 29 from intercurrent disease. Day 2 CRP concentrations were dichotomized. In univariable analysis, advanced tumour node metastasis stage (P = 0.002), a raised preoperative CRP level (P < 0.001) and the presence of hypoalbuminaemia (P = 0.043) were associated with poorer cancer-specific survival. CONCLUSION: Preoperative but not postoperative CRP concentrations are associated with poor tumour-specific survival in patients undergoing potentially curative resection for colorectal cancer.

The presence of a systemic inflammatory response predicts poorer survival in patients receiving adjuvant 5-FU chemotherapy following potentially curative resection for colorectal cancer.

There is increasing evidence that the presence of a systemic inflammatory response plays an important role in survival following curative resection for colorectal cancer. The present study evaluated the relationship between C-reactive protein concentrations and survival in a cohort of patients receiving adjuvant 5-fluorouracil (5-FU) chemotherapy following potentially curative resection for colorectal cancer. In all, 222 patients undergoing potentially curative resection for colorectal cancer were studied. Of these, 50 patients received adjuvant 5-FU-based chemotherapy. Circulating concentrations of C-reactive protein were measured prior to surgery. The minimum follow-up was 15 months; the median follow-up of the survivors was 38 months. During this period 61 patients died, 32 patients of their cancer and 29 of intercurrent disease. In those patients who did not receive adjuvant chemotherapy, age (P < 0.001), Dukes stage (P < 0.05) and an elevated C-reactive protein (P < 0.01) were significantly associated with survival. In those patients who did receive adjuvant chemotherapy, an elevated C-reactive protein concentration (P < 0.01) was significantly associated with survival. The presence of a systemic inflammatory response is an independent predictor of poor outcome in patients receiving adjuvant 5-FU-based chemotherapy following potentially curative resection for colorectal cancer.

Tactile VR for hand-eye coordination in simulated PTCA.

Percutaneous transluminal coronary angioplasty (PTCA) is a minimally invasive image-guided technique for treatment of coronary diseases. PTCA procedure requires physicians to have good skills of hand-eye coordination in performing the operation. Training of PTCA thus very much emphasizes skill building for hand-eye coordination. We have been developing virtual reality (VR) technology for medical simulation. In this paper, we will address the issue of VR-based simulation for the enhancement of hand-eye coordination for PTCA operation. Starting from the characterization of PTCA procedure, we examine what roles VR can play in training of PTCA physicians. We then describe a computerized PTCA training system we have developed which is composed of a tactile interface and a visual interface. The system is designed in such a way that real PTCA devices (including catheters and guide-wires) can be used to mimic the requirements of the CathLab. The backend computational engine supporting the real-time and realistic PTCA simulation is also presented.

Prospective study of the effect of rectopexy on colonic motility in patients with rectal prolapse.

BACKGROUND: Patients with rectal prolapse have abnormal hindgut motility. This study examined the effect of rectal prolapse surgery on colonic motility. METHODS: Twelve patients undergoing sutured rectopexy were studied before and 6 months after surgery by colonic manometry, colonic transit study and clinical assessment of bowel function. The results were compared with those from seven control subjects. RESULTS: Before surgery colonic pressure was greater in patients than controls (P < 0.050). Controls responded to a meal stimulus by increasing colonic pressure; this increase was absent in patients. After rectopexy, colonic pressure reduced towards control values and patients' colonic pressure response to a meal returned. High-amplitude propagated contractions (HAPCs) were seen in all controls but in only three patients before and two patients after surgery. Three patients had prolonged colonic transit before and eight after rectopexy. CONCLUSION: Patients with rectal prolapse have abnormal colonic motility associated with reduced HAPC activity. Rectopexy reduces colonic pressure but fails to restore HAPCs, reduce constipation or improve colonic transit. These observations help explain the pathophysiology of constipation associated with rectal prolapse.