Occult vs. overt upper gastrointestinal bleeding - inverse relationship and the use of mucosal damaging and protective drugs.

BACKGROUND: While efforts have focused on the prevention of overt upper gastrointestinal bleeding (UGIB), little is known about occult GIB, which might also originate from sites not protected by acid inhibition. AIM: To measure the incidence and outcomes of both overt and occult GIB over a 6-year period (2007-2012), and to assess the use of NSAIDs, anti-thrombotic therapy (ATT), proton pump inhibitors (PPIs), and iron therapy. METHODS: A sample of 300 patients (100 from each of three index years) with occult GIB was randomly selected and their outcomes were compared with those of patients with overt UGIB (N = 869). RESULTS: The incidence of overt UGIB fell from 140.1 per 100 000 population per annum in 2007 to 106.8 in 2010 and to 88.0 in 2012 (P < 0.001); while that of occult GIB rose from 243.1 to 263.6 and to 292.8 (P < 0.001) over the same period. The incidence of occult GIB was highly correlated with the number of prescriptions of PPIs per 1000 population (χ(2) trend = 11.80; P < 0.001). In the overt UGIB group, the median haemoglobin level on presentation was lowest (10.3) in patients taking NSAIDs/ATT plus PPIs compared with those taking PPIs alone (11.5), NSAIDs/ATT alone (10.4) or none of these drugs (12.7 g/dL) (P < 0.001, Kruskal-Wallis). CONCLUSIONS: An inverse trend seems to have formed in the incidence of overt vs. occult gastrointestinal bleeding in association with the wider use of PPIs and NSAIDs. An alternative approach to acid inhibition is needed to prevent gastrointestinal bleeding.

Clinical trial: the incidence and early mortality after peptic ulcer perforation, and the use of low-dose aspirin and nonsteroidal anti-inflammatory drugs.

BACKGROUND: It is not clear whether the incidence or early mortality related to peptic ulcer perforation has changed. AIM: To evaluate the incidence and mortality related to peptic ulcer perforation while considering the intake of low-dose aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs). METHODS: We recorded the numbers and details of all patients presenting in our region of Scotland with perforation between 1997 and 2006 including demography, drug usage and 30-day mortality. RESULTS: In subjects aged >65 years, the annual incidence of perforation was 32.7 per 10(5) of the age-specific population, of whom 10.7 per 10(5) were taking low-dose aspirin and 12.0 taking NSAIDs. These were all significantly higher (P < 0.001) than the corresponding incidence in subjects aged < or =65 years (6.6 per 10(5) overall, 1.1 taking aspirin and 2.5 taking NSAIDs). There was an increasing trend with time in the number of patients taking NSAIDs (chi(2) = 4.57, P = 0.03). Using univariate analysis, 30-day mortality was associated with aspirin [odds ratio, 2.32 (95% C.I., 1.20-4.47), P = 0.01] but not with NSAIDs. The strongest predictors of mortality were increasing age and comorbidity. CONCLUSIONS: Perforation remains common in elderly patients including users of NSAIDs and aspirin. Early mortality is also noted in association with increasing age and comorbidity, but not independently with drug intake.

The relationship between quality of life (EORTC QLQ-C30) and survival in patients with gastro-oesophageal cancer.

It remains unclear whether any aspect of quality of life has a role in predicting survival in an unselected cohort of patients with gastro-oesophageal cancer. Therefore the aim of the present study was to examine the relationship between quality of life (EORTC QLQ-C30), clinico-pathological characteristics and survival in patients with gastro-oesophageal cancer. Patients presenting with gastric or oesophageal cancer, staged using the UICC tumour node metastasis (TNM) classification and who received either potentially curative surgery or palliative treatment between November 1997 and December 2002 (n=152) participated in a quality of life study, using the EORTC QLQ-C30 core questionnaire. On univariate analysis, age (P<0.01), tumour length (P<0.0001), TNM stage (P<0.0001), weight loss (P<0.0001), dysphagia score (P<0.001), performance status (P<0.1) and treatment (P<0.0001) were significantly associated with cancer-specific survival. EORTC QLQ-C30, physical functioning (P<0.0001), role functioning (P<0.001), cognitive functioning (P<0.01), social functioning (P<0.0001), global quality of life (P<0.0001), fatigue (P<0.0001), nausea/vomiting (P<0.01), pain (P<0.001), dyspnoea (P<0.0001), appetite loss (P<0.0001) and constipation (P<0.05) were also significantly associated with cancer-specific survival. On multivariate survival analysis, tumour stage (P<0.0001), treatment (P<0.001) and appetite loss (P<0.0001) were significant independent predictors of cancer-specific survival. The present study highlights the importance of quality of life (EORTC QLQ-C30) measures, in particular appetite loss, as a prognostic factor in these patients.

Upper gastrointestinal bleeding and the changing use of COX-2 non-steroidal anti-inflammatory drugs and low-dose aspirin.

BACKGROUND: Rofecoxib was withdrawn in 2004. AIM: To assess the incidence of upper gastrointestinal bleeding in the context of the changing use of cyclo-oxygenase-2 non-steroidal anti-inflammatory drugs and low-dose aspirin. METHODS: We examined the characteristics of patients developing upper gastrointestinal bleeding in a defined population in south-west Scotland. The primary comparisons were made between two calendar years, preceding and following the withdrawal of rofecoxib. RESULTS: The overall incidence of upper gastrointestinal bleeding rose from 98.7 in 2002 to 143 per 10(5) of the population per annum in 2005 (chi(2) = 21.1; P < 0.001). The rise in the incidence was associated with using low-dose aspirin, from 26.6 to 38.4 per 10(5) (chi(2) = 5.4; P = 0.02), other antithrombotic drugs, from 12.1 to 30.2 per 10(5) (chi(2) = 19.6; P < 0.001), and excess alcohol, from 23.5 to 36.4 per 10(5) (chi(2) = 7.1; P = 0.008), but insignificantly with using non-steroidal anti-inflammatory drugs, from 13.3 to 16.1 per 10(5) (chi(2) = 0.64; P = 0.4). After adjustment for the concomitant use of these drugs, there was no significant trend in the incidence of upper gastrointestinal bleeding associated with non-steroidal anti-inflammatory drugs over the period of 1996-2005. CONCLUSION: The rise in the incidence of upper gastrointestinal bleeding was weakly related to the change in use of non-steroidal anti-inflammatory drugs. Instead, it probably reflected the increasing use of low-dose aspirin, other antithrombotic drugs and alcohol.

Comparison of P-POSSUM and O-POSSUM in predicting mortality after oesophagogastric resections.

BACKGROUND: P-POSSUM (Physiological and Operative Severity Score for the enumeration of Mortality and morbidity) predicts mortality and morbidity in general surgical patients providing an adjunct to surgical audit. O-POSSUM was designed specifically to predict mortality and morbidity in patients undergoing oesophagogastric surgery. AIM: To compare P-POSSUM and O-POSSUM in predicting surgical mortality in patients undergoing elective oesophagogastric cancer resections. METHODS: Elective oesophagogastric cancer resections in a district general hospital from 1990 to 2002 were scored by P-POSSUM and O-POSSUM methods. Observed mortality rates were compared to predicted mortality rates in six risk groups for each model using the Hosmer-Lemeshow goodness-of-fit test. The power to discriminate between patients who died and those who survived was assessed using the area under the receiver-operator characteristic (ROC) curve. RESULTS: 313 patients underwent oesophagogastric resections. 32 died within 30 days (10.2%). P-POSSUM predicted 36 deaths (chi2 = 15.19, df = 6, p = 0.019, Hosmer-Lemeshow goodness-of-fit test), giving a standardised mortality ratio (SMR) of 0.89. O-POSSUM predicted 49 deaths (chi2 = 16.51, df = 6, p = 0.011), giving an SMR of 0.65. The area under the ROC curve was 0.68 (95% confidence interval 0.59 to 0.76) for P-POSSUM and 0.61 (95% confidence interval 0.50 to 0.72) for O-POSSUM. CONCLUSION: Neither model accurately predicted the risk of postoperative death. P-POSSUM provided a better fit to observed results than O-POSSUM, which overpredicted total mortality. P-POSSUM also had superior discriminatory power.

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.

Evaluation of the relationship between the systemic inflammatory response and cancer-specific survival in patients with primary operable breast cancer.

The relationship between the systemic inflammatory response (as evidenced by elevated C-reactive protein and lowered albumin concentrations), clinico-pathologic status and relapse-free, cancer-specific and overall survival was examined in patients with invasive primary operable breast cancer (n=300). The median follow-up of the survivors was 46 months. During this period, 37 patients relapsed and 25 died of their cancer. On multivariate analysis, only tumour size (P<0.05), albumin (P<0.01) and systemic treatment (P<0.0001) were significant independent predictors of relapse-free, cancer-specific and overall survival. Lower serum albumin concentrations (

Selective continuous vascular occlusion and perioperative fluid restriction in partial hepatectomy. Outcomes in 101 consecutive patients.

BACKGROUND: This study documents patient outcomes with one department's approach to performing partial hepatectomy. METHODS: 101 consecutive patients underwent: preoperative dehydration; intraoperative CVP <5 cm H(2)O and selective continuous vascular occlusion. OUTCOME VARIABLES: pathology; type of hepatic resection; intraoperative blood loss and transfusion rate; 30 day morbidity and mortality; disease free and long term survival. Perioperative liver function was assessed by serial blood sampling. RESULTS: Of 101 resections: 90% malignant disease; 59% major resections and 35% synchronous procedures. Median estimated blood loss was 400 mL (mean 512 mL, range 50-3000 mL) with postoperative transfusions in 4%. Thirty day morbidity was 20% with no deaths. Median time to local recurrence after colorectal liver metastases resection was 17.1 months with 3 year survival of 51%. Distinct perioperative changes in hepatic function were seen. CONCLUSION: Selective continuous vascular occlusion and perioperative fluid restriction result in minimal blood loss, low morbidity and zero mortality in patients undergoing partial hepatectomy.

Clinical outcome in upper gastrointestinal bleeding complicating low-dose aspirin and antithrombotic drugs.

BACKGROUND: The current risk stratification systems in upper gastrointestinal bleeding do not correct for the intake of low-dose aspirin and other antithrombotic drugs. AIM: To test the Blatchford scores in evaluating the clinical outcome in bleeders using these drugs. METHODS: We calculated the Blatchford scores in 510 bleeders, including 123 on low-dose aspirin, 44 on other antithrombotic drugs, and 68 on non-steroidal anti-inflammatory drugs. RESULTS: The median clinical scores distributed according to aetiological risk factors were as follows: no risk factors, 5; non-steroidal anti-inflammatory drugs, 8; aspirin, 7; other antithrombotics, 6; excess alcohol, 4; multiple risk factors, 7; (P = 0.003, Kruskal-Wallis test). Scores correlated positively with the duration of admission in the entire group (r(s) = 0.285; P < 0.001) and in those taking aspirin and antithrombotics (r(s) = 0.211; P = 0.029). The median scores in patients requiring the blood transfusion were 10 in the entire group and 11 in users of aspirin or antithrombotics, compared with 3 and 4, respectively, in those not transfused (P < 0.001). CONCLUSIONS: The Blatchford scores are significantly elevated in users of non-steroidal anti-inflammatory drugs, low-dose aspirin, and other antithrombotic drugs. They correlate positively with the duration of admission and the need for blood transfusion.

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.

Upper gastrointestinal mucosal abnormalities and blood loss complicating low-dose aspirin and antithrombotic therapy.

BACKGROUND: Little is known about the site and nature of bleeding lesions related to low-dose aspirin and other antithrombotic agents. AIM: To describe the mucosal abnormalities in patients presenting with upper gastrointestinal bleeding while being treated with these drugs. METHODS: The endoscopic findings and clinical details were analysed in all patients presenting with haematemesis and/or melaena at a single centre during three calendar years. Associations between endoscopic findings and risk factors, including the intake of non-steroidal anti-inflammatory drugs, low-dose aspirin (75 mg daily) and other antithrombotic drugs including warfarin, clopidogrel, and dipyridamole, were assessed by logistic regression analysis. RESULTS: In 674 upper gastrointestinal bleeders, we found that the odds ratio for the presence of erosive oesophagitis in aspirin users was 2 (95% CI, 1-3; P = 0.03) and 3 (2-5; P = 0.0003) in patients taking other antithrombotic agents. In 41 patients with oesophagitis and taking these drugs, 36 (88%) had cardiovascular disease and only 4 (10%) had peptic symptoms. CONCLUSIONS: Erosive oesophagitis is common in patients with upper gastrointestinal bleeding taking low-dose aspirin or antithrombotic agents, and could potentially be confused with the coexisting heart disease.

IHC for Her2 with CBE356 antibody is a more accurate predictor of Her2 gene amplification by FISH than HercepTest in breast carcinoma.

BACKGROUND: Her2 (c-erbB-2/neu) overexpression in breast carcinoma predicts response to the anti-Her2 monoclonal antibody, trastuzumab, and is associated with a poor prognosis. When considering patients for trastuzumab treatment, Her2 protein expression is measured by imunohistochemistry (IHC) and, where staining is equivocal, by fluorescence in situ hybridisation (FISH) detection of Her2 gene amplification. AIMS: To compare IHC using CBE356 with IHC using the Food and Drug Administration approved HercepTesttrade mark. METHODS: CBE356 and HercepTest were analysed using 167 FISH characterised breast carcinomas. Immunohistochemical expression of Her2 was measured semiquantitatively. Sensitivity, specificity, predictive values, and overall accuracy were calculated for both IHC methods using gene amplification by FISH as the end point, and IHC and FISH assays were tested in Kaplan-Meier survival analysis. RESULTS: The accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of CBE356 positive (2+ and 3+) cases were 94%, 89%, 95%, 84%, and 97%, respectively, and of HercepTest positive (2+ and 3+) cases were 91%, 66%, 98%, 92%, and 91%, respectively. A positive result with CBE356, HercepTest, or FISH was associated with significantly decreased overall survival (log rank p = 0.005, p = 0.0017, and p = 0.0005, respectively). CONCLUSIONS: Positive IHC staining for Her2 using CBE356 is 3% more accurate and 23% more sensitive at predicting Her2 gene amplification by FISH than positive staining with HercepTest. Negative IHC using CBE356 antibody is 6% more likely to represent a truly negative result than negative staining with HercepTest. Overall, CBE356 was a more accurate predictor of Her2 gene amplification by FISH than HercepTest.

Upper gastrointestinal haemorrhage associated with low-dose aspirin and anti-thrombotic drugs - a 6-year analysis and comparison with non-steroidal anti-inflammatory drugs.

BACKGROUND: Low-dose aspirin and other anti-thrombotic therapy has been increasingly used for vascular protection. AIM: To assess the possibility that the incidence of upper gastrointestinal blood loss has changed in subjects using these agents in comparison with non-steroidal anti-inflammatory drugs. METHODS: We studied the characteristics of all patients with acute upper gastrointestinal haemorrhage and attending a single hospital at 3 points over a 6-year period: 1996 (n = 204), 1999 (n = 224) and in 2002 (n = 252). RESULTS: The incidence of haemorrhage in subjects taking low-dose aspirin rose from 15 per 100 000 of the population per annum in 1996, to 18 in 1999 and 27 in 2002 (P = 0.004). The respective incidence in subjects taking other anti-thrombotic drugs was 4, 8, and 12 (P < 0.001). No significant change was detected in non-steroidal anti-inflammatory drug users. However, acute myocardial infarction mortality was 216 per 100 000 in 1996, 221 in 1999 and fell to 169 in 2002 (P < 0.001). CONCLUSIONS: The incidence of upper gastrointestinal haemorrhage in users of low-dose aspirin and other anti-thrombotic drugs has been steadily rising. This has been paralleled by a fall in cardiac mortality.

A prospective longitudinal study of performance status, an inflammation-based score (GPS) and survival in patients with inoperable non-small-cell lung cancer.

The value of an inflammation-based prognostic score (Glasgow Prognostic score, GPS) was compared with performance status (ECOG-ps) in a longitudinal study of patients (n=101) with inoperable non-small-cell lung cancer (NSCLC). At diagnosis, stratified for treatment, only the GPS (HR 2.32, 95% CI 1.52-3.54, P<0.001) was a significant predictor of survival. In contrast, neither the GPS nor ECOG-ps measured at 3-6 months follow-up were significant predictors of residual survival. This study confirms the prognostic value of the GPS, at diagnosis, in patients with inoperable NSCLC. However, the role of the GPS and ECOG-ps during follow-up has not been established.

Gastric epithelial anti-microbial peptides--histological correlation and influence of anatomical site and peptic ulcer disease.

BACKGROUND AND AIMS: Natural anti-microbial peptides are increasingly recognised for their protective effects in mucosal surfaces. We, therefore, aimed at investigating their expression in the human stomach in a range of peptic conditions. METHODS: We assessed the expression of epithelial secretory leukocyte protease inhibitor, human beta-defensins (HBD1 and HBD2), and alpha-defensin (HD5) in gastric biopsies taken from 52 patients, median age of 55 years. Expression of peptide mRNA was determined using real-time quantitative polymerase chain reaction. The activity of gastritis was graded on a 0-3 scale. RESULTS: The antrum had a median secretory leukocyte protease inhibitor of 0.93 and HBD1 of 0.42, compared with 0.13 (P = 0.001) and 0.08 units (P = 0.002) respectively in the gastric body. The antral histological scores correlated positively with HBD2 expression (r = 0.69; P< 0.001) and negatively with HBD1 (r = -0.47; P = 0.006) particularly in the absence of aspirin. Patients with Helicobacter pylori gastritis, gastric or duodenal ulcers had lower expression of HBD1 and greater expression of HBD2 than in controls. The intake of aspirin by patients infected with H. pylori was associated with marked rise in the expression of HD5 and less expression of secretory leukocyte protease inhibitor. CONCLUSIONS: Gastric epithelial anti-microbial peptides are influenced by anatomical site, grade of gastritis, peptic ulceration, and can be modulated by aspirin.

The relationship between hypoalbuminaemia, tumour volume and the systemic inflammatory response in patients with colorectal liver metastases.

The relationship between hypoalbuminaemia, tumour volume and C-reactive protein was examined in patients with colorectal liver metastases (n=57). On multiple regression analysis, albumin concentrations were independently associated with C-reactive protein (r=0.56, P<0.001) but not percentage hepatic replacement (P=0.34). These results show that hypoalbuminaemia is associated with the presence of a systemic inflammatory response rather than tumour volume in patients with colorectal liver metastases.

Comparison of an inflammation-based prognostic score (GPS) with performance status (ECOG) in patients receiving platinum-based chemotherapy for inoperable non-small-cell lung cancer.

The value of an inflammation-based prognostic score (GPS) was compared with performance status (ECOG) in patients (n=109) receiving platinum-based chemotherapy for inoperable non-small-cell lung cancer. On multivariate analysis with ECOG, white cell count and the GPS entered as covariates, only the GPS was a significant independent predictor of survival (HR 1.88, 95% CI 1.25-2.84, P=0.002).

Oesophagitis and bile reflux gastritis--clinical and histological assessments.

BACKGROUND AND AIMS: Little is known concerning the relationship between oesophagitis and bile reflux (chemical) gastritis despite the numerous studies on gastritis related to Helicobacter pylori. Given the importance of bile in the pathogenesis of both gastric and oesophageal disorders, we aimed at assessing the chemical gastritis score in patients with or without oesophagitis. METHODS: Chemical/bile reflux gastritis score and bile reflux index were assessed in gastric biopsies taken from patients with oesophagitis and gastric surgery (group 1, n=9), gastric surgery without oesophagitis (group 2, n= 11), and oesophagitis without gastric surgery (group 3, n= 10). Endoscopic oesophageal damage was also graded on a 0-5 scale. RESULTS: Group 1 had a median (interquartile range) chemical score of 6 (4-9) compared with 8 (6-10) in group 2, and 1 (0-2) in group 3 (p=0.001; Kruskal-Wallis test for multiple group comparisons). Both the reflux gastritis score and bile reflux index were lowest in patients with intact stomachs. However, the oesophageal scores were 2 (1-2) in group 1 compared with 3 (2-5) in group 3 (p=0.01). CONCLUSION: Patients with post-surgical stomachs have similar chemical and related scores regardless of the presence or absence of oesophagitis. Despite the higher chemical gastritis scores, patients with gastric surgery, exposed mainly to bile reflux, have milder oesophagitis than those with intact stomachs, exposed to both gastric acid and bile.

Evaluation of cumulative prognostic scores based on the systemic inflammatory response in patients with inoperable non-small-cell lung cancer.

A score based on the combination of the systemic inflammatory response and albumin hazards ratio (HR) 1.70, 95% CI 1.23 - 2.35, P=0.001) was comparable in prognostic value to that based on stage and performance status (HR 1.48, 95% CI 1.12 - 1.95, P=0.006) in patients with inoperable non-small-cell lung cancer. The former is simple to measure and well standardised.