Geoffrey M. Forbes

A phase 2 study of allogeneic mesenchymal stromal cells for luminal crohn's disease refractory to biologic therapy

BACKGROUND & AIMS Transplantation of peripheral blood stem cells has been successful therapy for small numbers of patients with Crohns disease (CD), but requires prior myeloconditioning. Mesenchymal stromal cells (MSCs) escape immune recognition, so myeloconditioning is not required before their administration. We investigated the efficacy of allogeneic MSCs in patients with luminal CD. METHODS Our phase 2, open-label, multicenter study included 16 patients (21-55 y old; 6 men) with infliximab- or adalimumab-refractory, endoscopically confirmed, active luminal CD (CD activity index [CDAI], >250). Subjects were given intravenous infusions of allogeneic MSCs (2 × 10(6) cells/kg body weight) weekly for 4 weeks. The primary end point was clinical response (decrease in CDAI >100 points) 42 days after the first MSC administration; secondary end points were clinical remission (CDAI, <150), endoscopic improvement (a CD endoscopic index of severity [CDEIS] value, <3 or a decrease by >5), quality of life, level of C-reactive protein, and safety. RESULTS Among the 15 patients who completed the study, the mean CDAI score was reduced from 370 (median, 327; range, 256-603) to 203 (median, 129) at day 42 (P < .0001). The mean CDAI scores decreased after each MSC infusion (370 before administration, 269 on day 7, 240 on day 14, 209 on day 21, 182 on day 28, and 203 on day 42). Twelve patients had a clinical response (80%; 95% confidence interval, 72%-88%; mean reduction in CDAI, 211; range 102-367), 8 had clinical remission (53%; range, 43%-64%; mean CDAI at day 42, 94; range, 44-130). Seven patients had endoscopic improvement (47%), for whom the mean CDEIS scores decreased from 21.5 (range, 3.3-33) to 11.0 (range, 0.3-18.5). One patient had a serious adverse event (2 dysplasia-associated lesions), but this probably was not caused by MSCs. CONCLUSIONS In a phase 2 study, administration of allogeneic MSCs reduced CDAI and CDEIS scores in patients with luminal CD refractory to biologic therapy. ClinicalTrials.gov number, NCT01090817.

Long-term follow-up of gastric histology after Helicobacter pylori eradication.

Helicobacter pylori causes chronic active gastritis and is thought to be associated with the development of gastric atrophy, intestinal metaplasia and carcinoma. As the effect of H. pylori eradication on this process is poorly understood, we sought to determine the long‐term effects of H. pylori eradication on gastric histology. Fifty‐four patients with duodenal ulceration associated with H. pylori infection received H. pylori eradication therapy in 1985/86 and either remained infected (n= 22) or had the infection eradicated (n= 32); patients were followed up by endoscopy with gastric antral biopsy for 7.1 years (mean). Histopathological analysis of gastric antral mucosa from patients rendered H. pylori‐negative revealed a marked decrease in both inflammatory cells within the lamina propria and intraepithelial neutrophils and an increase in epithelial mucinogenesis. Gland atrophy remained unchanged in both H. pylori‐positive and ‐negative patients. When examined for the presence and severity of intestinal metaplasia, there was neither a difference between the two patient groups nor a change with time. These data demonstrate that significant long‐term improvements in gastric histology accompany H. pylori eradication when compared with histology in patients with persistent infection. Whether this confers a protective effect by reducing the risk of gastric carcinoma remains unknown.

Extracolonic findings at virtual colonoscopy: implications for screening programs.

OBJECTIVE:Virtual colonoscopy (VC) is an evolving technology proposed as a possible screening tool for colorectal cancer. In contrast to conventional colonoscopy, VC may detect extracolonic abdominal pathology. This may lead to unnecessary investigation of benign lesions, or may benefit the patient by identifying serious pathology at an early stage. The aim of this study was to assess the prevalence and characteristics of extracolonic pathology found in patients undergoing VC.METHODS:A total of 100 patients aged ≥55 yr, referred for colonoscopy for bowel symptoms or family history of bowel cancer, underwent VC. Axial views of the abdomen were reviewed prospectively by a single radiologist for extracolonic pathology. Patients with extracolonic abnormalities were referred to their local doctor or to a specialist clinic when appropriate. Case records were reviewed and treating doctors contacted to document subsequent investigations and procedures generated.RESULTS:Fifteen patients (15%) had extracolonic abnormalities detected. In four patients, the pathology had been diagnosed previously (umbilical hernia, gallbladder and renal calculi, 3.5-cm aortic aneurysm, ovarian cyst). Eleven patients had new abnormalities detected: ovarian cysts (three), liver cysts (two), uterine fibroids (two), gallstones (one), splenic calcifications (one), aortic aneurysm (one), and renal tumor (one). Two patients with ovarian cysts underwent surgery, and histology showed benign cysts.CONCLUSIONS:Extracolonic abnormalities are common at VC. Most are benign, but may lead to investigative and procedural costs. These data should be carefully evaluated in feasibility and cost-effectiveness studies on colorectal cancer screening using VC.

Community-Based Screening by Colonoscopy or Computed Tomographic Colonography in Asymptomatic Average-Risk Subjects

OBJECTIVES:Visualizing the entire colorectum in screening is an advantage of colonoscopy, and also computed tomographic (CT) colonography, another potentially suitable screening test. Our objective was to compare screening CT colonography and colonoscopy in an asymptomatic average-risk population, and to determine whether providing a choice of tests increased participation.METHODS:One thousand and four hundred subjects from the general community, randomly selected from the parliamentary electoral roll, were allocated one of three screening groups: colonoscopy, CT colonography, or a choice of these tests, and were sent an institutional letter of invitation. Those with symptoms, colorectal cancer in first-degree relatives, or colonoscopy within 5 yr were ineligible. Outcome measures were participation, acceptability of screening, and yield for advanced colorectal neoplasia in participants.RESULTS:Of the subjects, 24.9% were ineligible; the overall participation rate was 18.2% (184/1,009). Participation in each screening group was not different. Both tests were accompanied by the same high levels of acceptability; most participants found colonoscopy (87%) and CT colonography (67%, p < 0.001) less unpleasant than expected. About 29% (26/89) CT colonography subjects had a positive screening test. The yield of advanced colorectal neoplasia was 8.7% (95% CI 5–14%), with no difference in yield between tests.CONCLUSION:Colorectal neoplasia screening by colonoscopy or CT colonography was associated with modest participation, high levels of acceptability, and similar yield for advanced colorectal neoplasia. Providing a choice of test did not increase participation.

Computed Tomographic Colonography: Prevalence, Nature, and Clinical Significance of Extracolonic Findings in a Community Screening Program

OBJECTIVE:Colorectal neoplasia screening by computed tomographic colonography (CTC) may lead to the detection of incidental extracolonic findings. We report the prevalence and clinical significance of extracolonic pathology found within a community-based CTC screening program and the cost of clinical follow-up and further investigation of these findings.METHODS:A total of 432 asymptomatic subjects at an average risk of colorectal neoplasia, aged 50–69, had screening by CTC using a low radiation dose protocol. Axial images were prospectively examined for extracolonic lesions and those considered clinically relevant were followed up. All clinic visits and further investigations were tallied to calculate the incremental cost to the screening CTC.RESULTS:A total of 146 extracolonic lesions were detected in 118 (27.3%) subjects. Thirty-two (7.4%) subjects had clinically relevant extracolonic abnormalities and nine (2.1%) subjects may derive a clinical benefit from the detection of these lesions. A single CTC costed

Predictive and protective factors associated with upper gastrointestinal bleeding after percutaneous coronary intervention: a case-control study.

171.12, and following up extracolonic findings resulted in an additional

Nitrous oxide for colonoscopy: a randomized controlled study

24.37 (14.2%) per CTC. Limiting reporting to the aorta and kidneys would have reduced the number of subjects requiring follow-up to 14 (3.2%), and decreased the cost increment to 4.7% without detriment to clinical outcome.CONCLUSIONS:Extracolonic findings of screening CTC are common, but infrequent of clinical importance. The additional burden of following up these findings was modest and could have been further reduced if clear clinical and radiological criteria and pathways for their further investigation were defined.

Proteome analysis of Helicobacter pylori: major proteins of type strain NCTC 11637.

BACKGROUND:Hemorrhagic complications of acute coronary syndromes and percutaneous coronary intervention (PCI) are associated with increased mortality. Upper gastrointestinal (UGI) bleeding after PCI is a potential target for preventative strategies.OBJECTIVE:To evaluate the risk factors for UGI bleeding in a large cohort of contemporary PCI patients and assess the outcomes of medical and endoscopic management.METHOD:A case-control study evaluating UGI bleeding in the 30 days following PCI for stable angina and acute coronary syndromes, at one institution between 1998 and 2005. Cases were identified and outcomes assessed using linkage analysis of data from institutional PCI and endoscopy databases, statewide vital statistics and hospital discharge registries, and a detailed review of medical notes for each case and three matched controls. Analysis of the case and control groups for risk and protective factors was performed using the χ2 test with Fishers exact P value and logistic regression.RESULTS:The incidence of UGI bleeding following PCI was 1.2% (70 of 5,673 patients). The etiologies of these bleeds were diverse. Risk factors for UGI bleeding were primary PCI (OR 27.80, 95% CI 6.28–123.05, P < 0.001), cardiac arrest (OR 6.17, 95% CI 1.82–20.84, P = 0.003), inotropic requirement (OR 5.85, 95% CI 1.98–17.27, P = 0.001), thienopyridine use before PCI (OR 2.40, 95% CI 1.04–5.53, P = 0.02), and advanced age (OR 1.08, 95% CI 1.04–1.12, P < 0.001). Proton pump inhibitor use after PCI (OR 0.08, 95% CI 0.02–0.40, P = 0.002) was accompanied by a reduced risk of UGI bleeding. Endoscopy provided therapeutic intervention in 33% of patients. There were no serious complications of endoscopy. The 30-day mortality for cases was 11.9% and 0.5% for controls (P = 0.001).CONCLUSION:UGI bleeding after PCI is relatively common and associated with increased mortality. Those undergoing PCI for acute myocardial infarction or in the presence hemodynamic instability are at highest risk. Proton pump inhibition following PCI may reduce the bleeding risk, though when UGI bleeding occurs, therapeutic endoscopy is safe.

Liver disease complicating bone marrow transplantation: A clinical audit

BACKGROUND Intravenous sedation/analgesia for colonoscopy is accompanied with certain risks and postprocedure drowsiness. We sought to determine whether inhaled nitrous oxide (Entonox: 50% nitrous oxide, 50% oxygen) provides adequate analgesia for colonoscopy and the impact of this agent on recovery. METHODS All patients undergoing outpatient colonoscopy were considered for the study (n = 248) except those with previous colonic resection. Data for patients unsuitable for randomization (n = 58) and those who declined to participate (n = 88) were also analyzed. RESULTS One hundred two patients were randomized to receive inhaled Entonox alone (n = 56) or intravenous midazolam and meperidine (n = 46). Forty-nine (88%) patients randomized to Entonox underwent complete colonoscopy without conversion to intravenous medications. Entonox patients reported more pain (p < 0.0001), tolerated colonoscopy less well (p < 0.0001), were less satisfied (p = 0.01), and less willing to undergo colonoscopy again under the same circumstances (p = 0.04). Of patients receiving intravenous medication, 91% found colonoscopy less unpleasant and 9% as unpleasant as anticipated; this compares with 52% and 21% Entonox patients, respectively, and an additional 27% Entonox patients who found colonoscopy more unpleasant than anticipated. Recovery was faster among Entonox patients (median 30 versus 60 minutes, p < 0.0001). CONCLUSION Entonox is less effective than midazolam with meperidine for colonoscopy but is acceptable in many patients and allows faster recovery.

Proteome Analysis of Highly Immunoreactive Proteins of Helicobacter pylori

Summary Proteome analysis involves the simultaneous resolution and display of proteins produced by an organism, followed by the quantitation, characterisation and identification of these proteins. As part of an ongoing study mapping and comparing the proteins expressed by various strains of the pathogenic bacterium Helicobacter pylori, we have resolved and identified 93 of the most abundant proteins expressed by type reference strain NCTC 11637. Proteins were separated by two‐dimensional gel electrophoresis and stained with Coomassie G250. Intensely‐stained spots were excised and digested with trypsin, and the resulting peptides were characterised by mass spectrometry. Proteins were then identified by correlating actual peptide profiles with theoretical profiles generated from published nucleotide sequences. Ninety‐three of the most intensely‐stained protein spots were identified as the products of 35 genes, giving a ratio of 2.7 protein gene‐products per gene. The products of the tsaA, pfr, ureA and ureB genes were amongst several proteins present in multiple isoforms. Peptide mass fingerprinting data were used to identify probable post‐translational protein modifications. These results suggest that H. pylori proteins are subject to a high degree of post‐translational modification. Comparative proteomics of H. pylori strains should greatly assist in investigating the pathogenic properties of this bacterium.