Tumour budding as a prognostic biomarker in biopsies and resections of neoadjuvant-treated rectal adenocarcinoma.

BACKGROUND: Tumour budding (TB) is a marker of tumour aggressiveness which, when measured in rectal cancer resection specimens, predicts worse outcomes and response to neoadjuvant therapy. We investigated the utility of TB assessment in the setting of neoadjuvant treatment. METHODS AND RESULTS: A single-centre, retrospective cohort study was conducted. TB was assessed using the hot-spot International Tumour Budding Consortium (ITBCC) method and classified by the revised ITBCC criteria. Haematoxylin and eosin (H&E) and AE1/AE3 cytokeratin (CK) stains for ITB (intratumoural budding) in biopsies with PTB (peritumoural budding) and ITB (intratumoural budding) in resection specimens were compared. Logistic regression assessed budding as predictors of lymph node metastasis (LNM). Cox regression and Kaplan-Meier analyses investigated their utility as a predictor of disease-free (DFS) and overall (OS) survival. A total of 146 patients were included; 91 were male (62.3%). Thirty-seven cases (25.3%) had ITB on H&E and 79 (54.1%) had ITB on CK assessment of biopsy tissue. In univariable analysis, H&E ITB [odds (OR) = 2.709, 95% confidence interval (CI) = 1.261-5.822, P = 0.011] and CK ITB (OR = 2.165, 95% CI = 1.076-4.357, P = 0.030) predicted LNM. Biopsy-assessed H&E ITB (OR = 2.749, 95% CI = 1.258-6.528, P = 0.022) was an independent predictor of LNM. In Kaplan-Meier analysis, ITB identified on biopsy was associated with worse OS (H&E, P = 0.003, CK: P = 0.009) and DFS (H&E, P = 0.012; CK, P = 0.045). In resection specimens, CK PTB was associated with worse OS (P = 0.047), and both CK PTB and ITB with worse DFS (PTB, P = 0.014; ITB: P = 0.019). In multivariable analysis H&E ITB predicted OS (HR = 2.930, 95% CI = 1.261-6.809) and DFS (HR = 2.072, 95% CI = 1.031-4.164). CK PTB grading on resection also independently predicted OS (HR = 3.417, 95% CI = 1.45-8.053, P = 0.005). CONCLUSION: Assessment of TB using H&E and CK may be feasible in rectal cancer biopsy and post-neoadjuvant therapy-treated resection specimens and is associated with LNM and worse survival outcomes. Future management strategies for rectal cancer might be tailored to incorporate these findings.

Comparing neoadjuvant therapy followed by local excision to total mesorectal excision in the treatment of early stage rectal cancer: a systematic review and meta-analysis of randomised clinical trials.

INTRODUCTION: Total mesorectal excision (TME) is the standard-of-care in early, clinical stage (cT2-3 N0 M0) rectal cancer. Local excision (LE) may be an alternative after adequate response to neoadjuvant therapy (NAT), with either long-course chemoradiotherapy (nCRT) or short-course radiotherapy (SCRT), as a means of preserving the rectum and potentially obviating the morbidity of TME. METHODS: A systematic review was performed according to PRISMA guidelines for studies that randomly assigned patients with cT2-3 N0 M0 rectal cancer to either NAT + LE or TME that reported radiologic, oncologic, surgical, and morbidity outcomes. RESULTS: A total of 4 RCTs comprise 462 patients (232 patients receiving NAT + LE; nCRT n = 205; SCRT n = 27) and 230 undergoing TME, respectively. NAT compliance was 98.86%. The rate of early completion TME in the NAT + LE group was 22.3%, while the proportion of patients achieving durable organ preservation was 75.4% at mean follow-up of 5.6 years. There was no difference in disease-free survival (DFS) (HR [hazard ratio] 1.19; 95% CI 0.95, 1.49; p = 0.13) or overall survival (OS) (HR 0.94; 95% CI 0.72, 1.23; p = 0.63]) according to the assigned treatment arm. The local recurrence rate (LRR) (HR 1.22; 95% CI 0.5-3.02; p = 0.66) and distant metastases (HR 0.92; 95% CI 0.45, 1.90; p = 0.82) were also comparable between the groups. There was a significant reduction in major (OR 0.45; 95% CI 0.21, 0.95; p = 0.04) and minor morbidity (OR 0.45; 95% CI 0.24, 0.85; p = 0.01) for patients undergoing NAT + LE. Overall stoma formation was decreased in the NAT + LE group (OR 0.03; 95% CI 0.0, 0.23; p ≤ 0.00001). CONCLUSION: NAT + LE reduces adverse effects of TME, without any compromise in oncological outcomes, and the potential for an organ preserving strategy should be discussed with patients with T2-3N0 rectal cancers prior to treatment.

Surgical management strategies for colorectal malignancies of the splenic flexure - A systematic review and network meta-analysis.

BACKGROUND: Extended right hemicolectomy (ERHC) or left hemicolectomy (LHC) are accepted as the standard-of-care for colonic tumours of the splenic flexure. Lymphatic drainage at this site is poorly defined and subject to significant heterogeneity. Nevertheless, emerging evidence demonstrates the potential oncological safety of segmental splenic flexure colectomy (SFC). AIM: To perform a systematic review and network meta-analysis (NMA) to compare outcomes following ERHC, LHC and SFC for splenic flexure tumours (SFTs). METHODS: A systematic review was performed as per PRISMA guidelines. NMA was performed using R Shiny and Netmeta packages. RESULTS: A total of 13 studies, involving 6176 patients (ERHC n = 785; LHC n = 1527; SFC n = 3864) were included in the NMA. There was no difference in overall survival (OS) (SFC vs LHC Hazard Ratio [HR] 1.0, 95% Credible Interval [CrI] 0.76,1.34; SFC vs ERHC HR 1.18, 95% CrI 0.85,1.58) between the groups. SFC had a shorter operation time (Mean 176.37 min; Mean Difference [MD] SFC vs LHC 20.34 min 95% CrI 10.9, 29.97; SFC vs ERHC MD 22.19 95% CrI 11.09, 33.29) but also had a lower average lymph node yield (LNY) compared with ERHC (MD 7.15, 95% CrI 5.71, 8.60). ERHC had a significantly higher incidence of post-operative ileus (Odds Ratio [OR] 3.47, 95% CrI 1.11, 10.84). There was also no difference observed for minimally invasive approaches, anastomotic leak rate, perioperative mortality, reoperation rates or length of stay. CONCLUSIONS: While SFC may allow for reduced operative duration and improved bowel function postoperatively. SFC, LHC, ERHC are all acceptable approaches for curative resection of cancers of the splenic flexure, with no difference in OS observed. Thus, surgeon preference and candidate-specific factors will likely determine the management of SFTs.

Obesity, Sarcopenia and Myosteatosis: Impact on Clinical Outcomes in the Operative Management of Crohn's Disease.

BACKGROUND: Obesity, sarcopenia, and myosteatosis in inflammatory bowel disease may confer negative outcomes, but their prevalence and impact among patients with Crohn's disease (CD) have not been systematically studied. The aim of this study was to assess nutritional status and body composition among patients undergoing resectional surgery for CD and determine impact on operative outcomes. METHODS: Consecutive patients with CD undergoing resection from 2000 to 2018 were studied. Total, subcutaneous, and visceral fat areas and lean tissue area (LTA) and intramuscular adipose tissue (IMAT) were determined preoperatively by computed tomography at L3 using SliceOmatic (Tomovision, Canada). Univariable and multivariable linear, logistic, and Cox proportional hazards regression were performed. RESULTS: One hundred twenty-four consecutive patients were studied (ileocolonic disease 53%, n = 62, biologic therapy 34.4% n = 43). Mean fat mass was 22.7 kg, with visceral obesity evident in 23.9% (n = 27). Increased fat stores were associated with reduced risk of emergency presentation but increased corticosteroid use (ß 9.09, standard error 3.49; P = .011). Mean LBM was 9.9 kg. Sarcopenia and myosteatosis were associated with impaired baseline nutritional markers. Myosteatosis markers IMAT (P = .002) and muscle attenuation (P = .0003) were associated with increased grade of complication. On multivariable analysis, IMAT was independently associated with increased postoperative morbidity (odds ratio [OR], 1.08; 95% confidence interval (CI), 1.01-1.16; P = .037) and comprehensive complications index (P = .029). Measures of adiposity were not associated with overall morbidity; however, increased visceral fat area independently predicted venous thromboembolism (OR, 1.02; 95% CI, 1.00-1.05; P = .028), and TFA was associated with increased wound infection (OR, 1.00; 95% CI, 1.00-1.01; P = .042) on multivariable analysis. CONCLUSION: Myosteatosis is associated with nutritional impairment and predicts increased overall postoperative morbidity following resection for CD. Despite its association with specific increased postoperative risks, increased adiposity does not increase overall morbidity, reflecting preservation of nutritional status and relatively more quiescent disease phenotype. Impaired muscle mass and function represent an appealing target for patient optimization to improve outcomes in the surgical management of CD.

Myosteatosis was predictive of postoperative morbidity following surgery for Crohn's Disease. Increased adiposity does not increase overall morbidity, reflecting a more quiescent disease phenotype. Obesity, myosteatosis, and sarcopenia represent appealing targets for patient optimization to improve outcomes surgical outcomes in Crohn's Disease.

Evaluating the oncological safety of neoadjuvant chemotherapy in locally advanced colon carcinoma: a systematic review and meta-analysis of randomised clinical trials and propensity-matched studies.

PURPOSE: Use of neoadjuvant chemotherapy (NAC) for locally advanced colon cancer (LACC) remains controversial. An integrated analysis of data from high-quality studies may inform the long-term safety of NAC for this cohort. Our aim was to perform a systematic review and meta-analysis of randomised clinical trials (RCTs) and propensity-matched studies to assess the oncological safety of NAC in patients with LACC. METHODS: A systematic review was performed as per preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. Survival was expressed as hazard ratios using time-to-effect generic inverse variance methodology, while surgical outcomes were expressed as odds ratios (ORs) using the Mantel-Haenszel method. Data analysis was performed using Review Manager version 5.4. RESULTS: Eight studies (4 RCTs and 4 retrospective studies) including 31,047 patients with LACC were included. Mean age was 61.0 years (range: 19-93 years) and mean follow-up was 47.6 months (range: 2-133 months). Of those receiving NAC, 4.6% achieved a pathological complete response and 90.6% achieved R0 resection (versus 85.9%, P < 0.001). At 3 years, patients receiving NAC had improved disease-free survival (DFS) (OR: 1.28, 95% confidence interval (CI): 1.02-1.60, P = 0.030) and overall survival (OS) (OR: 1.76, 95% CI: 1.10-2.81, P = 0.020). When using time-to-effect modelling, a non-significant difference was observed for DFS (HR: 0.79, 95% CI: 0.57-1.09, P = 0.150) while a significant difference in favour of NAC was observed for OS (HR: 0.75, 95% CI: 0.58-0.98, P = 0.030). CONCLUSION: This study highlights the oncological safety of NAC for patients being treated with curative intent for LACC using RCT and propensity-matched studies only. These results refute current management guidelines which do not advocate for NAC to improve surgical and oncological outcomes in patients with LACC. TRIAL REGISTRATION: International Prospective Register of Systematic Review (PROSPERO) registration: CRD4202341723.

Total neoadjuvant therapy versus standard neoadjuvant treatment strategies for the management of locally advanced rectal cancer: network meta-analysis of randomized clinical trials.

BACKGROUND: This study compared the advantages and disadvantages of total neoadjuvant therapy (TNT) strategies for patients with locally advanced rectal cancer, compared with the more traditional multimodal neoadjuvant management strategies of long-course chemoradiotherapy (LCRT) or short-course radiotherapy (SCRT). METHODS: A systematic review and network meta-analysis of exclusively RCTs was undertaken, comparing survival, recurrence, pathological, radiological, and oncological outcomes. The last date of the search was 14 December 2022. RESULTS: In total, 15 RCTs involving 4602 patients with locally advanced rectal cancer, conducted between 2004 and 2022, were included. TNT improved overall survival compared with LCRT (HR 0.73, 95 per cent credible interval 0.60 to 0.92) and SCRT (HR 0.67, 0.47 to 0.95). TNT also improved rates of distant metastasis compared with LCRT (HR 0.81, 0.69 to 0.97). Reduced overall recurrence was observed for TNT compared with LCRT (HR 0.87, 0.76 to 0.99). TNT showed an improved pCR compared with both LCRT (risk ratio (RR) 1.60, 1.36 to 1.90) and SCRT (RR 11.32, 5.00 to 30.73). TNT also showed an improvement in cCR compared with LCRT (RR 1.68, 1.08 to 2.64). There was no difference between treatments in disease-free survival, local recurrence, R0 resection, treatment toxicity or treatment compliance. CONCLUSION: This study provides further evidence that TNT has improved survival and recurrence benefits compared with current standards of care, and may increase the number of patients suitable for organ preservation, without negatively influencing treatment toxicity or compliance.

Comparing minimally invasive surgical and open approaches to pelvic exenteration for locally advanced or recurrent pelvic malignancies - Systematic review and meta-analysis.

INTRODUCTION: Pelvic exenteration (PE) is a complex multivisceral surgical procedure indicated for locally advanced or recurrent pelvic malignancies. It poses significant technical challenges which account for the high risk of morbidity and mortality associated with the procedure. Developments in minimally invasive surgical (MIS) approaches and enhanced peri-operative care have facilitated improved long term outcomes. However, the optimum approach to PE remains controversial. METHODS: A systematic literature search was conducted in accordance with PRISMA guidelines to identify studies comparing MIS (robotic or laparoscopic) approaches for PE versus the open approach for patients with locally advanced or recurrent pelvic malignancies. The methodological quality of the included studies was assessed systematically and a meta-analysis was conducted. RESULTS: 11 studies were identified, including 2009 patients, of whom 264 (13.1%) underwent MIS PE approaches. The MIS group displayed comparable R0 resections (Risk Ratio [RR] 1.02, 95% Confidence Interval [95% CI] 0.98, 1.07, p = 0.35)) and Lymph node yield (Weighted Mean Difference [WMD] 1.42, 95% CI -0.58, 3.43, p = 0.16), and although MIS had a trend towards improved towards improved survival and recurrence outcomes, this did not reach statistical significance. MIS was associated with prolonged operating times (WMD 67.93, 95% CI 4.43, 131.42, p < 0.00001) however, this correlated with less intra-operative blood loss, and a shorter length of post-operative stay (WMD -3.89, 955 CI -6.53, -1.25, p < 0.00001). Readmission rates were higher with MIS (RR 2.11, 95% CI 1.11, 4.02, p = 0.02), however, rates of pelvic abscess/sepsis were decreased (RR 0.45, 95% CI 0.21, 0.95, p = 0.04), and there was no difference in overall, major, or specific morbidity and mortality. CONCLUSION: MIS approaches are a safe and feasible option for PE, with no differences in survival or recurrence outcomes compared to the open approach. MIS also reduced the length of post-operative stay and decreased blood loss, offset by increased operating time.

Comparison of Restorative Proctocolectomy with and Without Defunctioning Loop Ileostomy in Patients with Ulcerative Colitis: A Systematic Review and Meta-analysis.

BACKGROUND: Restorative proctocolectomy [RPC] without a defunctioning loop ileostomy [DLI] in patients with ulcerative colitis [UC] remains controversial. AIM: To compare safety and efficacy of RPC with and without DLI in patients exclusively with UC. METHODS: A systematic review was performed according to PRISMA/MOOSE guidelines. Dichotomous variables were pooled as odds ratios [OR]. Continuous variables were pooled as weighted mean differences [WMD]. Quality assessment was performed using the Newcastle-Ottawa score [NOS]. RESULTS: A total of 20 studies [five paediatric and 15 adult] with 4550 UC patients [without DLI, n = 2370, 52.09%; with DLI, n = 2180, 47.91%] were eligible for inclusion. The median NOS was 8 [range 6-9]. There was no increased risk of anastomotic leak [AL] (OR 1.13, 95% confidence interval [CI]: 0.92, 1.39; p = 0.25), pouch excision [OR 1.01, 95% CI: 0.68, 1.50; p = 0.97], or overall major morbidity [OR 1.44, 95% CI, 0.91, 2.29; p = 0.12] for RPC without DLI, and this technique was associated with fewer anastomotic strictures [OR 0.45, 95% CI: 0.29, 0.68; p = 0.0002] and less bowel obstruction [OR 0.73, 95% CI: 0.57, 0.93; p = 0.01]. However, RPC without DLI increased the likelihood of pelvic sepsis [OR 1.68, 95% CI: 1.03, 2.75; p = 0.04] and emergency reoperation [OR 1.74, 95% CI: 1.22, 2.50; p = 0.002]. CONCLUSION: RPC without DLI is not associated with increased clinically overt AL or pouch excision rates. However, it is associated with increased risk of pelvic sepsis and emergency reoperation. RPC without DLI is feasible, but should only be performed judiciously in select UC patient cohorts in high-volume, specialist, tertiary centres.

Colonoscopy-related injury among colonoscopists: an international survey.

Background and study aims Colonoscopy is physically demanding for endoscopists and patients. Repetitive movements during colonoscopy can lead to overuse injuries. We aimed to explore the prevalence and range of colonoscopy-related musculoskeletal injuries (CRIs) in endoscopists. Methods A cross-sectional electronic survey of 1825 endoscopists was performed. The sample was composed of members of the British Society of Gastroenterology, European Society of Gastrointestinal Endoscopy, and National Nurse Endoscopy Group (UK). The survey comprised 20 questions. These included: endoscopists' workload, level of experience, and their perceived CRIs. All endoscopists who perform colonoscopy independently were included in the analysis. Results A total of 368 questionnaires were completed of 1825 surveyed (20.16 %). Of those, 319 participants (17.48 %) were fully independent in colonoscopy. Of 319 endoscopists, 254 (79.6 %) have experienced musculoskeletal injuries. These were reported as either possibly (n = 143, 56.3 %) or definitely (n = 90, 35.4 %) related to colonoscopy. Commonly injured areas were the lower back (n = 85, 36.5 %), neck (n = 82, 35.2 %) and left thumb (n = 79, 33.9 %). Of the injured endoscopists, 98 (30.7 %) made some modification to their practice, such as stretching exercises and ergonomic changes. Of the endoscopists, 134 (42.0 %) thought that repetitive limb strain was a likely causative mechanism. Around 40 % believed that torquing the scope and challenging body position were precipitating CRIs. Several treatment modalities were used to treat CRIs. These included; physiotherapy (n = 109), medications (n = 70), rest (n = 43), splinting (n = 31), steroid injections (n = 26) and surgery (n = 11). Conclusions A significant proportion of colonoscopists experience CRIs. The majority of the suggested modifications to practice can be adopted by any endoscopist. These results highlight the need to recognise CRI as an important occupational health hazard and to adopt preventative strategies routinely in the future.

Bile duct clearance and cholecystectomy for choledocholithiasis: Definitive single-stage laparoscopic cholecystectomy with intraoperative endoscopic retrograde cholangiopancreatography versus staged procedures.

BACKGROUND: Clinical equipoise exists regarding optimal sequencing in the definitive management of choledocholithiasis. Our current study compares sequential biliary ductal clearance and cholecystectomy at an interval to simultaneous laparoendoscopic management on index admission in a pragmatic retrospective manner. METHODS: Records were reviewed for all patients admitted between January 2015 and December 2018 to a Swedish and an Irish university hospital. Both hospitals differ in their practice patterns for definitive management of choledocholithiasis. At the Swedish hospital, patients with choledocholithiasis underwent laparoscopic cholecystectomy with intraoperative rendezvous endoscopic retrograde cholangiopancreatography (ERCP) at index admission (one stage). In contrast, interval day-case laparoscopic cholecystectomy followed index admission ERCP (two stages) at the Irish hospital. Clinical characteristics, postprocedural complications, and inpatient duration were compared between cohorts. RESULTS: Three hundred fifty-seven patients underwent treatment for choledocholithiasis during the study period, of whom 222 (62.2%) underwent a one-stage procedure in Sweden, while 135 (37.8%) underwent treatment in two stages in Ireland. Patients in both cohorts were closely matched in terms of age, sex, and preoperative serum total bilirubin. Patients in the one-stage group exhibited a greater inflammatory reaction on index admission (peak C-reactive protein, 136 ± 137 vs. 95 ± 102 mg/L; p = 0.024), had higher incidence of comorbidities (age-adjusted Charlson Comorbidity Index, ≥3; 37.8% vs. 20.0%; p = 0.003), and overall were less fit for surgery (American Society of Anesthesiologists, ≥3; 11.7% vs. 3.7%; p < 0.001). Despite this, a significantly shorter mean time to definitive treatment, that is, cholecystectomy (3.1 ± 2.5 vs. 40.3 ± 127 days, p = 0.017), without excess morbidity, was seen in the one-stage compared with the two-stage cohort. Patients in the one-stage cohort experienced shorter mean postprocedure length of stay (3.0 ± 4.7 vs. 5.0 ± 4.6 days, p < 0.001) and total length of hospital stay (6.5 ± 4.6 vs. 9.0 ± 7.3 days, p = 0.002). The only significant difference in postoperative complications between the cohorts was urinary retention, with a higher incidence in the one-stage cohort (19% vs. 1%, p = 0.004). CONCLUSION: Where appropriate expertise and logistics exist within developing models of acute care surgery worldwide, consideration should be given to index-admission laparoscopic cholecystectomy with intraoperative ERCP for the treatment of choledocholithiasis. Our data suggest that this strategy significantly shortens the time to definitive treatment and decreases total hospital stay without any excess in adverse outcomes. LEVEL OF EVIDENCE: Therapeutic/Care Management Level IV.

A new composite measure of colonoscopy: the Performance Indicator of Colonic Intubation (PICI).

BACKGROUND AND STUDY AIM: Cecal intubation rate (CIR) is an established performance indicator of colonoscopy. In some patients, cecal intubation with acceptable tolerance is only achieved with additional sedation. This study proposes a composite Performance Indicator of Colonic Intubation (PICI), which combines CIR, comfort, and sedation. METHODS : Data from 20 085 colonoscopies reported in the 2011 UK national audit were analyzed. PICI was defined as the percentage of procedures achieving cecal intubation with median dose (2 mg) of midazolam or less, and nurse-assessed comfort score of 1 - 3/5. Multivariate logistic regression analysis evaluated possible associations between PICI and patient, unit, colonoscopist, and diagnostic factors. RESULTS : PICI was achieved in 54.1 % of procedures. PICI identified factors affecting performance more frequently than single measures such as CIR and polyp detection, or CIR + comfort alone. Older age, male sex, adequate bowel preparation, and a positive fecal occult blood test as indication were associated with a higher PICI. Unit accreditation, the presence of magnetic imagers in the unit, greater annual volume, fewer years' experience, and higher training/trainer status were associated with higher PICI rates. Procedures in which PICI was achieved were associated with significantly higher polyp detection rates than when PICI was not achieved. CONCLUSIONS : PICI provides a simpler picture of performance of colonoscopic intubation than separate measures of CIR, comfort, and sedation. It is associated with more factors that are amenable to change that might improve performance and with higher likelihood of polyp detection. It is proposed that PICI becomes the key performance indicator for intubation of the colon in colonoscopy quality improvement initiatives.

A randomized controlled trial comparing continuous and as-required nitrous oxide use during screening colonoscopy.

BACKGROUND AND STUDY AIMS: Entonox is a 50 : 50 combination of nitrous oxide and oxygen, which may be used to manage pain during colonoscopy. The optimal mode of Entonox administration is unknown. The aim of this study was therefore to compare continuous and as-required Entonox use. PATIENTS AND METHODS: Patients attending for screening colonoscopy at a single centre were randomized to continuous or as-required Entonox use. The primary outcome measure was the patient's overall pain rating at the time of discharge (verbally administered numerical ratings scale, 0=no pain and 10=extreme pain). Secondary outcome measures included the patients' experience of pain during the colonoscopy (rated every 2 min), side effects and the need for rescue intravenous medications. RESULTS: A total of 108 patients were randomized, and 100 completed the study (46 continuous, 54 as required). The overall pain scores at discharge did not differ between those who used Entonox continuously and as required (mean=2.4 vs. 3.2, P=0.08). There were also no differences in the experience of pain during colonoscopy (mean=1.8 vs. 2.2, P=0.28; peak=4.2 vs. 4.8, P=0.26; and area under curve=23 vs. 30, P=0.24). Patients with high anxiety had greater overall pain scores (mean=3.7 vs. 2.4, P=0.03). Light headedness occurred more often with continuous Entonox use (48 vs. 21%, P=0.009). CONCLUSION: Among patients attending for screening colonoscopy, comfort ratings were similar in those using Entonox continuously and as required, but light headedness was more common with continuous use (NCT identifier: 01865721).

Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage.

Preclinical studies show that epoxyeicosatrienoic acids (EETs) regulate cerebrovascular tone and protect against cerebral ischemia. We investigated the relationship between polymorphic genes involved in EET biosynthesis/metabolism, cytochrome P450 (CYP) eicosanoid levels, and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage (aSAH). Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid (DHET) cerebrospinal fluid (CSF) levels, as well as acute outcomes defined by delayed cerebral ischemia (DCI) or clinical neurologic deterioration (CND), were assessed over 14 days. Long-term outcomes were defined by Modified Rankin Scale (MRS) at 3 and 12 months. CYP2C8*4 allele carriers had 44% and 36% lower mean EET and DHET CSF levels (P=0.003 and P=0.007) and were 2.2- and 2.5-fold more likely to develop DCI and CND (P=0.039 and P=0.041), respectively. EPHX2 55Arg, CYP2J2*7, CYP2C8*1B, and CYP2C8 g.36785A allele carriers had lower EET and DHET CSF levels. CYP2C8 g.25369T and CYP2C8 g.36755A allele carriers had higher EET levels. Patients with CYP2C8*2C and EPHX2 404del variants had worse long-term outcomes while those with EPHX2 287Gln, CYP2J2*7, and CYP2C9 g.816G variants had favorable outcomes. Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3-month outcomes. Dihydroxyeicosatetraenoic acids were not associated with outcomes. No associations passed Bonferroni multiple testing correction. These are the first clinical data demonstrating the association between the EET biosynthesis/metabolic pathway and the pathophysiology of aSAH.

The national colonoscopy audit: a nationwide assessment of the quality and safety of colonoscopy in the UK.

OBJECTIVE: To perform a comprehensive audit of all colonoscopy undertaken in the UK over a 2-week period. DESIGN: Multi-centre survey. All adult (≥16 years of age) colonoscopies that took place in participating National Health Service hospitals between 28 February 2011 and 11 March 2011 were included. RESULTS: Data on 20,085 colonoscopies and 2681 colonoscopists were collected from 302 units. A validation exercise indicated that data were collected on over 94% of all procedures performed nationally. The unadjusted caecal intubation rate (CIR) was 92.3%. When adjusted for impassable strictures and poor bowel preparation the CIR was 95.8%. The polyp detection rate was 32.1%. The polyp detection rate for larger polyps (≥10 mm diameter) was 11.7%. 92.3% of resected polyps were retrieved. 90.2% of procedures achieved acceptable levels of patient comfort. A total of eight perforations and 52 significant haemorrhages were reported. Eight patients underwent surgery as a consequence of a complication. CONCLUSIONS: This is the first national audit of colonoscopy that has successfully captured the majority of adult colonoscopies performed across an entire nation during a defined time period. The data confirm that there has been a significant improvement in the performance of colonoscopy in the UK since the last study reported seven years ago (CIR 76.9%) and that performance is above the required national standards.

Tumor disposition of pegylated liposomal CKD-602 and the reticuloendothelial system in preclinical tumor models.

Liposomes, such as pegylated-liposomal CKD-602 (S-CKD602), undergo catabolism by macrophages and dendritic cells (DCs) of the reticuloendothelial system (RES). The relationship between plasma and tumor disposition of S-CKD602 and RES was evaluated in mice bearing A375 melanoma or SKOV-3 ovarian xenografts. Area under the concentration-time curves (AUCs) of liposomal encapsulated, released, and sum total (encapsulated + released) CKD-602 in plasma, tumor, and tumor extracellular fluid (ECF) were estimated. A375 and SKOV-3 tumors were stained with cd11b and cd11c antibodies as measures of macrophages and DC. The plasma disposition of S-CKD602 was similar in both xenograft models. The ratio of tumor sum total AUC to plasma sum total AUC was 1.7-fold higher in mice bearing human SKOV-3 xenografts, compared with A375. The ratio of tumor ECF AUC to tumor sum total AUC was 2-fold higher in mice bearing human SKOV-3 xenografts, compared with A375. The staining of cd11c was 4.5-fold higher in SKOV-3, compared with A375 (P < 0.0001). The increased tumor delivery and release of CKD-602 from S-CKD602 in the ovarian xenografts, compared with the melanoma xenografts, was consistent with increased cd11c staining, suggesting that variability in the RES may affect the tumor disposition of liposomal agents.

Mining, knowledge and decision support.

Decision support systems (DSS) are software entities that assist the physician in the decision making process. They have found application in medicine due to the large amounts of data (e.g. laboratory measurements such as blood pressure, heart rate, body-mass index) and information (e.g. patient history, population statistics based on age and sex) that must be considered before diagnosing any disease or recommending a therapy. A well known example is the embedded software in defibrillators which allows a 'shock' to be delivered, by analyzing the electrocardiogram for known conditions (heart attack). The shock can restart the heart and timely delivery can resuscitate the patient. As well as assisting in primary diagnosis, a DSS can reduce medical error, assist compliance with clinical guidelines, improve efficiency of care delivery and improve quality of care. Decision support still has significant acceptance issues in clinical routine, but can achieve more prominence, as systems are demonstrated to provide effective knowledge based support. Data mining is often used to provide some insight to a data set and update our accepted knowledge. In this section, we discuss a study which examines where electrocardiographic information should be recorded from a patient's torso in order to increase diagnostic yield.

Effects of electrode placement errors in the EASI-derived 12-lead electrocardiogram.

In this study, we assess the effects of electrode placement error on the EASI-derived 12-lead electrocardiogram (ECG). The study data set consisted of 744 body surface potential map (BSPM) recordings. The BSPMs, each of which was made up of 117 leads, were recorded from a mixture of healthy, myocardial infarction, and left ventricular hypertrophy subjects. The BSPMs were interpolated to increase the number of data points in the region of the EASI recording electrodes I, E, and A and the precordial leads. This facilitated 3 experiments. Firstly, recording sites I, E, and A were simultaneously moved ±5 cm vertically, in 0.5 cm increments, from their correct locations. Secondly, recording sites I and A were moved horizontally, again up to ±5 cm, in 0.5 cm increments. Finally, all 6 precordial leads were moved vertically in 0.5 cm increments up to ±5 cm. At each movement step, the resulting 12-lead ECG was compared with the original 12-lead ECG. Root mean square error was determined along with the absolute difference in J-point amplitude. Although the EASI leads were found to be less sensitive to electrode misplacement than the standard precordial leads, it was found that when precordial leads were moved up to ±3 cm vertically, the resulting 12-lead ECG more accurately resembled the original 12-lead ECG than a 12-lead ECG reconstructed from accurately positioned EASI leads. Further work is required to establish the effects of electrode misplacement beyond the ±5 cm limits assessed in this study.

Factors associated with abdominal discomfort during colonoscopy: a prospective analysis.

OBJECTIVES: Colonoscopy can be uncomfortable. To increase safety, there is a trend, in the UK, towards reduced sedative use. We aimed to determine factors predictive of discomfort during colonoscopy. METHODS: Prospectively recruited patients were asked to grade anticipated discomfort on a Numeric Rating Scale ranging from 0 to 10. Discomfort scores were recorded every 2 min during the procedure and during peaks of discomfort. An overall discomfort score was recorded. RESULTS: One hundred and nine patients [44 male, 65 female; median 61.5 (21-80) years] were recruited. One hundred and three procedures were completed. Forty-five patients received midazolam [median 2 (1.5-5) mg]. Mean overall Numeric Rating Scale score was 4.7 (men 4.0; women 5.2; P<0.01) and median peak score 7. Discomfort was usually greatest at the beginning of the procedure, while in the sigmoid colon. Discomfort scores were higher in patients with irritable bowel syndrome (P = 0.03); diverticular disease (P<0.01); midazolam (P = 0.02), buscopan (P<0.001) or nitrous oxide (P<0.001) use; endoscope tracker use (P = 0.01); incomplete procedures (P<0.001) or a preceding gastroscopy (P = 0.02), but were not correlated with discomfort during venous cannulation or digital rectal examination. Multivariate analysis showed that female sex, high anxiety, anticipation of high discomfort, longer intubation time and higher endoscopist's grade of procedural difficulty were independent factors significantly related to overall discomfort scores. Recollected discomfort scores 2-3 months later were lower (P<0.01). Low-dose midazolam had no appreciable amnesic effect. CONCLUSION: Factors indicative of difficult colonoscopy, and preceding gastroscopy, are associated with greater discomfort, as are the presence of female sex, irritable bowel, anxiety and anticipated discomfort. Low-dose midazolam neither relieves discomfort nor makes patients forget it. Selected patients may benefit from increased analgesia.

Dedicated bleed units: should they be advocated?

BACKGROUND: Upper gastrointestinal haemorrhage (UGIH) is a common emergency, however, dedicated bleed units only exist in selected hospitals in the UK. OBJECTIVE: To evaluate the rebleeding and mortality rate of patients admitted with UGIH to a tertiary centre bleed unit in comparison with the current national standards and earlier unit performance in 1995-1998. METHODS: A retrospective case note review of demographics, the Rockall scores and final outcome was conducted for all patients admitted to the bleed unit over 24 months. RESULTS: Two hundred and fifty-five cases were identified with a mean age of 62 years and a median Rockall score of 3. Eighty-two percent of gastroscopies were performed within 24 h. Of these, 29% were undertaken after 5 p.m. Peptic ulcer and varices (15%) were the commonest diagnosis. The rebleeding (12%) and mortality rate (9%) were comparable with that of the units previous audit (P=0.47, 0.51, respectively) and the current national audit (P=0.58, 0.76, respectively). The number of patients requiring surgery has reduced from 6 to 0.4% in our unit over the last 8 years. Preendoscopy and postendoscopy Rockall scores were predictive of rebleeding (P=0.013, 0.045) and mortality (P=0.003, 0.01). CONCLUSION: This study has shown a consistently low rebleeding and mortality rate in patients with UGIH in a dedicated bleed unit. However there are limitations to the degree of improvements which can be demonstrated due to factors such as age and comorbidity.

New vectors for co-expression of proteins: structure of Bacillus subtilis ScoAB obtained by high-throughput protocols.

The Bacillus subtilis genes scoA and scoB encode subunits of the heteromeric enzyme ScoAB, a putative succinyl-CoA:acetoacetate coenzyme A transferase. High-throughput, ligation-independent cloning (LIC) vectors used extensively for production and purification of single proteins were modified to allow simultaneous expression of interacting proteins and selective purification of functional complexes. Transfer of the LIC region of vector pMCSG7 (L. Stols, M. Gu, L. Dieckman, R. Raffen, F.R. Collart, M.I. Donnelly. A new vector for high-throughput, ligation-independent cloning encoding a tobacco etch virus protease cleavage site. Protein Expr. Purif. (2002) 25, 8-15) into commercial vectors with alternative, compatible origins of replication allowed introduction of standard LIC PCR products into the vectors by uniform protocols. Replacement of the His-tag encoding region of pMCSG7 with a sequence encoding the S-tag enabled selective purification of interacting proteins based on the His-tag associated with one member of the complex. When expressed separately and mixed, the ScoAB subunits failed to interact productively; no transferase activity was detected, and S-tagged ScoB failed to co-purify with His-tagged ScoA. Co-expression, in contrast, generated active transferase that catalyzed the predicted reaction. The ScoAB complex was purified by standard high-throughput metal-ion affinity chromatography procedures, crystallized robotically, and its structure was determined by molecular replacement.