Serum proteomic profiling at diagnosis predicts clinical course, and need for intensification of treatment in inflammatory bowel disease.

BACKGROUND: Success in personalized medicine in complex disease is critically dependent on biomarker discovery. We profiled serum proteins using a novel proximity extension assay [PEA] to identify diagnostic and prognostic biomarkers in inflammatory bowel disease [IBD]. METHODS: We conducted a prospective case-control study in an inception cohort of 552 patients [328 IBD, 224 non-IBD], profiling proteins recruited across six centres. Treatment escalation was characterized by the need for biological agents or surgery after initial disease remission. Nested leave-one-out cross-validation was used to examine the performance of diagnostic and prognostic proteins. RESULTS: A total of 66 serum proteins differentiated IBD from symptomatic non-IBD controls, including matrix metallopeptidase-12 [MMP-12; Holm-adjusted p = 4.1 × 10-23] and oncostatin-M [OSM; p = 3.7 × 10-16]. Nine of these proteins are associated with cis-germline variation [59 independent single nucleotide polymorphisms]. Fifteen proteins, all members of tumour necrosis factor-independent pathways including interleukin-1 (IL-1) and OSM, predicted escalation, over a median follow-up of 518 [interquartile range 224-756] days. Nested cross-validation of the entire data set allowed characterization of five-protein models [96% comprising five core proteins ITGAV, EpCAM, IL18, SLAMF7 and IL8], which define a high-risk subgroup in IBD [hazard ratio 3.90, confidence interval: 2.43-6.26], or allowed distinct two- and three-protein models for ulcerative colitis and Crohn's disease respectively. CONCLUSION: We have characterized a simple oligo-protein panel that has the potential to identify IBD from symptomatic controls and to predict future disease course. Further prospective work is required to validate our findings.

Whole Blood Profiling of T-cell-Derived microRNA Allows the Development of Prognostic models in Inflammatory Bowel Disease.

BACKGROUND: MicroRNAs [miRNAs] are cell-specific small non-coding RNAs that can regulate gene expression and have been implicated in inflammatory bowel disease [IBD] pathogenesis. Here we define the cell-specific miRNA profiles and investigate its biomarker potential in IBD. METHODS: In a two-stage prospective multi-centre case control study, next generation sequencing was performed on a discovery cohort of immunomagnetically separated leukocytes from 32 patients (nine Crohn's disease [CD], 14 ulcerative colitis [UC], eight healthy controls) and differentially expressed signals were validated in whole blood in 294 patients [97 UC, 98 CD, 98 non-IBD, 1 IBDU] using quantitative PCR. Correlations were analysed with phenotype, including need for early treatment escalation as a marker of progressive disease using Cox proportional hazards. RESULTS: In stage 1, each leukocyte subset [CD4+ and CD8+ T-cells and CD14+ monocytes] was analysed in IBD and controls. Three specific miRNAs differentiated IBD from controls in CD4+ T-cells, including miR-1307-3p [p = 0.01], miR-3615 [p = 0.02] and miR-4792 [p = 0.01]. In the extension cohort, in stage 2, miR-1307-3p was able to predict disease progression in IBD (hazard ratio [HR] 1.98, interquartile range [IQR]: 1.20-3.27; logrank p = 1.80 × 10-3), in particular CD [HR 2.81; IQR: 1.11-3.53, p = 6.50 × 10-4]. Using blood-based multimarker miRNA models, the estimated chance of escalation in CD was 83% if two or more criteria were met and 90% for UC if three or more criteria are met. INTERPRETATION: We have identified and validated unique CD4+ T-cell miRNAs that are differentially regulated in IBD. These miRNAs may be able to predict treatment escalation and have the potential for clinical translation; further prospective evaluation is now indicated.

Meta-analysis of the effect of perioperative intravenous lidocaine on return of gastrointestinal function after colorectal surgery.

BACKGROUND: Return of normal gastrointestinal (GI) function is a critical determinant of recovery after colorectal surgery. The aim of this meta-analysis was to evaluate whether perioperative intravenous (IV) lidocaine benefits return of gastrointestinal function after colorectal resection. METHODS: A comprehensive search of Ovid Medline, PubMed, Embase, Cochrane library, and clinicaltrials.org was performed on 1st July 2018. A manual search of reference lists was also performed. Inclusion criteria were as follows: randomized controlled trials (RCTs) of intravenous (IV) lidocaine administered perioperatively compared to placebo (0.9% saline infusion) as part of a multimodal perioperative analgesic regimen, human adults (> 16 years), and open or laparoscopic colorectal resectional surgery. EXCLUSION CRITERIA: non-colorectal surgery, non-placebo comparator, children, non-general anaesthetic, and pharmacokinetic studies. The primary endpoint was time to first bowel movement. Secondary endpoints were time to first passage of flatus, time to toleration of diet, nausea and vomiting, ileus, pain scores, opioid analgesia consumption, and length of stay. RESULTS: One hundred and ninety one studies were screened, with 9 RCTs meeting inclusion criteria (405 patients, four laparoscopic and five open surgery studies). IV lidocaine reduced time to first bowel movement compared to placebo [seven studies, 325 patients, mean weighted difference - 9.54 h, 95% CI 18.72-0.36, p = 0.04]. Ileus, pain scores, and length of stay were reduced with IV lidocaine compared with placebo. CONCLUSIONS: Perioperative IV lidocaine may improve recovery of gastrointestinal function after colorectal surgery. Large-scale effectiveness studies to measure effect size and evaluate optimum dose/duration are warranted.

Variability in the prescribing of intravenous fluids: A cross sectional multicentre analysis of clinical practice.

AIMS: Intravenous (IV) fluid administration continues to be a mainstay of care in General Surgery. Yet if they are prescribed incorrectly significant morbidity including electrolyte abnormalities, renal impairment and cardiac failure can develop. Despite this, it is frequently the responsibility of the most junior staff to prescribe IV fluids. We aim to analyse the understanding of IV fluid prescribing amongst junior doctors and to describe variability in clinical practice. METHODS: We undertook a multicentre questionnaire study. Foundation doctors and specialty trainees were invited to undertake a two part paper-based questionnaire. Part one analysed baseline knowledge of the concentration of commonly prescribed fluids. Part two consisted of four clinical vignettes requiring a IV fluid prescribing decision by the surveyed doctor. RESULTS: A total of 143 Doctors working in 8 hospitals were recruited. 65 (45.5%) doctors correctly stated the daily maintenance fluid requirements of water for an adult (25-30 mls/kg/day), while only 54 (37.8%) knew the sodium concentration of 0.9% NaCl. Lack of postgraduate experience (p = 0.011), qualifying from a medical school outside the United Kingdom (p < 0.0001) and working in one of the eight hospitals in this study (p < 0.0001) were associated with a lower knowledge level. There was limited consensus in prescribing in the responses to the 4 clinical scenarios, with 69 unique combinations of fluid choice, rate and volume prescribed. CONCLUSIONS: Knowledge of the constituents of common IV fluids and routine requirement for fluid and common electrolytes is poor across junior doctors of all grades, driving large variation in clinical practice.

An evidence-based treatment algorithm for colorectal polyp cancers: results from the Scottish Screen-detected Polyp Cancer Study (SSPoCS).

OBJECTIVES: Colorectal polyp cancers present clinicians with a treatment dilemma. Decisions regarding whether to offer segmental resection or endoscopic surveillance are often taken without reference to good quality evidence. The aim of this study was to develop a treatment algorithm for patients with screen-detected polyp cancers. DESIGN: This national cohort study included all patients with a polyp cancer identified through the Scottish Bowel Screening Programme between 2000 and 2012. Multivariate regression analysis was used to assess the impact of clinical, endoscopic and pathological variables on the rate of adverse events (residual tumour in patients undergoing segmental resection or cancer-related death or disease recurrence in any patient). These data were used to develop a clinically relevant treatment algorithm. RESULTS: 485 patients with polyp cancers were included. 186/485 (38%) underwent segmental resection and residual tumour was identified in 41/186 (22%). The only factor associated with an increased risk of residual tumour in the bowel wall was incomplete excision of the original polyp (OR 5.61, p=0.001), while only lymphovascular invasion was associated with an increased risk of lymph node metastases (OR 5.95, p=0.002). When patients undergoing segmental resection or endoscopic surveillance were considered together, the risk of adverse events was significantly higher in patients with incomplete excision (OR 10.23, p<0.001) or lymphovascular invasion (OR 2.65, p=0.023). CONCLUSION: A policy of surveillance is adequate for the majority of patients with screen-detected colorectal polyp cancers. Consideration of segmental resection should be reserved for those with incomplete excision or evidence of lymphovascular invasion.

Integrative epigenome-wide analysis demonstrates that DNA methylation may mediate genetic risk in inflammatory bowel disease.

Epigenetic alterations may provide important insights into gene-environment interaction in inflammatory bowel disease (IBD). Here we observe epigenome-wide DNA methylation differences in 240 newly-diagnosed IBD cases and 190 controls. These include 439 differentially methylated positions (DMPs) and 5 differentially methylated regions (DMRs), which we study in detail using whole genome bisulphite sequencing. We replicate the top DMP (RPS6KA2) and DMRs (VMP1, ITGB2 and TXK) in an independent cohort. Using paired genetic and epigenetic data, we delineate methylation quantitative trait loci; VMP1/microRNA-21 methylation associates with two polymorphisms in linkage disequilibrium with a known IBD susceptibility variant. Separated cell data shows that IBD-associated hypermethylation within the TXK promoter region negatively correlates with gene expression in whole-blood and CD8+ T cells, but not other cell types. Thus, site-specific DNA methylation changes in IBD relate to underlying genotype and associate with cell-specific alteration in gene expression.

MicroRNAs: new players in IBD.

MicroRNAs (miRNAs) are small non-coding RNAs, 18-23 nucleotides long, which act as post-transcriptional regulators of gene expression. miRNAs are strongly implicated in the pathogenesis of many common diseases, including IBDs. This review aims to outline the history, biogenesis and regulation of miRNAs. The role of miRNAs in the development and regulation of the innate and adaptive immune system is discussed, with a particular focus on mechanisms pertinent to IBD and the potential translational applications.

Comparison of mortality following hospitalisation for ulcerative colitis in Scotland between 1998-2000 and 2007-2009.

BACKGROUND: Scottish nationwide linkage data from 1998 to 2000 demonstrated high 3-year mortality in patients hospitalised with ulcerative colitis (UC). AIM: To compare 3-year mortality, and factors related to mortality, in Scottish patients hospitalised with UC between 1998-2000 and 2007-2009. METHODS: The Scottish Morbidity Records and linked datasets were used to assess 3-year mortality, standardised mortality ratio (SMR) and multivariate analyses of factors associated with 3-year mortality. The 3-year mortality was determined after four admission types: surgery-elective or emergency; medical-elective or emergency. Age-standardised mortality rates (ASR) were used to compare mortality rates between periods. RESULTS: Ulcerative colitis admissions increased from 10.6 in Period 1 to 11.6 per 100 000 population per year in Period 2 (P = 0.046). Crude and adjusted 3-year mortality fell between time periods (crude 12.2% to 8.3%; adjusted OR 0.59, CI 0.42-0.81, P = 0.04). Adjusted 3-year mortality following emergency medical admission (OR 0.58, CI 0.39-0.87, P = 0.003) and in patients >65 years (38.8% to 28.7%, P = 0.02) was lower in Period 2. The SMR in period 1 was 3.04 and 2.96 in Period 2. Directly age-standardised mortality decreased from 373 (CI 309-437) to 264 (CI 212-316) per 10 000 person-years. On multivariate analysis, increasing age (50-64 years OR 7.11 (CI 2.77-18.27, P < 0.05); 65-74 years OR 14.70 (CI 5.65-38.25 P < 0.05); >75 years OR 46.42 (CI 18.29-117.78, P < 0.001) and co-morbidity (OR 3.02, CI 1.72-5.28, P < 0.001) were significantly associated with 3-year mortality in Period 2. CONCLUSIONS: Comparisons of crude and adjusted mortality rates suggest significant improvement in outcome over the last decade - however, mortality remains high, and older age and co-morbidity are important predictors of outcome.

Systematic review and meta-analysis of continuous local anaesthetic wound infiltration versus epidural analgesia for postoperative pain following abdominal surgery.

BACKGROUND: Local anaesthetic wound infiltration techniques reduce opiate requirements and pain scores. Wound catheters have been introduced to increase the duration of action of local anaesthetic by continuous infusion. The aim was to compare these infiltration techniques with the current standard of epidural analgesia. METHODS: A meta-analysis of randomized clinical trials (RCTs) evaluating wound infiltration versus epidural analgesia in abdominal surgery was performed. The primary outcome was pain score at rest after 24 h on a numerical rating scale. Secondary outcomes were pain scores at rest at 48 h, and on movement at 24 and 48 h, with subgroup analysis according to incision type and administration regimen(continuous versus bolus), opiate requirements, nausea and vomiting, urinary retention, catheter-related complications and treatment failure. RESULTS: Nine RCTs with a total of 505 patients were included. No differences in pain scores at rest 24 h after surgery were detected between epidural and wound infiltration. There were no significant differences in pain score at rest after 48 h, or on movement at 24 or 48 h after surgery. Epidural analgesia demonstrated a non-significant a trend towards reduced pain scores on movement and reduced opiate requirements. There was a reduced incidence of urinary retention in the wound catheter group. CONCLUSION: Within a heterogeneous group of RCTs, use of local anaesthetic wound infiltration was associated with pain scores comparable to those obtained with epidural analgesia. Further procedure-specific RCTs including broader measures of recovery are recommended to compare the overall efficacy of epidural and wound infiltration analgesic techniques.

Long-term renal outcomes of consecutive patients undergoing open type IV thoracoabdominal aneurysm repair.

OBJECTIVE: To evaluate long-term renal outcomes after open type IV thoracoabdominal aneurysm (TAAA) repair. DESIGN: Retrospective analysis of a prospectively collected database of consecutive operated non-ruptured type IV TAAAs (2007-2011). METHODS: Renal function was analysed by serum creatinine concentration, estimated glomerular filtration rate (eGFR) and Kidney Disease Outcomes Quality Initiative (KDOQI) stage. The primary outcome was the change in creatinine concentration from before surgery to defined time points after surgery: peak postoperative; discharge; at follow-up (>1 year postoperatively). Secondary outcomes were change in eGFR, change in KDOQI stage, dialysis requirement, and 30-day mortality. RESULTS: Between 2007 and 2011, 53 open type IV TAAA repairs were performed. Median creatinine levels significantly increased in the immediate postoperative period, but returned to baseline by discharge. Thirteen patients (28.2%) had an improvement in follow-up eGFR of at least 20% compared with pre-operative eGFR or improved by one KDOQI stage. Twelve patients (26.1%) had a decline in eGFR of at least 20% or one KDOQI stage at follow-up. Three patients (7.5%) required temporary dialysis and one patient (1.9%) required permanent dialysis. The 30-day mortality was 1.9%. CONCLUSIONS: This study demonstrates acceptable renal outcomes following open type IV TAAA repair. Open type IV repair remains the standard against which newer techniques should be compared.

Prophylactic mesh placement of permanent stomas at index operation for colorectal cancer.

INTRODUCTION: Parastomal herniation occurs in 30-50% of colostomy formations. The aim of this study was to radiologically evaluate the mechanical defects at stoma sites in patients who had previously undergone a permanent colostomy with or without mesh at the index operation for colorectal cancer. METHODS: A study was performed of all colorectal cancer patients (n=41) having an end colostomy between 2002 and 2010, with or without Prolene(®) mesh plication, with blinded evaluation of the annual follow-up staging computed tomography (CT) for stomal characteristics. The presence of parastomal hernias, volume, dimensions, grade of the parastomal hernia and abdominal wall defect size were measured by two independent radiologists, and compared with demographic and operative variables. RESULTS: In those patients with radiological evidence of a parastomal hernia, Prolene(®) mesh plication significantly reduced the incidence of bowel containing parastomal hernias at one year following the procedure (p<0.05) and also reduced the diameter of the abdominal wall defect (p=0.006). CONCLUSIONS: Prophylactic mesh placement at the time of the index procedure reduces the diameter of abdominal wall aperture and the incidence of parastomal hernias containing bowel. Future studies should use both objective radiological as well as clinical endpoints when assessing parastomal hernia development with and without prophylactic mesh.

Open transversus abdominis plane block and analgesic requirements in patients following right hemicolectomy.

INTRODUCTION: Reducing exogenously administered opioids in the post-operative period is associated with early return of bowel function and decreased post-operative complication rates. We evaluated the effectiveness of a surgeon-delivered open transversus abdominis plane (TAP) block as a method to reduce post-operative opioid requirements, sedation and inpatient stay. METHODS: The patient cohort was identified from those who had undergone a right hemicolectomy for colonic cancer. Patients received either an open TAP block and post-operative patient controlled anaesthesia (PCA) ( n =20) or were part of a control group who received subcutaneous local anaesthetic infiltration and PCA ( n =16). RESULTS: PCA morphine use was reduced within the first 24 hours post-operatively in the TAP block group compared with controls (42.1mg vs 72.3mg, p =0.002). Sedation was also reduced significantly in the early post-operative period (p <0.04). There was a non-significant trend towards reduced length of stay in the intervention group (8.2 vs 8.73 days). There were no recorded complications attributable to the open TAP block. CONCLUSIONS: Open TAP blocks are safe and reduce post-operative opioid requirements and sedation after right hemicolectomies. They should be considered as part of a multimodal enhanced recovery approach to patients undergoing abdominal surgery via a transverse incision.

Clinical effectiveness of transversus abdominis plane (TAP) block in abdominal surgery: a systematic review and meta-analysis.

AIM: Reduced opioid use in the immediate postoperative period is associated with decreased complications. This study aimed to determine the effect of transversus abdominis plane (TAP) block on morphine requirements 24 h after abdominal surgery. Secondary outcomes included the effect of TAP block on morphine use 48 h after surgery, incidence of postoperative nausea and vomiting (PONV) and impact on reported pain scores (visual analogue scale). METHOD: A systematic review of the literature was conducted for randomised controlled trials (RCTs) evaluating the effects of TAP block in adults undergoing abdominal surgery. For continuous data, weighted mean differences (WMD) were formulated; for dichotomous data, odds ratios (OR) were calculated. Results were produced with a random effects model with 95% confidence intervals (CI). RESULTS: Nine studies, including published and unpublished data, containing a total of 413 patients were included. Of these 205 received a TAP block and 208 a placebo. Cumulative morphine utilization was statistically significantly reduced at 24 h. [WMD=23.71mg (38.66-8.76); P=0.002] and 48h [WMD=38.08mg (18.97-57.19); P<0.0001] in patients who received a TAP block and the incidence of PONV was significantly reduced [OR=0.41(0.22-0.74); P=0.003]. There was a nonsignificant reduction in the visual analogue scales of postoperative pain [WMD=0.73cm (1.84-0.38), P=0.2]. There were no reported adverse events following TAP block. CONCLUSION: Transversus abdominis plane block is safe, reduces postoperative morphine requirements, nausea and vomiting and possibly the severity of pain after abdominal surgery. It should be considered as part of a multimodal approach to anaesthesia and enhanced recovery in patients undergoing abdominal surgery.

Male breast cancer is rare: an initial presentation may be as an abscess.

Breast cancer in men is rare. Breast cancer presenting initially as an abscess has been described only a handful of times in the literature. We present the first described case of invasive adenocarcinoma presenting as an abscess in a man. An 80-year-old diabetic man presented with symptoms typical of a breast abscess. The abscess failed to respond to percutaneous therapy and excision of breast abscess was performed. Histology revealed an invasive carcinoma. He went on to have a mastectomy. Histology should be obtained from breast abscesses not resolving within 2 months of initial percutaneous therapy. Histology could be obtained by ultrasound-guided fine-needle aspiration (FNA), core or vacuum assisted biopsy, or by formal incision and drainage.