Oral vitamin D supplementation induces transcriptomic changes in rectal mucosa that are linked to anti-tumour effects.

BACKGROUND: The risk for several common cancers is influenced by the transcriptomic landscape of the respective tissue-of-origin. Vitamin D influences in vitro gene expression and cancer cell growth. We sought to determine whether oral vitamin D induces beneficial gene expression effects in human rectal epithelium and identify biomarkers of response. METHODS: Blood and rectal mucosa was sampled from 191 human subjects and mucosa gene expression (HT12) correlated with plasma vitamin D (25-OHD) to identify differentially expressed genes. Fifty subjects were then administered 3200IU/day oral vitamin D3 and matched blood/mucosa resampled after 12 weeks. Transcriptomic changes (HT12/RNAseq) after supplementation were tested against the prioritised genes for gene-set and GO-process enrichment. To identify blood biomarkers of mucosal response, we derived receiver-operator curves and C-statistic (AUC) and tested biomarker reproducibility in an independent Supplementation Trial (BEST-D). RESULTS: Six hundred twenty-nine genes were associated with 25-OHD level (P < 0.01), highlighting 453 GO-term processes (FDR<0.05). In the whole intervention cohort, vitamin D supplementation enriched the prioritised mucosal gene-set (upregulated gene-set P < 1.0E-07; downregulated gene-set P < 2.6E-05) and corresponding GO terms (P = 2.90E-02), highlighting gene expression patterns consistent with anti-tumour effects. However, only 9 individual participants (18%) showed a significant response (NM gene-set enrichment P < 0.001) to supplementation. Expression changes in HIPK2 and PPP1CC expression served as blood biomarkers of mucosal transcriptomic response (AUC=0.84 [95%CI 0.66-1.00]) and replicated in BEST-D trial subjects (HIPK2 AUC=0.83 [95%CI 0.77-0.89]; PPP1CC AUC=0.91 [95%CI 0.86-0.95]). CONCLUSIONS: Higher plasma 25-OHD correlates with rectal mucosa gene expression patterns consistent with anti-tumour effects, and this beneficial signature is induced by short-term vitamin D supplementation. Heterogenous gene expression responses to vitamin D may limit the ability of randomised trials to identify beneficial effects of supplementation on CRC risk. However, in the current study blood expression changes in HIPK2 and PPP1CC identify those participants with significant anti-tumour transcriptomic responses to supplementation in the rectum. These data provide compelling rationale for a trial of vitamin D and CRC prevention using easily assayed blood gene expression signatures as intermediate biomarkers of response.

Low plasma vitamin D is associated with adverse colorectal cancer survival after surgical resection, independent of systemic inflammatory response.

OBJECTIVE: We assessed the effect of surgical resection of colorectal cancer (CRC) on perioperative plasma vitamin D (25OHD) and C-reactive protein (CRP) level. We investigated the relationship between circulating vitamin D level and CRC survival. DESIGN: We sequentially sampled 92 patients undergoing CRC resection, and measured plasma 25OHD and CRP. For survival analyses, we assayed 25OHD and CRP in two temporally distinct CRC patient cohorts (n=2006, n=2100) and investigated the association between survival outcome, circulating vitamin D and systemic inflammatory response. RESULTS: Serial sampling revealed a postoperative fall (mean 17.3 nmol/L; p=3.6e-9) in plasma 25OHD (nadir days 1-2). CRP peaked 3-5 days postoperatively (143.1 mg/L; p=1.4e-12), yet the postoperative fall in 25OHD was independent of CRP. In cohort analyses, 25OHD was lower in the 12 months following operation (mean=48.8 nmol/L) than preoperatively (54.8 nmol/L; p=1.2e-5) recovering after 24 months (52.2 nmol/L; p=0.002). Survival analysis in American Joint Committee on Cancer stages I-III demonstrated associations between 25OHD tertile and CRC mortality (HR=0.69; 95% CI 0.46 to 0.91) and all-cause mortality (HR=0.68; 95% CI 0.50 to 0.85), and was independent of CRP. We observed interaction effects between plasma 25OHD and rs11568820 genotype (functional VDR polymorphism) with a strong protective effect of higher 25OHD only in patients with GG genotype (HR=0.51; 95% CI 0.21 to 0.81). We developed an online tool for predicted survival (https://apps.igmm.ed.ac.uk/mortalityCalculator/) that incorporates 25OHD with clinically useful predictive performance (area under the curve 0.77). CONCLUSIONS: CRC surgery induces a fall in circulating 25OHD. Plasma 25OHD level is a prognostic biomarker with low 25OHD associated with poorer survival, particularly in those with rs11568820 GG genotype. A randomised trial of vitamin D supplementation after CRC surgery has compelling rationale.

A Modified AUGIS Delphi Process to Establish Future Research Priorities in Benign Upper Gastrointestinal Surgery.

BACKGROUND: The aim of our study was to use a modified Delphi process to determine the research priorities amongst benign upper gastrointestinal (UGI) surgeons in the United Kingdom. METHODS: Delphi methodology may be utilised to develop consensus opinion amongst a group of experts. Members of the Association of Upper Gastrointestinal Surgeons of Great Britain and Ireland were invited to submit individual research questions via an online survey (phase I). Two rounds of prioritisation by multidisciplinary expert healthcare professionals (phase II and III) were completed to determine a final list of high-priority research questions. RESULTS: Four hundred and twenty-seven questions were submitted in phase I, and 51 with a benign UGI focus were taken forward for prioritisation in phase II. Twenty-eight questions were ranked in phase III. A final list of 11 high-priority questions had an emphasis on acute pancreatitis, Barrett's oesophagus and benign biliary disease. CONCLUSION: A modified Delphi process has produced a list of 11 high-priority research questions in benign UGI surgery. Future studies and awards from funding bodies should reflect this consensus list of prioritised questions in the interest of improving patient care and encouraging collaborative research.

Trainee experience of 'out of hours' surgical working in the UK: A cross-sectional analysis.

BACKGROUND: Changes to working practices and increasing service demand have contributed to low morale amongst UK surgical trainees, with pressures particularly acute 'out of hours' (OOH). Surgeons may be expected to be 'on call' for multiple hospitals, or to provide remote consultations, yet healthcare systems may undermine their professional safety and patient care. This cross-sectional study sought to define the perceptions of UK-based Royal College of Surgeons of Edinburgh (RCSEd) affiliated trainees of OOH surgical care and training. METHODS: The RCSEd Trainees' Committee conducted a design-thinking exercise to produce an online questionnaire. Non-consultant grade RCSEd Members and Fellows were invited to participate. Quantitative data was analysed using descriptive statistics, and qualitative data was coded to identify emergent themes. RESULTS: One hundred and fifty-five surgeons participated. Of those surgeons working in multiple hospitals OOH (n = 16), many did not receive access cards (12[75%]) or site-specific induction (13[81%]), and 8(50%) were not confident in using local electronic investigation and records systems. Only 14/114 (12%) of the surgeons providing remote opinion had access to a consultation record system, and most perceived dissatisfaction with the system. Emergent themes from qualitative data revealed that trainee surgeons desire specific training in OOH working, concerns that OOH work experience is diminishing, and that hospital infrastructure such as IT and communications, rest facilities and catering were inadequate in facilitating safe care. CONCLUSIONS: The participants perceived that the systems supporting delivery of safe surgical care OOH were inadequate. Hospital leaders should ensure that systems minimise risk to staff and patients.

The impact of vitamin D pathway genetic variation and circulating 25-hydroxyvitamin D on cancer outcome: systematic review and meta-analysis.

BACKGROUND: Vitamin D has been linked with improved cancer outcome. This systematic review and meta-analysis investigates the relationship between cancer outcomes and both vitamin D-related genetic variation and circulating 25-hydroxyvitamin D (25OHD) concentration. METHODS: A systematic review and meta-analysis of papers until November 2016 on PubMed, EMBASE and Web of Science pertaining to association between circulating vitamin D level, functionally relevant vitamin D receptor genetic variants and variants within vitamin D pathway genes and cancer survival or disease progression was performed. RESULTS: A total of 44 165 cases from 64 studies were included in meta-analyses. Higher 25OHD was associated with better overall survival (hazard ratio (HR=0.74, 95% CI: 0.66-0.82) and progression-free survival (HR=0.84, 95% CI: 0.77-0.91). The rs1544410 (BsmI) variant was associated with overall survival (HR=1.40, 95% CI: 1.05-1.75) and rs7975232 (ApaI) with progression-free survival (HR=1.29, 95% CI: 1.02-1.56). The rs2228570 (FokI) variant was associated with overall survival in lung cancer patients (HR=1.29, 95% CI: 1.0-1.57), with a suggestive association across all cancers (HR=1.26, 95% CI: 0.96-1.56). CONCLUSIONS: Higher 25OHD concentration is associated with better cancer outcome, and the observed association of functional variants in vitamin D pathway genes with outcome supports a causal link. This analysis provides powerful background rationale to instigate clinical trials to investigate the potential beneficial effect of vitamin D in the context of stratification by genotype.

The impact of a dedicated multidisciplinary team on the management of early rectal cancer.

AIM: Local excision of early rectal cancer (ERCa) offers comparable survival and reduced operative morbidity compared with radical surgery, yet it risks an adverse oncological outcome if performed in the wrong setting. This retrospective review considers the impact of the introduction of a specialist early rectal cancer multidisciplinary team (ERCa MDT) on the investigation and management of ERCa. METHOD: A retrospective comparative cohort study was undertaken. Patients with a final diagnosis of pT1 rectal cancer at our unit were identified for two 12-month periods before and after the introduction of the specialist ERCa MDT. Data on investigations and therapeutic interventions were compared. RESULTS: Nineteen patients from 2006 and 24 from 2011 were included. In 2006, 12 patients underwent MRI and four transrectal ultrasound (TRUS) examination, while in 2011, 18 and 20, respectively, received MRI and TRUS. In 2006 four patients underwent incidental ERCa polypectomy, with all having a positive resection margin leading to anterior resection. In 2011 only one case with a positive margin following extended endoscopic mucosal resection was identified. Definitive local excision without subsequent resection occurred in two patients in 2006 and in 16 in 2011. CONCLUSION: The study demonstrates an improvement in preoperative ERCa staging, a reduction in margin positivity and an increase in the use of local excision following the implementation of a specialist ERCa MDT. The increased detection of rectal neoplasms through screening and surveillance programmes requires further investigation and management. A specialist ERCa MDT will improve management and should be available to all practitioners involved with patients with ERCa.

Two-week wait symptoms are prevalent in screened patients with a positive faecal occult blood test but do not predict cancer.

AIM: Lower gastrointestinal (LGI) symptoms are prevalent in patients screened for bowel cancer yet do not predict a finding of cancer. This study evaluates symptoms in patients with these characteristics against the 2-week wait (2ww) criteria to determine whether they predicted cancer in these patients. METHOD: A prospective cohort study was performed. Patients with a positive faecal occult blood (FOB) test attending our unit over a 7-month period were included. Data on symptom prevalence, frequency and duration were collected and assessed against the 2ww criteria. Associations between symptom prevalence and patient outcome were investigated using the χ(2) test. RESULTS: Three hundred and ninety-seven patients were included and 37 (9%) were found to have colorectal cancer (CRC). The prevalence of undefined LGI symptoms was 71% and appeared comparable between those with and without CRC (65 vs 72%, P = 0.385). 2ww symptoms were reported in 147 (37%), with 2ww change in bowel habit in 10% and 2ww rectal bleeding in 31%. 2ww symptom prevalence was similar in those with and without cancer (38 vs 37%, P = 0.915). No significant differences in overall 2ww prevalence or prevalence of individual 2ww symptoms were demonstrated between those with a normal colonoscopy or one showing cancer, polyps or other pathology. Twenty nine per cent of patients with 2ww symptoms had reported these to their GP. CONCLUSION: Undefined LGI symptoms are prevalent in FOB-positive patients but do not predict CRC. 2ww symptoms are also highly prevalent, yet similarly fail to predict cancer. Further efforts to increase public awareness of cancer symptoms are required, whilst false reassurance from a negative FOB result should be discouraged.

Measures of performance and proficiency in robotic assisted surgery: a systematic review.

Robotic assisted surgery (RAS) has seen a global rise in adoption. Despite this, there is not a standardised training curricula nor a standardised measure of performance. We performed a systematic review across the surgical specialties in RAS and evaluated tools used to assess surgeons' technical performance. Using the PRISMA 2020 guidelines, Pubmed, Embase and the Cochrane Library were searched systematically for full texts published on or after January 2020-January 2022. Observational studies and RCTs were included; review articles and systematic reviews were excluded. The papers' quality and bias score were assessed using the Newcastle Ottawa Score for the observational studies and Cochrane Risk Tool for the RCTs. The initial search yielded 1189 papers of which 72 fit the eligibility criteria. 27 unique performance metrics were identified. Global assessments were the most common tool of assessment (n = 13); the most used was GEARS (Global Evaluative Assessment of Robotic Skills). 11 metrics (42%) were objective tools of performance. Automated performance metrics (APMs) were the most widely used objective metrics whilst the remaining (n = 15, 58%) were subjective. The results demonstrate variation in tools used to assess technical performance in RAS. A large proportion of the metrics are subjective measures which increases the risk of bias amongst users. A standardised objective metric which measures all domains of technical performance from global to cognitive is required. The metric should be applicable to all RAS procedures and easily implementable. Automated performance metrics (APMs) have demonstrated promise in their wide use of accurate measures.

Repeat 2-week wait referrals for colorectal cancer.

AIM: The inappropriate use of the '2-week wait' pathway for suspected colorectal cancer (CRC2ww) may overload urgent clinics and delay the assessment and investigation of other patients. Those who have been previously referred and investigated for suspected colorectal cancer may present one group that does not warrant repeat urgent referral. This paper aims to identify the incidence and diagnostic yield of repeat CRC2ww referrals. METHOD: All CRC2ww patients referred to our unit over a 4-year period were identified retrospectively. Referral indication, outcome and instances of repeat referral were identified from multidisciplinary team, endoscopy and imaging databases. RESULTS: In all, 2735 CRC2ww referrals were made over the study period. Of these, 122 were repeated CRC2ww referrals, with the incidence increasing from 2% in 2008 to 6% in 2010 (P = 0.0006). The median time to repeat referral was 1070 days. After initial referral 267 cancers were detected, including 212 colorectal cancers. The diagnostic yield was lower but not significantly so after repeated referral (six cancers) compared with initial referral (5%vs 10%, P = 0.07). CONCLUSION: The incidence of repeat referral is low but the diagnostic yield is not insignificant. Exclusion of these patients from urgent assessment and investigation will not significantly reduce workload and may risk missing some patients with cancer.

A feasibility study of perioperative vitamin D supplementation in patients undergoing colorectal cancer resection.

Background: Vitamin D supplementation improves colorectal cancer (CRC) survival outcomes in randomized trials. The aim of this study was to test the feasibility, safety and efficacy of vitamin D supplementation in the pre- and perioperative period in patients undergoing CRC surgery. Methods: Patients were given 3200IU oral cholecalciferol (D3) per day perioperatively. Serial serum 25-hydroxyvitamin (25OHD) was measured by liquid chromatography tandem mass spectrometry and compared to untreated CRC controls. 25OHD and C-reactive protein (CRP) levels were compared using adjusted generalized linear mixed-effects models. Results: A total of 122 patients underwent serial perioperative sampling, including 41 patients given high-dose perioperative supplementation. Supplementation was well-tolerated with no adverse or serious adverse events related to supplementation reported. Pre-operative supplementation increased 25OHD levels on the day of surgery (103.9 vs. 42.5 nmol/l, P = 8.2E-12). Supplementation increased 25OHD levels at all post-operative timepoints (P < 0.001) and attenuated the post-operative drop in 25OHD (46 vs. 24% drop, P = 3.0E-4). Rate of vitamin D peri-operative insufficiency was significantly less in those on supplementation (e.g., day 3-5, 14 vs. 84%, P = 1.41E-08), with multivariate modeling across all timepoints indicating a ∼59 nmol/l higher 25OHD compared to control patients (P = 3.7E-21). Post-operative CRP was lower in patients taking supplementation (e.g., day 3-5 timepoint; 129 vs. 81 mg/l, P = 0.04). Conclusion: High dose pre-operative vitamin D supplementation is associated with higher perioperative 25OHD levels, lower rates of vitamin D insufficiency and reduced early post-operative CRP. Alongside published evidence for a beneficial effect of vitamin D on CRC survival outcomes, these novel findings provide strong rationale for early initiation of vitamin D supplementation after a diagnosis of CRC.

A meta-analysis of the effectiveness of the opioid receptor antagonist alvimopan in reducing hospital length of stay and time to GI recovery in patients enrolled in a standardized accelerated recovery program after abdominal surgery.

BACKGROUND: Despite accelerated recovery programs and the widespread uptake of laparoscopic surgery, postoperative ileus remains a significant factor affecting length of stay after abdominal surgery. Alvimopan, an opioid-receptor antagonist, may reduce the incidence of postoperative ileus and expedite hospital discharge. OBJECTIVE: The aim of this study was to perform a meta-analysis to determine the role of alvimopan in accelerating GI recovery and hospital discharge after laparoscopic and open abdominal surgery performed within an accelerated recovery program. DATA SOURCES AND STUDY SELECTION: Cochrane (1999-2010), Embase (1980-2010), MEDLINE (1980-2010), and International Pharmaceutical Abstracts (1970-2010) were searched for relevant double-blinded, randomized controlled trials. INTERVENTIONS: Twelve milligrams of alvimopan and placebo were given to patients enrolled in an accelerated recovery program after abdominal surgery. MAIN OUTCOME MEASURES: The primary outcomes measured were the length of stay as defined by the writing of the hospital discharge order and GI-3 and GI-2 GI tract recovery. RESULTS: : Three trials were included that reported on a pooled modified intention-to-treat population of 1388 patients; 685 (49%) patients received alvimopan. On meta-analysis, alvimopan reduced time to the hospital discharge order (HR 1.37 (1.21, 1.62), p < 0.0001), GI-3 recovery (HR 1.42 (1.25, 1.62), p < 0.001), and GI-2 recovery (HR 1.49 (1.32, 1.68), p < 0.0001). LIMITATIONS: The search criteria identified only a small number of trials of alvimopan after abdominal surgery with no randomized trials of alvimopan after laparoscopic surgery. In addition, the use of length of hospital stay as the primary outcome measure may be inappropriate, because it is open to many confounding factors. Finally, adverse events, in particular, adverse cardiovascular events, were not considered. CONCLUSIONS: Alvimopan 12 mg can further reduce time to GI recovery and hospital discharge in patients undergoing abdominal surgery within an accelerated recovery program. Investigation into the effect of alvimopan following laparoscopic surgery and additional cost-benefit analyses are required to further define the role of this intervention.

A prospective case-control study of extralevator abdominoperineal excision (ELAPE) of the rectum versus conventional laparoscopic and open abdominoperineal excision: comparative analysis of short-term outcomes and quality of life.

BACKGROUND: Conventional abdominoperineal excision (APE) of the rectum is associated with higher circumferential resection margin (CRM) involvement, increased local recurrence, and reduced survival compared to anterior resection. A more radical extralevator APE (ELAPE) technique may improve oncological outcome. However, this technique may confer additional morbidity, and little comparative data on short-term outcomes have been reported. This study compares short-term outcomes and quality of life (QOL) after open and laparoscopic ELAPE, laparoscopic APE (LAPE), and open APE (OAPE). METHODS: Data on all ELAPE and 10 consecutive LAPE and OAPE were extracted from a prospective database. Perioperative care and follow-up were standardized. QOL was assessed using EORTC questionnaires. RESULTS: Sixteen ELAPE (14 laparoscopic), 10 LAPE, and 10 OAPE were included. Demographics, tumour stage, and neoadjuvant therapy use were comparable. Operative time was higher with ELAPE than LAPE and OAPE (295, 207.5, and 157.5 min, respectively, p = 0.01). A porcine collagen perineal mesh was used in 9 patients undergoing ELAPE but in no LAPE or OAPE patients. No difference in 30-day complications, re-admission, or length of stay was noted. ELAPE and LAPE were associated with earlier removal of urinary catheter (p = 0.02), yet other enhanced recovery after surgery (ERAS) parameters were equivalent. All ELAPE resections were R0 with no positive CRM identified. One LAPE and 2 OAPE were R1 resections. Analysis revealed no deterioration in QOL with ELAPE, with equivalent global health status. CONCLUSIONS: The results of this study suggest that ELAPE is not associated with deterioration in short-term outcomes or QOL when compared with LAPE or OAPE.

A systematic review and meta-analysis of baseline risk factors for the development of postoperative ileus in patients undergoing gastrointestinal surgery.

INTRODUCTION: Postoperative ileus occurs frequently following abdominal surgery. Identification of groups at high risk of developing ileus before surgery may allow targeted interventions. This review aimed to identify baseline risk factors for ileus. METHODS: A systematic review was conducted with reference to PRISMA and MOOSE guidelines. It was registered on PROSPERO (CRD42017068697). Searches of MEDLINE, EMBASE and CENTRAL were undertaken. Studies reporting baseline risk factors for the development of postoperative ileus based on cohort or trial data and published in English were eligible for inclusion. Dual screening of abstracts and full texts was undertaken. Independent dual extraction was performed. Bias assessment was undertaken using the quality in prognostic studies tool. Meta-analysis using a random effects model was undertaken where two or more studies assessed the same variable. FINDINGS: Searches identified 2,430 papers, of which 28 were included in qualitative analysis and 12 in quantitative analysis. Definitions and incidence of ileus varied between studies. No consistent significant effect was found for association between prior abdominal surgery, age, body mass index, medical comorbidities or smoking status. Male sex was associated with ileus on meta-analysis (odds ratio 1.12, 95% confidence interval 1.02-1.23), although this may reflect unmeasured factors. The literature shows inconsistent effects of baseline factors on the development of postoperative ileus. A large cohort study using consistent definitions of ileus and factors should be undertaken.

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.

A simple method to overcome the inhibitory effect of heparin on DNA amplification.

BACKGROUND: Genetic material from large patient cohorts is increasingly central to translational genetic research. However, patient blood samples are a finite resource and their supply and storage are often dictated by clinical and not research protocols. Our experience supports difficulty in amplifying DNA from blood stored in herparin; a scenario that other researchers may have or will encounter. This technical note describes a number of simple steps that enable successful PCR amplification. METHODS: DNA was extracted using the Illustra Nucleon Genomic DNA Extraction Kit. PCR amplification was attempted using a number of commercially available PCR mastermixes. RESULTS: PCR DNA amplification failed using ReddyMix™ PCR Master Mix, Thermo-Start® (Thermo Scientific Inc. US) and ZymoTaq™ (Zymo research, US) PCR mastermixes, as demonstrated absence of products on gel electrophoresis. However, using the Invitrogen™ (Thermo Scientific Inc., US) Platinum® Taq DNA Polymerase, PCR products were identified on a 1% agarose gel for all samples. PCR products were cleaned with ExoSAP-IT® (Affymetrix Inc., US) and a sequencing reaction undertaken using a standard Big Dye protocol. Subsequent genotyping was successful for all samples for alleles at the CDH1 locus. CONCLUSION: From our experience a standard phenol/chloroform purification and using the Invitrogen™ Platinum® Taq has enabled the amplification of whole blood samples taken into lithium heparin and stored frozen for up to a month. This simple method may enable investigators to utilise blood taken in lithium heparin for DNA extraction and amplification.

Systematic analysis of missed colorectal cancer cases and common pitfalls in diagnosis.

BACKGROUND: Missed colorectal cancer on endoscopic or radiological investigations may delay diagnosis and impact outcome. This study audits incidence of previous investigations in patients with colorectal cancer, considers outcome in 'missed' cancer cases and examines the diagnostic pathway in the derived case series to identify common pitfalls in diagnosis. METHODS: Patients diagnosed with colorectal cancer in 2011 at a single National Health Service (NHS) Trust were reviewed. Incidence of endoscopic and radiological investigations in the 3 years preceding diagnosis and outcome data were collected. Cases of prior investigation not leading to diagnosis were considered 'missed' cancers and survival compared with 'detected' cases. The diagnostic pathway in each 'missed' case was reviewed. RESULTS: 395 colorectal cancer cases were studied. Eighteen (4.6%) patients underwent previous investigation including colonoscopy (n=4), flexible sigmoidoscopy (n=5), barium enema (n=5) and diagnostic abdominal CT scan (n=12), median 708 days prior to diagnosis. Previous investigation predicted reduced overall and disease-free survival (HR 2.07, p=0.04 and HR 2.66, p<0.0001), after age and gender adjustment. Ten different categories termed 'pitfalls' were derived from analysis of the diagnostic pathway. These included CT scanning for abdominal pain without further investigation (n=7), rectosigmoid cancer following a previous diagnosis of diverticular disease (n=4) and incomplete diagnostic investigations without adequate follow-up (n=3). CONCLUSIONS: A proportion of patients diagnosed with colorectal cancer have previously been investigated for gastrointestinal symptoms and survival appears reduced in these patients. Regular audit and analysis of previous investigations can identify common pitfalls in diagnosis, which should be used to inform training and improve practice.