Dr Peter Pockney

Background: Familial adenomatous polyposis (FAP) is an autosomal dominant condition that predisposes patients to colorectal cancer. FAP is the result of a loss of APC function due to germline pathogenic variants disrupting gene expression. Genotype-phenotype correlations are described for FAP. For example attenuated forms of the disease are associated with pathogenic variants at the 5¿ and 3¿ ends of APC whilst severe forms of the disease appear to be linked to variants occurring in the mutation cluster region (MCR) of the gene. Variants occurring in the MCR are phenotypically associated with hundreds to thousands of adenomas carpeting the colon and rectum and patients harbouring changes in this region have a high propensity to develop colorectal cancer. Not all patients who carry pathogenic variants in this region have severe disease which may be a result of environmental factors. Alternatively, phenotypic variation observed in these patients could be due to modifier genes that either promote or inhibit disease expression. Mouse models of FAP have provided several plausible candidate modifier genes, but very few of these have survived scrutiny. One such genetic modifier that appears to be associated with disease expression is CD36. We previously reported a weak association between a polymorphism in CD36 and a later age of disease onset on a relatively small FAP patient cohort. Methods: In the current study, we enlarged the FAP cohort. 395 patients all carrying pathogenic variants in APC were tested against three CD36 Single Nucleotide Polymorphisms (SNP)s (rs1049673, rs1761667 rs1984112), to determine if any of them were associated with differences in the age of disease expression. Results: Overall, there appeared to be a statistically significant difference in the age of disease onset between carriers of the variant rs1984112 and wildtype. Furthermore, test equality of survivor functions for each SNP and mutation group suggested an interaction in the Log Rank, Wilcoxon, and Tarone-Ware methods for rs1049673, rs1761667, and rs1984112, thereby supporting the notion that CD36 modifies disease expression. Conclusions: This study supports and strengthens our previous findings concerning CD36 and an association with disease onset in FAP, AFAP and FAP-MCR affected individuals. Knowledge about the role CD36 in adenoma development may provide greater insight into the development of colorectal cancer.

Aim: This study aimed to describe the change in surgical practice and the impact of SARS-CoV-2 on mortality after surgical resection of colorectal cancer during the initial phases of the SARS-CoV-2 pandemic. Method: This was an international cohort study of patients undergoing elective resection of colon or rectal cancer without preoperative suspicion of SARS-CoV-2. Centres entered data from their first recorded case of COVID-19 until 19 April 2020. The primary outcome was 30-day mortality. Secondary outcomes included anastomotic leak, postoperative SARS-CoV-2 and a comparison with prepandemic European Society of Coloproctology cohort data. Results: From 2073 patients in 40 countries, 1.3% (27/2073) had a defunctioning stoma and 3.0% (63/2073) had an end stoma instead of an anastomosis only. Thirty-day mortality was 1.8% (38/2073), the incidence of postoperative SARS-CoV-2 was 3.8% (78/2073) and the anastomotic leak rate was 4.9% (86/1738). Mortality was lowest in patients without a leak or SARS-CoV-2 (14/1601, 0.9%) and highest in patients with both a leak and SARS-CoV-2 (5/13, 38.5%). Mortality was independently associated with anastomotic leak (adjusted odds ratio 6.01, 95% confidence interval 2.58¿14.06), postoperative SARS-CoV-2 (16.90, 7.86¿36.38), male sex (2.46, 1.01¿5.93), age >70¿years (2.87, 1.32¿6.20) and advanced cancer stage (3.43, 1.16¿10.21). Compared with prepandemic data, there were fewer anastomotic leaks (4.9% versus 7.7%) and an overall shorter length of stay (6 versus 7¿days) but higher mortality (1.7% versus 1.1%). Conclusion: Surgeons need to further mitigate against both SARS-CoV-2 and anastomotic leak when offering surgery during current and future COVID-19 waves based on patient, operative and organizational risks.

We conducted a systematic review of the literature to establish the prevalence of and predictive factors for parental decision regret in hypospadias surgery. A search strategy without language restrictions was developed with expert help, and two reviewers undertook independent study selection. Five studies were included in this review (four for quantitative analysis) with a total of 783 participants. The mean overall prevalence of parental decision regret was 65.2% (moderate to severe ¿ 20.3%). Although significant predictors of regret were identified (post-operative complications, small size glans, meatal location, decision conflict between parents, parental educational level and others), they had unexplained discordance between studies. Parental decision regret after proximal hypospadias surgery and refusing surgery was inadequately reported. In conclusion, even though the prevalence of parental decision regret after consenting for the hypospadias repair appears to be high, risk factors associated with it were discordant suggesting imprecision in estimates due to unknown confounders.

Background: The National Emergency Laparotomy Audit (NELA) highlights the importance of identifying high-risk patients due to the potential for significant morbidity and mortality. The NELA risk prediction calculator (NRPC) was developed from data in England and Wales and is one of several calculators available. We seek to determine the utility of NRPC in the Australian population and compare it with Portsmouth Physiological and Operative Severity Score for the enumeration of mortality and Morbidity (P-POSSUM) and American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) calculators. Methods: A retrospective review of all emergency laparotomies undertaken at four Australian centers was performed between January 2016 and December 2017. Data extracted from patient records were used to calculate NRPC, ACS-NSQIP, and P-POSSUM scores for 30-day mortality risk. The sensitivity of NRPC was assessed using the NELA high-risk cohort score of =10% and this was compared with the other two calculators. Results: There were 562 (M = 261, mean age = 66 [±17] y) patient charts reviewed in the study period. 59 patients died within 30 d (10.5%). NRPC was able to identify 52 (sensitivity = 88.1%) of these as being within the high-risk group. Using the NELA high-risk cutoff, NRPC identified 52 deaths of 205 (25.4%) high-risk patients, P-POSSUM identified 46 of 245 (18.8%), and ACS-NSQIP identified 46 of 201 (22.9%). Using the McNemar test, no significant difference was noted between NRPC and P-POSSUM (P = 0.07) or NRPC and ACS-NSQIP (P = 0.18). Conclusions: In the Australian context, the NRPC is a highly sensitive and useful tool for predicting 30-day mortality in high-risk emergency laparotomy patients and is comparable with P-POSSUM and ACS-NSQIP calculators.

Background: Anastomotic leak is a common complication after colorectal surgery, associated with increased morbidity and mortality, and poorer long-term survival after oncological resections. Early diagnosis improves short-term outcomes, and may translate into reduced cancer recurrence. Multiple studies have attempted to identify biomarkers to enable earlier diagnosis of anastomotic leak. One study demonstrated that the trajectory of C-reactive protein (CRP) levels was highly predictive of anastomotic leak requiring intervention, with an area under the curve of 0·961. The aim of the present study was to validate this finding externally. Methods: This was a prospective international multicentre observational study of adults undergoing elective colorectal resection with an anastomosis. CRP levels were measured before operation and for 5 days afterwards, or until day of discharge if earlier than this. The primary outcome was anastomotic leak requiring operative or radiological intervention. Results: Between March 2017 and July 2018, 933 patients were recruited from 20 hospitals across Australia, New Zealand, England and Scotland. Some 833 patients had complete CRP data and were included in the primary analysis, of whom 41 (4·9 per cent) developed an anastomotic leak. A change in CRP level exceeding 50 mg/l between any two postoperative days had a sensitivity of 0·85 for detecting a leak, and a high negative predictive value of 0·99 for ruling it out. A change in CRP concentration of more than 50 mg/l between either days 3 and 4 or days 4 and 5 after surgery had a high specificity of 0·96¿0·97, with positive likelihood ratios of 4·99¿6·44 for a leak requiring intervention. Conclusion: This study confirmed the value of CRP trajectory in accurately ruling out an anastomotic leak after colorectal resection.

Background: A direct access colonoscopy service (DACS) for the National Bowel Cancer Screening Program has become standard of care in Newcastle public hospitals because of the effect it has on time to colonoscopy. Cost-effectiveness has not been studied to date. Aim: The aim of this retrospective study was to analyse the cost-effectiveness of a DACS. Methods: Data were collected for patients referred to DACS between January 2014 and June 2016, and patients who were treated on the normal service pathway in 2013 prior to the introduction of the process. A cost-benefit analysis from the patient¿s and local health district¿s perspective was undertaken. Results: Introduction of the DACS produces a direct financial gain to patients in the form of reduced direct costs. It produces an indirect financial gain in terms of increased productivity if the patient is in work, and of increased leisure time if not in work. The DACS is modest income generating for the local health district, an evaluation which is sensitive to internal policies for distribution of government funding within a district. The DACS increases the availability of outpatient consultations to other patients, which is not a quantifiable economic benefit, but is likely to be an overall health benefit. Conclusion: The introduction of DACS in the public system in Australia is of financial benefit to patients and to the local health service provider. It is likely to produce health benefits to non-screening patients, by means of freeing consultations to be used for other indications.

Background: The 2017 National Bowel Cancer Screening Program report records a median time from positive faecal occult blood test to colonoscopy of 53 days. There is some intrinsic delay in accessing specialist medical opinion prior to colonoscopy. Aim: To examine the effect of the introduction of a Direct Access Colonoscopy Service (DACS). Methods: Using prospectively maintained databases, patients undergoing normal service (NS) colonoscopy and those referred to DACS were compared. The primary outcome measure was the time from general practitioner (GP) referral to colonoscopy. Secondary outcome measures included the proportion of patients who met the current recommended 30 days from GP referral to colonoscopy, and the proportion of patients who waited longer than 90 days. Results: There were 289 patients in the NS group, and 601 patients who progressed on the DACS pathway. The demographics of both groups were comparable. DACS patients had a median waiting time of 49 days, significantly shorter than NS patients whose median wait was 79 days (P < 0.0001). Approximately 15.1% patients in the DACS group had their colonoscopy within 30 days from GP referral, significantly better than in the NS group (4.5%, P < 0.001). In the NS group, 41.2% patients waited longer than 90 days from GP referral to colonoscopy, compared with 16.3% in the DACS group (P < 0.001). Conclusion: DACS reduces waiting times to colonoscopy and is associated with an increased proportion of patients undergoing colonoscopy in a timely manner.

Introduction: Previous studies have shown single CRP measurements at time of presentation to have limited predictive benefit for appendicitis. Our objective was to determine the diagnostic utility of serial CRP measurements (to determine CRP velocity [CRPv]) in patients with right iliac fossa (RIF) pain. Methods: A single-centre prospective observational study was conducted on adult patients admitted with RIF pain. CRP was measured on admission, at midnight, and the following morning. Appendicitis was diagnosed on histopathology, or diagnostic imaging in non-operatively managed patients. Therapeutic interventions included all appropriate operative procedures and effective non-operative treatment with antibiotics. Logistic regression was used to generate predictors of therapeutic intervention, and then used to create a new risk score incorporating CRPv. Results: 98 of 112 (87.5%) participants had complete CRP data. 58 patients met the criteria for appendicitis (59.2%). Most patients presented with intermediate Modified Alvarado Scores (MAS) 5¿6 (40.8%) or Appendicitis Inflammatory Response Scores (AIRS) 5¿8 (49%). Our risk score had an AUROC of 0.88 (95% CI 0.81¿0.96) in predicting therapeutic intervention. This score was superior to MAS, AIRS, and single admission biomarker measurements. Patients with an increasing CRPv had 14 times the odds (OR 14.07, 95% CI 0.63¿315.2) of complicated appendicitis, and no cases of complicated appendicitis were observed in patients with a flat CRPv. Conclusions: CRP velocity is superior to single CRP at predicting intervention. Our v-Score shows promise as a decision making-aide by predicting the need for surgical intervention in RIF pain. A flat CRPv identifies a group of patients with a very low risk of complicated appendicitis.

Background: Circulating tumour DNA (ctDNA) has emerged as an excellent candidate for the future of liquid biopsies for many cancers. There has been growing interest in blood-based liquid biopsy because of the potential of ctDNA to produce a noninvasive test that can be used for: the diagnosis of colorectal cancer, monitoring therapy response, and providing information on overall prognosis. The aim of this review was to collate and explore the current evidence regarding ctDNA as a screening tool for colorectal cancer (CRC). Methods: A systematic review of published articles in English over the past 20 y was performed using Medline, Embase, and Cochrane databases on May 23, 2017. After a full-text review, a total of 69 studies were included. Two assessment tools were used to review and compare the methodological quality of these studies. Results: Among the 69 studies included, 17 studies reviewed total cfDNA, whereas six studies looked at the DNA integrity index and 15 focused on ctDNA. There were a total of 40 studies that reviewed methylated cfDNA with 19 of these focussing specifically on SEPT9. Conclusions: The results of this review indicate that methylated epigenetic ctDNA markers are perhaps the most promising candidates for a blood-based CRC-screening modality using cell-free (cf) DNA. Methylated cfDNA appears to be less specific for CRC compared to ctDNA; however, they have demonstrated good sensitivity for early-stage CRC. Further research is required to determine which methylated cfDNA markers are the most accurate when applied to large cohorts of patients. In addition, reliable comparison of results across multiple studies would benefit from standardization of methodology for DNA extraction and PCR techniques in the future.

BACKGROUND: Lower GI hemorrhage is a common source of morbidity and mortality. Tranexamic acid is an antifibrinolytic that has been shown to reduce blood loss in a variety of clinical conditions. Information regarding the use of tranexamic acid in treating lower GI hemorrhage is lacking. OBJECTIVE: The aim of this trial was to determine the clinical efficacy of tranexamic acid when used for lower GI hemorrhage. DESIGN: This was a prospective, double-blind, placebo-controlled, randomized clinical trial. SETTINGS: The study was conducted at a tertiary referral university hospital in Australia. PATIENTS: Consecutive patients aged >18 years with lower GI hemorrhage requiring hospital admission from November 2011 to January 2014 were screened for trial eligibility (N = 265). INTERVENTIONS: A total of 100 patients were recruited after exclusions and were randomly assigned 1:1 to either tranexamic acid or placebo. MAIN OUTCOME MEASURES: The primary outcome was blood loss as determined by reduction in hemoglobin levels. The secondary outcomes were transfusion rates, transfusion volume, intervention rates for bleeding, length of hospital stay, readmission, and complication rates. RESULTS: There was no difference between groups with respect to hemoglobin drop (11 g/L of tranexamic acid vs 13 g/L of placebo; p = 0.9445). There was no difference with respect to transfusion rates (14/49 tranexamic acid vs 16/47 placebo; p = 0.661), mean transfusion volume (1.27 vs 1.93 units; p = 0.355), intervention rates (7/49 vs 13/47; p = 0.134), length of hospital stay (4.67 vs 4.74 d; p = 0.934), readmission, or complication rates. No complications occurred as a direct result of tranexamic acid use. LIMITATIONS: A larger multicenter trial may be required to determine whether there are more subtle advantages with tranexamic acid use in some of the secondary outcomes. CONCLUSIONS: Tranexamic acid does not appear to decrease blood loss or improve clinical outcomes in patients presenting with lower GI hemorrhage in the context of this trial. see Video Abstract at http://links.lww.com/DCR/A453.

Objective: This study aims to report short-term clinical and oncological outcomes from the international transanal Total Mesorectal Excision (taTME) registry for benign and malignant rectal pathology. Background: TaTME is the latest minimally invasive transanal technique pioneered to facilitate difficult pelvic dissections. Outcomes have been published from small cohorts, but larger series can further assess the safety and efficacy of taTME in the wider surgical population. Methods: Data were analyzed from 66 registered units in 23 countries. The primary endpoint was "good-quality TME surgery." Secondary endpoints were short-term adverse events. Univariate and multivariate regression analyses were used to identify independent predictors of poor specimen outcome. Results: A total of 720 consecutively registered cases were analyzed comprising 634 patients with rectal cancer and 86 with benign pathology. Approximately, 67% were males with mean BMI 26.5 kg/m 2. Abdominal or perineal conversion was 6.3% and 2.8%, respectively. Intact TME specimens were achieved in 85%, with minor defects in 11% and major defects in 4%. R1 resection rate was 2.7%. Postoperative mortality and morbidity were 0.5% and 32.6% respectively. Risk factors for poor specimen outcome (suboptimal TME specimen, perforation, and/or R1 resection) on multivariate analysis were positive CRM on staging MRI, low rectal tumor <2 cm from anorectal junction, and laparoscopic transabdominal posterior dissection to <4 cm from anal verge. Conclusions: TaTME appears to be an oncologically safe and effective technique for distal mesorectal dissection with acceptable short-term patient outcomes and good specimen quality. Ongoing structured training and the upcoming randomized controlled trials are needed to assess the technique further.