Lower polyunsaturated fatty acid levels and FADS2 expression in adult compared to neonatal keratinocytes are associated with FADS2 promotor hypermethylation.

Keratinocytes produce lipids that are critical for the skin barrier, however, little is known about the impact of age on fatty acid (FA) biosynthesis in these cells. We have examined the relationship between keratinocyte FA composition, lipid biosynthetic gene expression, gene promoter methylation and age. Expression of elongase (ELOVL6 and 7) and desaturase (FADS1 and 2) genes was lower in adult versus neonatal keratinocytes, and was associated with lower concentrations of n-7, n-9 and n-10 polyunsaturated FA in adult cells. Consistent with these findings, transient FADS2 knockdown in neonatal keratinocytes mimicked the adult keratinocyte FA profile in neonatal cells. Interrogation of methylation levels across the FADS2 locus (53 genomic sites) revealed differential methylation of 15 sites in neonatal versus adult keratinocytes, of which three hypermethylated sites in adult keratinocytes overlapped with a SMARCA4 protein binding site in the FADS2 promoter.

Surgical site infection prevention bundle in elective colorectal surgery.

OBJECTIVE: Surgical Site Infections (SSIs) are responsible for a significant economic burden as well as intangible costs suffered by the patient, with up to 60% deemed preventable. Colorectal patients are disproportionally affected by SSI due the risk of wound contamination with bowel content. We aimed to reduce the rate of superficial SSI after elective colorectal surgery using a bundle of evidence-based interventions. METHODS: An SSI prevention bundle was implemented in elective colorectal surgery, comprised of triclosan-coated sutures, 2% chlorhexidine skin preparation and use of warmed carbon dioxide (CO2) during laparoscopic procedures. The SSI reduction strategy was prospectively implemented and compared with historical controls. Our primary outcome measure was the overall rate of superficial SSI. Centres for Disease Control and Prevention criteria, which use microbiological evidence in conjunction with clinical features were used as the definition of SSI. RESULTS: The overall SSI rate was 27.4% in the pre-bundle group (N = 208) and 12.5% in the patients who received the SSI prevention bundle (N = 184) (adjusted odds ratio 0.38; confidence interval 0.21-0.67; P<0.001). The median time to SSI diagnosis was postoperative day 8. Overall patient length of stay (LOS) was unchanged from six days at baseline following implementation of the bundle. CONCLUSIONS: We have shown successful implementation of an SSI prevention bundle which has reduced superficial SSI rate. We recommend this SSI prevention bundle becomes standard practice in elective colorectal surgery and plan to extend the bundle to emergency general surgery.

Factors associated with advanced colorectal cancer differ between young and older adults in England: a population-based cohort study.

AIM: Advanced stage presentation of colorectal cancer is associated with poorer survival outcomes, particularly among young adults. This study aimed to determine whether demographic risk factors for advanced stage presentation differed between young and older adults. METHOD: Individual-level data on all incident colorectal cancers in people aged 20 years and above were extracted from the National Cancer Registration and Analysis Service database for the years 2012 to 2015. Patients were divided into two cohorts: young-onset colorectal cancer (YOCC) if aged 20-49 years and older-onset colorectal cancer (OOCC) if aged 50 years and above. Logistic regression was used to identify risk factors for advanced stage presentation, defined as TNM Stage III or IV, in each cohort. RESULTS: There were 7075 (5.2%) patients in the YOCC cohort and 128 345 (94.8%) patients in the OOCC cohort. Tumours in the YOCC cohort were more likely to be at an advanced stage (67.2% vs 55.3%, P < 0.001) and located distally (63.7% vs 55.4%, P < 0.001). No demographic factor was consistently associated with advanced stage presentation in the YOCC cohort. Among the OOCC cohort, increased social deprivation [OR (Index of Multiple Deprivation quintile 5 vs 1) = 1.11 (95% CI 1.07-1.16), P < 0.001], Black/Black British ethnicity [OR (baseline White) = 1.25 (95% CI 1.11-1.40), P < 0.001] and residence in the East Midlands [OR (baseline London) = 1.11 (95% CI 1.04-1.17), P = 0.001] were associated with advanced stage presentation. CONCLUSION: Demographic factors associated with advanced disease were influenced by age. The effects of social deprivation and ethnicity were only observed in older adults and mirror trends in screening uptake. Targeted interventions for high-risk groups are warranted.

Incisional hernia formation in hepatobiliary surgery using transverse and hybrid incisions: a systematic review and meta-analysis.

INTRODUCTION: Evidence suggests that midline incisions should be closed with the small-bite technique to reduce IH formation. No recommendations exist for the closure of transverse incisions used in hepatobiliary surgery. This work systematically summarises rates of IH formation and associated technical factors for these transverse incisions. METHODS: A systematic search was undertaken. Studies describing the incidence of IH were included. Incisions were classified as transverse (two incision types) or hybrid (transverse with midline extension, comprising five incision types). The primary outcome measure was the pooled proportion of IH. Subgroup analysis based on minimum follow-up of two years and a priori definition of IH with clinical and radiological diagnosis was undertaken. FINDINGS: Thirteen studies were identified and included 5,427 patients; 1,427 patients (26.3%) underwent surgery for benign conditions, 3,465 (63.8%) for malignancy and 535 (9.9%) for conditions that were not stated or classified as 'other'. The pooled incidence of IH was 6.0% (2.0-10.0%) at a weighted mean follow-up of 17.5 months in the transverse group, compared with 15.0% (11.0-19.0%) at a weighted mean follow-up of 42.0 months in the hybrid group (p = 0.045). Subgroup analysis did not demonstrate a statistical difference in IH formation between the hybrid versus transverse groups. CONCLUSION: Owing to the limitations in study design and heterogeneity, there is limited evidence to guide incision choice and methods of closure in hepatopancreatobiliary surgery. There is an urgent need for a high-quality prospective cohort study to understand the techniques used and their outcomes, to inform future research.

Demographic trends in the incidence of young-onset colorectal cancer: a population-based study.

BACKGROUND: Evidence is emerging that the incidence of colorectal cancer is increasing in young adults, but the descriptive epidemiology required to better understand these trends is currently lacking. METHODS: A population-based cohort study was carried out including all adults aged 20-49 years diagnosed with colorectal cancer in England between 1974 and 2015. Data were extracted from the National Cancer Registration and Analysis Service database using ICD-9/10 codes for colorectal cancer. Temporal trends in age-specific incidence rates according to sex, anatomical subsite, index of multiple deprivation quintile and geographical region were analysed using Joinpoint regression. RESULTS: A total of 56 134 new diagnoses of colorectal cancer were analysed. The most sustained increase in incidence rate was in the group aged 20-29 years, which was mainly driven by a rise in distal tumours. The magnitude of incident rate increases was similar in both sexes and across Index of Multiple Deprivation quintiles, although the most pronounced increases in incidence occurred in the southern regions of England. CONCLUSION: Colorectal cancer should no longer be considered a disease of older people. Changes in incidence rates should be used to inform future screening policy, preventative strategies and research agendas, as well as increasing public understanding that younger people need to be aware of the symptoms of colorectal cancer.

ANTECEDENTES: Están apareciendo evidencias de que la incidencia del cáncer colorrectal (colorectal cancer, CRC) está aumentando en adultos jóvenes, pero se carece de la epidemiología descriptiva necesaria para comprender mejor estas tendencias. MÉTODOS: Se realizó un estudio de cohortes de base poblacional de todos los adultos de 20 a 49 años diagnosticados de CRC en Inglaterra entre 1974 y 2015. Los datos se extrajeron de la base de datos NCRAS utilizando los códigos ICD9/10 para el CRC. Las tendencias temporales en las tasas de incidencia específicas por edad (incidence rates, IR) según el sexo, la localización anatómica, el quintil del índice de privación múltiple (index of multiple deprivation, IMD) y la región geográfica se analizaron mediante un modelo de regresión joinpoint. RESULTADOS: Se analizaron un total de 56.134 nuevos diagnósticos de CRC. El aumento más sostenido en la IR se produjo en el grupo de edad de 20 a 29 años, principalmente a expensas de un incremento de los tumores distales. La magnitud de los aumentos de IR fue similar en ambos sexos y en los quintiles del IMD, aunque los aumentos más pronunciados en la incidencia se registraron en las regiones del sur de Inglaterra. CONCLUSIÓN: El CRC ya no debe ser considerado una enfermedad de las personas mayores: los cambios en las tasas de incidencia deberán tenerse en cuenta en las futuras políticas de cribado, en las estrategias preventivas y en los proyectos de investigación, así como para aumentar la toma de conciencia de la población de que las personas más jóvenes deben estar al corriente de los síntomas del CRC.

A Systematic Review and Meta-Analysis of Prognostic Biomarkers in Anal Squamous Cell Carcinoma Treated With Primary Chemoradiotherapy.

Recent studies suggest that the treatment response and survival from head and neck tumours can be stratified according to biomarker status, particularly human papillomavirus (HPV) status and p16 expression, but the evidence for predictive biomarkers in anal squamous cell carcinoma (ASCC) remains limited. The aim of this study was to determine which biomarkers were associated with locoregional recurrence (LRR), overall survival and disease-free survival (DFS) in ASCC. A systematic search was undertaken of the MEDLINE, Embase, Cochrane Library, CINAHL and Web of Science databases using validated terms for ASCC, biomarkers and prognosis. Biomarkers were included in the meta-analysis if they were reported by at least four studies and provided sufficient data to permit the calculation of survival effect estimates. HPV status, p16, p53 and epidermal growth factor receptor (EGFR) met the inclusion criteria for meta-analysis and were reported by 17 retrospective cohort studies describing 1635 patients. When compared with HPV-negative tumours, HPV-positive tumours were associated with reduced LRR (pooled hazard ratio = 0.27 [95% confidence interval 0.16-0.48]; P < 0.001), improved overall survival (hazard ratio =0.26 [0.12-0.59]; P = 0.001) and DFS (hazard ratio = 0.33 [0.16-0.70]; P = 0.003). Likewise, p16-positive tumours were associated with reduced LRR (hazard ratio = 0.26 [0.13-0.52]; P < 0.001), improved overall survival (hazard ratio = 0.44 [0.24-0.81]; P = 0.009) and DFS (hazard ratio = 0.44 [0.23-0.83]; P = 0.012) when compared with p16-negative tumours. HPV-positive/p16-positive tumours had improved overall survival when compared with HPV-negative/p16-negative tumours (hazard ratio = 0.27 [0.15-0.48], P < 0.001), but not HPV-negative/p16-positive tumours (hazard ratio = 0.64 [0.21-1.90]; P = 0.421). p53 mutation was associated with worse DFS (hazard ratio = 1.63 [1.33-2.01]; P = 0.003). There was no association between EGFR status and any survival outcome. HPV status, p16 and p53 expression are of prognostic utility in ASCC. Future studies should prospectively validate these findings with a view to conducting subsequent randomised controlled trials where patients are stratified according to biomarker status and randomised to different treatment regimens.

A systematic review of local excision followed by adjuvant therapy in early rectal cancer: are pT1 tumours the limit?

AIM: Total mesorectal excision remains the cornerstone of treatment for rectal cancer. Significant morbidity means local excision may be more appropriate in selected patients. Adjuvant therapy reduces local recurrence and improves survival; however, there is a paucity of data on its impact following local excision, which this systematic review aims to address. METHODS: A systematic search of the MEDLINE, Embase and Cochrane databases using validated terms for rectal cancer, adjuvant therapy and local excision was performed. Included studies focused on local excision with adjuvant therapy for adenocarcinoma of the rectum. Primary outcome measures were local recurrence, survival and morbidity. Studies providing neoadjuvant therapy or local excision alone were excluded. RESULTS: Twenty-two studies described 804 patients. Indications for local excision included favourable histology, patient choice and comorbidities. T1, T2 and T3 tumours accounted for 35.1%, 58.0% and 6.9% of cases, respectively. The most frequent local excision technique was transanal excision (77.7%). Adjuvant therapy included long-course chemoradiation or radiotherapy. Median follow-up was 51 months (range 1-165). The pooled local recurrence was 5.8% (95% CI 3.0-9.5) for pT1, 13.8% (95% CI 10.1-17.9) for pT2 and 33.7% (95% CI 19.2-50.1) for pT3 tumours. The overall median disease-free survival was 88% (range 50%-100%) with a pooled overall morbidity of 15.1% (95% CI 11.0-18.7). CONCLUSIONS: This area remains highly relevant to modern clinical practice. The data suggest that local excision followed by adjuvant therapy can achieve acceptable long-term outcomes in high-risk pT1 tumours, but not in T2 tumours and above in whom radical surgery should be offered.

Compliance with enhanced recovery protocols in elderly patients undergoing colorectal resection.

Introduction Enhanced recovery after surgery (ERAS) is associated with reduced length of stay (LOS) and improved outcomes in colorectal surgery. It is unclear whether ERAS can be safely implemented in elderly patients undergoing complex colorectal resections. The aim of this study was to evaluate the feasibility of ERAS in patients of all ages undergoing colorectal surgery. Methods A prospective database of a consecutive series of patients undergoing colorectal resections with ERAS between August 2012 and December 2014 was evaluated. Patients were divided into four age groups. Outcomes studied were compliance with ERAS elements, LOS, morbidity and mortality. Results Of the 294 patients in the study cohort, 79 were <60 years, 81 were 60-69 years, 86 were 70-79 years and 48 were ≥80 years of age. There was no significant difference between age groups in compliance with ERAS elements. Age was not predictive of delayed discharge (LOS >6 days) or morbidity. Factors that were predictive of delayed discharge on multivariate analysis were open surgery (odds ratio [OR]: 2.23, p=0.003), conversion to open surgery (OR: 3.23, p=0.017), stoma formation (OR: 2.10, p=0.019) and chronic obstructive pulmonary disease (OR: 4.12, p=0.038). Factors predictive of morbidity on multivariate analysis comprised conversion to open surgery (OR: 7.72, p=0.004), high creatinine (OR: 1.03 per unit increase in creatinine, p=0.008) and stoma education (OR: 0.31, p=0.030). Conclusions ERAS can be successfully implemented in older patients. There was equal compliance with the ERAS programme across the four age groups and no significant effect of age on LOS or morbidity.

The use of artificial neural networks to predict delayed discharge and readmission in enhanced recovery following laparoscopic colorectal cancer surgery.

BACKGROUND: Artificial neural networks (ANNs) can be used to develop predictive tools to enable the clinical decision-making process. This study aimed to investigate the use of an ANN in predicting the outcomes from enhanced recovery after colorectal cancer surgery. METHODS: Data were obtained from consecutive colorectal cancer patients undergoing laparoscopic surgery within the enhanced recovery after surgery (ERAS) program between 2002 and 2009 in a single center. The primary outcomes assessed were delayed discharge and readmission within a 30-day period. The data were analyzed using a multilayered perceptron neural network (MLPNN), and a prediction tools were created for each outcome. The results were compared with a conventional statistical method using logistic regression analysis. RESULTS: A total of 275 cancer patients were included in the study. The median length of stay was 6 days (range 2-49 days) with 67 patients (24.4 %) staying longer than 7 days. Thirty-four patients (12.5 %) were readmitted within 30 days. Important factors predicting delayed discharge were related to failure in compliance with ERAS, particularly with the postoperative elements in the first 48 h. The MLPNN for delayed discharge had an area under a receiver operator characteristic curve (AUROC) of 0.817, compared with an AUROC of 0.807 for the predictive tool developed from logistic regression analysis. Factors predicting 30-day readmission included overall compliance with the ERAS pathway and receiving neoadjuvant treatment for rectal cancer. The MLPNN for readmission had an AUROC of 0.68. CONCLUSIONS: These results may plausibly suggest that ANN can be used to develop reliable outcome predictive tools in multifactorial intervention such as ERAS. Compliance with ERAS can reliably predict both delayed discharge and 30-day readmission following laparoscopic colorectal cancer surgery.

Factors predicting 30-day readmission after laparoscopic colorectal cancer surgery within an enhanced recovery programme.

AIM: Hospital readmission within 30 days of surgery has become a marker of poor quality patient care. This study aimed to investigate factors predictive of 30-day readmission after laparoscopic colorectal cancer surgery within an enhanced recovery after surgery (ERAS) programme. METHOD: Consecutive patients undergoing laparoscopic surgery for colorectal cancer within an ERAS programme between 2002 and 2009 were included. Data were collected relating to patient demographics, neoadjuvant chemoradiotherapy, ERAS compliance, and operative and postoperative outcomes. A logistic regression model was used to identify factors associated with readmissions after adjusting for the potential effect of covariables simultaneously. RESULTS: In all, 268 cancer patients underwent laparoscopic colorectal surgery (108 rectal resections), of whom 34 (12.7%) were readmitted due most commonly to bowel obstruction (29%) and surgical site infection (18%). The use of neoadjuvant therapy (odds ratio 4.49, 95% CI 1.41-14.35; P = 0.011) and ERAS compliance above 93% (odds ratio 0.38, 95% CI 0.18-0.84; P = 0.016) were independent predictors of readmission. CONCLUSION: Poor ERAS compliance and preoperative chemoradiotherapy were significant predictors of readmission following laparoscopic colorectal cancer surgery. Further research is required to expand the scope of ERAS beyond hospital discharge.

Five-year prospective follow-up of 430 laparoscopic totally extraperitoneal inguinal hernia repairs in 275 patients.

INTRODUCTION: Favourable short-term results, with respect to less postoperative pain and earlier return to physical activity, have been demonstrated with laparoscopic totally extraperitoneal (TEP) hernia repair compared with open mesh repair. However, there is limited data regarding long-term results. PATIENTS AND METHODS: The study cohort consisted of 275 consecutive patients undergoing TEP repair between 1996 and 2002. Patient demographics, details of surgery, postoperative complications, recurrence and chronic pain were collected from patient records and from a prospective database. All patients were seen at 6 weeks and then annually for 5 years following surgery. RESULTS: A total of 430 repairs were performed in the 275 patients (median age, 56 years; range, 20-94 years; men, 97.5%). Bilateral repair was performed in 168 patients (61.1%) and recurrent hernia repair in 79 patients (28.7%). Two patients were converted to an open procedure. Five-year follow-up was achieved in 72% of patients. Eleven patients (4%) died during the follow-up period due to unrelated causes. Hernia recurrence rate at 5 years was 1.1% per patient (three repairs). Recurrences were noted at 7 months, 2 years and 4 years following surgery. Chronic groin pain was reported by 21 patients (7.6%), seven of whom required referral to the pain team. CONCLUSIONS: TEP hernia repair is associated with a recurrence rate of 1% at 5 years in this series. Chronic groin symptoms are also acceptably few. This recurrence rate following TEP repair compares extremely favourably with open mesh repair, particularly as it includes a high proportion of recurrent repairs. As well as the proven early benefits, TEP repair can be considered a safe and durable procedure with excellent long-term results.

Flavin nucleotides, glutathione reductase and assessment of riboflavin status.

The in vitro effects of flavin nucleotides on human erythrocyte glutathione reductase were studied. Flavin mononucleotide was found to be a potent inhibitor of glutathione reductase in haemolysates, having an effect at a concentration of 1 muM. Flavin adenine dinucleotide inhibited at a concentration at least ten fold this, lower levels producing the expected stimulation of enzyme activity. Different assay conditions also altered the activity of the enzyme, although the flavin mononucleotide inhibition remained. The implications of these findings in our understanding of glutatione reductase and in using the enzyme to assess riboflavin status are discussed.