The costs of surgical site infection after abdominal surgery in middle-income countries: Key resource use In Wound Infection (KIWI) study.

BACKGROUND: Surgical site infection (SSI) is the most common complication of abdominal surgery, with substantial costs to patients and health systems. Heterogeneity in costing methods in existing SSI studies makes multi-country comparison challenging. The objective of the study was to assess the costs of SSI across middle-income countries. METHODS: Centres from a randomized controlled trial assessing interventions to reduce SSI (FALCON, ClinicalTrials.gov, NCT03700749NCT) were sampled from two upper-middle- (India, Mexico) and two lower-middle- (Ghana, Nigeria) income countries. The Key resource use In Wound Infection (KIWI) study collected data on postoperative resource use and costs from consecutive patients undergoing abdominal surgery with an incision >5 cm (including caesarean section) that were recruited to FALCON between April and October 2020. The overall costs faced by patients with and without SSI were compared by operative field contamination (clean-contaminated vs contaminated-dirty), country and timing (inpatient vs outpatient). FINDINGS: A total of 335 patients were included in KIWI; SSI occurred in 7% of clean-contaminated cases and 27% of contaminated-dirty cases. Overall, SSI was associated with an increase in postoperative healthcare costs by 75.3% (€412 international Euros) after clean-contaminated surgery and 66.6% (€331) after contaminated-dirty surgery. The highest and lowest cost increases were in India for clean-contaminated cases (€517) and contaminated-dirty cases (€223), respectively. Overall, inpatient costs accounted for 96.4% of the total healthcare costs after clean-contaminated surgery and 92.5% after contaminated-dirty surgery. CONCLUSION: SSI was associated with substantial additional postoperative costs across a range of settings. Investment in health technologies to reduce SSI may mitigate the financial burden to patients and low-resource health systems.

Mechanisms of immunogenicity in colorectal cancer.

BACKGROUND: The immune response in cancer is increasingly understood to be important in determining clinical outcomes, including responses to cancer therapies. New insights into the mechanisms underpinning the immune microenvironment in colorectal cancer are helping to develop the role of immunotherapy and suggest targeted approaches to the management of colorectal cancer at all disease stages. METHOD: A literature search was performed in PubMed, MEDLINE and Cochrane Library databases to identify relevant articles. This narrative review discusses the current understanding of the contributors to immunogenicity in colorectal cancer and potential applications for targeted therapies. RESULTS: Responsiveness to immunotherapy in colorectal cancer is non-uniform. Several factors, both germline and tumour-related, are potential determinants of immunogenicity in colorectal cancer. Current approaches target tumours with high immunogenicity driven by mutations in DNA mismatch repair genes. Recent work suggests a role for therapies that boost the immune response in tumours with low immunogenicity. CONCLUSION: With the development of promising therapies to boost the innate immune response, there is significant potential for the expansion of the role of immunotherapy as an adjuvant to surgical treatment in colorectal cancer.

ANTECEDENTES: La respuesta inmune en el cáncer se considera cada vez más importante por su influencia sobre los resultados clínicos, incluidas las respuestas a las diferentes modalidades de tratamiento. Los nuevos conocimientos sobre los mecanismos implicados en el microambiente inmunitario en el cáncer colorrectal están ayudando a definir el papel de la inmunoterapia y el desarrollo de terapias dirigidas para el tratamiento del cáncer colorrectal en todos los estadios de la enfermedad. MÉTODOS: Se realizó una búsqueda bibliográfica en las bases de datos PubMed, Medline y Cochrane para identificar artículos relevantes. Esta revisión descriptiva discute la comprensión actual de los factores que contribuyen a la inmunogenicidad en el cáncer colorrectal y las posibles aplicaciones en terapias dirigidas. RESULTADOS: La capacidad de respuesta a la inmunoterapia en el cáncer colorrectal no es uniforme. Varios factores, tanto relacionados con la línea germinal, como con el tumor son determinantes potenciales de la inmunogenicidad en el cáncer colorrectal. Los estudios actuales están dirigidos a tumores con alta inmunogenicidad provocada por mutaciones en los genes de reparación de apareamientos erróneos en el ADN. Trabajos recientes sugieren un papel para los tratamientos que estimulan la respuesta inmune en tumores con baja inmunogenicidad. CONCLUSIÓN: Con el desarrollo de tratamientos prometedores para estimular la respuesta inmune innata, existe un potencial significativo para la expansión del papel de la inmunoterapia como adyuvante del tratamiento quirúrgico en el cáncer colorrectal.

Consensus and controversies regarding follow-up after treatment with curative intent of nonmetastatic colorectal cancer: a synopsis of guidelines used in countries represented in the European Society of Coloproctology.

AIM: It is common clinical practice to follow patients for a period of years after treatment with curative intent of nonmetastatic colorectal cancer, but follow-up strategies vary widely. The aim of this systematic review was to provide an overview of recommendations on this topic in guidelines from member countries of the European Society of Coloproctology, with supporting evidence. METHOD: A systematic search of Medline, Embase and the guideline databases Trip database, BMJ Best Practice and Guidelines International Network was performed. Quality assessment included use of the AGREE-II tool. All topics with recommendations from included guidelines were identified and categorized. For each subtopic, a conclusion was made followed by the degree of consensus and the highest level of evidence. RESULTS: Twenty-one guidelines were included. The majority recommended that structured follow-up should be offered, except for patients in whom treatment of recurrence would be inappropriate. It was generally agreed that clinical visits, measurement of carcinoembryoinc antigen and liver imaging should be part of follow-up, based on a high level of evidence, although the frequency is controversial. There was also consensus on imaging of the chest and pelvis in rectal cancer, as well as endoscopy, based on lower levels of evidence and with a level of intensity that was contradictory. CONCLUSION: In available guidelines, multimodal follow-up after treatment with curative intent of colorectal cancer is widely recommended, but the exact content and intensity are highly controversial. International agreement on the optimal follow-up schedule is unlikely to be achieved on current evidence, and further research should refocus on individualized 'patient-driven' follow-up and new biomarkers.

Recommendations and consensus on the treatment of peritoneal metastases of colorectal origin: a systematic review of national and international guidelines.

AIM: This systematic review aimed to provide an overview of (inter)national guidelines on the treatment of peritoneal metastases of colorectal cancer origin (PMCRC) and to determine the degree of consensus and available evidence with identification of topics for future research. METHOD: A systematic search of MEDLINE, Embase, PubMed as well as Tripdatabase, National Guideline Clearinghouse, BMJ Best Practice and Guidelines International Network was performed to identify (inter)national guidelines and consensus statements from oncological or surgical societies on PMCRC. The quality of guidelines was assessed using the AGREE-II score. Topics followed by recommendations were extracted from the guidelines. The recommendations, highest level of supporting evidence and the degree of consensus were determined for each topic. RESULTS: Twenty-one guidelines were included, in most (15) of which cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) was recommended in selected patients based on level 1b evidence. Substantial consensus was also reached on the benefit of multidisciplinary team discussion and the achievability of a (near) complete cytoreduction (CC0-1) without supporting evidence. Both evidence and consensus were lacking regarding other aspects including preoperative positron emission tomography/CT, second look surgery in high risk patients, the optimal patient selection for CRS/HIPEC, procedural aspects of HIPEC and (perioperative) systemic therapy. CONCLUSION: In currently available guidelines, evidence and consensus on the treatment strategy for PMCRC are lacking. Updates of guidelines are ongoing and future (randomized) clinical trials should contribute to multidisciplinary and international consensus on treatment strategies for PMCRC.

Systematic review of evidence and consensus on perianal fistula: an analysis of national and international guidelines.

AIM: Treatment of perianal fistula has evolved with the introduction of new techniques and biologicals in Crohn's disease (CD). Several guidelines are available worldwide, but many recommendations are controversial or lack high-quality evidence. The aim of this work was to provide an overview of the current available national and international guidelines for perianal fistula and to analyse areas of consensus and areas of conflicting recommendations, thereby identifying topics and questions for future research. METHOD: MEDLINE, EMBASE and PubMed were systematically searched for guidelines on perianal fistula. Inclusion was limited to papers in English less than 10 years old. The included topics were classified as having consensus (unanimous recommendations in at least two-thirds of the guidelines) or controversy (fewer than three guidelines commenting on the topic or no consensus) between guidelines. The highest level of evidence was scored as sufficient (level 3a or higher of the Oxford Centre for Evidence-based Medicine Levels of Evidence 2009, http://www.cebm.net/oxford-centre-evidence-based-medicine-levels-evidence-march-2009/) or insufficient. RESULTS: Twelve guidelines were included and topics with recommendations were compared. Overall, consensus was present in 15 topics, whereas six topics were rated as controversial. Evidence levels varied from strong to lack of evidence. CONCLUSION: Evidence on the diagnosis and treatment of perianal fistulae (cryptoglandular or related to CD) ranged from nonexistent to strong, regardless of consensus. The most relevant research questions were identified and proposed as topics for future research.

Influence of day of surgery on mortality following elective colorectal resections.

BACKGROUND: The aim of this study was to investigate whether the increased mortality previously identified for surgery performed on Fridays was apparent following major elective colorectal resections and how this might be affected by case mix. METHODS: Patients undergoing elective colorectal resections in England from 2001 to 2011 were identified using Hospital Episode Statistics. Propensity scores were used to match patients having operations on a Friday in a 1 : 1 ratio with those undergoing surgery on other weekdays. Multivariable analyses were used to investigate overall deaths within 1 year of operation. RESULTS: A total of 204,669 records were extracted for patients undergoing major elective colorectal resections. Patients who had surgery on Fridays were more deprived (4780 (17.1 per cent) of 27,920 versus 28,317 (16.0 per cent) of 176,749; P < 0.001), a greater proportion had had an emergency admission in the 3 previous months (7870 (28.2 per cent) of 27,920 versus 48,623 (27.5 per cent) of 176,749; P = 0.019), underwent minimal access surgery (4565 (16.4 per cent) of 27,920 versus 23,783 (13.5 per cent) of 176,749; P < 0.001) and had surgery for benign diagnoses (6502 (23.3 per cent) of 27,920 versus 38,725 (21.9 per cent) of 176,749; P < 0.001) than those who had surgery on Mondays to Thursdays. In a matched analysis the odds ratio for 30-day mortality after colorectal resections performed on Fridays compared with other weekdays was 1.25 (95 per cent c.i. 1.13 to 1.37); odds ratios for 90-day and 1-year mortality were 1.16 (1.07 to 1.25) and 1.10 (1.04 to 1.16) respectively. CONCLUSION: Patients selected for colorectal resections on Fridays had a higher mortality rate than patients operated on from Monday to Thursday and had different characteristics, suggesting that increased mortality may reflect patient factors rather than hospital variables alone.

Biomarker-based treatment selection in early-stage rectal cancer to promote organ preservation.

BACKGROUND: Total mesorectal excision (TME) remains commonplace for T1-2 rectal cancer owing to fear of undertreating a small proportion of patients with node-positive disease. Molecular stratification may predict cancer progression. It could be used to select patients for organ-preserving surgery if specific biomarkers were validated. METHODS: Gene methylation was quantified using bisulphite pyrosequencing in 133 unirradiated rectal cancer TME specimens. KRAS mutation and microsatellite instability status were also defined. Molecular parameters were correlated with histopathological indices of disease progression. Predictive models for nodal metastasis, lymphovascular invasion (LVI) and distant metastasis were constructed using a multilevel reverse logistic regression model. RESULTS: Methylation of the retinoic acid receptor ß gene, RARB, and that of the checkpoint with forkhead and ring finger gene, CHFR, was associated with tumour stage (RARB: 51·9 per cent for T1-2 versus 33·9 per cent for T3-4, P < 0·001; CHFR: 5·5 per cent for T1-2 versus 12·6 per cent for T3-4, P = 0·005). Gene methylation associated with nodal metastasis included RARB (47·1 per cent for N- versus 31·7 per cent for N+; P = 0·008), chemokine ligand 12, CXCL12 (12·3 per cent for N- versus 8·9 per cent for N+; P = 0·021), and death-associated protein kinase 1, DAPK1 (19·3 per cent for N- versus 12·3 per cent for N+; P = 0·022). RARB methylation was also associated with LVI (45·1 per cent for LVI- versus 31·7 per cent for LVI+; P = 0·038). Predictive models for nodal metastasis and LVI achieved sensitivities of 91·1 and 85·0 per cent, and specificities of 55·3 and 45·3 per cent, respectively. CONCLUSION: This methylation biomarker panel provides a step towards accurate discrimination of indolent and aggressive rectal cancer subtypes. This could offer an improvement over the current standard of care, whereby fit patients are offered radical surgery.

Systematic review of evidence and consensus on diverticulitis: an analysis of national and international guidelines.

AIM: The study aimed to analyse the currently available national and international guidelines for areas of consensus and contrasting recommendations in the treatment of diverticulitis and thereby to design questions for future research. METHOD: MEDLINE, EMBASE and PubMed were systematically searched for guidelines on diverticular disease and diverticulitis. Inclusion was confined to papers in English and those < 10 years old. The included topics were classified as consensus or controversy between guidelines, and the highest level of evidence was scored as sufficient (Oxford Centre of Evidence-Based Medicine Level of Evidence of 3a or higher) or insufficient. RESULTS: Six guidelines were included and all topics with recommendations were compared. Overall, in 13 topics consensus was reached and 10 topics were regarded as controversial. In five topics, consensus was reached without sufficient evidence and in three topics there was no evidence and no consensus. Clinical staging, the need for intraluminal imaging, dietary restriction, duration of antibiotic treatment, the protocol for abscess treatment, the need for elective surgery in subgroups of patients, the need for surgery after abscess treatment and the level of the proximal resection margin all lack consensus or evidence. CONCLUSION: Evidence on the diagnosis and treatment of diverticular disease and diverticulitis ranged from nonexistent to strong, regardless of consensus. The most relevant research questions were identified and proposed as topics for future research.

Evaluation of serum lysyl oxidase as a blood test for colorectal cancer.

AIMS: Lysyl oxidase (LOX) expression is elevated in colorectal cancer (CRC) tissue and associated with disease progression. A blood test may form a more acceptable diagnostic test for CRC although LOX has not previously been measured in the serum. We therefore sought to determine the clinical usefulness of a serum LOX test for CRC in a symptomatic population. METHODS: Adult patients referred to a hospital colorectal clinic with bowel symptoms completed a questionnaire and provided a blood sample for serum LOX measurement. Associations between presenting symptoms, serum LOX concentrations and outcomes of investigations were tested by univariate and multivariate analyses to determine if serum LOX was clinically useful in the prediction of CRC. LOX expression in CRC and adjacent colon biopsies was evaluated by ELISA and immunohistochemistry. RESULTS: Thirty-one cases of colorectal cancer and 16 high-risk polyps were identified from a total of 962 participants. There was no association between serum LOX concentration and the presence of CRC, high-risk polyps or cancers at any site. LOX expression was significantly increased in CRC tissue compared to adjacent colon. CONCLUSION: Despite overexpression of LOX in CRC tissue, elevated serum levels could not be demonstrated. Serum LOX measurement is therefore not a clinically useful test for CRC.

Methylation profiling of rectal cancer identifies novel markers of early-stage disease.

BACKGROUND: Radical surgery is the de facto treatment for early rectal cancer. Conservative surgery with transanal endoscopic microsurgery can achieve high rates of cure but the histopathological measures of outcome used to select local treatment lack precision. Biomarkers associated with disease progression, particularly mesorectal nodal metastasis, are urgently required. The aim was to compare patterns of gene-specific hypermethylation in radically excised rectal cancers with histopathological stage. METHODS: Locus-specific hypermethylation of 24 tumour suppressor genes was measured in 105 rectal specimens (51 radically excised adenocarcinomas, 35 tissues adjacent to tumour and 19 normal controls) using the methylation-specific multiplex ligation-dependent probe assay (MS-MLPA). Methylation values were correlated with histopathological indices of disease progression and validated using bisulphite pyrosequencing. RESULTS: Five sites (ESR1, CDH13, CHFR, APC and RARB) were significantly hypermethylated in cancer compared with adjacent tissue and normal controls (P < 0·050). Methylation at these sites was higher in Dukes' A than Dukes' 'D' cancers (P = 0·013). Methylation at two sites (GSTP1 and RARB) was individually associated with localized disease (N0 and M0 respectively; P = 0·006 and P = 0·008). Hypermethylation of at least two of APC, RARB, TIMP3, CASP8 and GSTP1 was associated with early (N0 M0) disease (N0, P = 0·002; M0, P = 0·044). Methylation levels detected by MS-MLPA and pyrosequencing were concordant. CONCLUSION: Locus-specific hypermethylation was more prevalent in early- than late-stage disease. Hypermethylation of two or more of a panel of five tumour suppressor genes was associated with localized disease.

Wnt signalling in adenomas of familial adenomatous polyposis patients.

BACKGROUND: Epigenetic silencing of Wnt antagonists and expression changes in genes associated with Wnt response pathways occur in early sporadic colorectal tumourigenesis, indicating that tumour cells are more sensitive to Wnt growth factors and respond differently. In this study, we have investigated whether similar changes occur in key markers of the Wnt response pathways in the genetic form of the disease, familial adenomatous polyposis (FAP). METHODS: We investigated epigenetic and expression changes using pyrosequencing and real-time RT-PCR in samples from seven patients without neoplasia, and matched normal and tumour tissues from 22 sporadic adenoma and 14 FAP patients. RESULTS: We found that 17 out of 24 (71%) FAP adenomas were hypermethylated at sFRP1, compared with 20 out of 22 (91%) of sporadic cases. This was reflected at the level of sFRP1 transcription, where 73% of FAP and 100% of sporadic cases were down-regulated. Increased expression levels of c-myc and FZD3 were less common in FAP (35 and 46% respectively) than sporadic tumours (78 and 67% respectively). CONCLUSION: Overall, the changes in expression and methylation were comparable, although the degree of change was generally lower in the FAP adenomas. Molecular heterogeneity between multiple adenomas from individual FAP patients may reflect different developmental fates for these premalignant tumours.

Reorganisation of Wnt-response pathways in colorectal tumorigenesis.

In most colorectal tumours, APC mutation stabilises beta-catenin and mimics elements of Wnt growth factor signalling, but the high frequency of epigenetic loss of Wnt antagonists indicates an additional role for ligand-mediated Wnt signalling. Here, we have investigated the expression of key components of beta-catenin-independent Wnt response pathways to determine whether their profiles change during the transition from normal mucosa to colorectal adenomas. Transcription of the Wnt/planar cell polarity pathway determinant NKD1 (naked cuticle homologue 1) was induced in adenomas by a median 135-fold and in cancers by 7.4-fold. While some Frizzleds (FZDs) were downregulated in adenomas, the Wnt/Ca(2+) receptors FZD3 and FZD6 were induced by a median factor of 6.5 and 4.6, respectively. Naked cuticle homologue 1, FZD3 and FZD6 expression were coordinated in pre-malignant disease, but this relationship was lost in invasive cancers, where FZD induction was seen less frequently. Naked cuticle homologue 1 expression was associated with nuclear localisation of phospho-c-Jun in adenomas. In cultured cells, NKD1 transcription was induced by lithium chloride but FZD3 expression required Wnt growth factor treatment. These data show that Wnt responses are consistently directed towards both beta-catenin-independent routes in early colorectal tumorigenesis and elements of this are retained in more advanced cancers. These beta-catenin-independent Wnt signalling pathways may provide novel targets for chemoprevention of early colorectal tumours.

Hereditary colorectal cancer: screen the parents!

Hereditary nonpolyposis colorectal cancer is the most common form of hereditary colorectal cancer. Occasionally, the presentation of colorectal cancer may be at an early age when parents may be unidentified obligate carriers. The risk of colorectal cancer increases with increasing age, even in inherited disease. Therefore, it is important to screen parents of patients presenting at a young age and to obtain a complete pedigree to identify and screen those who are at risk. Two such families where the index case presented at a young age were encountered in our practice and both their mothers were found to have colorectal cancer on surveillance colonoscopy. We recommend that parents of the index cases should be screened and more detailed family pedigree obtained when patients present at a young age with colorectal cancer.

Frequency and impact of extracolonic findings detected at computed tomographic colonography in a symptomatic population.

BACKGROUND: Extracolonic findings are frequently recognized alongside colonic pathology at computed tomographic colonography (CTC). This study assessed the clinical impact of extracolonic findings in a symptomatic population at high risk of colorectal cancer. METHODS: CTC was performed in a consecutive cohort of patients assessed in a fast-track colorectal cancer clinic as being at high risk of colorectal cancer. A review of CTC findings and case notes was undertaken. Patients with extracolonic findings were followed up for at least 12 months. RESULTS: Thirty-one (13.8 per cent) of 225 patients investigated by CTC had colorectal cancer. Extracolonic findings were identified in 81 (53.3 per cent) of 152 patients with normal or non-neoplastic bowel findings, compared with 27 (37 per cent) of 73 patients with colorectal neoplasia (P = 0.025). Twenty-four patients (10.7 per cent) with extracolonic findings underwent further investigation or treatment. The median duration of investigation was 19.5 weeks. Seventy-five clinical events were recorded, including 14 surgical procedures. CONCLUSION: A prospective cost-benefit analysis of diagnostic CTC should be performed before it is established as a first-line investigation for colonic symptoms.

Resources and costs associated with incidental extracolonic findings from CT colonogaphy: a study in a symptomatic population.

CT colonography (CTC) is increasingly used to detect colonic polyps and cancers, but its impact in practice is also influenced by frequent detection of extracolonic lesions. We have previously documented the frequency and nature of such lesions. The current study was performed to assess the clinical resources and costs associated with the investigation and treatment of extracolonic lesions. We reviewed the reports of 225 consecutive CTC examinations carried out on patients with symptoms of bowel cancer. 116 of the 225 were reported to have one or more extracolonic findings. All 116 patients with an abnormality were followed up for 12-24 months. 24 patients underwent further actions (outpatient attendance, investigations, or surgical procedures) as a result of previously undiagnosed lesions unrelated to bowel cancer. The costs of these further actions were derived from the NHS Reference Costs manual 2004. The total cost for further investigations and interventions was 34,329 pounds sterling and the mean cost over the sample of 225 patients was 153 pounds sterling--more than the cost of the CTC itself. The costs were mainly generated by surgical procedures. Resources consumed as a result of extracolonic findings approximately doubled the costs of diagnostic CTC. These costs, along with inconvenience, anxiety, morbidity and occasionally even mortality suffered by patients, must be offset by the good done to some of those with sub-clinical but potentially lethal diseases.

The Wnt antagonist sFRP1 is downregulated in premalignant large bowel adenomas.

Our previous studies have implicated the Wnt antagonist, sFRP1, as a tumour suppressor gene in advanced colorectal cancer. In this study, we set out to investigate the relationship between sFRP1 expression and large bowel adenomas, a precursor of colorectal cancer. The induction of beta-catenin/TCF mediated transcription is both a frequent early event in colorectal neoplasia, and a key downstream effect of wnt growth factor signalling. Lithium treatment of a small bowel mucosal cell line (FHs 74 int) induced sFRP1 within 8 h, indicating that this gene is positively regulated by beta-catenin, contrasting with the suppression of sFRP1 expression, we saw previously in advanced colorectal cancers. We therefore investigated a series of 12 adenomas and matched large bowel mucosa samples. Real-time RT-PCR analysis showed a reduction in sFRP1 expression in all 12 dysplastic lesions (median 485-fold, IQR 120- to 1500-fold), indicating factors other than beta-catenin influence sFRP1 levels. In a second series of 11 adenomas, we identified methylation of the sFRP1 promotor region in all 11 samples, and this was increased compared with the surrounding normal mucosa in seven cases. Immunohistochemical analysis using a polyclonal antibody supported these findings, with sFRP1 expression reduced in many of the adenoma samples examined. sFRP1 staining in normal mucosa adjacent to the dysplastic tissue was also reduced compared with the normal controls, suggesting that sFRP1 expression may be suppressed in a field of mucosa rather than in individual cells. This study identifies sFRP1 inactivation at the premalignant stage of colorectal cancer development, indicating that these pathways may be useful targets for chemoprevention strategies in this common solid tumour.