Estimation of risk posed by malignant polyps amongst colorectal surgeons in Australia and New Zealand.

PURPOSE: The estimation of the risk posed by malignant polyps for residual or lymphatic disease plays a central role. This study investigated colorectal surgeons' assessment of these risks associated with malignant polyps. METHODS: A cross-sectional questionnaire was electronically administered to colorectal surgeons in Australia and New Zealand in October 2022. The questionnaire contained 17 questions on demographics, when surgeons consider colorectal resection appropriate, and the risk assessment for 5 hypothetical malignant polyps. RESULTS: The mean risk of residual or lymphatic disease that would prompt surgeons to recommend colonic resection was 5%. However, this increased to a mean risk of 10% if the malignant polyp was located in the rectum, and the only resection option was abdominoperineal resection with end-colostomy. There was high concordance between the estimated risk of residual or lymphatic disease by colorectal surgeons and the Association of Coloproctology of Great Britain and Ireland (ACPGBI) guidelines for the 5 hypothetical malignant polyps, with the ACPGBI estimated risk lying within the 95% confidence interval for 4 of the 5 malignant polyps. Nonetheless, 96.6% of surgeons felt that an online risk calculator would improve clinical practice. CONCLUSION: Colorectal surgeons in Australia and New Zealand accurately estimated the risk posed by malignant polyps. An online risk calculator may assist in better conveying risk to patients.

Malignant polyps in the COVID-19 era: a population-based analysis.

BACKGROUND: Malignant polyps represent the early development of colorectal adenocarcinoma. During 2020, there was widescale rationing of health-care resources in response to the COVID-19 pandemic. In particular there was deferral of some colonoscopy procedures required for timely malignant polyp detection. This study sought to assess how these deferrals affected the diagnosis of malignant polyps. METHODS: A population wide analysis was performed of 2079 malignant polyps, diagnosed in Queensland, Australia from 2011 to 2020. A regression analysis, with 95% prediction intervals, was produced to determine whether there was a significant impact on the number of malignant polyps diagnosed in 2020 compared to previous years. Univariate statistical analysis of patient, procedural, and pathological variables was also performed. RESULTS: In 2020 there were 211 malignant polyps diagnosed, which was significantly lower than was predicted by the univariate regression analysis (r2  = 0.85, 95% prediction interval: 255.07-323.91, P < 0.001). These malignant polyps were less likely to be diagnosed in a private setting (P < 0.001), and exhibited significantly less depth of submucosal invasion (P = 0.017). There was no significant difference in the management strategy (polypectomy, resection or trans-anal resection) between 2011 and 2019 and 2020. CONCLUSION: Because of the significant decrease in the number of malignant polyps, and the natural history of the disease, it is expected that there will be an increase in more advanced colorectal adenocarcinomas presenting in 2021 and beyond. This has implications for healthcare resources, particularly in light of the ongoing strain on health departments as a result of the COVID-19 pandemic.

Management of high and low risk malignant polyps: a population-wide analysis.

AIM: The management of malignant polyps is a treatment dilemma in selecting between polypectomy and colorectal resection. To assist clinicians, guidelines have been developed by the Association of Coloproctology of Great Britain and Ireland (ACPGBI) to provide treatment recommendations. METHODS: This study compared management strategy based on the ACPGBI risk categorization for malignant polyps. Univariable and multivariable statistical analysis was undertaken to assess the factors predicting management strategy. A population-wide analysis was performed of 1646 malignant polyps and the factors that predicted their management strategy, from Queensland, Australia, from 2011 to 2019. RESULTS: Overall, 31.55% of patients with very low or low risk disease proceeded to resection. Of those with high or very high risk disease, 36.69% did not proceed to resection. In very low and low risk polyps, age (P = 0.003) and polyp location (P < 0.001) were significantly different between the colorectal resection group and the polypectomy alone group. In those with very high or high risk polyps age (P < 0.001), type of facility (public or private) for the colonoscopy (P = 0.037), right colonic polyps compared to left colonic polyps (P = 0.015) and rectal polyps (P < 0.001) and mismatch repair mutations present (P = 0.027) were predictive of resection in high risk disease using a multivariable model. CONCLUSION: Over 30% of patients with very low and low risk malignant polyps proceeded to resection, against the advice of guidelines. Furthermore, over 35% of patients with very high or high risk malignant polyps did not proceed to resection. Education strategies may improve management decision choices. Furthermore, improvements in data collation will improve the understanding of management choices in the future.

In comparison with polypectomy, colorectal resection is associated with improved survival for patients diagnosed with malignant polyps.

AIM: Patients diagnosed with a malignant polyp generally have favourable overall survival (OS) and cancer-specific survival (CSS). However, it is unclear how choice in management for malignant polyps may affect survival. METHODS: Data from the Queensland Oncology Repository was analysed to derive a population wide assessment of the impact of management strategy on OS and CSS for patients diagnosed with malignant polyps. Log-rank testing, Kaplan-Meier and Cox-regression models were performed. Patients were matched using propensity score and Mahalanobis distance matching. RESULTS: A total of 1,646 patients were included with 240 deaths and 52 colorectal cancer related deaths until censor date. Following propensity score and Mahalanobis distance matching of patients undergoing polypectomy alone versus colorectal resection, there was no significant difference in the age groups (<60 years of age or ≥60 years of age), American Society of Anesthesiology score, comorbidity count or Association of ColoProctology of Great Britain and Ireland risk category. However, of note Log-rank testing demonstrated a significant difference in OS (p < 0.001) and CSS (p = 0.0061) between management strategies. Multivariable Cox-regression models in matched and un-matched patient cohorts demonstrated significantly lower hazards of death for OS with resection (p < 0.001). However, CSS was no longer significantly different between management groups in multivariable Cox-regression analysis (p = 0.073). CONCLUSION: Patients who underwent colorectal resection had significantly improved OS and CSS compared with polypectomy alone. Improved OS was furthermore seen on multivariable analysis, and in matched cohorts. Future research should investigate why this unexpected finding may be the case and whether updates to guidelines should be considered.

Missing parameters in malignant polyp histology reports: can appropriate decisions be made?

The treatment of colorectal malignant polyps is dependent upon quality reporting of the histopathological features known to predict the risk of residual disease or lymph node metastasis. The Royal College of Pathologists of Australasia (RCPA) has produced protocols covering mandatory and recommended pathological parameters to be included in the pathology reporting of malignant polyps. This paper aimed to assess the quality of the pathological reporting in a population-wide analysis from 2011-2019 in Queensland, Australia. A retrospective population-wide cohort study was performed using the Queensland Oncology Repository as a data source. The number of missing pathological parameters (assessed against the RCPA protocol standards and guidelines) for each patient was then summed. Demographic and other patient details were collated. The number of patients whose recommended treatment could theoretically be altered by the full reporting of missing parameters was calculated. A total of 1,646 histopathological reports of malignant polyps were reviewed. From this, 30.8% of all reports had a sufficient number of missing parameters that may have seen an alternate management strategy chosen. The most commonly under-reported parameter from the standards was either a Haggitt or Kikuchi level with 48.6% missing. Synoptic reporting significantly reduced the mean number of missing pathological parameters (p<0.001) There was a significant improvement in the number of missing pathological details over time (p<0.001). Accurate and complete pathology reports are essential to formulate appropriate surgical recommendations after the resection of malignant polyps. In this population-based study, pathology reports remain incomplete for the established parameters despite the introduction of an RCPA structured reporting protocol. Fortunately, the quality of pathological reporting has improved since the introduction of the first RCPA protocol covering reporting of malignant polyps.

Timing of surveillance colonoscopy following malignant colorectal polypectomy in Queensland.

INTRODUCTION: The management of malignant polyps presents a treatment challenge between a colorectal resection and polypectomy alone. Patients managed with polypectomy alone typically undergo surveillance for recurrent or metastatic disease, however, optimal timing of surveillance methods remains unclear. Guidelines recommend for completely resected malignant polyps, that a surveillance colonoscopy be perform 12 months from diagnosis. This study sought to clarify how patients with a malignant polyp were being colonoscopically surveilled if they did not undergo colorectal resection. METHODS: A retrospective, population-wide cohort analysis of all patients from 2011 to 2019 was performed using data from the Queensland Oncology Repository. Patient, procedural and pathological data were extracted for all patients diagnosed with a malignant polyp and timing of the first surveillance endoscopy was calculated. Statistical analysis comparing the timing of surveillance colonoscopy across multiple patients, procedural and histological characteristics were assessed. RESULTS: A total of 1646 patients were identified with a malignant polyp, with 797 patients managed with polypectomy and surveillance alone. The median time to surveillance endoscopy was 182 days with the mean 220.01 days. This was substantially sooner than the recommended clinical guidelines of 365 days. There were no patient or procedural characteristics which predicted a difference in the timing of surveillance colonoscopy. No pathological factors appeared to change the timing for surveillance endoscopy (P > 0.05). CONCLUSION: Overall, patients had surveillance endoscopy procedures substantially earlier than guideline recommendations. However, evidence underlying these guidelines and other surveillance methods for malignant polyps are not strong. Future technological developments, including improvements in imaging techniques, may provide additional options for surveillance of malignant polyps.

A population-based study of the management of rectal malignant polyps and the use of trans-anal surgery.

INTRODUCTION: Rectal malignant polyps can be managed by use of trans-anal resections (TAR). Traditional techniques of resection have been replaced by use of platforms such as trans-anal minimally invasive surgery (TAMIS) or trans-anal endoscopic microsurgery (TEM). This study reviewed the management of rectal malignant polyps, in particular focussing on when clinicians used TAR. METHODS: A population wide cohort study of all malignant rectal polyps diagnosed in Queensland, Australia from 2011 to 2018 was undertaken. Patient and pathological factors were compared across the management strategies of polypectomy, TAR and rectal resection. RESULTS: Overall 430 patients were diagnosed with a malignant rectal polyp during the study period, with 103 undergoing a TAR. There was increasing use of TAR across the study period as a management strategy (P < 0.001). Polypectomy alone was more likely to be the management strategy over TAR or rectal resection if there were clear margins (P < 0.001). The distance to the closest polypectomy margin was also significantly higher in the polypectomy group with mean clearance 2.09 mm in polypectomy group versus 0.86 mm in TAR group and 0.99 mm in resection group (P < 0.001). Rectal resection was more likely to be the management strategy over TAR if there was LVI (P < 0.001), depth of invasion was deeper (P < 0.001) and there was tumour budding (P = 0.001). CONCLUSION: TAR is an effective management strategy for rectal polyps and is utilized particularly in rectal malignant polyps when there are close or involved margins. Future guideline development should consider incorporation of TAR given the advances in techniques afforded by TAMIS or TEM platforms.

Patient and pathological predictors of management strategy for malignant polyps following polypectomy: a systematic review and meta-analysis.

PURPOSE: Malignant polyps present a treatment dilemma for clinicians and patients. This meta-analysis sought to identify the factors that predicted the management strategy for patients diagnosed with a malignant polyp. METHODS: A literature search was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the Cochrane Collaboration prognostic studies guidelines. Reports from 1985 onwards were included, data on patient and pathological factors were extracted and random effects meta-analysis models were used. RESULTS: Fifteen studies were included. Seven studies evaluated lymphovascular invasion (LVI). The odds of surgery were significantly higher in malignant polyps with LVI (OR 2.20, 95% CI 1.36-3.55). Ten studies revealed the odds of surgery were significantly higher with positive polypectomy margins (OR 8.09, 95% CI 4.88-13.40). Tumour differentiation was compared in eight studies. There were significantly lower odds of surgery in malignant polyps with well/moderate differentiation compared with poor differentiation (OR 0.31, 95% CI 0.21-0.46). There were non-significant trends favouring surgical resection in younger patients, males and Haggitt 4/Kikuchi Sm3 lesions. There was considerable heterogeneity in the meta-analyses for the variables age, gender, polyp morphology and Haggitt/Kikuchi level (I2 > 75%). CONCLUSION: This meta-analysis has demonstrated that LVI, positive polypectomy resection margins, and poor tumour differentiation significantly predict malignant polypectomy patients who underwent subsequent surgery. Age and gender were important factors predicting management, but not consistently across studies, whilst polyp morphology and Haggitt/Kikuchi levels did not significantly predict the management strategy. Further research may assist in understanding the management preferences.

Development of 3D Printed Biodegradable Mesh with Antimicrobial Properties for Pelvic Organ Prolapse.

To address the increasing demand for safe and effective treatment options for pelvic organ prolapse (POP) due to the worldwide ban of the traditional polypropylene meshes, this study introduced degradable polycaprolactone (PCL)/polyethylene glycol (PEG) composite meshes fabricated with melt-electrowriting (MEW). Two PCL/PEG mesh groups: 90:10 and 75:25 (PCL:PEG, wt%) were fabricated and characterized for their degradation rate and mechanical properties, with PCL meshes used as a control. The PCL/PEG composites showed controllable degradation rates by adjusting the PEG content and produced mechanical properties, such as maximal forces, that were higher than PCL alone. The antibacterial properties of the meshes were elicited by coating them with a commonly used antibiotic: azithromycin. Two dosage levels were used for the coating: 0.5 mg and 1 mg per mesh, and both dosage levels were found to be effective in suppressing the growth of S. aureus bacteria. The biocompatibility of the meshes was assessed using human immortalized adipose derived mesenchymal stem cells (hMSC). In vitro assays were used to assess the cell viability (LIVE/DEAD assay), cell metabolic activity (alamarBlue assay) and cell morphology on the meshes (fluorescent and electron microscopy). The cell attachment was found to decrease with increased PEG content. The freshly drug-coated meshes showed signs of cytotoxicity during the cell study process. However, when pre-released for 14 days in phosphate buffered saline, the initial delay in cell attachment on the drug-coated mesh groups showed full recovery at the 14-day cell culture time point. These results indicated that the PCL/PEG meshes with antibiotics coating will be an effective anti-infectious device when first implanted into the patients, and, after about 2 weeks of drug release, the mesh will be supporting cell attachment and proliferation. These meshes demonstrated a potential effective treatment option for POP that may circumvent the issues related to the traditional polypropylene meshes.

Preclinical Molecular PET-CT Imaging Targeting CDCP1 in Colorectal Cancer.

Colorectal cancer (CRC) is the third most common malignancy in the world, with 22% of patients presenting with metastatic disease and a further 50% destined to develop metastasis. Molecular imaging uses antigen-specific ligands conjugated to radionuclides to detect and characterise primary cancer and metastases. Expression of the cell surface protein CDCP1 is increased in CRC, and here we sought to assess whether it is a suitable molecular imaging target for the detection of this cancer. CDCP1 expression was assessed in CRC cell lines and a patient-derived xenograft to identify models suitable for evaluation of radio-labelled 10D7, a CDCP1-targeted, high-affinity monoclonal antibody, for preclinical molecular imaging. Positron emission tomography-computed tomography was used to compare zirconium-89 (89Zr)-10D7 avidity to a nonspecific, isotype control 89Zr-labelled IgGκ1 antibody. The specificity of CDCP1-avidity was further confirmed using CDCP1 silencing and blocking models. Our data indicate high avidity and specificity for of 89Zr-10D7 in CDCP1 expressing tumors at. Significantly higher levels than normal organs and blood, with greatest tumor avidity observed at late imaging time points. Furthermore, relatively high avidity is detected in high CDCP1 expressing tumors, with reduced avidity where CDCP1 expression was knocked down or blocked. The study supports CDCP1 as a molecular imaging target for CRC in preclinical PET-CT models using the radioligand 89Zr-10D7.

PET Imaging Quantifying 68Ga-PSMA-11 Uptake in Metastatic Colorectal Cancer.

At diagnosis, 22% of colorectal cancer (CRC) patients have metastases, and 50% later develop metastasis. Peptide receptor radionuclide therapy (PRRT), such as 177Lu-PSMA-617, is used to treat metastatic prostate cancer. 177Lu-PSMA-617 targets prostate-specific membrane antigen (PSMA), a cell-surface protein enriched in prostate cancer and the neovasculature of other solid tumors, including CRC. We performed 68Ga-PSMA-11 PET/CT imaging of 10 patients with metastatic CRC to assess metastasis avidity. Eight patients had lesions lacking avidity, and 2 had solitary metastases exhibiting very low avidity. Despite expression of PSMA in CRC neovasculature, none of the patients exhibited tumor avidity sufficient to be considered for 177Lu-PSMA-617 PRRT.

Effective targeting of intact and proteolysed CDCP1 for imaging and treatment of pancreatic ductal adenocarcinoma.

Background: CUB domain-containing protein 1 (CDCP1) is a cell surface receptor regulating key signalling pathways in malignant cells. CDCP1 has been proposed as a molecular target to abrogate oncogenic signalling pathways and specifically deliver anti-cancer agents to tumors. However, the development of CDCP1-targeting agents has been questioned by its frequent proteolytic processing which was thought to result in shedding of the CDCP1 extracellular domain limiting its targetability. In this study, we investigated the relevance of targeting CDCP1 in the context of pancreatic ductal adenocarcinoma (PDAC) and assess the impact of CDCP1 proteolysis on the effectiveness of CDCP1 targeting agents. Methods: The involvement of CDCP1 in PDAC progression was assessed by association analysis in several PDAC cohorts and the proteolytic processing of CDCP1 was evaluated in PDAC cell lines and patient-derived cells. The consequences of CDCP1 proteolysis on its targetability in PDAC cells was assessed using immunoprecipitation, immunostaining and biochemical assays. The involvement of CDCP1 in PDAC progression was examined by loss-of-function in vitro and in vivo experiments employing PDAC cells expressing intact or cleaved CDCP1. Finally, we generated antibody-based imaging and therapeutic agents targeting CDCP1 to demonstrate the feasibility of targeting this receptor for detection and treatment of PDAC tumors. Results: High CDCP1 expression in PDAC is significantly associated with poorer patient survival. In PDAC cells proteolysis of CDCP1 does not always result in the shedding of CDCP1-extracellular domain which can interact with membrane-bound CDCP1 allowing signal transduction between the different CDCP1-fragments. Targeting CDCP1 impairs PDAC cell functions and PDAC tumor growth independently of CDCP1 cleavage status. A CDCP1-targeting antibody is highly effective at delivering imaging radionuclides and cytotoxins to PDAC cells allowing specific detection of tumors by PET/CT imaging and superior anti-tumor effects compared to gemcitabine in in vivo models. Conclusion: Independent of its cleavage status, CDCP1 exerts oncogenic functions in PDAC and has significant potential to be targeted for improved radiological staging and treatment of this cancer. Its elevated expression by most PDAC tumors and lack of expression by normal pancreas and other major organs, suggest that targeting CDCP1 could benefit a significant proportion of PDAC patients. These data support the further development of CDCP1-targeting agents as personalizable tools for effective imaging and treatment of PDAC.

Protocol for faecal microbiota transplantation in ulcerative colitis (FMTUC): a randomised feasibility study.

BACKGROUND: The interaction of the gut microbiota with the human host is implicated in the pathogenesis of inflammatory and immunological diseases including ulcerative colitis (UC). Faecal microbiota transplantation (FMT) as a method of restoring gut microbial diversity is of increasing interest as a therapeutic approach in the management of UC. The current literature lacks consensus about the dose of FMT, route of administration and duration of response. METHODS AND ANALYSIS: This single-blinded randomised trial will explore the feasibility of FMT in 30 treatment-naïve patients with histologically confirmed distal UC limited to the recto-sigmoid region (up to 40 cm from the anal verge). This study aims to estimate the magnitude of treatment response to FMT under controlled conditions. The intervention (FMT) will be administered by rectal retention enema. It will test the feasibility of randomising patients to: (i) single FMT dose, (ii) five daily FMT doses or (iii) control (no FMT dose). All groups will receive standard antibiotic gut decontamination and bowel preparation before FMT. Recruitment will take place over a 24-month period with a 12-week patient follow-up. Trial objectives include evaluation of the magnitude of treatment response to FMT, investigation of the clinical value of metabolic phenotyping for predicting the clinical response to FMT and testing the recruitment rate of donors and patients for a study in FMT. This feasibility trial will enable an estimate of number of patients needed, help determine optimal study conditions and inform the choice of endpoints for a future definitive phase III study. ETHICS AND DISSEMINATION: The trial is approved by the regional ethics committee and is sponsored by Abertawe Bro Morgannwg University's Health Board. Written informed consent from all patients will be obtained. Serious adverse events will be reported to the sponsor. Trial results will be disseminated via peer review publication and shared with trial participants. TRIAL REGISTRATION NUMBER: ISRCTN 58082603; Pre-results.