Photoactive imaging and therapy for colorectal cancer using a CEA-Affimer conjugated Foslip nanoparticle.

Theranostic nanoparticles hold promise for simultaneous imaging and therapy in colorectal cancer. Carcinoembryonic antigen can be used as a target for these nanoparticles because it is overexpressed in most colorectal cancers. Affimer reagents are synthetic proteins capable of binding specific targets, with additional advantages over antibodies for targeting. We fabricated silica nanoparticles using a water-in-oil microemulsion technique, loaded them with the photosensitiser Foslip, and functionalised the surface with anti-CEA Affimers to facilitate fluorescence imaging and photodynamic therapy of colorectal cancer. CEA-specific fluorescence imaging and phototoxicity were quantified in colorectal cancer cell lines and a LS174T murine xenograft colorectal cancer model. Anti-CEA targeted nanoparticles exhibited CEA-specific fluorescence in the LoVo, LS174T and HCT116 cell lines when compared to control particles (p < 0.0001). No toxicity was observed in LS174T cancer mouse xenografts or other organs. Following photo-irradiation, the anti-CEA targeted particles caused significant cell death in LoVo (60%), LS174T (90%) and HCT116 (70%) compared to controls (p < 0.0001). Photodynamic therapy (PDT) at 24 h in vivo showed a 4-fold reduction in tumour volume compared to control mouse xenografts (p < 0.0001). This study demonstrates the efficacy of targeted fluorescence imaging and PDT using Foslip nanoparticles conjugated to anti-CEA Affimer nanoparticles in in vitro and in vivo colorectal cancer models.

Clinical and oncological outcomes of pelvic exenteration surgery for anal squamous cell carcinoma.

AIM: Anal cancer incidence and mortality rates are rising in the United Kingdom (UK). Surgery is an important treatment modality for persistent or recurrent disease. There is a paucity of data on outcomes for patients undergoing pelvic exenteration for anal squamous cell carcinoma (SCC) for persistent or recurrent disease. The aim of this study was to investigate the outcomes for patients who were treated with pelvic exenteration for anal SCC from two high-volume, high-complexity pelvic exenteration units in the UK. METHOD: A retrospective review of prospectively maintained databases from 2011 to 2020 was undertaken. Primary endpoints included R0 resection rates, overall and disease-free survival at 2 and 5 years. RESULTS: From 2011 to 2020, 35 patients with anal SCC were selected for exenteration. An R0 resection was achieved in 26 patients (77%). Of the remaining patients, seven patients had an R1 resection and one had a R2 resection. One further patient was excluded from additional analysis as the disease was inoperable at the time of laparotomy. With a median follow-up of 19.5 months (interquartile range 7.9-53.5 months), overall survival was 50% (17/34). Patients with an R1/2 resection had a significantly poorer overall survival [0.27 (0.09-0.76), p = 0.021] than those patients in whom R0 resection was achieved. Disease-free survival was 38.2% (13/34) and an R1/R2 resection was associated with a significantly reduced disease-free survival [0.12 (0.04-0.36), p < 0.001]. CONCLUSION: Complete R0 resection for recurrent or persistent anal SCC is possible in the majority of patients and improves overall and disease-free survival compared with R1/R2 resection.

Estimating postoperative mortality in colorectal surgery- a systematic review of risk prediction models.

PURPOSE: Risk prediction models are frequently used to support decision-making in colorectal surgery but can be inaccurate. Machine learning (ML) is becoming increasingly popular, and its application may increase predictive accuracy. We compared conventional risk prediction models for postoperative mortality (based on regression analysis) with ML models to determine the benefit of the latter approach. METHODS: The study was registered in PROSPERO(CRD42022364753). Following the PRISMA guidelines, a systematic search of three databases (MEDLINE, EMBASE, WoS) was conducted (from 1/1/2000 to 29/09/2022). Studies were included if they reported the development of a risk model to estimate short-term postoperative mortality for patients undergoing colorectal surgery. Discrimination and calibration performance metrics were compared. Studies were evaluated against CHARMS and TRIPOD criteria. RESULTS: 3,052 articles were screened, and 45 studies were included. The total sample size was 1,356,058 patients. Six studies used ML techniques for model development. Most studies (n = 42) reported the area under the receiver operating characteristic curve (AUROC) as a measure of discrimination. There was no significant difference in the mean AUROC values between regression models (0.833 s.d. ± 0.52) and ML (0.846 s.d. ± 0.55), p = 0.539. Calibration statistics, which measure the agreement between predicted estimates and observed outcomes, were less consistent. Risk of bias assessment found most concerns in the data handling and analysis domains of eligible studies. CONCLUSIONS: Our study showed comparable predictive performance between regression and ML methods in colorectal surgery. Integration of ML in colorectal risk prediction is promising but further refinement of the models is required to support routine clinical adoption.

Inflammatory Bowel Disease-Associated Colorectal Cancer Epidemiology and Outcomes: An English Population-Based Study.

INTRODUCTION: Patients with inflammatory bowel diseases (IBDs) of the colon are at an increased risk of colorectal cancer (CRC). This study investigates the epidemiology of IBD-CRC and its outcomes. METHODS: Using population data from the English National Health Service held in the CRC data repository, all CRCs with and without prior diagnosis of IBD (Crohn's, ulcerative colitis, IBD unclassified, and IBD with cholangitis) between 2005 and 2018 were identified. Descriptive analyses and logistic regression models were used to compare the characteristics of the 2 groups and their outcomes up to 2 years. RESULTS: Three hundred ninety thousand six hundred fourteen patients diagnosed with CRC were included, of whom 5,141 (1.3%) also had a previous diagnosis of IBD. IBD-CRC cases were younger (median age at CRC diagnosis [interquartile range] 66 [54-76] vs 72 [63-79] years [ P < 0.01]), more likely to be diagnosed with CRC as an emergency (25.1% vs 16.7% [ P < 0.01]), and more likely to have a right-sided colonic tumor (37.4% vs 31.5% [ P < 0.01]). Total colectomy was performed in 36.3% of those with IBD (15.4% of Crohn's, 44.1% of ulcerative colitis, 44.5% of IBD unclassified, and 67.7% of IBD with cholangitis). Synchronous (3.2% vs 1.6% P < 0.01) and metachronous tumors (1.7% vs 0.9% P < 0.01) occurred twice as frequently in patients with IBD compared with those without IBD. Stage-specific survival up to 2 years was worse for IBD-associated cancers. DISCUSSION: IBD-associated CRCs occur in younger patients and have worse outcomes than sporadic CRCs. There is an urgent need to find reasons for these differences to inform screening, surveillance, and treatment strategies for CRC and its precursors in this high-risk group.

Management of Perineal Wounds Following Pelvic Surgery.

Despite advancements in understanding and technique, there remain significant challenges in the management of a complex perineal wound following pelvic surgery. Complications including wound sepsis, fistulation, persistent sinus, and herniation produce additional morbidity and health care costs. This article details the methods of optimizing patient and operative factors to mitigate this risk, alongside strategies to deal with sequelae of wound failure.

A Comparison of Perineal Myocutaneous Flaps Following Abdominoperineal Excision of the Rectum for Anorectal Pathology.

BACKGROUND: Flap-based reconstruction following abdominoperineal resection has been used to address the resultant soft tissue defect and reduce postoperative wound complications. Vertical rectus abdominis myocutaneous flaps have been the traditional choice, but locoregional flaps have attracted attention in minimally invasive resection because they avoid additional abdominal dissection. However, few data exist comparing flap types. OBJECTIVE: To compare outcomes for different types of perineal reconstruction in patients undergoing abdominoperineal resection exclusively for anorectal pathology. DESIGN: This was a retrospective comparative study. SETTING: This study was conducted at a large, tertiary referral institution. PATIENTS: Following Institutional Review Board approval, prospectively maintained clinical and financial databases were interrogated and cross-referenced for patients undergoing proctectomy or abdominoperineal resection with flap reconstruction from 2007 to 2018. Patients with primary gynecological or urological pathology were excluded. MAIN OUTCOME MEASURES: The primary outcome was flap complication rate. Secondary outcomes included perineal hernia rate, donor site complications, emergency department consult after discharge, readmission <90 days, and length of stay. Data were analyzed using univariate and multivariate techniques. RESULTS: A total of 135 patients (79 female, median age 58 years) were included: 68 rectus, 52 gluteal, and 15 gracilis flap reconstructions. Median follow-up was 46 months. Rates of both major and minor flap complications were similar for rectus and gluteal flaps, even when controlling for differences between groups via multivariate analysis ( p > 0.9), including extent of resection and use of mesh. For all flaps, American Society of Anesthesiology score ≥3 was the only independent predictor of major, but not minor, flap complications. For rectus and gluteal flaps, smoking, female sex, and American Society of Anesthesiology score ≥3 were independent predictors of major flap complications ( p < 0.05). LIMITATIONS: This study was limited by its retrospective nature and potential selection bias associated with flap choice; it was also impossible to quantify defect size. CONCLUSION: Gluteal flaps have similar complication rates to rectus flaps and may be considered for patients who are otherwise suitable for minimally invasive abdominoperineal resection. See Video Abstract at http://links.lww.com/DCR/B866 .Una comparación de los colgajos miocutáneos perineales después de la escisión abdominoperineal del recto para patología anorectal. ANTECEDENTES: La reconstrucción con colgajo después de la resección abdominoperineal se ha utilizado para abordar el defecto de tejido blando resultante y reducir las complicaciones postoperatorias de la herida. Los colgajos miocutáneos verticales del recto abdominal han sido la elección tradicional, pero los colgajos locorregionales han atraído la atención en la resección mínimamente invasiva porque evitan la disección abdominal adicional. Sin embargo, existen pocos datos que comparen los tipos de colgajos.

A novel fluorescent c-met targeted imaging agent for intra-operative colonic tumour mapping: Translation from the laboratory into a clinical trial.

BACKGROUND: The c-Met protein is overexpressed in many gastrointestinal cancers. We explored EMI-137, a novel c-Met targeting fluorescent probe, for application in fluorescence-guided colon surgery, in HT-29 colorectal cancer (CRC) cell line and an in vivo murine model. METHODS: HT-29 SiRNA transfection confirmed specificity of EMI-137 for c-Met. A HT-29 CRC xenograft model was developed in BALB/c mice, EMI-137 was injected and biodistribution analysed through in vivo fluorescent imaging. Nine patients, received a single intravenous EMI-137 bolus (0.13 mg/kg), 1-3 h before laparoscopic-assisted colon cancer surgery (NCT03360461). Tumour and LN fluorescence was assessed intraoperatively and correlated with c-Met expression in eight samples by immunohistochemistry. FINDINGS: c-Met expression HT-29 cells was silenced and imaged with EMI-137. Strong EMI-137 uptake in tumour xenografts was observed up to 6 h post-administration. At clinical trial, no serious adverse events related to EMI-137 were reported. Marked background fluorescence was observed in all participants, 4/9 showed increased tumour fluorescence over background; 5/9 had histological LN metastases; no fluorescent LN were detected intraoperatively. All primary tumours (8/8) and malignant LN (15/15) exhibited high c-Met protein expression. INTERPRETATION: EMI-137, binds specifically to the human c-Met protein, is safe, and with further refinement, shows potential for application in fluorescence-guided surgery.

The utility of c-Met as a diagnostic tissue biomarker in primary colorectal cancer.

The transmembrane protein, c-Met, is thought to be overexpressed and activated in colorectal cancer (CRC). This study explored its potential as a diagnostic tissue biomarker for CRC in a large human CRC tissue collection obtained from a randomized clinical trial. Tissue microarrays of matched normal colorectal epithelium and primary cancer were prepared from specimens obtained from 280 patients recruited to the MRC CLASICC trial (ISRCTN 74883561) and interrogated using immunohistochemistry for c-Met expression. The distribution and intensity of immunopositivity was graded using a validated, semi-quantifiable score, and differences in median scores analysed using the Wilcoxon signed-rank test. A receiver operating characteristic (ROC) curve was plotted to measure the diagnostic accuracy of c-Met as a biomarker in CRC. Epithelial cell membrane expression of c-Met differed significantly between CRC and normal colorectal tissue: median 12.00 (Interquartile range (IQR) 6-15) versus median 6.00 (IQR 2.70-12.00) respectively (P = <.0001). ROC-AUC analysis of c-Met expression yielded a CRC diagnostic probability of 0.66 (95% CI: 0.61 to 0.70; P < .0001). A score of ≥14.50 showed high specificity at 85.32% (95% CI 80.33%-89.45%) but sensitivity of only 30.92% (CI 25.37%-36.90%). Thus c-Met is consistently overexpressed in human CRC as compared to normal colorectal epithelium tissue. c-Met expression may have a role in diagnosis and prognostication if combined with other biomarkers.

Information needs for recovery after colorectal surgery: a patient focus group study.

AIM: The provision of information to patients is an important part of recovery after colorectal surgery. This study aimed to define patient information needs, barriers to effective understanding and insights into how information provision may be improved. METHOD: A patient focus group was convened. This comprised a broad, convenience sample of 11 participants from across the United Kingdom with experience of major colorectal surgery. A semistructured topic guide was used to facilitate discussion about previous experiences of information provision and how this may be improved. Data were analysed thematically and are presented as major themes. RESULTS: Overall, participants felt that their information needs are poorly prioritized by healthcare professionals. Barriers to understanding and retaining information include highly emotional situations (such as receiving bad news) and inappropriate information design (such as the use of inaccessible language). Participants expressed how information resources should: (a) address patients' individual information needs; (b) empower patients to take an active role in their recovery; (c) support patients with meaningful education and sign-posted resources; and (d) recognize patients' heightened need for information during recovery at home. CONCLUSION: This study provides key insights into the information needs of patients undergoing colorectal surgery. These should inform the development of future information resources, whose format, timing and design are currently supported by low-quality evidence.

Global academic response to COVID-19: Cross-sectional study.

This study explores the response to COVID-19 from investigators, editors, and publishers and seeks to define challenges during the early stages of the pandemic. A cross-sectional bibliometric review of COVID-19 literature was undertaken between 1 November 2019 and 24 March 2020, along with a comparative review of Middle East respiratory syndrome (MERS) literature. Investigator responsiveness was assessed by measuring the volume and type of research published. Editorial responsiveness was assessed by measuring the submission-to-acceptance time and availability of original data. Publisher-responsiveness was assessed by measuring the acceptance-to-publication time and the provision of open access. Three hundred and ninety-eight of 2,835 COVID-19 and 55 of 1,513 MERS search results were eligible. Most COVID-19 studies were clinical reports (n = 242; 60.8%). The submission-to-acceptance [median: 5 days (IQR: 3-11) versus 71.5 days (38-106); P < .001] and acceptance-to-publication [median: 5 days (IQR: 2-8) versus 22.5 days (4-48·5-; P < .001] times were strikingly shorter for COVID-19. Almost all COVID-19 (n = 396; 99.5%) and MERS (n = 55; 100%) studies were open-access. Data sharing was infrequent, with original data available for 104 (26.1%) COVID-19 and 10 (18.2%) MERS studies (P = .203). The early academic response was characterized by investigators aiming to define the disease. Studies were made rapidly and openly available. Only one-in-four were published alongside original data, which is a key target for improvement. Key points: COVID-19 publications show rapid response from investigators, specifically aiming to define the disease.Median time between submission and acceptance of COVID-19 articles is 5 days demonstrating rapid decision-making compared with the median of 71.5 days for MERS articles.Median time from acceptance to publication of COVID-19 articles is 5 days, confirming the ability to introduce rapid increases at times of crisis, such as during the SARS outbreak.The majority of both COVID-19 and MERS articles are available open-access.

Enhanced Recovery After Surgery: Recent Developments in Colorectal Surgery.

Enhanced recovery after surgery (ERAS) has been established as a safe and effective tool for early recovery and discharge after colorectal resection. This article reviews the latest additions and refinements to ERAS protocols and also examines those interventions that seem to have limited clinical benefit for colorectal patients.

The HubBLe Trial: haemorrhoidal artery ligation (HAL) versus rubber band ligation (RBL) for symptomatic second- and third-degree haemorrhoids: a multicentre randomised controlled trial and health-economic evaluation.

BACKGROUND: Optimal surgical intervention for low-grade haemorrhoids is unknown. Rubber band ligation (RBL) is probably the most common intervention. Haemorrhoidal artery ligation (HAL) is a novel alternative that may be more efficacious. OBJECTIVE: The comparison of HAL with RBL for the treatment of grade II/III haemorrhoids. DESIGN: A multicentre, parallel-group randomised controlled trial. PERSPECTIVE: UK NHS and Personal Social Services. SETTING: 17 NHS Trusts. PARTICIPANTS: Patients aged ≥ 18 years presenting with grade II/III (second- and third-degree) haemorrhoids, including those who have undergone previous RBL. INTERVENTIONS: HAL with Doppler probe compared with RBL. OUTCOMES: Primary outcome - recurrence at 1 year post procedure; secondary outcomes - recurrence at 6 weeks; haemorrhoid severity score; European Quality of Life-5 Dimensions, 5-level version (EQ-5D-5L); Vaizey incontinence score; pain assessment; complications; and cost-effectiveness. RESULTS: A total of 370 participants entered the trial. At 1 year post procedure, 30% of the HAL group had evidence of recurrence compared with 49% after RBL [adjusted odds ratio (OR) = 2.23, 95% confidence interval (CI) 1.42 to 3.51; p = 0.0005]. The main reason for the difference was the number of extra procedures required to achieve improvement/cure. If a single HAL is compared with multiple RBLs then only 37.5% recurred in the RBL arm (adjusted OR 1.35, 95% CI 0.85 to 2.15; p = 0.20). Persistence of significant symptoms at 6 weeks was lower in both arms than at 1 year (9% HAL and 29% RBL), suggesting significant deterioration in both groups over the year. Symptom score, EQ-5D-5L and Vaizey score improved in both groups compared with baseline, but there was no difference between interventions. Pain was less severe and of shorter duration in the RBL group; most of the HAL group who had pain had mild to moderate pain, resolving by 3 weeks. Complications were low frequency and not significantly different between groups. It appeared that HAL was not cost-effective compared with RBL. In the base-case analysis, the difference in mean total costs was £1027 higher for HAL. Quality-adjusted life-years (QALYs) were higher for HAL; however, the difference was very small (0.01) resulting in an incremental cost-effectiveness ratio of £104,427 per additional QALY. CONCLUSIONS: At 1 year, although HAL resulted in fewer recurrences, recurrence was similar to repeat RBL. Symptom scores, complications, EQ-5D-5L and continence score were no different, and patients had more pain in the early postoperative period after HAL. HAL is more expensive and unlikely to be cost-effective in terms of incremental cost per QALY. LIMITATIONS: Blinding of participants and site staff was not possible. FUTURE WORK: The incidence of recurrence may continue to increase with time. Further follow-up would add to the evidence regarding long-term clinical effectiveness and cost-effectiveness. The polysymptomatic nature of haemorrhoidal disease requires a validated scoring system, and the data from this trial will allow further assessment of validity of such a system. These data add to the literature regarding treatment of grade II/III haemorrhoids. The results dovetail with results from the eTHoS study [Watson AJM, Hudson J, Wood J, Kilonzo M, Brown SR, McDonald A, et al. Comparison of stapled haemorrhoidopexy with traditional excisional surgery for haemorrhoidal disease (eTHoS): a pragmatic, multicentre, randomised controlled trial. Lancet 2016, in press.] comparing stapled haemorrhoidectomy with excisional haemorrhoidectomy. Combined results will allow expansion of analysis, allowing surgeons to tailor their treatment options to individual patients. TRIAL REGISTRATION: Current Controlled Trials ISRCTN41394716. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 88. See the NIHR Journals Library website for further project information.

The HubBLe trial: haemorrhoidal artery ligation (HAL) versus rubber band ligation (RBL) for haemorrhoids.

BACKGROUND: Haemorrhoids (piles) are a very common condition seen in surgical clinics. After exclusion of more sinister causes of haemorrhoidal symptoms (rectal bleeding, perianal irritation and prolapse), the best option for treatment depends upon persistence and severity of the symptoms. Minor symptoms often respond to conservative treatment such as dietary fibre and reassurance. For more severe symptoms treatment such as rubber band ligation may be therapeutic and is a very commonly performed procedure in the surgical outpatient setting. Surgery is usually reserved for those who have more severe symptoms, as well as those who do not respond to non-operative therapy; surgical techniques include haemorrhoidectomy and haemorrhoidopexy. More recently, haemorrhoidal artery ligation has been introduced as a minimally invasive, non destructive surgical option.There are substantial data in the literature concerning efficacy and safety of 'rubber band ligation including multiple comparisons with other interventions, though there are no studies comparing it to haemorrhoidal artery ligation. A recent overview has been carried out by the National Institute for Health and Clinical Excellence which concludes that current evidence shows haemorrhoidal artery ligation to be a safe alternative to haemorrhoidectomy and haemorrhoidopexy though it also highlights the lack of good quality data as evidence for the advantages of the technique. METHODS/DESIGN: The aim of this study is to establish the clinical effectiveness and cost effectiveness of haemorrhoidal artery ligation compared with conventional rubber band ligation in the treatment of people with symptomatic second or third degree (Grade II or Grade III) haemorrhoids. DESIGN: A multi-centre, parallel group randomised controlled trial. OUTCOMES: The primary outcome is patient-reported symptom recurrence twelve months following the intervention. Secondary outcome measures relate to symptoms, complications, health resource use, health related quality of life and cost effectiveness following the intervention. PARTICIPANTS: 350 patients with grade II or grade III haemorrhoids will be recruited in surgical departments in up to 14 NHS hospitals. RANDOMISATION: A multi-centre, parallel group randomised controlled trial. Block randomisation by centre will be used, with 175 participants randomised to each group. DISCUSSION: The results of the research will help inform future practice for the treatment of grade II and III haemorrhoids. TRIAL REGISTRATION: ISRCTN41394716.