Tumour budding as a prognostic biomarker in biopsies and resections of neoadjuvant-treated rectal adenocarcinoma.

BACKGROUND: Tumour budding (TB) is a marker of tumour aggressiveness which, when measured in rectal cancer resection specimens, predicts worse outcomes and response to neoadjuvant therapy. We investigated the utility of TB assessment in the setting of neoadjuvant treatment. METHODS AND RESULTS: A single-centre, retrospective cohort study was conducted. TB was assessed using the hot-spot International Tumour Budding Consortium (ITBCC) method and classified by the revised ITBCC criteria. Haematoxylin and eosin (H&E) and AE1/AE3 cytokeratin (CK) stains for ITB (intratumoural budding) in biopsies with PTB (peritumoural budding) and ITB (intratumoural budding) in resection specimens were compared. Logistic regression assessed budding as predictors of lymph node metastasis (LNM). Cox regression and Kaplan-Meier analyses investigated their utility as a predictor of disease-free (DFS) and overall (OS) survival. A total of 146 patients were included; 91 were male (62.3%). Thirty-seven cases (25.3%) had ITB on H&E and 79 (54.1%) had ITB on CK assessment of biopsy tissue. In univariable analysis, H&E ITB [odds (OR) = 2.709, 95% confidence interval (CI) = 1.261-5.822, P = 0.011] and CK ITB (OR = 2.165, 95% CI = 1.076-4.357, P = 0.030) predicted LNM. Biopsy-assessed H&E ITB (OR = 2.749, 95% CI = 1.258-6.528, P = 0.022) was an independent predictor of LNM. In Kaplan-Meier analysis, ITB identified on biopsy was associated with worse OS (H&E, P = 0.003, CK: P = 0.009) and DFS (H&E, P = 0.012; CK, P = 0.045). In resection specimens, CK PTB was associated with worse OS (P = 0.047), and both CK PTB and ITB with worse DFS (PTB, P = 0.014; ITB: P = 0.019). In multivariable analysis H&E ITB predicted OS (HR = 2.930, 95% CI = 1.261-6.809) and DFS (HR = 2.072, 95% CI = 1.031-4.164). CK PTB grading on resection also independently predicted OS (HR = 3.417, 95% CI = 1.45-8.053, P = 0.005). CONCLUSION: Assessment of TB using H&E and CK may be feasible in rectal cancer biopsy and post-neoadjuvant therapy-treated resection specimens and is associated with LNM and worse survival outcomes. Future management strategies for rectal cancer might be tailored to incorporate these findings.

Model-based bioequivalence approach for sparse pharmacokinetic bioequivalence studies: Model selection or model averaging?

Conventional pharmacokinetic (PK) bioequivalence (BE) studies aim to compare the rate and extent of drug absorption from a test (T) and reference (R) product using non-compartmental analysis (NCA) and the two one-sided test (TOST). Recently published regulatory guidance recommends alternative model-based (MB) approaches for BE assessment when NCA is challenging, as for long-acting injectables and products which require sparse PK sampling. However, our previous research on MB-TOST approaches showed that model misspecification can lead to inflated type I error. The objective of this research was to compare the performance of model selection (MS) on R product arm data and model averaging (MA) from a pool of candidate structural PK models in MBBE studies with sparse sampling. Our simulation study was inspired by a real case BE study using a two-way crossover design. PK data were simulated using three structural models under the null hypothesis and one model under the alternative hypothesis. MB-TOST was applied either using each of the five candidate models or following MS and MA with or without the simulated model in the pool. Assuming T and R have the same PK model, our simulation shows that following MS and MA, MB-TOST controls type I error rates at or below 0.05 and attains similar or even higher power than when using the simulated model. Thus, we propose to use MS prior to MB-TOST for BE studies with sparse PK sampling and to consider MA when candidate models have similar Akaike information criterion.

Total neoadjuvant therapy versus standard neoadjuvant treatment strategies for the management of locally advanced rectal cancer: network meta-analysis of randomized clinical trials.

BACKGROUND: This study compared the advantages and disadvantages of total neoadjuvant therapy (TNT) strategies for patients with locally advanced rectal cancer, compared with the more traditional multimodal neoadjuvant management strategies of long-course chemoradiotherapy (LCRT) or short-course radiotherapy (SCRT). METHODS: A systematic review and network meta-analysis of exclusively RCTs was undertaken, comparing survival, recurrence, pathological, radiological, and oncological outcomes. The last date of the search was 14 December 2022. RESULTS: In total, 15 RCTs involving 4602 patients with locally advanced rectal cancer, conducted between 2004 and 2022, were included. TNT improved overall survival compared with LCRT (HR 0.73, 95 per cent credible interval 0.60 to 0.92) and SCRT (HR 0.67, 0.47 to 0.95). TNT also improved rates of distant metastasis compared with LCRT (HR 0.81, 0.69 to 0.97). Reduced overall recurrence was observed for TNT compared with LCRT (HR 0.87, 0.76 to 0.99). TNT showed an improved pCR compared with both LCRT (risk ratio (RR) 1.60, 1.36 to 1.90) and SCRT (RR 11.32, 5.00 to 30.73). TNT also showed an improvement in cCR compared with LCRT (RR 1.68, 1.08 to 2.64). There was no difference between treatments in disease-free survival, local recurrence, R0 resection, treatment toxicity or treatment compliance. CONCLUSION: This study provides further evidence that TNT has improved survival and recurrence benefits compared with current standards of care, and may increase the number of patients suitable for organ preservation, without negatively influencing treatment toxicity or compliance.

Evaluating the oncological safety of neoadjuvant chemotherapy in locally advanced colon carcinoma: a systematic review and meta-analysis of randomised clinical trials and propensity-matched studies.

PURPOSE: Use of neoadjuvant chemotherapy (NAC) for locally advanced colon cancer (LACC) remains controversial. An integrated analysis of data from high-quality studies may inform the long-term safety of NAC for this cohort. Our aim was to perform a systematic review and meta-analysis of randomised clinical trials (RCTs) and propensity-matched studies to assess the oncological safety of NAC in patients with LACC. METHODS: A systematic review was performed as per preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. Survival was expressed as hazard ratios using time-to-effect generic inverse variance methodology, while surgical outcomes were expressed as odds ratios (ORs) using the Mantel-Haenszel method. Data analysis was performed using Review Manager version 5.4. RESULTS: Eight studies (4 RCTs and 4 retrospective studies) including 31,047 patients with LACC were included. Mean age was 61.0 years (range: 19-93 years) and mean follow-up was 47.6 months (range: 2-133 months). Of those receiving NAC, 4.6% achieved a pathological complete response and 90.6% achieved R0 resection (versus 85.9%, P < 0.001). At 3 years, patients receiving NAC had improved disease-free survival (DFS) (OR: 1.28, 95% confidence interval (CI): 1.02-1.60, P = 0.030) and overall survival (OS) (OR: 1.76, 95% CI: 1.10-2.81, P = 0.020). When using time-to-effect modelling, a non-significant difference was observed for DFS (HR: 0.79, 95% CI: 0.57-1.09, P = 0.150) while a significant difference in favour of NAC was observed for OS (HR: 0.75, 95% CI: 0.58-0.98, P = 0.030). CONCLUSION: This study highlights the oncological safety of NAC for patients being treated with curative intent for LACC using RCT and propensity-matched studies only. These results refute current management guidelines which do not advocate for NAC to improve surgical and oncological outcomes in patients with LACC. TRIAL REGISTRATION: International Prospective Register of Systematic Review (PROSPERO) registration: CRD4202341723.

Comparing neoadjuvant therapy followed by local excision to total mesorectal excision in the treatment of early stage rectal cancer: a systematic review and meta-analysis of randomised clinical trials.

INTRODUCTION: Total mesorectal excision (TME) is the standard-of-care in early, clinical stage (cT2-3 N0 M0) rectal cancer. Local excision (LE) may be an alternative after adequate response to neoadjuvant therapy (NAT), with either long-course chemoradiotherapy (nCRT) or short-course radiotherapy (SCRT), as a means of preserving the rectum and potentially obviating the morbidity of TME. METHODS: A systematic review was performed according to PRISMA guidelines for studies that randomly assigned patients with cT2-3 N0 M0 rectal cancer to either NAT + LE or TME that reported radiologic, oncologic, surgical, and morbidity outcomes. RESULTS: A total of 4 RCTs comprise 462 patients (232 patients receiving NAT + LE; nCRT n = 205; SCRT n = 27) and 230 undergoing TME, respectively. NAT compliance was 98.86%. The rate of early completion TME in the NAT + LE group was 22.3%, while the proportion of patients achieving durable organ preservation was 75.4% at mean follow-up of 5.6 years. There was no difference in disease-free survival (DFS) (HR [hazard ratio] 1.19; 95% CI 0.95, 1.49; p = 0.13) or overall survival (OS) (HR 0.94; 95% CI 0.72, 1.23; p = 0.63]) according to the assigned treatment arm. The local recurrence rate (LRR) (HR 1.22; 95% CI 0.5-3.02; p = 0.66) and distant metastases (HR 0.92; 95% CI 0.45, 1.90; p = 0.82) were also comparable between the groups. There was a significant reduction in major (OR 0.45; 95% CI 0.21, 0.95; p = 0.04) and minor morbidity (OR 0.45; 95% CI 0.24, 0.85; p = 0.01) for patients undergoing NAT + LE. Overall stoma formation was decreased in the NAT + LE group (OR 0.03; 95% CI 0.0, 0.23; p ≤ 0.00001). CONCLUSION: NAT + LE reduces adverse effects of TME, without any compromise in oncological outcomes, and the potential for an organ preserving strategy should be discussed with patients with T2-3N0 rectal cancers prior to treatment.

Impact of model misspecification on model-based tests in PK studies with parallel design: real case and simulation studies.

This article evaluates the performance of pharmacokinetic (PK) equivalence testing between two formulations of a drug through the Two-One Sided Tests (TOST) by a model-based approach (MB-TOST), as an alternative to the classical non-compartmental approach (NCA-TOST), for a sparse design with a few time points per subject. We focused on the impact of model misspecification and the relevance of model selection for the reference data. We first analysed PK data from phase I studies of gantenerumab, a monoclonal antibody for the treatment of Alzheimer's disease. Using the original rich sample data, we compared MB-TOST to NCA-TOST for validation. Then, the analysis was repeated on a sparse subset of the original data with MB-TOST. This analysis inspired a simulation study with rich and sparse designs. With rich designs, we compared NCA-TOST and MB-TOST in terms of type I error and study power. With both designs, we explored the impact of misspecifying the model on the performance of MB-TOST and adding a model selection step. Using the observed data, the results of both approaches were in general concordance. MB-TOST results were robust with sparse designs when the underlying PK structural model was correctly specified. Using the simulated data with a rich design, the type I error of NCA-TOST was close to the nominal level. When using the simulated model, the type I error of MB-TOST was controlled on rich and sparse designs, but using a misspecified model led to inflated type I errors. Adding a model selection step on the reference data reduced the inflation. MB-TOST appears as a robust alternative to NCA-TOST, provided that the PK model is correctly specified and the test drug has the same PK structural model as the reference drug.

Modelling mobile-based technology adoption among people with dementia.

The work described in this paper builds upon our previous research on adoption modelling and aims to identify the best subset of features that could offer a better understanding of technology adoption. The current work is based on the analysis and fusion of two datasets that provide detailed information on background, psychosocial, and medical history of the subjects. In the process of modelling adoption, feature selection is carried out followed by empirical analysis to identify the best classification models. With a more detailed set of features including psychosocial and medical history information, the developed adoption model, using kNN algorithm, achieved a prediction accuracy of 99.41% when tested on 173 participants. The second-best algorithm built, using NN, achieved 94.08% accuracy. Both these results have improved accuracy in comparison to the best accuracy achieved (92.48%) in our previous work, based on psychosocial and self-reported health data for the same cohort. It has been found that psychosocial data is better than medical data for predicting technology adoption. However, for the best results, we should use a combination of psychosocial and medical data where it is preferable that the latter is provided from reliable medical sources, rather than self-reported.

Factors that potentially influence successful weight loss for adults with intellectual disabilities: A qualitative comparison.

BACKGROUND: People with intellectual disabilities are more at risk of obesity than the general population. Emerging literature indicates that multicomponent interventions are most effective, however, individual results are variable and little research exists as to why this is the case. METHODS: Focus groups were conducted to explore lived experiences between two groups of adults with intellectual disabilities; an overweight group (n = 6) and a group identified as successful in losing weight (n = 6). Similarities and differences were explored across four domains. Transcripts were produced and analysed using Theoretical Thematic Analysis. RESULTS: Similarities included service centre supports, basic food knowledge and issues restricting independence. The successful weight loss group had also internalised health messages, engaged with external reinforcement programmes, responded to positive feedback and demonstrated healthier dietary habits. CONCLUSION: Weight management interventions would benefit from understanding the influence that internalisation of health messages, effective reinforcement systems and positive feedback can have on supporting the adoption of healthier habits.

A new composite measure of colonoscopy: the Performance Indicator of Colonic Intubation (PICI).

BACKGROUND AND STUDY AIM: Cecal intubation rate (CIR) is an established performance indicator of colonoscopy. In some patients, cecal intubation with acceptable tolerance is only achieved with additional sedation. This study proposes a composite Performance Indicator of Colonic Intubation (PICI), which combines CIR, comfort, and sedation. METHODS : Data from 20 085 colonoscopies reported in the 2011 UK national audit were analyzed. PICI was defined as the percentage of procedures achieving cecal intubation with median dose (2 mg) of midazolam or less, and nurse-assessed comfort score of 1 - 3/5. Multivariate logistic regression analysis evaluated possible associations between PICI and patient, unit, colonoscopist, and diagnostic factors. RESULTS : PICI was achieved in 54.1 % of procedures. PICI identified factors affecting performance more frequently than single measures such as CIR and polyp detection, or CIR + comfort alone. Older age, male sex, adequate bowel preparation, and a positive fecal occult blood test as indication were associated with a higher PICI. Unit accreditation, the presence of magnetic imagers in the unit, greater annual volume, fewer years' experience, and higher training/trainer status were associated with higher PICI rates. Procedures in which PICI was achieved were associated with significantly higher polyp detection rates than when PICI was not achieved. CONCLUSIONS : PICI provides a simpler picture of performance of colonoscopic intubation than separate measures of CIR, comfort, and sedation. It is associated with more factors that are amenable to change that might improve performance and with higher likelihood of polyp detection. It is proposed that PICI becomes the key performance indicator for intubation of the colon in colonoscopy quality improvement initiatives.

Modelling assistive technology adoption for people with dementia.

PURPOSE: Assistive technologies have been identified as a potential solution for the provision of elderly care. Such technologies have in general the capacity to enhance the quality of life and increase the level of independence among their users. Nevertheless, the acceptance of these technologies is crucial to their success. Generally speaking, the elderly are not well-disposed to technologies and have limited experience; these factors contribute towards limiting the widespread acceptance of technology. It is therefore important to evaluate the potential success of technologies prior to their deployment. MATERIALS AND METHODS: The research described in this paper builds upon our previous work on modelling adoption of assistive technology, in the form of cognitive prosthetics such as reminder apps and aims at identifying a refined sub-set of features which offer improved accuracy in predicting technology adoption. Consequently, in this paper, an adoption model is built using a set of features extracted from a user's background to minimise the likelihood of non-adoption. The work is based on analysis of data from the Cache County Study on Memory and Aging (CCSMA) with 31 features covering a range of age, gender, education and details of health condition. In the process of modelling adoption, feature selection and feature reduction is carried out followed by identifying the best classification models. FINDINGS: With the reduced set of labelled features the technology adoption model built achieved an average prediction accuracy of 92.48% when tested on 173 participants. CONCLUSIONS: We conclude that modelling user adoption from a range of parameters such as physical, environmental and social perspectives is beneficial in recommending a technology to a particular user based on their profile.

Gene selection and cloning approaches for co-expression and production of recombinant protein-protein complexes.

Multiprotein complexes play essential roles in all cells and X-ray crystallography can provide unparalleled insight into their structure and function. Many of these complexes are believed to be sufficiently stable for structural biology studies, but the production of protein-protein complexes using recombinant technologies is still labor-intensive. We have explored several strategies for the identification and cloning of heterodimers and heterotrimers that are compatible with the high-throughput (HTP) structural biology pipeline developed for single proteins. Two approaches are presented and compared which resulted in co-expression of paired genes from a single expression vector. Native operons encoding predicted interacting proteins were selected from a repertoire of genomes, and cloned directly to expression vector. In an alternative approach, Helicobacter pylori proteins predicted to interact strongly were cloned, each associated with translational control elements, then linked into an artificial operon. Proteins were then expressed and purified by standard HTP protocols, resulting to date in the structure determination of two H. pylori complexes.

The national colonoscopy audit: a nationwide assessment of the quality and safety of colonoscopy in the UK.

OBJECTIVE: To perform a comprehensive audit of all colonoscopy undertaken in the UK over a 2-week period. DESIGN: Multi-centre survey. All adult (≥16 years of age) colonoscopies that took place in participating National Health Service hospitals between 28 February 2011 and 11 March 2011 were included. RESULTS: Data on 20,085 colonoscopies and 2681 colonoscopists were collected from 302 units. A validation exercise indicated that data were collected on over 94% of all procedures performed nationally. The unadjusted caecal intubation rate (CIR) was 92.3%. When adjusted for impassable strictures and poor bowel preparation the CIR was 95.8%. The polyp detection rate was 32.1%. The polyp detection rate for larger polyps (≥10 mm diameter) was 11.7%. 92.3% of resected polyps were retrieved. 90.2% of procedures achieved acceptable levels of patient comfort. A total of eight perforations and 52 significant haemorrhages were reported. Eight patients underwent surgery as a consequence of a complication. CONCLUSIONS: This is the first national audit of colonoscopy that has successfully captured the majority of adult colonoscopies performed across an entire nation during a defined time period. The data confirm that there has been a significant improvement in the performance of colonoscopy in the UK since the last study reported seven years ago (CIR 76.9%) and that performance is above the required national standards.

What works, how and in which contexts when supporting parents to implement intensive speech and language therapy at home for children with speech sound disorder? A protocol for a realist review.

INTRODUCTION: Speech and language therapists (SLTs) worldwide report challenges with providing recommended, evidence-based intervention intensity for children with speech sound disorder (SSD). Challenges such as service constraints and/or family contexts impact on access to optimal therapy intensity. Existing research indicates that empowering and training parents to deliver intervention at home, alongside SLT support, offers one possible solution to increasing the intensity of intervention children with SSD receive. Digital health could increase accessibility to intensive home practice and help sustain engagement with therapy activities. Further exploration is needed around what makes parent-implemented interventions for children with SSD effective, for who and in which situations. This paper outlines the protocol for a realist review which aims to explore the active ingredients and contextual factors of effective digital parent-led interventions. METHODS AND ANALYSIS: A realist review will explore the research question, following six stages. The scope of the review will be determined, and initial programme theories will be developed about what works in digital parent-implemented interventions for SSD, for whom, how, why and in what circumstances. Relevant secondary data, identified through a formal search strategy, will be selected, appraised, analysed and synthesised using realist principles to test and further refine the initial programme theories. This process will develop refined underpinning explanatory theories which capture the interaction between contexts, mechanisms and outcomes of the intervention. An expert steering group will provide insight to inform explanatory theories, searches, and dissemination. ETHICS AND DISSEMINATION: Ethical approval is not required for this review. The refined programme theories from the review will inform the next stages of a wider study. A subsequent realist evaluation will test and further refine theories with key stakeholders. Following this, the underpinning programme theory will be used to coproduce a digital tool, to support parents to deliver home intervention alongside SLT support.

Heart rate variability biofeedback to reduce anxiety in autism spectrum disorder - a mini review.

There is a reported high prevalence of anxiety in people with autism spectrum disorder. This mini review appraises existing research investigating heart rate variability biofeedback to help manage symptoms of anxiety in people with autism spectrum disorder. A thorough search of electronic databases was conducted to find relevant literature. Consultation with experts and a librarian helped develop search terms following the PICO framework. Five databases were searched, and screening was undertaken using Covidence software, with the process outlined in a PRISMA flowchart. The latest review showed positive short-term effects but there is a need for long-term follow-up. Future investigations should consider device type, training settings, and control interventions. Accurate heart rate variability assessment independent of biofeedback devices is crucial. Additional measures like cortisol assessment and user feedback are recommended for comprehensive evaluation. The findings highlight progress in the evidence base and offer insight to future directions.

New LIC vectors for production of proteins from genes containing rare codons.

In the effort to produce proteins coded by diverse genomes, structural genomics projects often must express genes containing codons that are rare in the production strain. To address this problem, genes expressing tRNAs corresponding to those codons are typically coexpressed from a second plasmid in the host strain, or from genes incorporated into production plasmids. Here we describe the modification of a series of LIC pMCSG vectors currently used in the high-throughput (HTP) production of proteins to include crucial tRNA genes covering rare codons for Arg (AGG/AGA) and Ile (AUA). We also present variants of these new vectors that allow analysis of ligand binding or co-expression of multiple proteins introduced through two independent LIC steps. Additionally, to accommodate the cloning of multiple large proteins, the size of the plasmids was reduced by approximately one kilobase through the removal of non-essential DNA from the base vector. Production of proteins from core vectors of this series validated the desired enhanced capabilities: higher yields of proteins expressed from genes with rare codons occurred in most cases, biotinylated derivatives enabled detailed automated ligand binding analysis, and multiple proteins introduced by dual LIC cloning were expressed successfully and in near balanced stoichiometry, allowing tandem purification of interacting proteins.

Evaluation of model-based bioequivalence approach for single sample pharmacokinetic studies.

In a traditional pharmacokinetic (PK) bioequivalence (BE) study, a two-way crossover study is conducted, PK parameters (namely the area under the time-concentration curve [AUC] and the maximal concentration [ C max ]) are obtained by noncompartmental analysis (NCA), and the BE analysis is performed using the two one-sided test (TOST) method. For ophthalmic drugs, however, only one sample of aqueous humor, in one eye, per eye can be obtained in each patient, which precludes the traditional BE analysis. To circumvent this issue, the U.S. Food and Drug Administration (FDA) has proposed an approach coupling NCA with either parametric or nonparametric bootstrap (NCA bootstrap). The model-based TOST (MB-TOST) has previously been proposed and evaluated successfully for various settings of sparse PK BE studies. In this paper, we evaluate, via simulations, MB-TOST in the specific setting of single sample PK BE study and compare its performance to NCA bootstrap. We performed BE study simulations using a published PK model and parameter values and evaluated multiple scenarios, including study design (parallel or crossover), sampling times (5 or 10 spread across the dosing interval), and geometric mean ratio (of 0.8, 0.9, 1, and 1.25). Using the simulated structural PK model, MB-TOST performed similarly to NCA bootstrap for AUC. For C max , the latter tended to be conservative and less powerful. Our research suggests that MB-TOST may be considered as an alternative BE approach for single sample PK studies, provided that the PK model is correctly specified and the test drug has the same structural model as the reference drug.

Surgical management strategies for colorectal malignancies of the splenic flexure - A systematic review and network meta-analysis.

BACKGROUND: Extended right hemicolectomy (ERHC) or left hemicolectomy (LHC) are accepted as the standard-of-care for colonic tumours of the splenic flexure. Lymphatic drainage at this site is poorly defined and subject to significant heterogeneity. Nevertheless, emerging evidence demonstrates the potential oncological safety of segmental splenic flexure colectomy (SFC). AIM: To perform a systematic review and network meta-analysis (NMA) to compare outcomes following ERHC, LHC and SFC for splenic flexure tumours (SFTs). METHODS: A systematic review was performed as per PRISMA guidelines. NMA was performed using R Shiny and Netmeta packages. RESULTS: A total of 13 studies, involving 6176 patients (ERHC n = 785; LHC n = 1527; SFC n = 3864) were included in the NMA. There was no difference in overall survival (OS) (SFC vs LHC Hazard Ratio [HR] 1.0, 95% Credible Interval [CrI] 0.76,1.34; SFC vs ERHC HR 1.18, 95% CrI 0.85,1.58) between the groups. SFC had a shorter operation time (Mean 176.37 min; Mean Difference [MD] SFC vs LHC 20.34 min 95% CrI 10.9, 29.97; SFC vs ERHC MD 22.19 95% CrI 11.09, 33.29) but also had a lower average lymph node yield (LNY) compared with ERHC (MD 7.15, 95% CrI 5.71, 8.60). ERHC had a significantly higher incidence of post-operative ileus (Odds Ratio [OR] 3.47, 95% CrI 1.11, 10.84). There was also no difference observed for minimally invasive approaches, anastomotic leak rate, perioperative mortality, reoperation rates or length of stay. CONCLUSIONS: While SFC may allow for reduced operative duration and improved bowel function postoperatively. SFC, LHC, ERHC are all acceptable approaches for curative resection of cancers of the splenic flexure, with no difference in OS observed. Thus, surgeon preference and candidate-specific factors will likely determine the management of SFTs.

Comparison of Restorative Proctocolectomy with and Without Defunctioning Loop Ileostomy in Patients with Ulcerative Colitis: A Systematic Review and Meta-analysis.

BACKGROUND: Restorative proctocolectomy [RPC] without a defunctioning loop ileostomy [DLI] in patients with ulcerative colitis [UC] remains controversial. AIM: To compare safety and efficacy of RPC with and without DLI in patients exclusively with UC. METHODS: A systematic review was performed according to PRISMA/MOOSE guidelines. Dichotomous variables were pooled as odds ratios [OR]. Continuous variables were pooled as weighted mean differences [WMD]. Quality assessment was performed using the Newcastle-Ottawa score [NOS]. RESULTS: A total of 20 studies [five paediatric and 15 adult] with 4550 UC patients [without DLI, n = 2370, 52.09%; with DLI, n = 2180, 47.91%] were eligible for inclusion. The median NOS was 8 [range 6-9]. There was no increased risk of anastomotic leak [AL] (OR 1.13, 95% confidence interval [CI]: 0.92, 1.39; p = 0.25), pouch excision [OR 1.01, 95% CI: 0.68, 1.50; p = 0.97], or overall major morbidity [OR 1.44, 95% CI, 0.91, 2.29; p = 0.12] for RPC without DLI, and this technique was associated with fewer anastomotic strictures [OR 0.45, 95% CI: 0.29, 0.68; p = 0.0002] and less bowel obstruction [OR 0.73, 95% CI: 0.57, 0.93; p = 0.01]. However, RPC without DLI increased the likelihood of pelvic sepsis [OR 1.68, 95% CI: 1.03, 2.75; p = 0.04] and emergency reoperation [OR 1.74, 95% CI: 1.22, 2.50; p = 0.002]. CONCLUSION: RPC without DLI is not associated with increased clinically overt AL or pouch excision rates. However, it is associated with increased risk of pelvic sepsis and emergency reoperation. RPC without DLI is feasible, but should only be performed judiciously in select UC patient cohorts in high-volume, specialist, tertiary centres.

Comparing minimally invasive surgical and open approaches to pelvic exenteration for locally advanced or recurrent pelvic malignancies - Systematic review and meta-analysis.

INTRODUCTION: Pelvic exenteration (PE) is a complex multivisceral surgical procedure indicated for locally advanced or recurrent pelvic malignancies. It poses significant technical challenges which account for the high risk of morbidity and mortality associated with the procedure. Developments in minimally invasive surgical (MIS) approaches and enhanced peri-operative care have facilitated improved long term outcomes. However, the optimum approach to PE remains controversial. METHODS: A systematic literature search was conducted in accordance with PRISMA guidelines to identify studies comparing MIS (robotic or laparoscopic) approaches for PE versus the open approach for patients with locally advanced or recurrent pelvic malignancies. The methodological quality of the included studies was assessed systematically and a meta-analysis was conducted. RESULTS: 11 studies were identified, including 2009 patients, of whom 264 (13.1%) underwent MIS PE approaches. The MIS group displayed comparable R0 resections (Risk Ratio [RR] 1.02, 95% Confidence Interval [95% CI] 0.98, 1.07, p = 0.35)) and Lymph node yield (Weighted Mean Difference [WMD] 1.42, 95% CI -0.58, 3.43, p = 0.16), and although MIS had a trend towards improved towards improved survival and recurrence outcomes, this did not reach statistical significance. MIS was associated with prolonged operating times (WMD 67.93, 95% CI 4.43, 131.42, p < 0.00001) however, this correlated with less intra-operative blood loss, and a shorter length of post-operative stay (WMD -3.89, 955 CI -6.53, -1.25, p < 0.00001). Readmission rates were higher with MIS (RR 2.11, 95% CI 1.11, 4.02, p = 0.02), however, rates of pelvic abscess/sepsis were decreased (RR 0.45, 95% CI 0.21, 0.95, p = 0.04), and there was no difference in overall, major, or specific morbidity and mortality. CONCLUSION: MIS approaches are a safe and feasible option for PE, with no differences in survival or recurrence outcomes compared to the open approach. MIS also reduced the length of post-operative stay and decreased blood loss, offset by increased operating time.

Obesity, Sarcopenia and Myosteatosis: Impact on Clinical Outcomes in the Operative Management of Crohn's Disease.

BACKGROUND: Obesity, sarcopenia, and myosteatosis in inflammatory bowel disease may confer negative outcomes, but their prevalence and impact among patients with Crohn's disease (CD) have not been systematically studied. The aim of this study was to assess nutritional status and body composition among patients undergoing resectional surgery for CD and determine impact on operative outcomes. METHODS: Consecutive patients with CD undergoing resection from 2000 to 2018 were studied. Total, subcutaneous, and visceral fat areas and lean tissue area (LTA) and intramuscular adipose tissue (IMAT) were determined preoperatively by computed tomography at L3 using SliceOmatic (Tomovision, Canada). Univariable and multivariable linear, logistic, and Cox proportional hazards regression were performed. RESULTS: One hundred twenty-four consecutive patients were studied (ileocolonic disease 53%, n = 62, biologic therapy 34.4% n = 43). Mean fat mass was 22.7 kg, with visceral obesity evident in 23.9% (n = 27). Increased fat stores were associated with reduced risk of emergency presentation but increased corticosteroid use (ß 9.09, standard error 3.49; P = .011). Mean LBM was 9.9 kg. Sarcopenia and myosteatosis were associated with impaired baseline nutritional markers. Myosteatosis markers IMAT (P = .002) and muscle attenuation (P = .0003) were associated with increased grade of complication. On multivariable analysis, IMAT was independently associated with increased postoperative morbidity (odds ratio [OR], 1.08; 95% confidence interval (CI), 1.01-1.16; P = .037) and comprehensive complications index (P = .029). Measures of adiposity were not associated with overall morbidity; however, increased visceral fat area independently predicted venous thromboembolism (OR, 1.02; 95% CI, 1.00-1.05; P = .028), and TFA was associated with increased wound infection (OR, 1.00; 95% CI, 1.00-1.01; P = .042) on multivariable analysis. CONCLUSION: Myosteatosis is associated with nutritional impairment and predicts increased overall postoperative morbidity following resection for CD. Despite its association with specific increased postoperative risks, increased adiposity does not increase overall morbidity, reflecting preservation of nutritional status and relatively more quiescent disease phenotype. Impaired muscle mass and function represent an appealing target for patient optimization to improve outcomes in the surgical management of CD.

Myosteatosis was predictive of postoperative morbidity following surgery for Crohn's Disease. Increased adiposity does not increase overall morbidity, reflecting a more quiescent disease phenotype. Obesity, myosteatosis, and sarcopenia represent appealing targets for patient optimization to improve outcomes surgical outcomes in Crohn's Disease.