Risk of Bowel Obstruction in Patients Undergoing Neoadjuvant Chemotherapy for High-risk Colon Cancer:A Nested Case-control Matched Analysis of an International, Multi-centre, Randomised Controlled Trial (FOxTROT)

OBJECTIVE: This study aimed to identify risk-criteria available before the point of treatment initiation that can be used to stratify risk of obstruction in patients undergoing neoadjuvant chemotherapy (NAC) for high-risk colon cancer.SUMMARY BACKGROUND DATA: Global implementation of neoadjuvant chemotherapy (NAC) for colon cancer, informed by the FOxTROT trial, may increase risk of bowel obstruction.METHODS: A case-control study, nested within an international randomised controlled trial (FOxTROT. ClinicalTrials.gov: NCT00647530). Patients with high-risk operable colon cancer (radiologically-staged T3-4 N0-2 M0) that were randomised to NAC and developed large bowel obstruction were identified. Firstly, clinical outcomes were compared between patients receiving NAC in FOxTROT that did and did not develop obstruction. Secondly, obstructed patients (cases) were age- and sex-matched with patients that did not develop obstruction (controls) in a 1:3 ratio using random sampling. Bayesian conditional mixed-effects logistic regression modelling was used to explore clinical, radiological, and pathological features associated with obstruction. Absolute risk of obstruction based on the presence or absence of risk criteria was estimated for all patients receiving NAC.RESULTS: Of 1053 patients randomised in FOxTROT, 699 received NAC, of whom 30 (4.3%) developed obstruction. Patients underwent care in European hospitals including 88 UK, 7 Danish and 3 Swedish centres. There was more open surgery (65.4% vs. 38.0%, P =0.01) and a higher pR1 rate in obstructed patients (12.0% vs. 3.8%, P =0.004), but otherwise comparable postoperative outcomes. In the case-control matched Bayesian model, two independent risk criteria were identified: (1) obstructing disease on endoscopy and/or being unable to pass through the tumour (adjusted odds ratio: 9.09, 95% credible interval: 2.34-39.66) and stricturing disease on radiology or endoscopy (OR: 7.18, 95% C.I.: 1.84-32.34). Three risk groups were defined according to the presence or absence of these criteria: 63.4% (443/698) of patients were at very low risk (&lt;1%), 30.7% (214/698) at low risk (&lt;10%), and 5.9% (41/698) at high risk (&gt;10%).CONCLUSIONS: Safe selection for NAC for colon cancer can be informed by using two features that are available before treatment initiation and identify a small number of patients with high risk of preoperative obstruction.</p

Developing a pathway for remote assessment of surgical wounds with partners in low- and middle-income countries: An approach for efficient trials and resilient perioperative systems

Background: Surgical site infection (SSI) is the most common complication of abdominal surgery, and commonly occurs after hospital discharge. When patients in low- and middle-income countries (LMICs) undergo surgery, they are three times more likely to have a SSI than patients in high-income countries. Returning to hospital for routine face-to-face follow-up is the accepted gold standard for diagnosing a SSI but can be challenging in many environments, and resource intensive for healthcare teams. Aims: The overall aim of this thesis was to develop a high-quality pathway for remote surgical wound assessment using telemedicine that can be delivered flexibly across diverse healthcare settings. First, I aimed to evaluate the feasibility and accuracy of telemedicine in the detection of SSI in existing data. Second, I aimed to explore the cross-cultural equivalence of a Wound Healing Questionnaire (WHQ) across several LMICs and make recommendations for its adaptation for use in global surgery research and practice. Third, I aimed to test the feasibility and accuracy of the adapted WHQ in diagnosis of SSI. Methods: The primary outcome of interest in this thesis was SSI reported up to 30-days after surgery using the US Centres for Disease Control criteria. First, I compared the rates of SSI using telemedicine to those with in-person review in two data sources: (A) an international cohort study of adult patients discharged from hospital before 30-days after abdominal surgery; (B) a systematic review with meta-analysis of rates of SSI detection conducted in accordance with PRIMSA guidelines (PROSPERO:192596). Second, to recommend adaptations to the WHQ outcome measure for global implementation, I conducted a mixed-methods study across seven LMICs. Qualitative data were obtained from interviews and focus groups with local researchers with deductive coding aligned to cognitive theory. Quantitative data were collected in a prospective cohort study and Rasch analysis was used to explore measurement properties of the WHQ. I triangulated these data to make recommendations for cross-cultural and cross-language adaptation. Third, I conducted a validation cohort study within a randomised trial (FALCON, NCT03700749) where consecutive patients undergoing abdominal surgery for a range of indications underwent telephone assessment with the WHQ (index test) up to 72-hours before their face-to-face assessment (reference test). I worked with Community Engagement and Involvement (CEI) partners to optimise the measurement pathway. Results: The SSI rate reported using telemedicine in the cohort data was lower than with in-person follow-up (11.1% versus 13.4%, p4 demonstrated sensitivity of 0.701 (0.610-0.792), specificity of 0.911 (0.878-0.9430), positive predictive value of 0.723 (0.633-0.814) and negative predictive value of 0.901 (0.867-0.935). Discussion: Current methods for remote detection of SSI are inadequate, missing 1 in 3 patients with infection. This thesis describes the adaptation and validation of the WHQ, demonstrating that a telephone pathway for wound assessment is feasible and moderately accurate. The adapted WHQ is now ready for global implementation in research and routine postoperative surveillance, using the co-designed toolkit to optimise local measurement processes

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARSCoV- 2 infection: an international cohort study.

Background The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p<0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p<0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p<0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research.pre-print450 K

Death following pulmonary complications of surgery before and during the SARS-CoV-2 pandemic

Peer reviewe

Expression of hepatocyte growth factor-like protein in human wound tissue and its biological functionality in human keratinocytes

Hepatocyte growth factor-like protein (HGFl) and its receptor, Recepteur d'Origine Nantais (RON), have been implicated in the development of wound chronicity. HGFl and RON expression was detected in acute wound tissue, chronic wound tissue and in normal skin using quantitative polymerase chain reaction (Q-PCR). HGFl and RON expression was also assessed in chronic healing and chronic non-healing wound tissues using Q-PCR and immunohistochemical staining. Expression was similarly detected in the HaCaT immortalized human keratinocyte cell line using reverse transcription polymerase chain reaction (RT-PCR). rhHGFl was used to assess the impact of this molecule on HaCaT cell functionality using in vitro growth assays and electric cell-substrate impendence sensing (ECIS) migration assays. HGFl and RON transcript expression were significantly increased in acute wound tissue compared to chronic wound tissue and were also elevated, though non-significantly, in comparison to normal skin. Minimal expression was seen in both healing and non-healing chronic wounds. Treatment of HaCaT cells with rhHGFl had no effect on growth rates but did enhance cell migration. This effect was abolished by the addition of a phospholipase C gamma (PLCγ) small molecule inhibitor. The increased expression of HGFl and RON in acute, healing wounds and the pro-migratory effect of HGFl in an in vitro human keratinocyte model, may indicate a role for HGFl in active wound healing

Elective surgery system strengthening: development, measurement, and validation of the surgical preparedness index across 1632 hospitals in 119 countries

Background The 2015 Lancet Commission on global surgery identified surgery and anaesthesia as indispensable parts of holistic health-care systems. However, COVID-19 exposed the fragility of planned surgical services around the world, which have also been neglected in pandemic recovery planning. This study aimed to develop and validate a novel index to support local elective surgical system strengthening and address growing backlogs. Methods First, we performed an international consultation through a four-stage consensus process to develop a multidomain index for hospital-level assessment (surgical preparedness index; SPI). Second, we measured surgical preparedness across a global network of hospitals in high-income countries (HICs), middle-income countries (MICs), and low-income countries (LICs) to explore the distribution of the SPI at national, subnational, and hospital levels. Finally, using COVID-19 as an example of an external system shock, we compared hospitals' SPI to their planned surgical volume ratio (SVR; ie, operations for which the decision for surgery was made before hospital admission), calculated as the ratio of the observed surgical volume over a 1-month assessment period between June 6 and Aug 5, 2021, against the expected surgical volume based on hospital administrative data from the same period in 2019 (ie, a pre-pandemic baseline). A linear mixed-effects regression model was used to determine the effect of increasing SPI score. Findings In the first phase, from a longlist of 103 candidate indicators, 23 were prioritised as core indicators of elective surgical system preparedness by 69 clinicians (23 [33%] women; 46 [67%] men; 41 from HICs, 22 from MICs, and six from LICs) from 32 countries. The multidomain SPI included 11 indicators on facilities and consumables, two on staffing, two on prioritisation, and eight on systems. Hospitals were scored from 23 (least prepared) to 115 points (most prepared). In the second phase, surgical preparedness was measured in 1632 hospitals by 4714 clinicians from 119 countries. 745 (45·6%) of 1632 hospitals were in MICs or LICs. The mean SPI score was 84·5 (95% CI 84·1–84·9), which varied between HIC (88·5 [89·0–88·0]), MIC (81·8 [82·5–81·1]), and LIC (66·8 [64·9–68·7]) settings. In the third phase, 1217 (74·6%) hospitals did not maintain their expected SVR during the COVID-19 pandemic, of which 625 (51·4%) were from HIC, 538 (44·2%) from MIC, and 54 (4·4%) from LIC settings. In the mixed-effects model, a 10-point increase in SPI corresponded to a 3·6% (95% CI 3·0–4·1; p<0·0001) increase in SVR. This was consistent in HIC (4·8% [4·1–5·5]; p<0·0001), MIC (2·8 [2·0–3·7]; p<0·0001), and LIC (3·8 [1·3–6·7%]; p<0·0001) settings. Interpretation The SPI contains 23 indicators that are globally applicable, relevant across different system stressors, vary at a subnational level, and are collectable by front-line teams. In the case study of COVID-19, a higher SPI was associated with an increased planned surgical volume ratio independent of country income status, COVID-19 burden, and hospital type. Hospitals should perform annual self-assessment of their surgical preparedness to identify areas that can be improved, create resilience in local surgical systems, and upscale capacity to address elective surgery backlogs