Stress-induced Rab11a-exosomes induce amphiregulin-mediated cetuximab resistance in colorectal cancer.

Exosomes are secreted vesicles made intracellularly in the endosomal system. We have previously shown that exosomes are not only made in late endosomes, but also in recycling endosomes marked by the monomeric G-protein Rab11a. These vesicles, termed Rab11a-exosomes, are preferentially secreted under nutrient stress from several cancer cell types, including HCT116 colorectal cancer (CRC) cells. HCT116 Rab11a-exosomes have particularly potent signalling activities, some mediated by the epidermal growth factor receptor (EGFR) ligand, amphiregulin (AREG). Mutant activating forms of KRAS, a downstream target of EGFR, are often found in advanced CRC. When absent, monoclonal antibodies, such as cetuximab, which target the EGFR and block the effects of EGFR ligands, such as AREG, can be administered. Patients, however, inevitably develop resistance to cetuximab, either by acquiring KRAS mutations or via non-genetic microenvironmental changes. Here we show that nutrient stress in several CRC cell lines causes the release of AREG-carrying Rab11a-exosomes. We demonstrate that while soluble AREG has no effect, much lower levels of AREG bound to Rab11a-exosomes from cetuximab-resistant KRAS-mutant HCT116 cells, can suppress the effects of cetuximab on KRAS-wild type Caco-2 CRC cells. Using neutralising anti-AREG antibodies and an intracellular EGFR kinase inhibitor, we show that this effect is mediated via AREG activation of EGFR, and not transfer of activated KRAS. Therefore, presentation of AREG on Rab11a-exosomes affects its ability to compete with cetuximab. We propose that this Rab11a-exosome-mediated mechanism contributes to the establishment of resistance in cetuximab-sensitive cells and may explain why in cetuximab-resistant tumours only some cells carry mutant KRAS.

Disruption, discontinuity and a licence to live: Responding to cancer diagnoses.

Although a diagnosis of a life-limiting cancer is likely to evoke emotions, such as fear, panic and anxiety, for some people it can also provide an opportunity to live life differently. This article is based on research undertaken in Aotearoa New Zealand on the topic of exceptional cancer trajectories. Eighty-one participants who had been identified as living with a cancer diagnosis longer than clinically expected were interviewed, along with 25 people identified by some of the participants as supporters in their journey. For some participants the diagnosis provided the opportunity to rethink their lives, to undertake lifestyle and consumption changes, to be culturally adventurous, to take up new skills, to quit work and to change relationships with others. The concepts of biographical disruption and posttraumatic growth are considered in relation to these accounts, and it is argued that the event of a cancer diagnosis can give license for people to breach social norms.

Coproducing health research with Indigenous peoples.

The coproduction of health research represents an important advance in the realm of participatory methodologies, which have evolved over the past five decades. This transition to a collaborative approach emphasizes shared control between academic researchers and their partners, fostering a more balanced influence on the research process. This shift not only enhances the quality of the research and the evidence generated, but also increases the likelihood of successful implementation. For Indigenous peoples, coproduced research represents a critical development, enabling a shift from being mere 'subjects' of research to being active controllers of the process-including addressing the extractive and oppressive practices of the past. In this Review, we explore how research coproduction with Indigenous peoples is evolving. An 'Indigenous turn' embraces the concept of shared control while also considering the principles of reciprocity, the incommensurability of Western and Indigenous knowledge systems, divergent ethical standards, strategic and political differences, and the broader impact of processes and outcomes. To illustrate these ideas, we present examples involving New Zealand's Maori communities and offer recommendations for further progress.

A perspective on green, blue, and grey spaces, biodiversity, microbiota, and human health.

Humans have lived from equator to poles for millennia but are now increasingly intruding into the wild spaces of other species and steadily extruding ourselves from our own wild spaces, with a profound impact on: our relationship with the natural world; survival of other species; pollution; climate change; etc. We have yet to grasp how these changes directly impact our own health. The primary focus of this paper is on the beneficial influence of proximity to the natural environment. We summarize the evidence for associations between exposure to green space and blue space and improvements in health. In contrast, grey space - the urban landscape - largely presents hazards as well as reducing exposure to green and blue space and isolating us from the natural environment. We discuss various hypotheses that might explain why green, blue, and grey space affect health and focus particularly on the importance of the biodiversity hypothesis and the role of microbiota. We discuss possible mechanisms and exposure routes - air, soil, and water. We highlight the problem of exposure assessment, noting that many of our current tools are not fit for the purpose of understanding exposure to green and blue space, aerosols, soils, and water. We briefly discuss possible differences between indigenous perspectives on the nature of our relationship with the environment and the more dominant international-science view. Finally, we present research gaps and discuss future directions, particularly focusing on the ways in which we might - even in the absence of a full understanding of the mechanisms by which blue, green, and grey space affect our health - begin to implement policies to restore some balance to our environment of with the aim of reducing the large global burden of ill health.

Outcomes of rectal prolapse surgery in patients with benign joint hypermobility syndrome.

BACKGROUND: Rectal prolapse is a debilitating disorder of the pelvic floor, and treatment outcomes are variable. Previous studies have identified underlying benign joint hypermobility syndrome (BJHS) in some patients. We sought to determine the outcomes of these patients after undergoing ventral rectopexy surgery (VMR). METHODS: All consecutive patients who were referred to the pelvic floor unit at our institution between February 2010 and December 2011 were considered for recruitment into the study. Following recruitment, they were assessed using the Beighton criteria to determine the presence or absence of benign joint hypermobility syndrome. Both groups underwent similar surgical interventions and were then followed up. The need for revisional surgery was recorded in both groups. RESULTS: Fifty-two patients [34 normal; M:F, 1:6; median age 61 (range 22-84) years; 18 BJHS; M:F, 0:1; median age 52 (range 25-79) years] were recruited. A total of 42 patients completed the full 1-year follow-up (26 normal, 16 benign joint hypermobility syndrome). Patients with benign joint hypermobility syndrome were significantly younger (median age 52 versus 61 years, p < 0.001) with male to female ratio of 0:1 versus 1:6, respectively. In addition, they were significantly more likely to require revisional surgery than those without the condition (31% versus 8% p < 0.001). In most cases, this was in the form of a posterior stapled transanal resection of the rectum procedure. CONCLUSIONS: Patients with BJHS presenting for rectal prolapse surgery were younger and are more likely to require further surgery for rectal prolapse recurrence than those without the condition.

Pelvic pain is a common prolapse symptom and improvement after ventral mesh rectopexy is more frequent than deterioration or de novo pain.

AIM: The aim of this work was to assess the relationship between pelvic pain and rectal prolapse both before prolapse surgery and in the long term after ventral mesh rectopexy (VMR). METHOD: Patients undergoing VMR between 2004 and 2017 were contacted. Outcomes including the severity of pelvic pain were recorded using a numeric rating scale. RESULTS: Four hundred and seventy eight of the 749 patients (64%) were successfully contacted. Of these, 39% reported pre-existing pelvic pain prior to VMR (group A) and 61% were pain free (group B). The median follow-up time was 8.0 years (interquartile range 5.0-10.0 years). Symptoms of obstructed defaecation were significantly more common (p = 0.002) in group A (91/187, 49%) than in group B (101/291, 35%). In contrast, faecal incontinence was more common (p = 0.007) in group B (75/291, 26%) than in group A (29/187, 15%). In group A, 76% showed improvement in pelvic pain after VMR: 61% were pain free and 39% had partial improvement in their pre-existing pelvic pain. Patients with persistent pelvic pain were younger (p = 0.01) and more likely to have revisional surgery after VMR (p = 0.0003), but there was no relation to the indication for surgery (p = 0.59). In group B, 15% reported de novo pelvic pain after VMR, and this was more common in women under 50 years old (p = 0.001), when obstructed defaecation was the indication (p = 0.03), in mesh erosion (p = <0.05) and when associated with revisional surgery (p = 0.005). CONCLUSION: Pelvic pain is common (39%) in patients undergoing prolapse surgery, and VMR improves this pain in most patients (76%). However, a significant number of patients fail to improve (12%), experience worsening of pain (12%) or develop de novo pelvic pain (15%).

Use of fluorescence imaging and indocyanine green during colorectal surgery: Results of an intercontinental Delphi survey.

BACKGROUND: Fluorescence imaging with indocyanine green is increasingly being used in colorectal surgery to assess anastomotic perfusion, and to detect sentinel lymph nodes. METHODS: In this 2-round, online, Delphi survey, 35 international experts were asked to vote on 69 statements pertaining to patient preparation and contraindications to fluorescence imaging during colorectal surgery, indications, technical aspects, potential advantages/disadvantages, and effectiveness versus limitations, and training and research. Methodological steps were adopted during survey design to minimize risk of bias. RESULTS: More than 70% consensus was reached on 60 of 69 statements, including moderate-strong consensus regarding fluorescence imaging's value assessing anastomotic perfusion and leak risk, but not on its value mapping sentinel nodes. Similarly, although consensus was reached regarding most technical aspects of its use assessing anastomoses, little consensus was achieved for lymph-node assessments. Evaluating anastomoses, experts agreed that the optimum total indocyanine green dose and timing are 5 to 10 mg and 30 to 60 seconds pre-evaluation, indocyanine green should be dosed milligram/kilogram, lines should be flushed with saline, and indocyanine green can be readministered if bright perfusion is not achieved, although how long surgeons should wait remains unknown. The only consensus achieved for lymph-node assessments was that 2 to 4 injection points are needed. Ninety-six percent and 100% consensus were reached that fluorescence imaging will increase in practice and research over the next decade, respectively. CONCLUSION: Although further research remains necessary, fluorescence imaging appears to have value assessing anastomotic perfusion, but its value for lymph-node mapping remains questionable.

Human papillomavirus self-testing among unscreened and under-screened Maori, Pasifika and Asian women in Aotearoa New Zealand: A preference survey among responders and interviews with clinical-trial nonresponders.

INTRODUCTION: Maori, Pasifika and Asian women are less likely to attend cervical screening and Maori and Pasifika women are more likely to be diagnosed with later-stage cervical cancer than other women in Aotearoa New Zealand. This study-with under-screened women taking part in a randomized-controlled trial comparing self-testing and standard screening-explored the acceptability of a human papillomavirus (HPV) self-test kit and the preferred method for receiving it. METHODS: Maori, Pasifika and Asian women (N= 376) completed a cross-sectional postal questionnaire. Twenty-six women who had not accepted the trial invitation were interviewed to understand their reasons for nonparticipation. RESULTS: Most women found the self-test kit easy and convenient to use and reported that they did not find it painful, uncomfortable or embarrassing. This was reflected in the preference for a self-test over a future smear test on the same grounds. Most women preferred to receive the kit by mail and take the test themselves, rather than having it done by a doctor or nurse. There was a range of preferences relating to how to return the kit. Phone calls with nonresponders revealed that, although most had received the test kit, the reasons for not choosing to be involved included not wanting to, being too busy or forgetting. CONCLUSION: HPV self-testing was acceptable for Maori, Pasifika and Asian women in Aotearoa New Zealand. HPV self-testing has considerable potential to reduce the inequities in the current screening programme and should be made available with appropriate delivery options as soon as possible. PATIENT OR PUBLIC CONTRIBUTION: This study explored the acceptability of HPV self-testing and their preferences for engaging with it among Maori, Pasifika and Asian women. Thus, women from these underserved communities were the participants and focus of this study.

Investigation of healthcare-associated SARS-CoV-2 infection: Learning outcomes from an investigative process in the initial phase of the pandemic.

Background: Healthcare-associated (HCA) SARS-CoV-2 infection is a significant contributor to the spread of the 2020 pandemic. Timely review of HCA cases is essential to identify learning to inform infection prevention and control (IPC) policies and organisational response. Aim: To identify key areas for improvement through rapid investigation of HCA SARS-CoV-2 cases and to implement change. Methods: Cases were identified based on date of first positive SARS-CoV-2 PCR sample in relation to date of hospital admission. Cases were reviewed using a structured gap analysis tool to identify key learning points. These were discussed in weekly multidisciplinary meetings to gain consensus on learning outcomes, level of harm incurred by the patient and required actions. Learning was then promptly fed back to individual teams and the organisation. Findings: Of the 489 SARS-CoV-2 cases admitted between 10th March and 23rd June 2020, 114 suspected HCA cases (23.3%) were reviewed; 58/489 (11.8%) were ultimately deemed to be HCA. Five themes were identified: individual patient vulnerability, communication, IPC implementation, policy issues and organisational response. Adaptations to policies based on these reviews were completed within the course of the initial phase of the pandemic. Conclusion: This approach enabled timely learning and implementation of control measures and policy development.

A scoping review of non-pharmacological perinatal interventions impacting maternal sleep and maternal mental health.

BACKGROUND: A woman's vulnerability to sleep disruption and mood disturbance is heightened during the perinatal period and there is a strong bidirectional relationship between them. Both sleep disruption and mood disturbance can result in significant adverse outcomes for women and their infant. Thus, supporting and improving sleep in the perinatal period is not only an important outcome in and of itself, but also a pathway through which future mental health outcomes may be altered. METHODS: Using scoping review methodology, we investigated the nature, extent and characteristics of intervention studies conducted during the perinatal period (pregnancy to one-year post-birth) that reported on both maternal sleep and maternal mental health. Numerical and descriptive results are presented on the types of studies, settings, sample characteristics, intervention design (including timeframes, facilitation and delivery), sleep and mood measures and findings. RESULTS: Thirty-seven perinatal interventions were identified and further described according to their primary focus (psychological (n = 9), educational (n = 15), lifestyle (n = 10), chronotherapeutic (n = 3)). Most studies were conducted in developed Western countries and published in the last 9 years. The majority of study samples were women with existing sleep or mental health problems, and participants were predominantly well-educated, not socio-economically disadvantaged, in stable relationships, primiparous and of White race/ethnicity. Interventions were generally delivered across a relatively short period of time, in either the second trimester of pregnancy or the early postnatal period and used the Pittsburgh Sleep Quality Index (PSQI) to measure sleep and the Edinburgh Postnatal Depression Scale (EPDS) to measure mood. Retention rates were high (mean 89%) and where reported, interventions were well accepted by women. Cognitive Behavioural Therapies (CBT) and educational interventions were largely delivered by trained personnel in person, whereas other interventions were often self-delivered after initial explanation. CONCLUSIONS: Future perinatal interventions should consider spanning the perinatal period and using a stepped-care model. Women may be better supported by providing access to a range of information, services and treatment specific to their needs and maternal stage. The development of these interventions must involve and consider the needs of women experiencing disadvantage who are predominantly affected by poor sleep health and poor mental health.

Indoor air quality, largely neglected and in urgent need of a refresh.

Nil.

Visceral-to-subcutaneous fat ratio exhibits strongest association with early post-operative outcomes in patients undergoing surgery for advanced rectal cancer.

AIM: Despite their promise as prognostic factors in colorectal cancer, anthropometric data are frequently contradictory or difficult to interpret, with single body-composition parameters often investigated in isolation or heterogeneous clinical cohorts used in analyses. We sought to assess a spectrum of body-composition parameters in a highly selected cohort with locally advanced rectal cancer in a bid to determine those with strongest prognostic potential in this specific setting. MATERIALS/METHODS: Between 2014 and 2020, 78 individuals received neoadjuvant chemotherapy, or chemoradiotherapy, followed by radical surgery in the treatment of locally advanced rectal adenocarcinoma at Oxford University Hospitals Trust. Demographic, treatment-related, perioperative, and short-term outcomes data were assessed. Body-composition parameters included BMI, and those derived from pre-operative computed-tomography imaging: skeletal mass index (SMI), visceral fat area (VFA), subcutaneous fat area (SFA), perinephric fat area (PFA) visceral-to-subcutaneous fat ratio (V/S), sarcopenia, and sarcopenic obesity (SO). RESULTS: Pre-operative body-composition parameters exhibited particularly strong correlation with post-operative outcomes, with VFA (p = 0.002), V/S (p = 0.019), SO (p = 0.012), and PFA (p = 0.0016) all associated with an increased length of hospital stay. Univariate and multivariate analyses demonstrated V/S to be the sole independent body-composition risk factor to be associated with an increased risk of developing Clavien-Dindo complications ≥ 2 (p = 0.033) as well as an increased length of stay (p = 0.005). CONCLUSION: Among patients with locally advanced rectal cancer, high visceral-to-subcutaneous fat ratio is the body-composition parameter most strongly associated with poor early post-operative outcomes. This should be considered in patient selection and prehabilitation protocols. WHAT DOES THIS PAPER ADD TO THE LITERATURE? : Our study demonstrates that among body composition parameters, high visceral-to-subcutaneous fat ratio is strongly associated with increased risk of post-operative complications and increased length of stay in patients undergoing surgery for advanced rectal cancer.

Establishing a colorectal cancer research database from routinely collected health data: the process and potential from a pilot study.

OBJECTIVE: Colorectal cancer is a common cause of death and morbidity. A significant amount of data are routinely collected during patient treatment, but they are not generally available for research. The National Institute for Health Research Health Informatics Collaborative in the UK is developing infrastructure to enable routinely collected data to be used for collaborative, cross-centre research. This paper presents an overview of the process for collating colorectal cancer data and explores the potential of using this data source. METHODS: Clinical data were collected from three pilot Trusts, standardised and collated. Not all data were collected in a readily extractable format for research. Natural language processing (NLP) was used to extract relevant information from pseudonymised imaging and histopathology reports. Combining data from many sources allowed reconstruction of longitudinal histories for each patient that could be presented graphically. RESULTS: Three pilot Trusts submitted data, covering 12 903 patients with a diagnosis of colorectal cancer since 2012, with NLP implemented for 4150 patients. Timelines showing individual patient longitudinal history can be grouped into common treatment patterns, visually presenting clusters and outliers for analysis. Difficulties and gaps in data sources have been identified and addressed. DISCUSSION: Algorithms for analysing routinely collected data from a wide range of sites and sources have been developed and refined to provide a rich data set that will be used to better understand the natural history, treatment variation and optimal management of colorectal cancer. CONCLUSION: The data set has great potential to facilitate research into colorectal cancer.

An evaluation of the serum carbon isotope ratio as a candidate predictive biomarker of the dietary animal protein ratio (animal protein/total protein) in a 15-day controlled feeding study of US adults.

BACKGROUND: The serum natural abundance carbon isotope ratio (CIR) was recently identified as a candidate biomarker of animal protein intake in postmenopausal women. Such a biomarker would help clarify the relation between dietary protein source (plant or animal) and chronic disease risk. OBJECTIVES: We aimed to evaluate the performance of the serum CIR as a biomarker of dietary protein source in a controlled feeding study of men and women of diverse age and BMI. METHODS: We conducted a 15-d feeding study of 100 adults (age: 18-70 y, 55% women) in Phoenix, AZ. Participants were provided individualized diets that approximated habitual food intakes. Serum was collected at the end of the feeding period for biomarker measurements. RESULTS: Median [IQR] animal protein intake was 67 g/d [55-88 g/d], which was 64% of total protein. The serum CIR was positively correlated with animal protein and inversely correlated with plant protein intake, leading to a strong correlation (r2 = 0.76) with the dietary animal protein ratio (APR; animal/total protein). Regressing serum CIR on the APR, serum nitrogen isotope ratio (NIR), gender, age, and body weight generated an R2 of 0.78. Following the measurement error model for predictive biomarkers, the resulting regression equation was then inverted to develop a calibrated biomarker equation for APR. Added sugars ratio (added/total sugars intake) and corn intakes also influenced the serum CIR but to a much lesser degree than the APR; variations in these intakes had only small effects on biomarker-estimated APR. CONCLUSIONS: Based on our findings in this US cohort of mixed sex and age, we propose the serum CIR alongside NIR as a predictive dietary biomarker of the APR. We anticipate using this biomarker to generate calibrated estimates based on self-reported intake and ultimately to obtain more precise disease risk estimates according to dietary protein source.

Patients' Perception of Long-term Outcome After Laparoscopic Ventral Mesh Rectopexy; Single Tertiary Center Experience.

OBJECTIVE: To assess patients' long-term outcome and satisfaction after laparoscopic ventral mesh rectopexy (LVMR). SUMMARY OF BACKGROUND DATA: Data on the long-term outcome and satisfaction of patients undergoing LVMR are limited. METHODS: Patients who underwent LVMR between 2004 and 2017 were identified from a prospectively maintained database. We attempted to contact all patients by telephone for an interview using a standardized questionnaire to record pre-LVMR symptoms, long-term outcome, and overall satisfaction. RESULTS: Total number of patients who underwent LVMR was 848 and 99(12%) were deceased at follow-up. In the end, 544 (64%) patients were contacted successfully and 478 (56%) were able to complete the questionnaire. Median time elapsed since surgery was 7 years and mean age was 62 years. Patients' reported preoperative symptoms were obstructed defecation syndrome in 40%, fecal incontinence in 22%, combination of obstructed defecation syndrome and fecal incontinence in 21% and other conditions in 17%. Bowel symptoms were reported as improved by 69% of patients and worse by 12%. Pelvic pain was reported to be improved in 47% of the patients after LVMR but new onset of pelvic pain appeared in 15%. Sexual function was reported to be better and worse with equal frequency. Overall, 63% of the patients were satisfied with the outcome and 76% would recommend this procedure to others with similar symptoms. CONCLUSION: LVMR offers acceptable long-term outcomes and satisfaction. There is a mixed impact on pelvic pain and sexual function which requires careful consideration in counseling patients for this procedure.

Laparoscopic Colorectal Surgery Outcomes Improved After National Training Program (LAPCO) for Specialists in England.

OBJECTIVE: To examine the impact of The National Training Program for Lapco on the rate of laparoscopic surgery and clinical outcomes of cases performed by Lapco surgeons after completion of training. SUMMARY OF BACKGROUND DATA: Lapco provided competency-based supervised clinical training for specialist colorectal surgeons in England. METHODS: We compared the rate of laparoscopic surgery, mortality, and morbidity for colorectal cancer resections by Lapco delegates and non-Lapco surgeons in 3-year periods preceding and following Lapco using difference in differences analysis. The changes in the rate of post-Lapco laparoscopic surgery with the Lapco sign-off competency assessment and in-training global assessment scores were examined using risk-adjusted cumulative sum to determine their predictive clinical validity with predefined competent scores of 3 and 5 respectively. RESULTS: One hundred eight Lapco delegates performed 4586 elective colo-rectal resections pre-Lapco and 5115 post-Lapco while non-Lapco surgeons performed 72,930 matched cases. Lapco delegates had a 37.8% increase in laparoscopic surgery which was greater than non-Lapco surgeons by 20.9% [95% confidence interval (CI), 18.5-23.3, P < 0.001) with a relative decrease in 30-day mortality by -1.6% (95% CI, -3.4 to -0.2, P = 0.039) and 90-day mortality by -2.3% (95% CI, -4.3 to -0.4, P = 0.018). The change point of risk-adjusted cumulative sum was 3.12 for competency assessment tool and 4.74 for global assessment score whereas laparoscopic rate increased from 44% to 66% and 40% to 56%, respectively. CONCLUSIONS: Lapco increased the rate of laparoscopic colorectal cancer surgery and reduced mortality and morbidity in England. In-training competency assessment tools predicted clinical performance after training.