Spatiotemporal analysis of human intestinal development at single-cell resolution.

Development of the human intestine is not well understood. Here, we link single-cell RNA sequencing and spatial transcriptomics to characterize intestinal morphogenesis through time. We identify 101 cell states including epithelial and mesenchymal progenitor populations and programs linked to key morphogenetic milestones. We describe principles of crypt-villus axis formation; neural, vascular, mesenchymal morphogenesis, and immune population of the developing gut. We identify the differentiation hierarchies of developing fibroblast and myofibroblast subtypes and describe diverse functions for these including as vascular niche cells. We pinpoint the origins of Peyer's patches and gut-associated lymphoid tissue (GALT) and describe location-specific immune programs. We use our resource to present an unbiased analysis of morphogen gradients that direct sequential waves of cellular differentiation and define cells and locations linked to rare developmental intestinal disorders. We compile a publicly available online resource, spatio-temporal analysis resource of fetal intestinal development (STAR-FINDer), to facilitate further work.

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.

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%).

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.

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.

Dataset for Pathology Reporting of Colorectal Cancer: Recommendations From the International Collaboration on Cancer Reporting (ICCR).

OBJECTIVE: The aim of this study to describe a new international dataset for pathology reporting of colorectal cancer surgical specimens, produced under the auspices of the International Collaboration on Cancer Reporting (ICCR). BACKGROUND: Quality of pathology reporting and mutual understanding between colorectal surgeon, pathologist and oncologist are vital to patient management. Some pathology parameters are prone to variable interpretation, resulting in differing positions adopted by existing national datasets. METHODS: The ICCR, a global alliance of major pathology institutions with links to international cancer organizations, has developed and ratified a rigorous and efficient process for the development of evidence-based, structured datasets for pathology reporting of common cancers. Here we describe the production of a dataset for colorectal cancer resection specimens by a multidisciplinary panel of internationally recognized experts. RESULTS: The agreed dataset comprises eighteen core (essential) and seven non-core (recommended) elements identified from a review of current evidence. Areas of contention are addressed, some highly relevant to surgical practice, with the aim of standardizing multidisciplinary discussion. The summation of all core elements is considered to be the minimum reporting standard for individual cases. Commentary is provided, explaining each element's clinical relevance, definitions to be applied where appropriate for the agreed list of value options and the rationale for considering the element as core or non-core. CONCLUSIONS: This first internationally agreed dataset for colorectal cancer pathology reporting promotes standardization of pathology reporting and enhanced clinicopathological communication. Widespread adoption will facilitate international comparisons, multinational clinical trials and help to improve the management of colorectal cancer globally.

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.

Progression Rates by Age, Sex, Treatment, and Disease Activity by AASLD and EASL Criteria: Data for Precision Medicine.

BACKGROUND & AIMS: Antiviral treatment criteria are based on disease progression risk, and hepatocellular carcinoma (HCC) surveillance recommendations for patients with chronic hepatitis B (CHB) without cirrhosis is based on an annual incidence threshold of 0.2%. However, accurate and precise disease progression estimate data are limited. Thus, we aimed to determine rates of cirrhosis and HCC development stratified by age, sex, treatment status, and disease activity based on the 2018 American Association for the Study of Liver Diseases and 2017 European Association for the Study of the Liver guidelines. METHODS: We analyzed 18,338 patients (8914 treated, 9424 untreated) from 6 centers from the United States and 27 centers from Asia-Pacific countries. The Kaplan-Meier method was used to estimate annual progression rates to cirrhosis or HCC in person-years. RESULTS: The cohort was 63% male, with a mean age of 46.19 years, with baseline cirrhosis of 14.3% and median follow up of 9.60 years. By American Association for the Study of Liver Diseases criteria, depending on age, sex, and disease activity, annual incidence rates ranged from 0.07% to 3.94% for cirrhosis, from 0.04% to 2.19% for HCC in patients without cirrhosis, and from 0.40% to 8.83% for HCC in patients with cirrhosis. Several subgroups of patients without cirrhosis including males younger than 40 years of age and females younger than 50 years of age had annual HCC risk near or exceeding 0.2%. Similar results were found using European Association for the Study of the Liver criteria. CONCLUSION: There is great variability in CHB disease progression rates even among "lower-risk" populations. Future CHB modeling studies, public health planning, and HCC surveillance recommendation should be based on more precise disease progression rates based on sex, age, and disease activity, plus treatment status.

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.

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.

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.

Stromal composition predicts recurrence of early rectal cancer after local excision.

AIMS: After local excision of early rectal cancer, definitive lymph node status is not available. An alternative means for accurate assessment of recurrence risk is required to determine the most appropriate subsequent management. Currently used measures are suboptimal. We assess three measures of tumour stromal content to determine their predictive value after local excision in a well-characterised cohort of rectal cancer patients without prior radiotherapy. METHODS AND RESULTS: A total of 143 patients were included. Haematoxylin and eosin (H&E) sections were scanned for (i) deep neural network (DNN, a machine-learning algorithm) tumour segmentation into compartments including desmoplastic stroma and inflamed stroma; and (ii) digital assessment of tumour stromal fraction (TSR) and optical DNA ploidy analysis. 3' mRNA sequencing was performed to obtain gene expression data from which stromal and immune scores were calculated using the ESTIMATE method. Full results were available for 139 samples and compared with disease-free survival. All three methods were prognostic. Most strongly predictive was a DNN-determined ratio of desmoplastic to inflamed stroma >5.41 (P < 0.0001). A ratio of ESTIMATE stromal to immune score <1.19 was also predictive of disease-free survival (P = 0.00051), as was stromal fraction >36.5% (P = 0.037). CONCLUSIONS: The DNN-determined ratio of desmoplastic to inflamed ratio is a novel and powerful predictor of disease recurrence in locally excised early rectal cancer. It can be assessed on a single H&E section, so could be applied in routine clinical practice to improve the prognostic information available to patients and clinicians to inform the decision concerning further management.

Local excision after (near) complete response of rectal cancer to neoadjuvant radiation: does it add value?

PURPOSE: Neoadjuvant radiotherapy is commonly used in rectal cancer. When used prior to radical surgery in locally advanced disease, up to one-quarter of patients have no residual cancer at surgery suggesting that radical surgery was unnecessary; those with complete clinical response may be managed on a rectal-preserving 'watch-and-wait' pathway. In those receiving radiotherapy for early stage cancer, local excision of small volume residual or recurrent tumour is possible, but its value is unclear. METHODS: Data were collected from two institutions (UK and Denmark) which maintain prospective databases on all patients undergoing local excision by transanal endoscopic microsurgery (TEM). The study group was all patients who had TEM after neoadjuvant radiation for rectal cancer over an 11-year period. RESULTS: Forty-five patients had TEM after neoadjuvant radiation, 18 after short course radiotherapy (SCRT) and 27 after chemoradiotherapy (CRT). Local recurrence occurred in 13 (29%) and distant metastases in 11 (24%). Complete pathological response was noted in 10 (22%), 28% after SCRT and 19% after CRT, p = 0.02. However, local recurrence still occurred in 60% of those with ypT0 after SCRT. The recurrence rate may be higher in those with residual disease at TEM compared with complete responders (40 vs 30%). CONCLUSION: If complete response can be determined clinically, local excision of the scar does not confer benefit, but follow-up should be maintained. If there is regrowth or residual tumour at TEM, further recurrence is common, and the benefits of TEM may not outweigh the risks, except in those unsuitable for radical surgery.

Local excision after polypectomy for rectal polyp cancer: when is it worthwhile?

AIM: The optimal management of a polyp cancer that has been removed endoscopically is unclear. Further local excision is often advocated to remove the polyp stalk or scar or to ensure clear margins, but the benefit of this is unclear. The aim of this paper is to determine whether the indications for further local excision can be better defined. METHOD: Data were collected from two institutions (in UK and Denmark) which maintain prospective databases to collect information on all patients undergoing transanal endoscopic microsurgery (TEM). The study group was all patients who had a TEM after macroscopically complete polypectomy for rectal cancer. Data covering an 11-year period were analysed. RESULTS: Sixty three patients had TEM with no residual cancer after macroscopically complete polypectomy. Residual adenoma was found in 23 (37%). A postpolypectomy endoscopy had not detected the residual adenoma in three. Malignant local recurrence occurred in five patients (8%) and distant metastases in another two (3%). Recurrence occurred in 4/23 (17%) when there was residual adenoma in the TEM specimen and in 3/40 (7.5%) where there was scar only, although this did not reach significance. In two instances recurrence was around 10 years after TEM. Those with residual adenoma at TEM tended to have poorer survival. CONCLUSION: Further local excision often reveals no residual cancer despite microscopically involved polypectomy margins. Careful endoscopy is required to assess the polypectomy site as residual tumour can be missed. In the absence of residual adenoma, TEM does not appear to be of benefit, although a small risk of recurrence exists.

Maintaining Standards in Colorectal Cancer Surgery During the Global Pandemic: A Cohort Study.

AIM: Cancer surgery in the COVID-19 pandemic presents many new challenges. For each patient, the risk of contracting COVID-19 during the perioperative period, with the potential for life-threatening sequelae (1), has to be weighed against the risk of delaying treatment. We assessed the response and short-term outcomes from elective colorectal cancer surgery during the pandemic at our institution. METHOD: We report a prospective cohort study of all elective colorectal surgery cases performed at our Trust during the 11 weeks following the national UK lockdown on 23rd March 2020, compared with the same time period in 2019. RESULTS: Eighty-five colorectal operations were performed during the 2020 (COVID) time period, and 179 performed in the 2019 (non-COVID) time period. A significantly higher proportion of cases during the COVID period were cancer-related (66% vs 26%, p < 0.00001). There was no difference in length of hospital stay, complications or readmissions. There were no mortalities in either cohort. Among the cancer patients, there were no differences in TMN staging, R1 resection rate or lymph node yields. No elective patient tested positive for COVID-19 during the perioperative period. CONCLUSION: At the height of the COVID pandemic, we maintained delivery the of high-quality elective colorectal cancer surgery, with no worsening of short-term outcomes and no compromise in the quality of cancer resections. Ongoing monitoring of this cohort is essential. The risks associated with COVID-19 will continue for some time, necessitating adaptive responses to maintain high-quality cancer services.

A routine third trimester growth ultrasound in the obese pregnant woman does not reliably identify fetal growth abnormalities: A retrospective cohort study.

BACKGROUND: In response to the challenges of assessing fetal growth in obese women, guidelines recommend routine third trimester ultrasound scans. AIM: The aim of this study was to assess the diagnostic performance of this routine scan in obese women (body mass index (BMI) ≥ 35 kg/m2 ). METHODS: A retrospective cohort study of 1008 pregnancies with maternal BMI ≥ 35 kg/m2 born after 37 weeks gestation at a Victorian hospital from 2015 to 2017. Multiple pregnancies and those affected by diabetes were excluded. Growth ultrasounds were performed between 34 + 0 and 36 + 6 weeks gestation. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for the detection of large for gestational age (LGA > 90%) and small for gestational age (SGA < 10%) were calculated using ultrasound estimated fetal weight (EFW) or abdominal circumference (AC) and compared with gestational age and gender-based birthweight percentiles. RESULTS: Using EFW, sensitivity for detecting SGA at birth was 8.1% (six of 74) with a PPV of 100%. Sensitivity for detecting LGA at birth was 61.0% (119 of 195), PPV 54.8%. Sensitivity, specificity, PPV and NPV percentages were all lower using AC. Only 40% of actual birthweight percentiles (405/1008) were within ±10 percentiles of their growth ultrasound EFW percentile. CONCLUSION: The performance of a routine third trimester ultrasound in women with BMI ≥ 35 kg/m2 suggests limited utility in helping identify aberrant fetal growth. This has important implications for the management of obese pregnant women.

Exploiting differential Wnt target gene expression to generate a molecular biomarker for colorectal cancer stratification.

OBJECTIVE: Pathological Wnt pathway activation is a conserved hallmark of colorectal cancer. Wnt-activating mutations can be divided into: i) ligand-independent (LI) alterations in intracellular signal transduction proteins (Adenomatous polyposis coli, ß-catenin), causing constitutive pathway activation and ii) ligand-dependent (LD) mutations affecting the synergistic R-Spondin axis (RNF43, RSPO-fusions) acting through amplification of endogenous Wnt signal transmembrane transduction. Our aim was to exploit differential Wnt target gene expression to generate a mutation-agnostic biomarker for LD tumours. DESIGN: We undertook harmonised multi-omic analysis of discovery (n=684) and validation cohorts (n=578) of colorectal tumours collated from publicly available data and the Stratification in Colorectal Cancer Consortium. We used mutation data to establish molecular ground truth and subdivide lesions into LI/LD tumour subsets. We contrasted transcriptional, methylation, morphological and clinical characteristics between groups. RESULTS: Wnt disrupting mutations were mutually exclusive. Desmoplastic stromal upregulation of RSPO may compensate for absence of epithelial mutation in a subset of stromal-rich tumours. Key Wnt negative regulator genes were differentially expressed between LD/LI tumours, with targeted hypermethylation of some genes (AXIN2, NKD1) occurring even in CIMP-negative LD cancers. AXIN2 mRNA expression was used as a discriminatory molecular biomarker to distinguish LD/LI tumours (area under the curve >0.93). CONCLUSIONS: Epigenetic suppression of appropriate Wnt negative feedback loops is selectively advantageous in LD tumours and differential AXIN2 expression in LD/LI lesions can be exploited as a molecular biomarker. Distinguishing between LD/LI tumour types is important; patients with LD tumours retain sensitivity to Wnt ligand inhibition and may be stratified at diagnosis to clinical trials of Porcupine inhibitors.

Correction to: Comparison of two invitation-based methods for human papillomavirus (HPV) self-sampling with usual care among un- and under-screened Maori, Pacific and Asian women: study protocol for a randomised controlled community trial to examine the effect of self-sampling on participation in cervical-cancer screening.

Following publication of the original article [1], the authors reported an error in the authorship list associated with the paper. Georgina McPherson has therefore been added.

Comparison of two invitation-based methods for human papillomavirus (HPV) self-sampling with usual care among un- and under-screened Maori, Pacific and Asian women: study protocol for a randomised controlled community trial to examine the effect of self-sampling on participation in cervical-cancer screening.

BACKGROUND: Maori, Pacific and Asian women in New Zealand have lower cervical-cancer screening rates than European women, and there are persistent inequities in cervical cancer outcomes for Maori and Pacific women. Innovative ways to address access barriers are required. New Zealand is transitioning to screening with human papillomavirus (HPV) DNA testing, which could allow women themselves, rather than a clinician, to take the sample. Internationally, self-sampling has been found to increase screening participation rates. The aim of this open-label community-based randomised controlled trial is to investigate whether self-sampling increases screening participation among un- and under-screened Maori, Pacific and Asian women in New Zealand. METHODS/DESIGN: We aim to invite at least 3550 un- or under-screened (≥5 years overdue) Maori, Pacific and Asian women (1050, 1250, 1250 respectively), aged 30-69 years, for screening. The three study arms are: usual care in which women are invited to attend a clinic for a standard clinician-collected cytology test; clinic-based self-sampling in which women are invited to take a self-sample at their usual general practice; and mail-out self-sampling in which women are mailed a kit and invited to take a self-sample at home. Women will be randomised 3:3:1 to the clinic and mail-out self-sampling groups, and usual care. There is also a nested sub-study in which non-responding women in all allocation groups, when they subsequently present to the clinic for other reasons, are offered clinic or home-kit self-sampling. The primary outcome will be the proportion of women who participate (by taking a self-sample or cytology test). DISCUSSION: This trial is the first to evaluate the effectiveness of mailed self-sampling in New Zealand and will be one of the first internationally to evaluate the effectiveness of opportunistic in-clinic invitations for self-sampling. The trial will provide robust evidence on the impact on participation proportions from different invitation approaches for HPV self-sampling in New Zealand un- and under-screened Maori, Pacific and Asian women. TRIAL REGISTRATION: ANZCTR Identifier: ACTRN12618000367246 (date registered 12/3/2018) https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=371741&isReview=true; UTN: U1111-1189-0531.

Impact of Suture Type on Erosion Rate After Laparoscopic Ventral Mesh Rectopexy: A Case-Matched Study.

BACKGROUND: There has been increasing concern and scrutiny in the use of mesh for certain pelvic organ prolapse procedures. However, mesh erosion was often associated with sites of suture fixation of the mesh to the rectum or vagina. Thus, in response to this finding, we replaced our suture material with absorbable monofilament suture. OBJECTIVE: The purpose of this study was to compare the rates of mesh-related complications after laparoscopic ventral mesh rectopexy, according to the type of suture used in fixation of mesh. DESIGN: This was retrospective cohort study. SETTINGS: This study was performed at a high-volume, tertiary care center. It was conducted using a prospective database including patients who underwent laparoscopic ventral mesh rectopexy over a 7-year period. PATIENTS: A total of 495 cases were included; 296 (60%) laparoscopic ventral mesh rectopexies were performed using a nonabsorbable suture compared with 199 (40%) with an absorbable suture in a case-matched analysis. In addition, 151 cases of laparoscopic ventral mesh rectopexy with nonabsorbable were matched based on age, sex, and time of follow-up, with an equal number of patients using absorbable monofilament suture. MAIN OUTCOMES MEASURES: Primary outcome was symptomatic mesh erosion after rectopexy. Secondary outcomes included other mesh-related complications and/or reoperations. RESULTS: The erosion rate was 2% (6/495) in the nonabsorbable suture group, including 4 erosions into the rectum and 2 into the vagina. There was no erosion in the group with absorbable suture. This difference was maintained after matching: after a median follow-up of 6 (12) months, there was no erosion in the absorbable suture group versus 3.3% erosion (n = 5) in the nonabsorbable suture group (p = 0.03). LIMITATIONS: This study was limited by its retrospective design. CONCLUSIONS: Mesh-related complications are reduced using absorbable sutures compared with nonabsorbable sutures when performing laparoscopic ventral mesh rectopexy with synthetic mesh without an increase in rectopexy failures. See Video Abstract at http://links.lww.com/DCR/B49. IMPACTO DEL TIPO DE SUTURA EN LA TASA DE EROSIóN DESPUéS DE LA RECTOPEXIA VENTRAL LAPAROSCóPICA CON MALLA: UN ESTUDIO DE CASOS EMPAREJADOS: Ha habido una creciente preocupación y escrutinio en el uso de la malla para ciertos procedimientos de prolapso de órganos pélvicos. Sin embargo, la erosión de la malla a menudo se asoció con sitios de fijación de sutura de la malla al recto o la vagina. Por lo tanto, en respuesta a este hallazgo, reemplazamos nuestro material de sutura con sutura de monofilamento absorbible.Comparar las tasas de complicaciones relacionadas con la malla después de la rectopexia laparoscópica de malla ventral, de acuerdo al tipo de sutura utilizada en la fijación de la malla.Este fue un estudio de cohorte retrospectivo.Este estudio se realizó en un centro de atención de tercer nivel de alto volumen. Se realizó utilizando una base de datos prospectiva que incluía pacientes que se sometieron a una rectopexia de malla ventral laparoscópica durante un período de 7 años.Se incluyeron un total de 495 casos; 296 (60%) rectopexias de malla ventral laparoscópica utilizando una sutura no reabsorbible en comparación con 199 (40%) con una sutura absorbible en un análisis de casos emparejados. Además, 151 casos de rectopexia ventral laparoscópica con malla no absorbible se emparejaron según la edad, el sexo y el tiempo de seguimiento con un número igual de pacientes que usaban sutura de monofilamento absorbible.La medida de resultado primaria fue la erosión sintomática de la malla después de la rectopexia. La medida de resultado secundarias incluyeron otras complicaciones y/o reoperaciones relacionadas con la malla.La tasa de erosión fue del 2% (6/495) en el grupo de sutura no absorbible; 4 erosiones en el recto y 2 en la vagina. No hubo erosión en el grupo con sutura absorbible. Esta diferencia se mantuvo después del emparejamiento: después de una mediana de seguimiento de 6 (12) meses, no hubo erosión en el grupo de sutura absorbible versus 3.3% de erosión (n = 5) en el grupo de sutura no absorbible (p = 0.03).Este estudio estuvo limitado por su diseño retrospectivo.Las complicaciones relacionadas con la malla se reducen utilizando suturas absorbibles en comparación con las suturas no absorbibles cuando se realiza la rectopexia de malla ventral laparoscópica con malla sintética, sin un aumento en los fracasos de rectopexia. Vea el Resumen del Video en http://links.lww.com/DCR/B49.