Neil Ryan

The University of Edinburgh | UoE · College of Medicine and Veterinary Medicine

Lynch syndrome (LS) is an autosomal dominant condition that increases an individual's risk of a constellation of cancers. LS is defined when an individual has inherited pathogenic variants in the mismatch repair genes. Currently, most people with LS are undiagnosed. Early detection of LS is vital as those with LS can be enrolled in cancer reduction...

Background & aims: Constitutional mismatch repair deficiency (CMMRD) is a rare recessive childhood cancer predisposition syndrome caused by germline mismatch repair (MMR) variants. Constitutional microsatellite instability (cMSI) is a CMMRD diagnostic hallmark and may associate with cancer risk. We quantified cMSI in a large CMMRD patient cohort t...

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...

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...

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 inde...

Background People with genetic predispositions to cancer are faced with complex health decisions about managing their risk. Decision aids can support informed, values-based decisions, alongside shared decision-making with a clinician. Whilst diagnoses of genetic predispositions to cancer are increasing, there is no scalable decision aid to support...

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...

Reflex mismatch repair immunohistochemistry (MMR IHC) testing for MLH1, PMS2, MSH2 and MSH6 is used to screen for Lynch syndrome. Recently MMR-deficiency (MMRd) has been approved as a pan-cancer predictive biomarker for checkpoint inhibitor therapy, leading to a vast increase in the use of MMR IHC in clinical practice. We explored whether immunohis...

Background: The CovidSurg-Cancer consortium aimed to explore the impact of COVID-19 in surgical patients and services for solid cancers at the start of the pandemic. The CovidSurg-GO Cancer subgroup was particularly concerned about the magnitude of adverse outcomes caused by the disrupted surgical gynecological cancer care during the COVID-19 pand...

Purpose: Single-nucleotide variations (SNVs) (formerly single-nucleotide polymorphism [SNV]) influence genetic predisposition to endometrial cancer. We hypothesized that a polygenic risk score (PRS) comprising multiple SNVs may improve endometrial cancer risk prediction for targeted screening and prevention. Methods: We developed PRSs from SNVs...

Ovarian cancer (OC) is the least survivable gynaecological malignancy and presents late. Five‐year survival for OC is around 45% increasing the need for innovative treatments. Checkpoint inhibitors have shown significant clinical efficacy in mismatch repair deficient (MMRd) cancers and could be a powerful treatment in OC. However, their application...

Background Endometrial cancer is the most common gynaecological cancer in high-income countries. Elevated body mass index (BMI) is an established modifiable risk factor for this condition and is estimated to confer a larger effect on endometrial cancer risk than any other cancer site. However, the molecular mechanisms underpinning this association...

Defective DNA mismatch repair (dMMR) causes elevated tumour mutational burden (TMB) and microsatellite instability (MSI) in multiple cancer types. dMMR/MSI colorectal cancers (CRCs) have enhanced T cell infiltrate and favourable outcome, however this association has not been reliably detected in other tumour types, including endometrial cancer (EC)...

Background: Ovarian cancer is the sixth most common cancer in women world-wide. Epithelial ovarian cancer (EOC) is the most common; three-quarters of women present when disease has spread outside the pelvis (stage III or IV). Treatment consists of a combination of surgery and platinum-based chemotherapy. Although initial responses to chemotherapy...

Background: Endometrial cancer is the most common gynaecological cancer in high-income countries. Elevated body mass index (BMI) is an established modifiable risk factor for this condition and is estimated to confer a larger effect on endometrial cancer risk than any other cancer site. However, the molecular mechanisms underpinning this association...

Novel diagnostics for uterine cancer are urgently needed to reduce the burden of invasive testing for the majority of healthy women with postmenopausal bleeding. We have previously shown that uterine cancer cells can be detected by cytology in urine and vaginal samples with high diagnostic accuracy. Here, we demonstrate its potential to distinguish...

Endometrial cancer is the commonest gynaecological malignancy in developed countries, and women presenting with high risk or advanced disease have poor outcomes. Thyroid hormones play a key role in cellular metabolism and can influence cancer growth and invasion. Our aim was to evaluate the association between clinical and biochemical thyroid dysfu...

Background Surgery is the main modality of cure for solid cancers and was prioritised to continue during COVID-19 outbreaks. This study aimed to identify immediate areas for system strengthening by comparing the delivery of elective cancer surgery during the COVID-19 pandemic in periods of lockdown versus light restriction.

Background: Surgery is the main modality of cure for solid cancers and was prioritised to continue during COVID-19 outbreaks. This study aimed to identify immediate areas for system strengthening by comparing the delivery of elective cancer surgery during the COVID-19 pandemic in periods of lockdown versus light restriction. Methods: This internati...

Background: Mismatch repair deficient (MMRd) tumours may arise from somatic events acquired during carcinogenesis or in the context of Lynch syndrome (LS), an inherited cancer predisposition condition caused by germline MMR pathogenic variants. Our aim was to explore whether sporadic and hereditary MMRd endometrial cancers (EC) display distinctive...

SARS-CoV-2 has been associated with an increased rate of venous thromboembolism in critically ill patients. Since surgical patients are already at higher risk of venous thromboembolism than general populations, this study aimed to determine if patients with peri-operative or prior SARS-CoV-2 were at further increased risk of venous thromboembolism....

Intrauterine progestin is a treatment option for women with atypical hyperplasia or low-risk endometrial cancer who wish to preserve their fertility, or whose poor surgical fitness precludes safe hysterectomy. We hypothesized that in such women with obesity, weight loss during progestin treatment may improve oncological outcomes. We conducted a pro...

Peri-operative SARS-CoV-2 infection increases postoperative mortality. The aim of this study was to determine the optimal duration of planned delay before surgery in patients who have had SARS-CoV-2 infection. This international, multicentre, prospective cohort study included patients undergoing elective or emergency surgery during October 2020. Su...

The diagnosis of visceral perforation during pregnancy is often delayed and the management complex. A 32-year-old primigravid woman in her second trimester presented with abdominal pain and a pre-existing ileoanal pouch. Initial imaging was negative but later imaging was suggestive of serious pathology. At laparotomy, a caesarean section was perfor...

Background: Preoperative SARS-CoV-2 vaccination could support safer elective surgery. Vaccine numbers are limited so this study aimed to inform their prioritization by modelling.

Objective: To describe the current testing practice, referral pathways and gynaecological services available to women with Lynch syndrome (LS) in the United Kingdom. Design: Cross sectional nationwide survey of gynaecological oncologists and women with LS. Setting: United Kingdom METHODS: Gynaecological oncologists were contacted directly. Wom...

Postmenopausal bleeding triggers urgent investigation by sequential invasive tests that are avoidable for the 90–95% of women who do not have endometrial cancer. A simple, non-invasive tool that accurately identifies cancer and safely reassures healthy women could transform patient care. Here we report, in a cross-sectional diagnostic accuracy stud...

Background: Surgical services are preparing to scale up in areas affected by COVID-19. This study aimed to evaluate the association between preoperative SARS-CoV-2 testing and postoperative pulmonary complications in patients undergoing elective cancer surgery. Methods: This international cohort study included adult patients undergoing elective sur...

Background Testing cancers for mismatch repair deficiency (dMMR) by immunohistochemistry (IHC) is a quick and inexpensive means of triaging individuals for germline Lynch syndrome testing. The aim of this study was to evaluate tumour dMMR and the prevalence of Lynch syndrome in patients referred to the Manchester Centre for Genomic Medicine, which...

Purpose To determine impact of risk-reducing hysterectomy and bilateral salpingo-oophorectomy (BSO) on gynecological cancer incidence and death in heterozygotes of pathogenic MMR ( path_MMR ) variants. Methods The Prospective Lynch Syndrome Database was used to investigate the effects of gynecological risk-reducing surgery (RRS) at different ages....

Background Surgical services are preparing to scale up in areas affected by COVID-19. This study aimed to evaluate the association between preoperative SARS-CoV-2 testing and postoperative pulmonary complications in patients undergoing elective cancer surgery. Methods This international cohort study included adult patients undergoing elective surge...

Key content Lynch syndrome is an autosomal dominant condition closely associated with colorectal, endometrial and ovarian cancer. Women with Lynch syndrome are at increased risk of both endometrial and ovarian cancer and should be offered personalised counselling regarding family planning, red flag symptoms and risk‐reducing strategies. Surveillanc...

Introduction Older patients undergoing cancer surgery are at increased risk of post-operative morbidity and mortality. Frailty is particularly prevalent in this patient cohort and is a major contributor to adverse outcomes. A survey was conducted to assess the confidence and knowledge of trainees in obstetrics and gynaecology (O&G) regarding identi...

Introduction Older patients undergoing cancer surgery are at increased risk of post-operative complications, prolonged hospital stay, and mortality. Identification of frailty can help predict patients at high risk of peri-operative complications and allow a collaborative, multidisciplinary team approach to their care. A survey was conducted to asse...

Background Lynch syndrome (LS) predisposes to endometrial cancer (EC), colorectal cancer, and other cancers through inherited pathogenic variants affecting mismatch-repair (MMR) genes. Diagnosing LS in women with EC can reduce subsequent cancer mortality through colonoscopic surveillance and aspirin chemoprevention; it also enables cascade testing...

Background: Hereditary causes of ovarian cancer include Lynch syndrome, which is due to inherited pathogenic variants affecting one of the four mismatch repair genes involved in DNA repair. The aim of this study was to evaluate tumour mismatch repair deficiency and prevalence of Lynch syndrome in high-risk women referred to the Manchester Centre f...

Background An association between BRCA pathogenic variants and an increased endometrial cancer risk, specifically serous-like endometrial cancer, has been postulated but remains unproven, particularly for BRCA2 carriers. Mechanistic evidence is lacking, and any link may be related to tamoxifen exposure or testing bias. Hysterectomy during risk-redu...

Purpose: To survey risk-reducing hysterectomy and bilateral salpingo-oophorectomy (BSO) practice and advice regarding hormone replacement therapy (HRT) in women with Lynch syndrome. Methods: We conducted a survey in 31 contributing centers from the Prospective Lynch Syndrome Database (PLSD), which incorporates 18 countries worldwide. The survey...

A barrier to Lynch syndrome testing is the need for prior genetic counselling, a resource demanding process for both patients and healthcare services. We explored the impact of gynaecologist led Lynch syndrome testing in women with endometrial cancer. Women were approached before surgery, on the day of surgery or during routine follow up. Lynch syn...

Background: Lynch syndrome is the most common genetic predisposition for hereditary cancer but remains underdiagnosed. Large prospective observational studies have recently increased understanding of the effectiveness of colonoscopic surveillance and the heterogeneity of cancer risk between genotypes. The need for gene- and gender-specific guideli...

A barrier to Lynch syndrome testing is the need for prior genetic counselling, a resource demanding process for both patients and healthcare services. We explored the impact of gynaecologist led Lynch syndrome testing in women with endometrial cancer. Women were approached before surgery, on the day of surgery or during routine follow up. Lynch syn...

Lynch syndrome (LS) is a hereditary cancer syndrome responsible for 3% of all endometrial cancer and 5% in those aged under 70 years. It is unclear whether universal testing for LS in endometrial cancer patients would be cost-effective. The Manchester approach to identifying LS in endometrial cancer patients uses immunohistochemistry (IHC) to detec...

Endometrial cancer is the sixth most common cancer in women, with a rising incidence worldwide. Current approaches for the diagnosis and screening of endometrial cancer are invasive, expensive or of moderate diagnostic accuracy, limiting their clinical utility. There is a need for cost-effective and minimally invasive approaches to facilitate the e...

Introduction: Endometrial cancer is one of the most commonly diagnosed cancers in women. Although there is a hereditary component to endometrial cancer, most cases are thought to be sporadic and lifestyle related. The aim of this study was to systematically review prospective and retrospective case–control studies, meta-analyses and genome-wide ass...

The levonorgestrel-releasing intrauterine system (LNG-IUS) is a conservative management option for atypical hyperplasia (AH) and low grade early stage endometrial cancer (EEC), but around 1 in 3 patients fail to respond to treatment. The aim of this study was to investigate if serum and/or tissue HE4 expression could predict response to LNG-IUS the...

Around 30% of endometrial cancers (EC) are mismatch repair (MMR) deficient, mostly as a consequence of mutations acquired during tumorigenesis, but a significant minority is caused by Lynch syndrome (LS). This inherited cancer predisposition syndrome primes an anti-cancer immune response, even in healthy carriers. We sought to explore the intra-tum...

Background: Lynch syndrome is a hereditary cancer syndrome caused by constitutional pathogenic variants in the DNA mismatch repair (MMR) system, leading to increased risk of colorectal, endometrial and other cancers. The study aimed to identify the incremental costs and consequences of strategies to identify Lynch syndrome in women with endometria...

Purpose: Endometrial cancer (EC) is often the sentinel cancer in women with Lynch syndrome (LS). However, efforts to implement universal LS screening in EC patients have been hampered by a lack of evidence detailing the proportion of EC patients that would be expected to screen positive for LS. Methods: Studies were identified by electronic searche...

Aim: Lynch Syndrome (LS) is associated with an increased risk of developing endometrial carcinoma (EC) and ovarian carcinoma (OC). There is considerable variability in current practices and opinions related to screening newly diagnosed patients with EC/OC for LS. An online survey was undertaken to explore the extent of these differences. Methods:...

Introduction: Lynch syndrome (LS) is the most common inherited cause of endometrial cancer (EC); however testing is not routine. Identifying LS determines eligibility for immunotherapy trials, enables surveillance to reduce colorectal cancer deaths, and promotes cascade testing of relatives. Methods: We performed a systematic review with meta-anal...

Purpose: There are no internationally agreed upon clinical guidelines as to which women with gynecological cancer would benefit from Lynch syndrome screening or how best to manage the risk of gynecological cancer in women with Lynch syndrome. The Manchester International Consensus Group was convened in April 2017 to address this unmet need. The ai...

Background: Lynch syndrome is the most common inherited cause of endometrial cancer. Identifying individuals affected by Lynch syndrome enables risk-reducing interventions including colorectal surveillance, and cascade testing of relatives. Methods: We conducted a micro-costing study of screening all women with endometrial cancer for Lynch syndrome...

Background: Lynch syndrome is the most common inherited cancer syndrome, which predisposes individuals to a number of different cancers, principally colorectal and endometrial cancer. The early diagnosis of Lynch syndrome enables colorectal surveillance, which has been shown to save lives through the detection and removal of premalignant polyps an...

Table S1. List of verbatim outcomes, ‘standardised outcome terms’ and domains. Table S2. Summaries for study characteristics. Table S3. Standardised outcome terms identified by categories of study numbers. Table S4. Criteria used to define treatment response. Table S5. Outcomes extracted from Quality of Life Measurement Instruments.

In Reply We are grateful for the opportunity to respond to Bogani and colleagues about our report of an association between type of mismatch repair mutation and age of cancer onset in Lynch syndrome.¹ They correctly state that neither endometrial nor ovarian cancers are single disease entities; their histological subtypes reflect vast differences i...

The article "Recognizing Gynecological Cancer in Primary Care: Risk Factors, Red Flags, and Referrals", written by Garth Funston, Helena O'Flynn, Neil A. J. Ryan, Willie Hamilton, Emma J. Crosbie was originally published electronically on the publisher's internet portal (currently Springer-Link) on March 07, 2018 without open access.

Background Hyperemesis gravidarum (HG) is a major health burden affecting between 1-2% of all pregnancies. The sequelae of the condition can be fatal. There is current equipoise as to how best to manage the condition; that is inpatient versus outpatient management. Objective This study investigated the total length of stay for patients diagnosed w...

Aim Six phase III randomised trials have determined the effectiveness of chemoradiotherapy as primary treatment for anal squamous cell carcinoma (ASCC), but outcomes reported in these trials varied widely, hindering evidence synthesis. To improve reporting in all future trials, we aim to develop a core set of outcomes (COS). As the first stage of C...