Magnetic resonance guided focused ultrasound surgery - a novel treatment for uterine fibroids

Uterine fibroids are the most common tumour of the reproductive tract in women of reproductive age. Although they are benign tumours that are often asymptomatic, they may cause debilitating symptoms in many women, such as abnormal uterine bleeding, abdominal pain, increased abdominal girth, urinary frequency, constipation, pregnancy loss, dyspareunia, and in some cases infertility. Several approaches are available for the treatment of uterine fibroids. These include pharmacologic options, such as hormonal therapies and gonadotropinreleasing hormone agonists; surgical approaches, such as hysterectomy, myomectomy; myolysis, laparoscopic uterine artery occlusion, uterine artery embolisation and magnetic resonance imaging-guided focused ultrasound surgery. The choice of approach may be dictated by factors such as the patient’s desire to become pregnant in the future, the importance of uterine preservation, symptom severity, and tumour characteristics. There is however, no widely agreed therapeutic strategy. There is a widespread view that hysterectomy is overused in the UK; the Chief Medical Officer in his annual report ‘On the state of public health’ in 2005, highlighted that hysterectomy in younger women is associated with complications, hospital stays, procedure-related interference with normal life and is costly. In addition he outlined the need to reduce the number of hysterectomies. This, along with the change in cultural attitudes amongst patients, who are becoming increasingly reluctant to undergo these conventional invasive procedures, has increased the need for new treatment options. Ideally new treatment options for uterine fibroids would be minimally invasive, have long-term data demonstrating efficacy and safety, have minimal or no incidence of fibroid recurrence, be easy to perform, preserve fertility, and be cost effective. New treatment approaches are under investigation, with the goals of being effective, safe, and less invasive. MRgFUS is a non-invasive thermo-ablative hybrid technique which uses both MR and ultrasound to destroy tumours. It is an outpatient procedure, which avoids the need for an anaesthetic, has a short recovery period, and is uterine sparing. The main objective of this work was to set out the rationale for using Magnetic Resonance guided Focused Ultrasound Surgery (MRgFUS) for the treatment of uterine fibroids. In order to achieve this aim, four main bodies of work are necessary; 1) Identifying patient selection criteria and investigating mitigating techniques to increase the pool of women for whom this treatment can be offered. 2) Investigating a method designed to overcome the problem of safely treating women with abdominal scars for whom this treatment can cause potential morbidity. 3) Investigating the potentiality of using MRgFUS to prolong the tumour shrinkage effect of GnRH analogue injections. 4) Investigating the safety of MRgFUS in treating symptomatic women who wish to preserve fertility. Results: the first aim of this project was to identify patient selection criteria and to investigate methods to widen the selection criteria. In our retrospective review it was found that 74% of women presenting were deemed technically suitable to proceed with treatment and several mitigating techniques that solved current technical difficulties were identified and allowed for less restrictive MRgFUS selection criteria for treatment of symptomatic uterine fibroids. These less restrictive criteria are expected to expand the pool of patients for whom MRgFUS is a viable treatment option for uterine fibroid symptoms. The second aim was to identify a method of overcoming the problem of treating women with previous abdominal scars safely. We identified a unique method of highlighting the scar by painting it with a paramagnetic iron oxide material which clearly outlined the scar on MR scanning allowing complete avoidance of the scar using MR guidance. In this small pilot study, all women were treated safely with no skin burns. The third aim of this project looked at the potentiality of prolonging the shrinkage effect of GnRH analogues by following a course of 3 injections with MRgFUS treatment. In this prospective study of fifty women, there was a 50% reduction in the mean symptoms severity score at 6 months which was maintained for 24 months post treatment. There was an average reduction in target fibroid volume which was maintained for 24 months. The final aim of the project was to investigate the safety of using MRgFUS as a treatment option for those women who wished to preserve their fertility. In this multicentre international study, One hundred and sixteen women were recruited from five centres. There were sixty four reported pregnancies in Sixty one women, with 30 completed deliveries. There were no reported cases of uterine rupture, premature labour, abnormal placentation or placental abruption. Conclusion: There is a growing body of data from clinical trials and more than four years of clinical experience to validate the safety and efficacy of MRgFUS for the treatment of uterine fibroids. MRgFUS is a totally non-invasive outpatient procedure that is not associated with the typical surgical risks of bleeding, infection and has minimal recovery time. Additionally, the procedure allows women to address their symptoms whilst preserving the uterus. Consequently, MRgFUS is an alternative treatment option for suitable patients who have refused other interventions due to concerns about lost productivity, risks of surgical complications or future fertility

Immune-metabolic adaptations in pregnancy: A potential stepping-stone to sepsis

Physiological shifts during pregnancy predispose women to a higher risk of developing sepsis resulting from a maladapted host-response to infection. Insightful studies have delineated subtle point-changes to the immune system during pregnancy. Here, we present an overlay of these point-changes, asking what changes and when, at a physiological, cellular, and molecular systems-level in the context of sepsis. We identify distinct immune phases in pregnancy delineated by placental hormone-driven changes in homeostasis setpoints of the immune and metabolic systems that subtly mirrors changes observed in sepsis. We propose that pregnancy immune-metabolic setpoint changes impact feedback thresholds that increase risk for a maladapted host-response to infection and thus act as a stepping-stone to sepsis. Defining maternal immune-metabolic setpoint changes is not only vital for tailoring the right diagnostic tools for early management of maternal sepsis but will facilitate an unravelling of the pathophysiological pathways that predispose an individual to sepsis

mSep: investigating physiological and immune-metabolic biomarkers in septic and healthy pregnant women to predict feto-maternal immune health – a prospective observational cohort study protocol

Introduction: Maternal sepsis remains a leading cause of death in pregnancy. Physiological adaptations to pregnancy obscure early signs of sepsis and can result in delays in recognition and treatment. Identifying biomarkers that can reliably diagnose sepsis will reduce morbidity and mortality and antibiotic overuse. We have previously identified an immune-metabolic biomarker network comprising three pathways with a >99% accuracy for detecting bacterial neonatal sepsis. In this prospective study, we will describe physiological parameters and novel biomarkers in two cohorts—healthy pregnant women and pregnant women with suspected sepsis—with the aim of mapping pathophysiological drivers and evaluating predictive biomarkers for diagnosing maternal sepsis. Methods and analysis: Women aged over 18 with an ultrasound-confirmed pregnancy will be recruited to a pilot and two main study cohorts. The pilot will involve blood sample collection from 30 pregnant women undergoing an elective caesarean section. Cohort A will follow 100 healthy pregnant women throughout their pregnancy journey, with collection of blood samples from participants at routine time points in their pregnancy: week 12 ‘booking’, week 28 and during labour. Cohort B will follow 100 pregnant women who present with suspected sepsis in pregnancy or labour and will have at least two blood samples taken during their care pathway. Study blood samples will be collected during routine clinical blood sampling. Detailed medical history and physiological parameters at the time of blood sampling will be recorded, along with the results of routine biochemical tests, including C reactive protein, lactate and white blood cell count. In addition, study blood samples will be processed and analysed for transcriptomic, lipidomic and metabolomic analyses and both qualitative and functional immunophenotyping. Ethics and dissemination: Ethical approval has been obtained from the Wales Research Ethics Committee 2 (SPON1752-19, 30 October 2019). Trial registration number: NCT05023954

nSeP: immune and metabolic biomarkers for early detection of neonatal sepsis-protocol for a prospective multicohort study

Introduction Diagnosing neonatal sepsis is heavily dependent on clinical phenotyping as culture-positive body fluid has poor sensitivity, and existing blood biomarkers have poor specificity. A combination of machine learning, statistical and deep pathway biology analyses led to the identification of a tripartite panel of biologically connected immune and metabolic markers that showed greater than 99% accuracy for detecting bacterial infection with 100% sensitivity. The cohort study described here is designed as a large-scale clinical validation of this previous work. Methods and analysis This multicentre observational study will prospectively recruit a total of 1445 newborn infants (all gestations)—1084 with suspected early—or late-onset sepsis, and 361 controls—over 4 years. A small volume of whole blood will be collected from infants with suspected sepsis at the time of presentation. This sample will be used for integrated transcriptomic, lipidomic and targeted proteomics profiling. In addition, a subset of samples will be subjected to cellular phenotype and proteomic analyses. A second sample from the same patient will be collected at 24 hours, with an opportunistic sampling for stool culture. For control infants, only one set of blood and stool sample will be collected to coincide with clinical blood sampling. Along with detailed clinical information, blood and stool samples will be analysed and the information will be used to identify and validate the efficacy of immune-metabolic networks in the diagnosis of bacterial neonatal sepsis and to identify new host biomarkers for viral sepsis

Immune and metabolic markers for identifying and investigating severe Coronavirus disease and Sepsis in children and young people (pSeP/COVID ChYP study): protocol for a prospective cohort study

Introduction Early recognition and appropriate management of paediatric sepsis are known to improve outcomes. A previous system’s biology investigation of the systemic immune response in neonates to sepsis identified immune and metabolic markers that showed high accuracy for detecting bacterial infection. Further gene expression markers have also been reported previously in the paediatric age group for discriminating sepsis from control cases. More recently, specific gene signatures were identified to discriminate between COVID-19 and its associated inflammatory sequelae. Through the current prospective cohort study, we aim to evaluate immune and metabolic blood markers which discriminate between sepses (including COVID-19) from other acute illnesses in critically unwell children and young persons, up to 18 years of age.Methods and analysis We describe a prospective cohort study for comparing the immune and metabolic whole-blood markers in patients with sepsis, COVID-19 and other illnesses. Clinical phenotyping and blood culture test results will provide a reference standard to evaluate the performance of blood markers from the research sample analysis. Serial sampling of whole blood (50 μL each) will be collected from children admitted to intensive care and with an acute illness to follow time dependent changes in biomarkers. An integrated lipidomics and RNASeq transcriptomics analyses will be conducted to evaluate immune-metabolic networks that discriminate sepsis and COVID-19 from other acute illnesses. This study received approval for deferred consent.Ethics and dissemination The study has received research ethics committee approval from the Yorkshire and Humber Leeds West Research Ethics Committee 2 (reference 20/YH/0214; IRAS reference 250612). Submission of study results for publication will involve making available all anonymised primary and processed data on public repository sites.Trial registration number NCT04904523