Recent Submissions

  • Cohort profile: BIOVASC-late, a prospective multicentred study of imaging and blood biomarkers of carotid plaque inflammation and risk of late vascular recurrence after non-severe stroke in Ireland.

    McCabe, John Joseph; Giannotti, Nicola; McNulty, Jonathan; Collins, Sean; Coveney, Sarah; Murphy, Sean; Barry, Mary; Harbison, Joseph; Cronin, Simon; Williams, David; et al. (2020-07-19)
    Purpose: Inflammation is important in stroke. Anti-inflammatory therapy reduces vascular events in coronary patients. 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) identifies plaque inflammation-related metabolism. However, long-term prospective cohort studies investigating the association between carotid plaque inflammation, identified on 18F-FDG PET and the risk of recurrent vascular events, have not yet been undertaken in patients with stroke. Participants: The Biomarkers Imaging Vulnerable Atherosclerosis in Symptomatic Carotid disease (BIOVASC) study and Dublin Carotid Atherosclerosis Study (DUCASS) are two prospective multicentred observational cohort studies, employing near-identical methodologies, which recruited 285 patients between 2008 and 2016 with non-severe stroke/transient ischaemic attack and ipsilateral carotid stenosis (50%-99%). Patients underwent coregistered carotid 18F-FDG PET/CT angiography and phlebotomy for measurement of inflammatory cytokines. Plaque 18F-FDG-uptake is expressed as maximum standardised uptake value (SUVmax) and tissue-to-background ratio. The BIOVASC-Late study is a follow-up study (median 7 years) of patients recruited to the DUCASS/BIOVASC cohorts. Findings to date: We have reported that 18F-FDG-uptake in atherosclerotic plaques of patients with symptomatic carotid stenosis predicts early recurrent stroke, independent of luminal narrowing. The incorporation of 18F-FDG plaque uptake into a clinical prediction model also improves discrimination of early recurrent stroke, when compared with risk stratification by luminal stenosis alone. However, the relationship between 18F-FDG-uptake and late vascular events has not been investigated to date. Future plans: The primary aim of BIOVASC-Late is to investigate the association between SUVmax in symptomatic 'culprit' carotid plaque (as a marker of systemic inflammatory atherosclerosis) and the composite outcome of any late major vascular event (recurrent ischaemic stroke, coronary event or vascular death). Secondary aims are to investigate associations between: (1) SUVmax in symptomatic plaque, and individual vascular endpoints (2) SUVmax in asymptomatic contralateral carotid plaque and SUVmax in ipsilateral symptomatic plaque (3) SUVmax in asymptomatic carotid plaque and major vascular events (4) inflammatory cytokines and vascular events. Keywords: adult neurology; cardiovascular imaging; preventive medicine; stroke.
  • Competing mortality risks: predicted cardiovascular disease risk versus predicted risk of breast cancer mortality in patients receiving adjuvant chemotherapy in a single Irish center.

    Prior, Lisa; Featherstone, Hannah; O'Reilly, David; Nugent, Killian; Lim, Marvin; McCaffrey, John; Higgins, Michaela J; Kelly, Catherine M (2021-02-23)
    Background: Due to advances in care, most women diagnosed with breast cancer do not die from the disease itself. Instead, cardiovascular disease (CVD) remains the most frequent cause of death. Many breast cancer patients are older and have established CVD risk factors. They are at further risk due to exposure to anthracyclines, HER2 targeted agents, endocrine therapy and radiotherapy. In this study, we compared the 10-year predicted risk of breast cancer mortality versus that of cardiovascular (CV) morbidity/mortality in breast cancer patients receiving adjuvant chemotherapy using online predictive risk calculators. Furthermore, we evaluated the predicted outcome of CV risk factor optimisation on their overall CV risk. Methods: This was a cross sectional study. All patients with resected Stage I-III breast cancer who received adjuvant chemotherapy at our centre from September 2015 to November 2016 were identified. Data recorded included demographics, tumor characteristics, treatments and CV risk factors. To calculate predicted 10-year risk of CVD and impact of lifestyle changes, we used the JBS3 (Joint British Society) online risk calculator. To calculate the predicted 10-year risk of breast cancer mortality, we used the PREDICT calculator. Biostatistical methods included Wilcoxon signed rank test for predicted CVD risk pre and post cardiovascular risk optimization. Results: We identified 102 patients. Of this cohort, 76 patients were ≥ 50 years & 26 were < 50 years of age. The group had significant baseline cardiovascular risk factors: increased BMI (68 %, n = 70), ex-smoking (34 %, n = 35), current smoking (13 %, n = 13), hypertension (47 %, n = 47) and dyslipidemia (57 %). Of the total group, 48 % had a high (> 20 %) and 37 % had a moderate (10-20 %) 10-year predicted breast cancer mortality risk. Regarding 10-year predicted risk of CVD, 11 % and 22 % fell into the high (> 20 %) and moderate (10-20 %) risk categories, respectively. Assuming CV risk factor optimisation, there was a predicted improvement in median 10-year CV risk from 26.5 to 9.9 % (p = .005) in the high CVD risk group and from 14.0 to 6.6 % (p < .001) in the moderate CVD risk group. Conclusions: Benefits predicted with a CVD risk intervention model indicates that this should be incorporated into routine breast oncology care.
  • P084 The impact of the SARS-CoV-2 pandemic on people living with cystic fibrosis in Ireland: real-world data from the Irish cystic fibrosis registry

    Rees, H.; Babu, S.; Fletcher, G.; Kirwan, L. (Journal of Cystic Fibrosis, 2021-06-11)
    The impact of the SARS-CoV-2 pandemic on people living with cystic fibrosis (PWCF) in Ireland was investigated by comparing the utilisation of regular hospital facilities in 2020, with data collected in 2019.
  • Association of artificial turf and concussion in competitive contact sports: a systematic review and meta-analysis.

    O' Leary, Frank; Acampora, Nic; Hand, Fiona; O' Donovan, James (2020-05-26)
    Objective: To determine the incidence of head injuries and concussion in contact sports, comparing natural grass with artificial turf surfaces. Design: Systematic review and meta-analysis via the RevMan V.5.3 software. Eligibility criteria for selecting studies: All studies describing competitive contact sports played on both natural grass and artificial turf. The primary outcome measured was occurrence of head injury and concussion. Data sources: The databases include PubMed, Embase, Cochrane, Medline and Sport Discus. The last search took place on 23 May 2019. The Newcastle-Ottawa Quality Assessment Scale evaluated the methodological quality of the selected studies with a funnel plot designed to determine publication bias. Study screening and data extraction were performed by two independent reviewers. Results: Initial screening generated 42 publications, with 12 meeting criteria for inclusion. Eight studies described concussion only. The rate ratio (RR) of head injury and concussion was less on artificial turf compared with natural grass (RR=0.89, 95% CI 0.77 to 1.04) as was the rate ratio of concussion only (RR=0.72, 95% CI 0.58 to 0.89). Conclusion: Analysis of published data demonstrates a decreased incidence of head injury and concussion when contact sports are played on artificial turf. This difference was most marked for sports such as rugby and American football. However, artificial turf has no association with the incidence of head injury or concussion while playing soccer. Keywords: concussion; contact sports; environment; head; injuries.
  • Current concepts and outcomes in cemented femoral stem design and cementation techniques: the argument for a new classification system.

    Cassar-Gheiti, Adrian J; McColgan, Rosie; Kelly, Martin; Cassar-Gheiti, Theresa M; Kenny, Paddy; Murphy, Colin G (2020-04-02)
    Cemented implant fixation design principles have evolved since the 1950s, and various femoral stem designs are currently in use to provide a stable construct between the implant-cement and cement-bone interfaces. Cemented stems have classically been classified into two broad categories: taper slip or force closed, and composite beams or shaped closed designs. While these simplifications are acceptable general categories, there are other important surgical details that need to be taken into consideration such as different broaching techniques, cementing techniques and mantle thickness. With the evolution of cemented implants, the introduction of newer implants which have hybrid properties, and the use of different broaching techniques, the classification of a very heterogenous group of implants into simple binary categories becomes increasingly difficult. A more comprehensive classification system would aid in comparison of results and better understanding of the implants' biomechanics. We review these differing stem designs, their respective cementing techniques and geometries. We then propose a simple four-part classification system and summarize the long-term outcomes and international registry data for each respective type of cemented prosthesis. Cite this article: EFORT Open Rev 2020;5:241-252. DOI: 10.1302/2058-5241.5.190034.
  • A model for occupational stress amongst paediatric and adult critical care staff during COVID-19 pandemic.

    Feeley, T; Ffrench-O'Carroll, R; Tan, M H; Magner, C; L'Estrange, K; O'Rathallaigh, E; Whelan, S; Lyons, B; O'Connor, E (2021-02-25)
    Purpose: The coronavirus 2019 pandemic has placed all intensive care unit (ICU) staff at increased risk of psychological distress. To date, measurement of this distress has largely been by means of validated assessment tools. We believe that qualitative data may provide a richer view of staff experiences during this pandemic. Methods: We conducted a cross-sectional, observational study using online and written questionnaires to all ICU staff which consisted of validated tools to measure psychological distress (quantitative findings) and open-ended questions with free-text boxes (qualitative findings). Here, we report our qualitative findings. We asked four questions to explore causes of stress, need for supports and barriers to accessing supports. A conventional content analysis was undertaken. Results: In total, 269 of the 408 respondents (65.9%) gave at least one response to a free-text question. Seven overarching themes were found, which contribute to our proposed model for occupational stress amongst critical care staff. The work environment played an important role in influencing the perceived psychological impact on healthcare workers. Extra-organisational factors, which we termed the "home-work interface" and uncertainty about the future, manifested as anticipatory anxiety, had a proportionally larger influence on worker well-being than would be expected in non-pandemic conditions. Conclusion: Our findings have important implications for appropriate allocation of resources and ensuring well-being of the ICU multidisciplinary team for this and future pandemics. Keywords: Anticipatory anxiety; COVID-19; Critical care staff; Home-work interface; Occupational stress; Pandemic; Work intensification.
  • Clinical experience with the AKT1 inhibitor miransertib in two children with PIK3CA-related overgrowth syndrome.

    Forde, Karina; Resta, Nicoletta; Ranieri, Carlotta; Rea, David; Kubassova, Olga; Hinton, Mark; Andrews, Katrina A; Semple, Robert; Irvine, Alan D; Dvorakova, Veronika (2021-02-27)
    Background: PIK3CA-related overgrowth spectrum (PROS) refers to a group of rare disorders, caused by somatic activating mutations in PIK3CA, resulting in abnormal PI3K-AKT-mTOR pathway signalling. Significant associated morbidity is frequently observed, and approved treatments are lacking. Miransertib (ARQ 092) is a novel, orally available, selective pan-AKT inhibitor with proven in vitro efficacy. Following recent results of the use of AKT inhibitors in Proteus syndrome (PS) and AKT-mutant cancers, we investigated its therapeutic use in two patients with severe PROS who had exhausted conventional treatment methods. Results: Two patients, one with CLOVES variant (P1) and one with facial infiltrating lipomatosis and hemimegalencephaly (P2), were commenced on miransertib treatment on a compassionate use basis. In patient one, intra-abdominal and paraspinal overgrowth had resulted in respiratory compromise, obstructive uropathy, dysfunctional seating and lying postures, and chronic pain. In patient two, hemifacial overgrowth and hemimegalencephaly had caused difficulties with articulation and oral function, and refractory epilepsy. Miransertib treatment was continued for a median duration of 22 months (range 22-28). In patient one, alleviation of respiratory compromise was observed and functionally, seating and lying postures improved. Serial volumetric MRI analysis revealed 15% reduction in calculated volumes of fatty overgrowth between treatment commencement and end. In patient two, reduction in seizure burden and improved parent-reported quality of life measures were reported. Treatment was discontinued in both patients due to lack of sustained response, and poor compliance in year two of treatment (P2). No significant toxicities were reported. Conclusion: We report the first paediatric case series of the use of miransertib in two children with PROS. Objective clinical response was observed in patient one, and improvement in key qualitative outcomes was reported in patient two. Treatment was well tolerated with no significant toxicities reported. This case series highlights the potential therapeutic utility of miransertib in selected paediatric patients with severe PROS, and further demonstrates the potential for re-purposing targeted therapies for the treatment of rare diseases. An open label, Phase 1/2 study of miransertib in children with PROS and PS is underway to more accurately assess the efficacy of miransertib in the treatment of PROS disorder (NCT03094832).
  • Rare chromosomal abnormalities: Can they be identified using conventional first trimester combined screening methods?

    Kane, Daniel; D'Alton, Mary E; Malone, Fergal D (2021-02-27)
    Objective: To evaluate the performance of first trimester combined screening for the detection of rare chromosomal abnormalities, other than Trisomies 21, 18 or 13 or 45 × . Study design: A database containing 36,254 pregnancies was analyzed. These patients were recruited at 15 US centers and included singleton pregnancies from 10 3/7-13 6/7 weeks. All patients had a nuchal translucency (NT) scan and those without a cystic hygroma (N = 36,120) underwent a combined first trimester screening test ('FTS' - NT, PAPP-A and fbHCG). A risk cut-off of 1:300, which was used for defining high risk for Trisomy 21, was also used to evaluate the detection rate for rare chromosomal abnormalities using the combined FTS test. Results: 36,120 patients underwent combined FTS. Of these, 123 were found to have one of the following chromosomal abnormalities: Trisomy 21, Trisomy 18, Trisomy 13 or Turner syndrome. This study focuses on 40 additional patients who were found to have 'other' rare chromosomal abnormalities such as triploidy, structural chromosomal abnormalities, sex chromosome abnormalities or unusual chromosomal abnormalities (e.g. 47XX + 16), giving an incidence of 1.1 in 1000 for these rare chromosomal abnormalities. Of these 40 pregnancies, only 2 (5%) had an NT measurement of ≥3 mm. The detection rate for combined FTS, using a risk cut-off of ≥1:300, was 35 % (14 of 40 cases). Therefore, 65 % of cases of rarer fetal chromosomal abnormalities had a 'normal' combined FTS risk (<1:300) and 95 % had a 'normal' NT (<3 mm). Conclusion: Traditional FTS methods are unable to identify the vast majority of rare chromosomal abnormalities. Our data do not support the potential detection of rare fetal chromosomal abnormalities as a reason to favour nuchal translucency-based first trimester screening over NIPT.
  • Incidence and risk factors of delirium in surgical intensive care unit.

    Ali, Muhammad Asghar; Hashmi, Madiha; Ahmed, Waqas; Raza, Syed Amir; Khan, Muhammad Faisal; Salim, Bushra (2021-03-03)
    Background: To evaluate the incidence and modifiable risk factors of delirium in surgical intensive care unit (SICU) of tertiary care hospital in a low-income and middle-income country. Methods: We conducted a single cohort observational study in patients over 18 years of age who were admitted to the SICU for >24 hours in Aga Khan University Hospital from January to December 2016. Patients who had pre-existing cognitive dysfunction were excluded. Intensive Care Delirium Screening Checklist was used to assess delirium. Incidence of delirium was computed, and univariate and multivariable analyses were performed to observe the relationship between outcome and associated factors. Results: The average patient age was 43.29±17.38 and body mass index was 26.25±3.57 kg/m2. Delirium was observed in 19 of 87 patients with an incidence rate of 21.8%. Multivariable analysis showed chronic obstructive pulmonary disease, pain score >4 and hypernatremia were strong predictors of delirium. Midazolam (adjusted OR (aOR)=7.37; 95% CI 2.04 to 26.61) and propofol exposure (aOR=7.02; 95% CI 1.92 to 25.76) were the strongest independent predictors of delirium while analgesic exposures were not statistically significant to predict delirium in multivariable analysis. Conclusion: Delirium is a significant risk factor of poor outcome in SICU. There was an independent association between pain, sedation, COPD, hypernatremia and fever in developing delirium.
  • Impact of COVID-19 on the pain and disability of patients with adult spinal deformity.

    Kieser, D C; Bourghli, A; Larrieu, D; Cawley, D T; Hayashi, K; Jakinapally, S; Pizones, J; Boissiere, L; Obeid, I (2021-03-02)
    Purpose: To evaluate the pain and functional effect of the COVID-19 pandemic on patients with ASD reflected by their response to SRS-22, ODI, and SF-36 questionnaires. Methods: Patients who had stable pain and functional outcome scores over the preceding 2 years were enrolled in a local prospectively collected adult spinal deformity (ASD) database. A reanalysis of their SRS22, ODI and SF-36 data 14 days into confinement were compared to their last pre-confinement scores. Results: 89 patients were included in this study (average age 60.7 years, 91% female) with an average time from last FU until confinement of 9.6 months. The ODI total score worsened by 5 points post-confinement with no difference seen in personal care, walking and social life. In contrast, the SRS-22 score showed small improvements in function/activity and satisfaction, but no significant differences for the other domains. Similarly, the SF-36 showed small improvements in physical function, physical and emotional role, vitality and PCS. Conclusion: The global COVID-19 pandemic and ensuing confinement had variable overall effects on ASD patients, without the expected marked worsening. In addition, this study illustrates that the SRS-22 questionnaire is less influenced by environmental and psychological factors than the ODI supporting its objectivity and accuracy in the evaluation of the QoL of ASD patients.
  • Progressive resistance training in a post-acute, older, inpatient setting: A randomised controlled feasibility study.

    Coleman, Sinéad A; Cunningham, Conal J; Murphy, Niamh; Feaheny, Jean; Robinson, David; Lannon, Rosaleen; McCarroll, Kevin; Casey, Miriam; Harbison, Joseph; Horgan, N Frances (2021-03-01)
    Objectives: Progressive resistance training can successfully target functional decline in healthy older community-dwelling adults. There are concerns about the safety and acceptance of its use in frail older populations. The aim of this study was to evaluate the feasibility of using progressive resistance training in an older, post-acute, inpatient setting. Methods: A randomised controlled feasibility study was conducted. Appropriate older inpatients undergoing post-acute rehabilitation were recruited. Feasibility measures examined were safety, recruitment, outcome measurement, adherence and retention rates and satisfaction. A range of clinical measures were used to capture changes in body structure and function, activity and participation. Assessments were performed on admission to the study and six weeks later. Results: A sample of 33 patients were included and randomised to the treatment group (n=16) or the control group (n=17). There were no serious adverse events, adherence rates were 63% and retention rates were 82%. While both groups improved between time 1 and 2, there were no significant differences in clinical measures between the groups. Conclusion: Progressive resistance training is a safe and acceptable intervention for use with this population. Further work on the effectiveness of progressive resistance training in this setting is now required.
  • Dynamic left ventricular outflow tract gradient resulting from Takotsubo cardiomyopathy ameliorated by intra-aortic balloon pump counterpulsation: a case report.

    O'Brien, Jim; Mahony, Stephen; Byrne, Roger J; Byrne, Robert A (2021-03-03)
    Background: Takotsubo cardiomyopathy is a variant of acute coronary syndrome with characteristic acute left ventricular apical ballooning. Uncommonly, there can be associated left ventricular outflow tract (LVOT) obstruction causing cardiogenic shock refractory to inotropic support. The use of afterload-reducing mechanical support such as intra-aortic balloon pump (IABP) counterpulsation is not routinely employed in instances of this kind. Case summary: In our case report, we describe a 66-year-old female with acute Takotsubo cardiomyopathy and associated LVOT obstruction which failed to respond to high-dose dobutamine and whose clinical trajectory was worsened by fast atrial fibrillation with rapid ventricular response. Within 24 h of admission, the patient had an IABP placed which rapidly improved her haemodynamics. Two days later, IABP was removed and within 6 days of admission, apical ballooning and LVOT obstruction had fully recovered. Conclusion: We recommend early use of mechanical support with IABP counterpulsation to expedite recovery in patients with acute Takotsubo cardiomyopathy with associated LVOT obstruction.
  • Neonatal Screening in Europe Revisited: An ISNS Perspective on the Current State and Developments Since 2010.

    Loeber, J Gerard; Platis, Dimitris; Zetterström, Rolf H; Almashanu, Shlomo; Boemer, François; Bonham, James R; Borde, Patricia; Brincat, Ian; Cheillan, David; Dekkers, Eugenie; et al. (2021-03-05)
    Neonatal screening (NBS) was initiated in Europe during the 1960s with the screening for phenylketonuria. The panel of screened disorders ("conditions") then gradually expanded, with a boost in the late 1990s with the introduction of tandem mass spectrometry (MS/MS), making it possible to screen for 40-50 conditions using a single blood spot. The most recent additions to screening programmes (screening for cystic fibrosis, severe combined immunodeficiency and spinal muscular atrophy) were assisted by or realised through the introduction of molecular technologies. For this survey, we collected data from 51 European countries. We report the developments between 2010 and 2020 and highlight the achievements reached with the progress made in this period. We also identify areas where further progress can be made, mainly by exchanging knowledge and learning from experiences in neighbouring countries. Between 2010 and 2020, most NBS programmes in geographical Europe matured considerably, both in terms of methodology (modernised) and with regard to the panel of conditions screened (expanded). These developments indicate that more collaboration in Europe through European organisations is gaining momentum. We can only accomplish the timely detection of newborn infants potentially suffering from one of the many rare diseases and take appropriate action by working together.
  • Novel case of a scleroderma-mimicking syndrome associated with gastrointestinal stromal tumour.

    Butt, Zaran Ahmad; Ng, Wan Lin; Osman, Kamal; Howard, Donough (2021-03-04)
    We report a case of a 54-year-old man who developed an atypical systemic syndrome involving Raynaud's phenomenon, pulmonary fibrosis and skin thickening. These features were initially suggestive of newly diagnosed scleroderma. However, he displayed atypical clinical features of same, antinuclear antibody was negative and symptoms were refractory to various immunosuppressive therapies. CT imaging revealed a gastric mass, which later proved to be a gastrointestinal stromal tumour (GIST). Resection of the GIST leads to minimal symptomatic improvement. Surveillance imaging 1 year later revealed metastatic deposits. He was subsequently initiated on imatinib therapy, which led to a rapid improvement in fibrotic changes within weeks. While there have been previous descriptions of paraneoplastic fibrotic disorders, this is the first description of a scleroderma mimic in the setting of a GIST. It highlights an important potential overlap in the pathogenesis of these disease processes and the potential efficacy of tyrosine kinase inhibitors for scleroderma-like fibrotic disorders.
  • Cardiovascular magnetic resonance predictors of heart failure in hypertrophic cardiomyopathy: the role of myocardial replacement fibrosis and the microcirculation.

    Raphael, Claire E; Mitchell, Frances; Kanaganayagam, Gajen Sunthar; Liew, Alphonsus C; Di Pietro, Elisa; Vieira, Miguel Silva; Kanapeckaite, Lina; Newsome, Simon; Gregson, John; Owen, Ruth; et al. (2021-03-08)
    Introduction: Heart failure (HF) in hypertrophic cardiomyopathy (HCM) is associated with high morbidity and mortality. Predictors of HF, in particular the role of myocardial fibrosis and microvascular ischemia remain unclear. We assessed the predictive value of cardiovascular magnetic resonance (CMR) for development of HF in HCM in an observational cohort study. Methods: Serial patients with HCM underwent CMR, including adenosine first-pass perfusion, left atrial (LA) and left ventricular (LV) volumes indexed to body surface area (i) and late gadolinium enhancement (%LGE- as a % of total myocardial mass). We used a composite endpoint of HF death, cardiac transplantation, and progression to NYHA class III/IV. Results: A total of 543 patients with HCM underwent CMR, of whom 94 met the composite endpoint at baseline. The remaining 449 patients were followed for a median of 5.6 years. Thirty nine patients (8.7%) reached the composite endpoint of HF death (n = 7), cardiac transplantation (n = 2) and progression to NYHA class III/IV (n = 20). The annual incidence of HF was 2.0 per 100 person-years, 95% CI (1.6-2.6). Age, previous non-sustained ventricular tachycardia, LV end-systolic volume indexed to body surface area (LVESVI), LA volume index ; LV ejection fraction, %LGE and presence of mitral regurgitation were significant univariable predictors of HF, with LVESVI (Hazard ratio (HR) 1.44, 95% confidence interval (95% CI) 1.16-1.78, p = 0.001), %LGE per 10% (HR 1.44, 95%CI 1.14-1.82, p = 0.002) age (HR 1.37, 95% CI 1.06-1.77, p = 0.02) and mitral regurgitation (HR 2.6, p = 0.02) remaining independently predictive on multivariable analysis. The presence or extent of inducible perfusion defect assessed using a visual score did not predict outcome (p = 0.16, p = 0.27 respectively). Discussion: The annual incidence of HF in a contemporary ambulatory HCM population undergoing CMR is low. Myocardial fibrosis and LVESVI are strongly predictive of future HF, however CMR visual assessment of myocardial perfusion was not.
  • Development of a Novel Weighted Ranking Method for Immunohistochemical Quantification of a Heterogeneously Expressed Protein in Gastro-Esophageal Cancers.

    Richards, Cathy E; Sheehan, Katherine M; Kay, Elaine W; Hedner, Charlotta; Borg, David; Fay, Joanna; O'Grady, Anthony; Hill, Arnold D K; Jirström, Karin; Hopkins, Ann M (2021-03-13)
    High expression of Junctional Adhesion Molecule-A (JAM-A) has been linked with poor prognosis in several cancers, including breast cancers overexpressing the human epidermal growth factor receptor-2 (HER2). Furthermore, JAM-A expression has been linked with regulating that of HER2, and associated with the development of resistance to HER2-targeted therapies in breast cancer patients. The purpose of this study was to establish a potential relationship between JAM-A and HER2 in HER2-overexpressing gastro-esophageal (GE) cancers. Interrogation of gene expression datasets revealed that high JAM-A mRNA expression was associated with poorer survival in HER2-positive gastric cancer patients. However, high intra-tumoral heterogeneity of JAM-A protein expression was noted upon immunohistochemical scoring of a GE cancer tissue microarray (TMA), precluding a simple confirmation of any relationship between JAM-A and HER2 at protein level. However, in a test-set of 25 full-face GE cancer tissue sections, a novel weighted ranking system proved effective in capturing JAM-A intra-tumoral heterogeneity and confirming statistically significant correlations between JAM-A/HER2 expression. Given the growing importance of immunohistochemistry in stratifying cancer patients for the receipt of new targeted therapies, this may sound a cautionary note against over-relying on cancer TMAs in biomarker discovery studies of heterogeneously expressed proteins. It also highlights a timely need to develop validated mechanisms of capturing intra-tumoral heterogeneity to aid in future biomarker/therapeutic target development for the benefit of cancer patients.
  • Visceral Obesity, Metabolic Syndrome, and Esophageal Adenocarcinoma.

    Elliott, Jessie A; Reynolds, John V (2021-03-12)
    Esophageal adenocarcinoma (EAC) represents an exemplar of obesity-associated carcinogenesis, with a progressive increase in EAC risk with increased body mass index. In this context, there is increased focus on visceral adipose tissue and associated metabolic dysfunction, including hypertension, diabetes mellitus and hyperlipidemia, or combinations of these in the metabolic syndrome. Visceral obesity (VO) may promote EAC via both directly impacting on gastro-esophageal reflux disease and Barrett's esophagus, as well as via reflux-independent effects, involving adipokines, growth factors, insulin resistance, and the microbiome. In this review these pathways are explored, including the impact of VO on the tumor microenvironment, and on cancer outcomes. The current evidence-based literature regarding the role of dietary, lifestyle, pharmacologic and surgical interventions to modulate the risk of EAC is explored.
  • Inter-clinician delineation variation for a new highly-conformal flank target volume in children with renal tumors: A SIOP-Renal Tumor Study Group international multicenter exercise.

    Mul, Joeri; Melchior, Patrick; Seravalli, Enrica; Saunders, Daniel; Bolle, Stephanie; Cameron, Alison L; Gurtner, Kristin; Harrabi, Semi; Lassen-Ramshad, Yasmin; Lavan, Naomi; et al. (2021-03-11)
    Background and purpose: Recently, the SIOP-RTSG developed a highly-conformal flank target volume definition for children with renal tumors. The aims of this study were to evaluate the inter-clinician delineation variation of this new target volume definition in an international multicenter setting and to explore the necessity of quality assurance. Materials and methods: Six pediatric renal cancer cases were transferred to ten radiation oncologists from seven European countries ('participants'). These participants delineated the pre- and postoperative Gross Tumor Volume (GTVpre/post), and Clinical Target Volume (CTV) during two test phases (case 1-2 and 3-4), followed by guideline refinement and a quality assurance phase (case 5-6). Reference target volumes (TVref) were established by three experienced radiation oncologists. The Dice Similarity Coefficient between the reference and participants (DSCref/part) was calculated per case. Delineations of case 5-6 were graded by four independent reviewers as 'per protocol' (0-4 mm), 'minor deviation' (5-9 mm) or 'major deviation' (≥10 mm) from the delineation guideline using 18 standardized criteria. Also, a major deviation resulting in underestimation of the CTVref was regarded as an unacceptable variation. Results: A total of 57/60 delineation sets were completed. The median DSCref/part for the CTV was 0.55 without improvement after sequential cases (case 3-4 vs. case 5-6: p = 0.15). For case 5-6, a major deviation was found for 5/18, 12/17, 18/18 and 4/9 collected delineations of the GTVpre, GTVpost, CTV-T and CTV-N, respectively. An unacceptable variation from the CTVref was found for 7/9 participants for case 5 and 6/9 participants for case 6. Conclusion: This international multicenter delineation exercise demonstrates that the new consensus for highly-conformal postoperative flank target volume delineation leads to geometrical variation among participants. Moreover, standardized review showed an unacceptable delineation variation in the majority of the participants. These findings strongly suggest the need for additional training and centralized pre-treatment review when this target volume delineation approach is implemented on a larger scale.
  • The Iron Chelator Desferrioxamine Increases the Efficacy of Bedaquiline in Primary Human Macrophages Infected with BCG.

    Cahill, Christina; O'Connell, Fiona; Gogan, Karl M; Cox, Donal J; Basdeo, Sharee A; O'Sullivan, Jacintha; Gordon, Stephen V; Keane, Joseph; Phelan, James J (2021-03-13)
    For over 50 years, patients with drug-sensitive and drug-resistant tuberculosis have undergone long, arduous, and complex treatment processes with several antimicrobials. With the prevalence of drug-resistant strains on the rise and new therapies for tuberculosis urgently required, we assessed whether manipulating iron levels in macrophages infected with mycobacteria offered some insight into improving current antimicrobials that are used to treat drug-resistant tuberculosis. We investigated if the iron chelator, desferrioxamine, can support the function of human macrophages treated with an array of second-line antimicrobials, including moxifloxacin, bedaquiline, amikacin, clofazimine, linezolid and cycloserine. Primary human monocyte-derived macrophages were infected with Bacillus Calmette-Guérin (BCG), which is pyrazinamide-resistant, and concomitantly treated for 5 days with desferrioxamine in combination with each one of the second-line tuberculosis antimicrobials. Our data indicate that desferrioxamine used as an adjunctive treatment to bedaquiline significantly reduced the bacterial load in human macrophages infected with BCG. Our findings also reveal a link between enhanced bactericidal activity and increases in specific cytokines, as the addition of desferrioxamine increased levels of IFN-γ, IL-6, and IL-1β in BCG-infected human monocyte-derived macrophages (hMDMs) treated with bedaquiline. These results provide insight, and an in vitro proof-of-concept, that iron chelators may prove an effective adjunctive therapy in combination with current tuberculosis antimicrobials.

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