A stakeholder analysis to prepare for real-world evaluation of integrating artificial intelligent algorithms into breast screening (PREP-AIR study): a qualitative study using the WHO guide.

BACKGROUND: The national breast screening programme in the United Kingdom is under pressure due to workforce shortages and having been paused during the COVID-19 pandemic. Artificial intelligence has the potential to transform how healthcare is delivered by improving care processes and patient outcomes. Research on the clinical and organisational benefits of artificial intelligence is still at an early stage, and numerous concerns have been raised around its implications, including patient safety, acceptance, and accountability for decisions. Reforming the breast screening programme to include artificial intelligence is a complex endeavour because numerous stakeholders influence it. Therefore, a stakeholder analysis was conducted to identify relevant stakeholders, explore their views on the proposed reform (i.e., integrating artificial intelligence algorithms into the Scottish National Breast Screening Service for breast cancer detection) and develop strategies for managing 'important' stakeholders. METHODS: A qualitative study (i.e., focus groups and interviews, March-November 2021) was conducted using the stakeholder analysis guide provided by the World Health Organisation and involving three Scottish health boards: NHS Greater Glasgow & Clyde, NHS Grampian and NHS Lothian. The objectives included: (A) Identify possible stakeholders (B) Explore stakeholders' perspectives and describe their characteristics (C) Prioritise stakeholders in terms of importance and (D) Develop strategies to manage 'important' stakeholders. Seven stakeholder characteristics were assessed: their knowledge of the targeted reform, position, interest, alliances, resources, power and leadership. RESULTS: Thirty-two participants took part from 14 (out of 17 identified) sub-groups of stakeholders. While they were generally supportive of using artificial intelligence in breast screening programmes, some concerns were raised. Stakeholder knowledge, influence and interests in the reform varied. Key advantages mentioned include service efficiency, quicker results and reduced work pressure. Disadvantages included overdiagnosis or misdiagnosis of cancer, inequalities in detection and the self-learning capacity of the algorithms. Five strategies (with considerations suggested by stakeholders) were developed to maintain and improve the support of 'important' stakeholders. CONCLUSIONS: Health services worldwide face similar challenges of workforce issues to provide patient care. The findings of this study will help others to learn from Scottish experiences and provide guidance to conduct similar studies targeting healthcare reform. STUDY REGISTRATION: researchregistry6579, date of registration: 16/02/2021.

Autoimmune conditions and gastric cancer risk in a population-based study in the United Kingdom.

BACKGROUND: Although overall incidence of gastric cancer is decreasing, incidence has been increasing among young people in some Western countries. This trend may stem from the increase in autoimmune conditions. METHODS: A nested case-control study of gastric cancer in UK Clinical Practice Research Datalink. Up to ten cancer-free controls were matched to cases by age and sex. Conditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) for associations between analyzable autoimmune conditions (n = 34) and gastric cancer with Bonferroni correction. We evaluated associations between pernicious anaemia and other conditions. A meta-analysis of published prospective studies and ours was conducted. RESULTS: Among 6586 cases (1156 cardia, 1104 non-cardia, and 4334 overlapping/unspecified tumours) and 65,687 controls, any autoimmune condition was associated with gastric cancer (OR = 1.10; 95% CI: 1.01-1.20). Individuals with pernicious anaemia had higher gastric cancer risk than those without (OR = 2.75; 2.19-3.44). Among controls, pernicious anaemia was associated with seven other conditions (OR range: 2.21-29.80). The pooled estimate for any autoimmune condition and gastric cancer was 1.17 (1.14-1.21; n = 47,126 cases). CONCLUSION: Autoimmunity increases gastric cancer risk. Some autoimmune conditions may be indirectly associated with gastric cancer via pernicious anaemia. Pernicious anaemia could be considered for gastric cancer risk stratification and screening.

Service and clinical impacts of reader bias in breast cancer screening: a retrospective study.

OBJECTIVES: To determine factors influencing reader agreement in breast screening and investigate the relationship between agreement level and patient outcomes. METHODS: Reader pair agreement for 83 265 sets of mammograms from the Scottish Breast Screening service (2015-2020) was evaluated using Cohen's kappa statistic. Each mammography examination was read by two readers, per routine screening practice, with the second initially blinded but able to choose to view the first reader's opinion. If the two readers disagreed, a third reader arbitrated. Variation in reader agreement was examined by: whether the reader acted as the first or second reader, reader experience, and recall, cancer detection and arbitration recall rate. RESULTS: Readers' opinions varied by whether they acted as the first or second reader. Furthermore, reader 2 was more likely to agree with reader 1 if reader 1 was more experienced than they were, and less likely to agree if they themselves were more experienced than reader 1 (P < .001). Agreement was not significantly associated with cancer detection rate, overall recall rate or arbitration recall rates (P > .05). Lower agreement between readers led to a higher arbiter workload (P < .001). CONCLUSIONS: In mammography screening, the second reader's opinion is influenced by the first reader's opinion, with the degree of influence dependent on the readers' relative experience levels. ADVANCES IN KNOWLEDGE: While less-experienced readers relied on their more experienced reading partner, no adverse impact on service outcomes was observed. Allowing access to the first reader's opinion may benefit newly qualified readers, but reduces independent evaluation, which may lower cancer detection rates.

The JAK2V617F mutation and the role of therapeutic agents in alleviating myeloproliferative neoplasm symptom burden.

Alleviating symptom burden in patients with myeloproliferative neoplasms (MPNs) is imperative to achieving optimal management. Research remains to elucidate the relationship between the JAK2V617F (Janus kinase 2) mutation present in many MPN patients, and the symptomatology they experience. This retrospective study analysed data collected from MPN patients included in the Myeloproliferative Neoplasms: An In-depth Case-Control (MOSAICC) pilot study. The MPN Symptom Assessment Form was administered, and median symptom scores were compared between JAK2V617F-positive and JAK2V617F-negative groups. Multivariate logistic regression analysis adjusted for confounding variables. Overall, 106 MPN patients participated: 65.1% were JAK2V617F positive, 30.2% were JAK2V617F negative and 4.7% had an unknown status. Multivariate analysis revealed a low symptom burden for early satiety (p < 0.01), dizziness (p < 0.05), cough (p < 0.05) and bone pain (p < 0.01) in those receiving venesection alone. Interferon alpha was significantly associated (p < 0.05) with severe burden for 16 of the 27 symptoms. JAK2V617F-positive females experienced a greater symptom burden than JAK2V617F-positive males. There was no discernible relationship between the JAK2V617F mutation and symptom burden in MPN patients, unlike the therapeutic agents investigated. Larger studies are required to validate these results and identify mechanisms of symptom development and control in MPN patients.

Impact of Different Mammography Systems on Artificial Intelligence Performance in Breast Cancer Screening.

Artificial intelligence (AI) tools may assist breast screening mammography programs, but limited evidence supports their generalizability to new settings. This retrospective study used a 3-year dataset (April 1, 2016-March 31, 2019) from a U.K. regional screening program. The performance of a commercially available breast screening AI algorithm was assessed with a prespecified and site-specific decision threshold to evaluate whether its performance was transferable to a new clinical site. The dataset consisted of women (aged approximately 50-70 years) who attended routine screening, excluding self-referrals, those with complex physical requirements, those who had undergone a previous mastectomy, and those who underwent screening that had technical recalls or did not have the four standard image views. In total, 55 916 screening attendees (mean age, 60 years ± 6 [SD]) met the inclusion criteria. The prespecified threshold resulted in high recall rates (48.3%, 21 929 of 45 444), which reduced to 13.0% (5896 of 45 444) following threshold calibration, closer to the observed service level (5.0%, 2774 of 55 916). Recall rates also increased approximately threefold following a software upgrade on the mammography equipment, requiring per-software version thresholds. Using software-specific thresholds, the AI algorithm would have recalled 277 of 303 (91.4%) screen-detected cancers and 47 of 138 (34.1%) interval cancers. AI performance and thresholds should be validated for new clinical settings before deployment, while quality assurance systems should monitor AI performance for consistency. Keywords: Breast, Screening, Mammography, Computer Applications-Detection/Diagnosis, Neoplasms-Primary, Technology Assessment Supplemental material is available for this article. © RSNA, 2023.

AI in breast screening mammography: breast screening readers' perspectives.

OBJECTIVES: This study surveyed the views of breast screening readers in the UK on how to incorporate Artificial Intelligence (AI) technology into breast screening mammography. METHODS: An online questionnaire was circulated to the UK breast screening readers. Questions included their degree of approval of four AI implementation scenarios: AI as triage, AI as a companion reader/reader aid, AI replacing one of the initial two readers, and AI replacing all readers. They were also asked to rank five AI representation options (discrete opinion; mammographic scoring; percentage score with 100% indicating malignancy; region of suspicion; heat map) and indicate which evidence they considered necessary to support the implementation of AI into their practice among six options offered. RESULTS: The survey had 87 nationally accredited respondents across the UK; 73 completed the survey in full. Respondents approved of AI replacing one of the initial two human readers and objected to AI replacing all human readers. Participants were divided on AI as triage and AI as a reader companion. A region of suspicion superimposed on the image was the preferred AI representation option. Most screen readers considered national guidelines (77%), studies using a nationally representative dataset (65%) and independent prospective studies (60%) as essential evidence. Participants' free-text comments highlighted concerns and the need for additional validation. CONCLUSIONS: Overall, screen readers supported the introduction of AI as a partial replacement of human readers and preferred a graphical indication of the suspected tumour area, with further evidence and national guidelines considered crucial prior to implementation.

eQTL Set-Based Association Analysis Identifies Novel Susceptibility Loci for Barrett Esophagus and Esophageal Adenocarcinoma.

BACKGROUND: Over 20 susceptibility single-nucleotide polymorphisms (SNP) have been identified for esophageal adenocarcinoma (EAC) and its precursor, Barrett esophagus (BE), explaining a small portion of heritability. METHODS: Using genetic data from 4,323 BE and 4,116 EAC patients aggregated by international consortia including the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON), we conducted a comprehensive transcriptome-wide association study (TWAS) for BE/EAC, leveraging Genotype Tissue Expression (GTEx) gene-expression data from six tissue types of plausible relevance to EAC etiology: mucosa and muscularis from the esophagus, gastroesophageal (GE) junction, stomach, whole blood, and visceral adipose. Two analytical approaches were taken: standard TWAS using the predicted gene expression from local expression quantitative trait loci (eQTL), and set-based SKAT association using selected eQTLs that predict the gene expression. RESULTS: Although the standard approach did not identify significant signals, the eQTL set-based approach identified eight novel associations, three of which were validated in independent external data (eQTL SNP sets for EXOC3, ZNF641, and HSP90AA1). CONCLUSIONS: This study identified novel genetic susceptibility loci for EAC and BE using an eQTL set-based genetic association approach. IMPACT: This study expanded the pool of genetic susceptibility loci for EAC and BE, suggesting the potential of the eQTL set-based genetic association approach as an alternative method for TWAS analysis.

Supporting someone with cancer during the COVID-19 pandemic: A mixed methods analysis of cancer carer's health, Quality of Life and need for support.

The COVID-19 pandemic has greatly affected the delivery of cancer care. Due to social restrictions and reductions in health service contact, it is expected that the burdens experienced by informal carers have risen. This study provides an analysis of cancer carer's experiences and needs as a consequence of the pandemic. An online mixed method design was used. The survey included open-ended responses to explore carer's experiences and measures of health status (EQ-5D-5L), Quality of Life (WHOQoL-BREF) and impact of COVID-19. Open-ended responses were analysed thematically according to Miles and Huberman techniques and quantitative data were analysed descriptively. One hundred and ninety-six cancer carers participated in the online survey. Mixed method analysis demonstrated that carers were experiencing major difficulties. Of these n = 142/72.4% experienced challenges related to anxiety and depression; 35.2% rated these problems as slight with 25% rating these as moderate and 11.2% as severe. Qualitative analysis identified significant and sustained negative impacts of the pandemic on psychological health, social isolation, finance and access to health services with carers requiring urgent information and support. Carer's challenges have deepened throughout the COVID-19 pandemic. There is an urgent need to develop innovative ways to provide support for carers to provide palliative and supportive care at home now and during recovery from the pandemic. Due to the need for infection control meaningful development and integration of urgent digital technology might be the most feasible solution.

Patient's perspectives of living with a precancerous condition: Monoclonal gammopathy of undetermined significance (MGUS).

PURPOSE: The aim of this study was to investigate patient experiences of living with monoclonal gammopathy of undetermined significance (MGUS). Living with a premalignant condition such as MGUS may elicit negative psychosocial effects including increased anxiety and fear of progression to cancer. To date, no study utilising qualitative methodology has explored the lived experiences of MGUS patients. METHODS: Data was collected via two focus groups and six telephone interviews. MGUS patients (n=14) were recruited via nurse-led haematology telephone-clinics in Northern Ireland. Interviews were transcribed verbatim and the data subjected to thematic analysis. OUTCOME: Thematic analysis identified 3 overarching themes; (1) The psychosocial impact of an MGUS diagnosis, (2) Knowledge of MGUS and (3) Experiences of MGUS health services. Patients with MGUS reported experiencing poor psychological adjustment to their condition particularly at the point of diagnosis and approaching follow-up appointments. Feelings of isolation, poor information-provision, increased uncertainty and limited psychosocial support for MGUS patients were also reported. Patients did however reflect positively on their experience of being followed up via nurse-led telephone clinics. CONCLUSIONS: Provision of patient friendly information guides at diagnosis, and additional psychosocial support services such as nurse-led telephone clinics and coordinated patient groups may help MGUS patients adjust better to their diagnosis and in doing so improve quality of life in this patient population.

Does Risk of Progression from Barrett's Esophagus to Esophageal Adenocarcinoma Change Based on the Number of Non-dysplastic Endoscopies?

BACKGROUND: There is a large Barrett's esophagus patient population undergoing endoscopic surveillance. Methods to stratify patients into higher and lower risk groups may enable more varied surveillance intervals for patients with non-dysplastic Barrett's esophagus that could optimize use of endoscopy resources. OBJECTIVE: We aimed to assess whether risk of progression to esophageal adenocarcinoma differed in patients with multiple endoscopic biopsies negative for dysplasia. METHODS: We conducted a retrospective cohort study among individuals from the population-based Northern Ireland Barrett's register with a histologically confirmed diagnosis of non-dysplastic Barrett's esophagus (with intestinal metaplasia) between 1993 and 2010, who had at least one endoscopic biopsy conducted at least 12 months after diagnosis. We used Poisson regression to estimate incidence rate ratios (IRR) and 95% confidence intervals (CI) for the association between number of successive endoscopies showing non-dysplastic Barrett's esophagus and risk of esophageal adenocarcinoma alone, and combined with high-grade dysplasia, at the next endoscopy. RESULTS: We identified 1761 individuals who met our eligibility criteria. Subsequent risk of progression to esophageal adenocarcinoma was lower at the next endoscopy following two endoscopies showing non-dysplastic Barrett's esophagus (IRR 0.26, 95% CI 0.10-0.66) than following one endoscopy showing non-dysplastic Barrett's esophagus. Similar findings were apparent for risk of progression to esophageal adenocarcinoma or high-grade dysplasia (IRR 0.41, 95% CI 0.22-0.79). CONCLUSION: The lower risk of malignant progression in individuals with persistent non-dysplastic Barrett's esophagus over two consecutive endoscopic biopsies but not for longer term persistence does not support hypotheses of persistence being an indicator of less biologically aggressive lesions. Instead, the initial difference may be attributable to post-endoscopy cancers and support the necessity of adhering to robust quality standards for endoscopic procedures.

Germline variation in the insulin-like growth factor pathway and risk of Barrett's esophagus and esophageal adenocarcinoma.

Genome-wide association studies (GWAS) of esophageal adenocarcinoma (EAC) and its precursor, Barrett's esophagus (BE), have uncovered significant genetic components of risk, but most heritability remains unexplained. Targeted assessment of genetic variation in biologically relevant pathways using novel analytical approaches may identify missed susceptibility signals. Central obesity, a key BE/EAC risk factor, is linked to systemic inflammation, altered hormonal signaling and insulin-like growth factor (IGF) axis dysfunction. Here, we assessed IGF-related genetic variation and risk of BE and EAC. Principal component analysis was employed to evaluate pathway-level and gene-level associations with BE/EAC, using genotypes for 270 single-nucleotide polymorphisms (SNPs) in or near 12 IGF-related genes, ascertained from 3295 BE cases, 2515 EAC cases and 3207 controls in the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) GWAS. Gene-level signals were assessed using Multi-marker Analysis of GenoMic Annotation (MAGMA) and SNP summary statistics from BEACON and an expanded GWAS meta-analysis (6167 BE cases, 4112 EAC cases, 17 159 controls). Global variation in the IGF pathway was associated with risk of BE (P = 0.0015). Gene-level associations with BE were observed for GHR (growth hormone receptor; P = 0.00046, false discovery rate q = 0.0056) and IGF1R (IGF1 receptor; P = 0.0090, q = 0.0542). These gene-level signals remained significant at q < 0.1 when assessed using data from the largest available BE/EAC GWAS meta-analysis. No significant associations were observed for EAC. This study represents the most comprehensive evaluation to date of inherited genetic variation in the IGF pathway and BE/EAC risk, providing novel evidence that variation in two genes encoding cell-surface receptors, GHR and IGF1R, may influence risk of BE.

Sex-Specific Genetic Associations for Barrett's Esophagus and Esophageal Adenocarcinoma.

BACKGROUND & AIMS: Esophageal adenocarcinoma (EA) and its premalignant lesion, Barrett's esophagus (BE), are characterized by a strong and yet unexplained male predominance (with a male-to-female ratio in EA incidence of up to 6:1). Genome-wide association studies (GWAS) have identified more than 20 susceptibility loci for these conditions. However, potential sex differences in genetic associations with BE/EA remain largely unexplored. METHODS: Given strong genetic overlap, BE and EA cases were combined into a single case group for analysis. These were compared with population-based controls. We performed sex-specific GWAS of BE/EA in 3 separate studies and then used fixed-effects meta-analysis to provide summary estimates for >9 million variants for male and female individuals. A series of downstream analyses were conducted separately in male and female individuals to identify genes associated with BE/EA and the genetic correlations between BE/EA and other traits. RESULTS: We included 6758 male BE/EA cases, 7489 male controls, 1670 female BE/EA cases, and 6174 female controls. After Bonferroni correction, our meta-analysis of sex-specific GWAS identified 1 variant at chromosome 6q11.1 (rs112894788, KHDRBS2-MTRNR2L9, PBONF = .039) that was statistically significantly associated with BE/EA risk in male individuals only, and 1 variant at chromosome 8p23.1 (rs13259457, PRSS55-RP1L1, PBONF = 0.057) associated, at borderline significance, with BE/EA risk in female individuals only. We also observed strong genetic correlations of BE/EA with gastroesophageal reflux disease in male individuals and obesity in female individuals. CONCLUSIONS: The identified novel sex-specific variants associated with BE/EA could improve the understanding of the genetic architecture of the disease and the reasons for the male predominance.

Improving Identification of Cognitive Impairment in Fragility Fracture Patients: Impact of Educational Guidelines on Current Practice.

INTRODUCTION: Cognitive impairment can hinder a fracture patient's capacity to consent to surgery and negatively impact their postoperative recovery and rehabilitation. National guidelines recommend screening for cognitive impairment upon admission, and the Abbreviated Mental Test Score (AMTS) is a commonly used tool for this. This project aimed to assess current practice regarding documentation of AMTS among frail fracture patients upon admission and to improve AMTS documentation following a simple intervention. METHODS: Baseline data were obtained by inpatient chart review throughout November to December 2018 in a district general hospital with emergency fracture services. All patients admitted with a fragility hip fracture and patients over 65 years with any fracture were included. National guidelines and baseline results were then distributed among junior doctors. Following an intervention, further data were collected throughout January to February 2019. RESULTS: Preintervention, 40 suitable patients (mean age: 82 years) were identified; 9 (22.0%) of whom had an AMTS recorded upon admission. Among the hip fracture subgroup (n = 25), 7 (26.9%) had an AMTS recorded. Postintervention, 39 patients (mean age: 80 years) were identified; 15 (38.5%) of whom had an AMTS recorded. Among the hip fracture subgroup (n = 30), 11 (36.7%) had an AMTS recorded. Statistical analysis demonstrated a significant improvement in AMTS documentation both among the overall cohort (P = .001) and hip fracture patients (P = .019). No significant association was found between AMTS documentation and patient age (P = .566), grade of admitting doctor (P = .058), or prior cognitive/mental health disorder (P = .256). DISCUSSION: A small yet significant improvement in AMTS documentation among elderly/hip fracture patients was observed following distribution of educational material. Further work should explore the effect of cognitive impairment on outcomes related to orthopedic injuries beyond hip fractures.

Cancer Incidence Projections in Northern Ireland to 2040.

BACKGROUND: Data on historic trends and estimates of future cancer incidence are essential if cancer services are to be adequately resourced in future years. METHODS: Age-standardized incidence rates (ASIR) for all cancers combined and 19 common cancers diagnosed during 1993-2017 were determined by sex, year of diagnosis, and age. Data were fitted using an age-period-cohort model, which was used to predict rates in future years up to 2040. These were combined with population projections to provide estimates of the future case number. RESULTS: Compared with the annual average in 2013-2017, for all cancers (excluding nonmelanoma skin) ASIRs are expected by 2040 to fall 9% among males and rise 12% among females, while the number of cases diagnosed is projected to increase by 45% for males and 58% for females. Case volume is projected to rise for all cancer types except for cervical and stomach cancer, with the annual number of cases diagnosed projected to more than double among males for melanoma, liver, and kidney cancers, and among females for liver, pancreatic, and lung cancers. CONCLUSIONS: Increased numbers of cancer cases is projected, due primarily to projected increases in the number of people aged 60 years and over. IMPACT: Projected increases will significantly impact the health services which diagnose and treat cancer. However, while population growth is primarily responsible, reduction of exposure to cancer risk factors, especially tobacco use, obesity, alcohol consumption, and UV radiation, could attenuate the predicted increase in cancer cases.

Modifiable Lifestyle and Medical Risk Factors Associated With Myeloproliferative Neoplasms.

Despite the identification of acquired genetic mutations associated with Myeloproliferative Neoplasms (MPNs) there is a paucity of information relating to modifiable risk factors that may lead to these mutations. The MOSAICC Study was an exploratory case-control study of polycythemia vera (PV), essential thrombocythemia (ET), and Myelofibrosis (MF). MPN patients and population controls (identified by General Practitioners) and non-blood relative/friend controls were recruited from 2 large UK centers. Participants completed a telephone-based questionnaire analyzed by unconditional logistic regression analysis adjusting for potential confounders. Risk factors for MPNs identified included increasing childhood household density [odds ratio (OR) 2.55, 95% confidence interval (CI) 1.16-5.62], low childhood socioeconomic status (OR 2.30, 95%CI 1.02-5.18) and high pack years smoking (OR 2.19, 95%CI 1.03-4.66) and current smoking restricted to JAK2 positive PV cases (OR 3.73, 95%CI 1.06-13.15). Obesity was linked with ET (OR 2.59, 95%CI 1.02-6.58) confirming results in previous cohort studies. Receipt of multiple CT scans was associated with a strongly increased risk of MPN although with wide confidence intervals (OR 5.38, 95%CI 1.67-17.3). Alcohol intake was inversely associated with risk of PV (OR 0.41, 95%CI 0.19-0.92) and ET (OR 0.48, 95%CI 0.24-0.98). The associations with childhood household density, high pack years smoking and alcohol were also seen in multivariate analysis. This is the largest case control study in MPNs to date and confirms the previously reported associations with obesity and cigarette smoking from cohort studies in addition to novel associations. In particular, the role of smoking and JAK2 mutation cases merits further evaluation.

Comparison of Molecular Assays for HPV Testing in Oropharyngeal Squamous Cell Carcinomas: A Population-Based Study in Northern Ireland.

BACKGROUND: Determination of human papillomavirus (HPV) status has become clinically relevant for patient stratification under UICC TNM8 staging. Within the United Kingdom, a combination of p16 IHC and HPV DNA-ISH is recommended for classifying HPV status. This study will assess a series of clinically applicable second-line molecular tests to run in combination with p16 IHC to optimally determine HPV status. METHODS: The ability of HPV RNA-ISH, HPV DNA-ISH, and HPV DNA-PCR to identify p16-positive/HPV-positive patients was investigated in a population-based oropharyngeal squamous cell carcinoma (OPSCC) cohort of patients diagnosed in Northern Ireland from 2000 to 2011. RESULTS: Only 41% of the Northern Irish OPSCC patient population was associated with HPV-driven carcinogenesis. Both ISH assays were more specific than the DNA-PCR assay (100% and 95% vs. 67%) and were less likely to be affected by preanalytic factors such as increasing block age. A pooled HPV genotype probe for RNA-ISH was found to be the most accurate molecular assay assessed (95% accuracy) when compared with p16 positivity. CONCLUSIONS: Our study demonstrates the advantage of tissue-based molecular assays when determining HPV status in retrospective samples. Specifically, we demonstrate the enhanced sensitivity and specificity of ISH techniques compared with PCR-based methodology when working with formalin-fixed paraffin-embedded tissue, and found HPV RNA-ISH to be the most effective assay for determining HPV status. IMPACT: As p16 IHC is a relatively inexpensive, accessible, and sensitive test for stratifying patients by HPV status, this study finds that more patients would benefit from first-line p16 IHC followed by specific HPV testing using HPV RNA-ISH to confirm HPV status.

Association Between Levels of Sex Hormones and Risk of Esophageal Adenocarcinoma and Barrett's Esophagus.

BACKGROUND & AIMS: Esophageal adenocarcinoma (EAC) occurs most frequently in men. We performed a Mendelian randomization analysis to investigate whether genetic factors that regulate levels of sex hormones are associated with risk of EAC or Barrett's esophagus (BE). METHODS: We conducted a Mendelian randomization analysis using data from patients with EAC (n = 2488) or BE (n = 3247) and control participants (n = 2127), included in international consortia of genome-wide association studies in Australia, Europe, and North America. Genetic risk scores or single-nucleotide variants were used as instrumental variables for 9 specific sex hormones. Logistic regression provided odds ratios (ORs) with 95% CIs. RESULTS: Higher genetically predicted levels of follicle-stimulating hormones were associated with increased risks of EAC and/or BE in men (OR, 1.14 per allele increase; 95% CI, 1.01-1.27) and in women (OR, 1.28; 95% CI, 1.03-1.59). Higher predicted levels of luteinizing hormone were associated with a decreased risk of EAC in men (OR, 0.92 per SD increase; 95% CI, 0.87-0.99) and in women (OR, 0.93; 95% CI, 0.79-1.09), and decreased risks of BE (OR, 0.88; 95% CI, 0.77-0.99) and EAC and/or BE (OR, 0.89; 95% CI, 0.79-1.00) in women. We found no clear associations for other hormones studied, including sex hormone-binding globulin, dehydroepiandrosterone sulfate, testosterone, dihydrotestosterone, estradiol, progesterone, or free androgen index. CONCLUSIONS: In a Mendelian randomization analysis of data from patients with EAC or BE, we found an association between genetically predicted levels of follicle-stimulating and luteinizing hormones and risk of BE and EAC.

Diabetes in relation to Barrett's esophagus and adenocarcinomas of the esophagus: A pooled study from the International Barrett's and Esophageal Adenocarcinoma Consortium.

BACKGROUND: Diabetes is positively associated with various cancers, but its relationship with tumors of the esophagus/esophagogastric junction remains unclear. METHODS: Data were harmonized across 13 studies in the International Barrett's and Esophageal Adenocarcinoma Consortium, comprising 2309 esophageal adenocarcinoma (EA) cases, 1938 esophagogastric junction adenocarcinoma (EGJA) cases, 1728 Barrett's esophagus (BE) cases, and 16,354 controls. Logistic regression was used to estimate study-specific odds ratios (ORs) and 95% CIs for self-reported diabetes in association with EA, EGJA, and BE. Adjusted ORs were then combined using random-effects meta-analysis. RESULTS: Diabetes was associated with a 34% increased risk of EA (OR, 1.34; 95% CI, 1.00-1.80; I2  = 48.8% [where 0% indicates no heterogeneity, and larger values indicate increasing heterogeneity between studies]), 27% for EGJA (OR, 1.27; 95% CI, 1.05-1.55; I2  = 0.0%), and 30% for EA/EGJA combined (OR, 1.30; 95% CI, 1.06-1.58; I2  = 34.9%). Regurgitation symptoms modified the diabetes-EA/EGJA association (P for interaction = .04) with a 63% increased risk among participants with regurgitation (OR, 1.63; 95% CI, 1.19-2.22), but not among those without regurgitation (OR, 1.03; 95% CI, 0.74-1.43). No consistent association was found between diabetes and BE. CONCLUSIONS: Diabetes was associated with increased EA and EGJA risk, which was confined to individuals with regurgitation symptoms. Lack of an association between diabetes and BE suggests that diabetes may influence progression of BE to cancer.