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The impact of human IgE glycosylation on structure, function and disease mechanisms is not fully elucidated, and heterogeneity in different studies renders drawing conclusions challenging. Previous reviews discussed IgE glycosylation focusing on specific topics such as health versus disease, FcεR binding or impact on function. We present the first systematic review of human IgE glycosylation conducted utilizing the PRISMA guidelines. We sought to define the current consensus concerning the roles of glycosylation on structure, biology and disease. Despite diverse analytical methodologies, source, expression systems and the sparsity of data on IgE antibodies from non-allergic individuals, collectively evidence suggests differential glycosylation profiles, particularly in allergic diseases compared with healthy states, and indicates functional impact, and contributions to IgE-mediated hypersensitivities and atopic diseases. Beyond allergic diseases, dysregulated terminal glycan structures, including sialic acid, may regulate IgE metabolism. Glycan sites such as N394 may contribute to stabilizing IgE structure, with alterations in these glycans likely influencing both structure and IgE-FcεR interactions. This systematic review therefore highlights critical IgE glycosylation attributes in health and disease that may be exploitable for therapeutic intervention, and the need for novel analytics to explore pertinent research avenues., (© 2024 The Author(s). Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Rapid diagnostic clinics (RDCs) provide a streamlined holistic pathway for patients presenting with non-site specific (NSS) symptoms concerning of malignancy. The current study aimed to: 1) assess the prevalence of anxiety and depression, and 2) identify a combination of patient characteristics and symptoms associated with severe anxiety and depression at Guy's and St Thomas' Foundation Trust (GSTT) RDC in Southeast London. Additionally, we compared standard statistical methods with machine learning algorithms for predicting severe anxiety and depression., Methods: Patients seen at GSTT RDC between June 2019 and January 2023 completed the General Anxiety Disorder Questionnaire (GAD-7) and Patient Health Questionnaire (PHQ-8) questionnaires, at baseline. We used logistic regression (LR) and 2 machine learning (ML) algorithms (random forest (RF), support vector machine (SVM)) to predict risk of severe anxiety and severe depression. The models were constructed using a set of sociodemographic and clinical variables., Results: A total of 1734 patients completed GAD-7 and PHQ-8 questionnaires. Of these, the mean age was 59 years (Standard Deviation: 15.5), and 61.5% (n:1067) were female. Prevalence of severe anxiety (GAD-7 score ≥15) was 13.8% and severe depression (PHQ-8 score≥20) was 9.3%. LR showed that a combination of previous mental health condition (PMH, Adjusted Odds Rario (AOR) 3.28; 95% confidence interval (CI) 2.36-4.56), symptom duration >6 months (AOR 2.20; 95%CI 1.28-3.77), weight loss (AOR 1.88; 95% CI 1.36-2.61), progressive pain (AOR 1.71; 95%CI 1.26-2.32), and fatigue (AOR 1.36; 95%CI 1.01-1.84), was positively associated with severe anxiety. Likewise, a combination PMH condition (AOR 3.95; 95%CI 2.17-5.75), fatigue (AOR 2.11; 95%CI 1.47-3.01), symptom duration >6 months (AOR 1.98; 95%CI 1.06-3.68), weight loss (AOR 1.66; 95%CI 1.13-2.44), and progressive pain (AOR 1.50; 95%CI 1.04-2.16), was positively associated with severe depression. LR and SVM had highest accuracy levels for severe anxiety (LR: 86%, SVM: 85%) and severe depression (SVM: 89%, LR: 86%)., Conclusion: High prevalence of severe anxiety and severe depression was found. PMH, fatigue, weight loss, progressive pain, and symptoms >6 months emerged as combined risk factors for both these psychological comorbidities. RDCs offer an opportunity to alleviate distress in patients with concerning symptoms by expediting diagnostic evaluations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Monroy-Iglesias, Russell, Martin, Fox, Moss, Bruno, Millwaters, Steward, Murtagh, Cargaleiro, Bater, Lavelle, Simpson, Onih, Haire, Reeder, Jones, Smith, Santaolalla, Van Hemelrijck and Dolly.)

Advancements in comprehending myelodysplastic neoplasms (MDS) have unfolded significantly in recent years, elucidating a myriad of cellular and molecular underpinnings integral to disease progression. While molecular inclusions into prognostic models have substantively advanced risk stratification, recent revelations have emphasized the pivotal role of immune dysregulation within the bone marrow milieu during MDS evolution. Nonetheless, immunotherapy for MDS has not experienced breakthroughs seen in other malignancies, partly attributable to the absence of an immune classification that could stratify patients toward optimally targeted immunotherapeutic approaches. A pivotal obstacle to establishing "immune classes" among MDS patients is the absence of validated accepted immune panels suitable for routine application in clinical laboratories. In response, we formed International Integrative Innovative Immunology for MDS (i4MDS), a consortium of multidisciplinary experts, and created the following recommendations for standardized methodologies to monitor immune responses in MDS. A central goal of i4MDS is the development of an immune score that could be incorporated into current clinical risk stratification models. This position paper first consolidates current knowledge on MDS immunology. Subsequently, in collaboration with clinical and laboratory specialists, we introduce flow cytometry panels and cytokine assays, meticulously devised for clinical laboratories, aiming to monitor the immune status of MDS patients, evaluating both immune fitness and identifying potential immune "risk factors." By amalgamating this immunological characterization data and molecular data, we aim to enhance patient stratification, identify predictive markers for treatment responsiveness, and accelerate the development of systems immunology tools and innovative immunotherapies., Competing Interests: Shahram Kordasti: Novartis: Advisory Board, Speakers bureau, Alexion: Speakers bureau, Beckman Coulter: Speakers bureau, MorphoSys: Research Support (none is related to this publication). Wolfgang Kern declares part‐ownership of MLL Munich Leukemia Laboratory. Austin Kulasekararaj: Research support (to institution): Celgene/BMS and Novartis. Speaker's fees: Alexion/AstraZeneca, Akari, Apellis, Celgene/BMS, Novartis, Pfizer, Ra Pharma/UCB, Roche, SOBI. Scientific advisory board: Alexion/Astra Zeneca, Apellis, Amgen, Agios, Biocryst, Celgene/BMS, Novartis, Pfizer, Regeneron, Roche, SOBI, Janssen, Samsung and Novo Nordisk (none is related to this publication)., (© 2024 The Authors. HemaSphere published by John Wiley & Sons Ltd on behalf of European Hematology Association.)

Purpose: There is limited evidence regarding the prognostic effects of pathologic lymph node (LN) regression after neoadjuvant chemotherapy for esophageal adenocarcinoma, and a definition of LN response is lacking. This study aimed to evaluate how LN regression influences survival after surgery for esophageal adenocarcinoma., Methods: Multicenter cohort study of patients with esophageal adenocarcinoma treated with neoadjuvant chemotherapy followed by surgical resection at five high-volume centers in the United Kingdom. LNs retrieved at esophagectomy were examined for chemotherapy response and given a LN regression score (LNRS)-LNRS 1, complete response; 2, <10% residual tumor; 3, 10%-50% residual tumor; 4, >50% residual tumor; and 5, no response. Survival analysis was performed using Cox regression adjusting for confounders including primary tumor regression. The discriminatory ability of different LN response classifications to predict survival was evaluated using Akaike information criterion and Harrell C-index., Results: In total, 17,930 LNs from 763 patients were examined. LN response classified as complete LN response (LNRS 1 ≥1 LN, no residual tumor in any LN; n = 62, 8.1%), partial LN response (LNRS 1-3 ≥1 LN, residual tumor ≥1 LN; n = 155, 20.3%), poor/no LN response (LNRS 4-5; n = 303, 39.7%), or LN negative (no tumor/regression; n = 243, 31.8%) demonstrated superior discriminatory ability. Mortality was reduced in patients with complete LN response (hazard ratio [HR], 0.35; 95% CI, 0.22 to 0.56), partial LN response (HR, 0.72; 95% CI, 0.57 to 0.93) or negative LNs (HR, 0.32; 95% CI, 0.25 to 0.42) compared with those with poor/no LN response. Primary tumor regression and LN regression were discordant in 165 patients (21.9%)., Conclusion: Pathologic LN regression after neoadjuvant chemotherapy was a strong prognostic factor and provides important information beyond pathologic TNM staging and primary tumor regression grading. LN regression should be included as standard in the pathologic reporting of esophagectomy specimens.

Purpose: The post-COVID-19 funding landscape for cancer research globally has become increasingly challenging, particularly in resource-challenged regions (RCRs) lacking strong research ecosystems. We aimed to produce a list of priority areas for cancer research in countries with limited resources, informed by researchers and patients., Methods: Cancer experts in lower-resource health care systems (as defined by the World Bank as low- and middle-income countries; N = 151) were contacted to participate in a modified consensus-seeking Delphi survey, comprising two rounds. In round 1, participants (n = 69) rated predetermined areas of potential research priority (ARPs) for importance and suggested missing ARPs. In round 2, the same participants (n = 49) rated an integrated list of predetermined and suggested ARPs from round 1, then undertook a forced choice priority ranking exercise. Composite voting scores ( T -scores) were used to rank the ARPs. Importance ratings were summarized descriptively. Findings were discussed with international patient advocacy organization representatives., Results: The top ARP was research into strategies adapting guidelines or treatment strategies in line with available resources (particularly systemic therapy) ( T = 83). Others included cancer registries ( T = 62); prevention ( T = 52); end-of-life care ( T = 53); and value-based and affordable care ( T = 51). The top COVID-19/cancer ARP was strategies to incorporate what has been learned during the pandemic that can be maintained posteriorly ( T = 36). Others included treatment schedule interruption ( T = 24); cost-effective reduction of COVID-19 morbidity/mortality ( T = 19); and pandemic preparedness ( T = 18)., Conclusion: Areas of strategic priority favored by cancer researchers in RCRs are related to adaptive treatment guidelines; sustainable implementation of cancer registries; prevention strategies; value-based and affordable cancer care; investments in research capacity building; epidemiologic work on local risk factors for cancer; and combatting inequities of prevention and care access.

Background: Currently, follow-up protocols are applied equally to men on active surveillance (AS) for prostate cancer (PCa) regardless of findings at their initial follow-up biopsy. To determine whether less intensive follow-up is suitable following negative biopsy findings, we assessed the risk of converting to active treatment, any subsequent upgrading, volume progression (>33% positive cores), and serious upgrading (grade group >2) for negative compared with positive findings on initial follow-up biopsy., Methods: 13,161 men from 24 centres participating in the Global Action Plan Active Surveillance Prostate Cancer [GAP3] consortium database, with baseline grade group ≤2, PSA ≤ 20 ng/mL, cT-stage 1-2, diagnosed after 1995, and ≥1 follow-up biopsy, were included in this study. Risk of converting to treatment was assessed using multivariable mixed-effects survival regression. Odds of volume progression, any upgrading and serious upgrading were assessed using mix-effects binary logistic regression for men with ≥2 surveillance biopsies., Results: 27% of the cohort (n = 3590) had no evidence of PCa at their initial biopsy. Over 50% of subsequent biopsies in this group were also negative. A negative initial biopsy was associated with lower risk of conversion (adjusted hazard ratio: 0.45; 95% confidence interval [CI]: 0.42-0.49), subsequent upgrading (adjusted odds ratio [OR]: 0.52; 95%CI: 0.45-0.62) and serious upgrading (OR: 0.74; 95%CI: 0.59-92). Radiological progression was not assessed due to limited imaging data., Conclusion: Despite heterogeneity in follow-up schedules, findings from this global study indicated reduced risk of converting to treatment, volume progression, any upgrading and serious upgrading among men whose initial biopsy findings were negative compared with positive. Given the low risk of progression and high likelihood of further negative biopsy findings, consideration should be given to decreasing follow-up intensity for this group to reduce unnecessary invasive biopsies., (© 2022. The Author(s).)

Objectives: 2-deoxy-2[ 18 F]Fluoro-D-glucose (FDG) PET-CT has an emerging role in assessing response to neoadjuvant therapy in oesophageal cancer. This study evaluated FDG PET-CT in predicting pathological tumour response (pTR), pathological nodal response (pNR) and survival., Methods: Cohort study of 75 patients with oesophageal or oesophago-gastric junction (GOJ) adenocarcinoma treated with neoadjuvant chemotherapy then surgery at Guy's and St Thomas' NHS Foundation Trust, London (2017-2020). Standardised uptake value (SUV) metrics on pre- and post-treatment FDG PET-CT in the primary tumour (mTR) and loco-regional lymph nodes (mNR) were derived. Optimum SUV max thresholds for predicting pathological response were identified using receiver operating characteristic analysis. Predictive accuracy was compared to PERCIST (30% SUV max reduction) and MUNICON (35%) criteria. Survival was assessed using Cox regression., Results: Optimum tumour SUV max decrease for predicting pTR was 51.2%. A 50% cut-off predicted pTR with 73.5% sensitivity, 69.2% specificity and greater accuracy than PERCIST or MUNICON (area under the curve [AUC] 0.714, PERCIST 0.631, MUNICON 0.659). Using a 30% SUV max threshold, mNR predicted pNR with high sensitivity but low specificity (AUC 0.749, sensitivity 92.6%, specificity 57.1%, p = 0.010). pTR, mTR, pNR and mNR were independent predictive factors for survival (pTR hazard ratio [HR] 0.10 95% confidence interval [CI] 0.03-0.34; mTR HR 0.17 95% CI 0.06-0.48; pNR HR 0.17 95% CI 0.06-0.54; mNR HR 0.13 95% CI 0.02-0.66)., Conclusions: Metabolic tumour and nodal response predicted pTR and pNR, respectively, in patients with oesophageal or GOJ adenocarcinoma. However, currently utilised response criteria may not be optimal. pTR, mTR, pNR and mNR were independent predictors of survival., Key Points: • FDG PET-CT has an emerging role in evaluating response to neoadjuvant therapy in patients with oesophageal cancer. • Prospective cohort study demonstrated that metabolic response in the primary tumour and lymph nodes was predictive of pathological response in a cohort of patients with adenocarcinoma of the oesophagus or oesophago-gastric junction treated with neoadjuvant chemotherapy followed by surgical resection. • Patients who demonstrated a response to neoadjuvant chemotherapy in the primary tumour or lymph nodes on FDG PET-CT demonstrated better survival and reduced rates of tumour recurrence., (© 2023. The Author(s).)

Background: Survival rates for ovarian cancer remain poor, and monitoring and prediction of therapeutic response may benefit from additional markers. Ovarian cancers frequently overexpress Folate Receptor alpha (FRα) and the soluble receptor (sFRα) is measurable in blood. Here we investigated sFRα as a potential biomarker., Methods: We evaluated sFRα longitudinally, before and during neo-adjuvant, adjuvant and palliative therapies, and tumour FRα expression status by immunohistrochemistry. The impact of free FRα on the efficacy of anti-FRα treatments was evaluated by an antibody-dependent cellular cytotoxicity assay., Results: Membrane and/or cytoplasmic FRα staining were observed in 52.7% tumours from 316 ovarian cancer patients with diverse histotypes. Circulating sFRα levels were significantly higher in patients, compared to healthy volunteers, specifically in patients sampled prior to neoadjuvant and palliative treatments. sFRα was associated with FRα cell membrane expression in the tumour. sFRα levels decreased alongside concurrent tumour burden in patients receiving standard therapies. High concentrations of sFRα partly reduced anti-FRα antibody tumour cell killing, an effect overcome by increased antibody doses., Conclusions: sFRα may present a non-invasive marker for tumour FRα expression, with the potential for monitoring patient response to treatment. Larger, prospective studies should evaluate FRα for assessing disease burden and response to systemic treatments., (© 2022. The Author(s).)

Increasing evidence has linked the humoral immune response with the development of various cancers. Therefore, there is growing interest in investigating the predictive value of antibodies to assess overall and tissue site-specific cancer risk. Given the large amount of antibody types and the broad scope of the search (i.e. cancer risk), the primary aim of this systematic review was to present an overview of the most researched antibodies (i.e. immunoglobulin (Ig) isotypes (IgG, IgM, IgA, and IgE), tumour and self-antigen-reactive antibodies, infection-related antibodies) in relation to overall and site-specific cancer risk. We identified various antibody types that have been associated with the risk of cancer. While no significant associations were found for IgM serum levels, studies found an inconsistent association among IgE, IgA, and IgG serum levels in relation to cancer risk. When evaluating antibodies against infectious agents, most studies reported a positive link with specific cancers known to be associated with the specific agent recognized by serum antibodies (i.e. helicobacter pylori and gastric cancer, hepatitis B virus and hepatocellular carcinoma, and human papillomavirus and cervical cancer). Several reports identified autoantibodies, as single biomarkers (e.g. anti-p53, anti-MUC1, and anti-CA125) but especially in panels of multiple autoantibodies, to have potential as diagnostic biomarkers for specific cancer types. Overall, there is emerging evidence associating certain antibodies to cancer risk, especially immunoglobulin isotypes, tumour-associated antigen-specific, and self-reactive antibodies. Further experimental studies are necessary to assess the efficacy of specific antibodies as markers for the early diagnosis of cancer., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Immunology.)

Background: The optimal interval for repeat biopsy during active surveillance (AS) for prostate cancer is yet to be defined. This study examined whether risk of upgrading (to grade group ≥ 2) or risk of converting to treatment varied according to intensity of repeat biopsy using data from the GAP3 consortium's global AS database., Materials and Methods: Intensity of surveillance biopsy schedules was categorized according to centers' protocols: (a) Prostate Cancer Research International Active Surveillance project (PRIAS) protocols with biopsies at years 1, 4, and 7 (10 centers; 7532 men); (b) biennial biopsies, that is, every other year (8 centers; 4365 men); and (c) annual biopsy schedules (4 centers; 1602 men). Multivariable Cox regression was used to compare outcomes according to biopsy intensity., Results: Out of the 13,508 eligible participants, 56% were managed according to PRIAS protocols (biopsies at years 1, 4, and 7), 32% via biennial biopsy, and 12% via annual biopsy. After adjusting for baseline characteristics, risk of converting to treatment was greater for those on annual compared with PRIAS biopsy schedules (hazard ratio [HR] = 1.66; 95% confidence interval [CI] = 1.51-1.83; p < 0.001), while risk of upgrading did not differ (HR = 0.96; 95% CI = 0.84-1.10)., Conclusion: Results suggest more frequent biopsy schedules may deter some men from continuing AS despite no evidence of grade progression., (© 2022 The Authors. The Prostate published by Wiley Periodicals LLC.)

Background: There is increasing evidence for the use of exercise in cancer patients and data supporting enhanced tumour volume reduction following chemotherapy in animal models. To date, there is no reported histopathological evidence of a similar oncological benefit in oesophageal cancer., Methods: A prospective non-randomised trial compared a structured prehabilitation exercise intervention during neoadjuvant chemotherapy and surgery versus conventional best-practice for oesophageal cancer patients. Biochemical and body composition analyses were performed at multiple time points. Outcome measures included radiological and pathological markers of disease regression. Logistic regression calculated ORs with 95% CI for the likelihood of pathological response adjusting for chemotherapy regimen and chemotherapy delivery., Results: Comparison of the Intervention (n=21) and Control (n=19) groups indicated the Intervention group had higher rates of tumour regression (Mandard TRG 1-3 Intervention n=15/20 (75%) vs Control n=7/19 (36.8%) p=0.025) including adjusted analyses (OR 6.57; 95% CI 1.52 to 28.30). Combined tumour and node downstaging (Intervention n=9 (42.9%) vs Control n=3 (15.8%) p=0.089) and Fat Free Mass index were also improved (Intervention 17.8 vs 18.7 kg/m 2 ; Control 16.3 vs 14.7 kg/m 2 , p=0.026). Differences in markers of immunity (CD-3 and CD-8) and inflammation (IL-6, VEGF, INF-y, TNFa, MCP-1 and EGF) were observed., Conclusion: The results suggest improved tumour regression and downstaging in the exercise intervention group and should prompt larger studies on this topic., Trial Registration Number: NCT03626610., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: To assess the outcomes of patients with early esophageal cancer and high-grade dysplasia comparing esophagectomy, the historical treatment of choice, to endoscopic eradication therapy (EET)., Methods: Retrospective cohort study of consecutive patients with early esophageal cancer/high-grade dysplasia, treated between 2000 and 2018 at a tertiary center. Primary outcomes were all-cause and disease-specific mortality assessed by multivariable Cox regression and a propensity score matching sub analysis, providing hazard ratios (HR) with 95% confidence intervals (CI) adjusted for age, tumor grade (G1/2 vs. G3), tumor stage, and lymphovascular invasion. Secondary outcomes included complications, hospital stay, and overall costs., Results: Among 269 patients, 133 underwent esophagectomy and 136 received EET. Adjusted survival analysis showed no difference between groups regarding all-cause mortality (HR 1.85, 95% CI 0.73, 4.72) and disease-specific mortality (HR 1.10, 95% CI 0.26, 4.65). In-hospital and 30-day mortality was 0% in both groups. The surgical group had a significantly higher rate of complications (Clavien-Dindo ≥3 26.3% vs. endoscopic therapy 0.74%), longer in-patient stay (median 14 vs. 0 days endoscopic therapy) and higher hospital costs(£16 360 vs. £8786 per patient)., Conclusion: This series of patients treated during a transition period from surgery to EET, demonstrates a primary endoscopic approach does not compromise oncological outcomes with the benefit of fewer complications, shorter hospital stays, and lower costs compared to surgery. It should be available as the gold standard treatment for patients with early esophageal cancer. Those with adverse prognostic features may still benefit from esophagectomy., (© The Author(s) 2021. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Peri-operative chemotherapy improves survival in patients with locally advanced oesophago-gastric adenocarcinoma. Two regimens with proven survival benefits are epirubicin, cisplatin plus capecitabine or fluorouracil (Medical Research Council Adjuvant Gastric Infusional Chemotherapy, MAGIC) and fluorouracil plus leucovorin, oxaliplatin, and docetaxel (FLOT). This study aimed to compare the effect of these regimens on survival (primary aim) and pathological response, surgical complications, adverse events and chemotherapy completion rates., Methods: Cohort study including 946 patients treated with FLOT (n = 257) or MAGIC (n = 689) who underwent surgical resection for oesophageal (n = 743) or gastric (n = 203) adenocarcinoma between 2002 and 2021 at St Thomas' Hospital or The Royal Marsden Hospital, London, UK. Survival analysis was performed using multivariable Cox regression, providing hazard ratios (HRs) with 95% confidence intervals (CIs) adjusted for age, sex, clinical T-stage, clinical N-stage, tumour grade and presence of signet ring cells., Results: Patients treated with FLOT had better overall survival (HR = 0.69, 95% CI 0.50-0.94) and disease-free survival (HR = 0.75, 95% CI 0.58-0.98) than MAGIC. Patients treated with FLOT were more likely to have a complete pathological response (9.5% FLOT versus 5.5% MAGIC, p = 0.027) and were less likely to have a positive resection margin (19.1% FLOT versus 32.2% MAGIC, p < 0.001). The stratified analysis revealed similar results for oesophageal and gastric tumours. Rates of surgical complications, chemotherapy-associated adverse events and completion were similarly distributed between treatment groups., Conclusions: Patients with oesophageal or gastric adenocarcinoma treated with peri-operative FLOT had better survival and pathological response than those treated with peri-operative MAGIC. Rates of surgical complications, adverse events and chemotherapy completion were comparable., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction. Prostate cancer (PCa) is the most frequent cancer diagnosis in men worldwide. Our ability to identify those men whose cancer will decrease their lifespan and/or quality of life remains poor. The ReIMAGINE Consortium has been established to improve PCa diagnosis. Materials and methods. MRI will likely become the future cornerstone of the risk-stratification process for men at risk of early prostate cancer. We will, for the first time, be able to combine the underlying molecular changes in PCa with the state-of-the-art imaging. ReIMAGINE Screening invites men for MRI and PSA evaluation. ReIMAGINE Risk includes men at risk of prostate cancer based on MRI, and includes biomarker testing. Results. Baseline clinical information, genomics, blood, urine, fresh prostate tissue samples, digital pathology and radiomics data will be analysed. Data will be de-identified, stored with correlated mpMRI disease endotypes and linked with long term follow-up outcomes in an instance of the Philips Clinical Data Lake, consisting of cloud-based software. The ReIMAGINE platform includes application programming interfaces and a user interface that allows users to browse data, select cohorts, manage users and access rights, query data, and more. Connection to analytics tools such as Python allows statistical and stratification method pipelines to run profiling regression analyses. Discussion. The ReIMAGINE Multimodal Warehouse comprises a unique data source for PCa research, to improve risk stratification for PCa and inform clinical practice. The de-identified dataset characterized by clinical, imaging, genomics and digital pathology PCa patient phenotypes will be a valuable resource for the scientific and medical community., Competing Interests: TH is employed by Philips Research. JD is employed by Philips. HA research is supported by core funding from the United Kingdom’s National Institute of Health Research (NIHR) Imperial Biomedical Research Centre. He currently receives funding from the Wellcome Trust, Medical Research Council (UK), Cancer Research UK, Prostate Cancer UK, National Institute for Health Research (UK), The Urology Foundation, BMA Foundation, Imperial Health Charity, NIHR Imperial BRC, Sonacare Inc, Trod Medical and Sophiris Biocorp for trials in prostate cancer. He was a paid medical consultant for Sophiris Biocorp in the previous 3 years. He is a proctor for HIFU and cryotherapy and paid for training other surgeons in this procedure. CM is supported by the National Institute for Health Research, and has funding from Movember, Prostate Cancer UK, Cancer Research UK and The Urology Foundation. She has received speaker fees from Astellas and Janssen, and is paid for training surgeons in focal therapy procedures. ME serves as a consultant/educator/trainer for Sonacare, Exact Imaging, Angiodynamics, and Profound Medical; and receives research support from the NIHR UCLH/UCL Biomedical Research Centre. AC receives funding from Cancer Research UK and is director of Saddle Point Science. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Santaolalla, Hulsen, Davis, Ahmed, Moore, Punwani, Attard, McCartan, Emberton, Coolen and Van Hemelrijck.)

Bilirubin has strong antioxidant properties that have been hypothesized to be preventive against the development of cancer. Thus, we aimed to investigate the association between serum total bilirubin (STB) and risk of overall and site-specific cancers in the large Swedish Apolipoprotein Mortality Risk (AMORIS) cohort. We also performed a systematic review and meta-analysis for specific cancer types (colorectal, breast and lung). We found no association between high levels of STB and risk of overall cancer. Regarding site-specific cancer, there was an inverse association between increased STB and lung cancer (Hazard Ratio (HR) for the 4th quartile (Q4) vs. Q1: 0.50; 95%CI: 0.44-0.59) and gynecological cancer (HR for Q4 vs. Q1: 0.86; 95%CI: 0.76-0.99). A positive association was found with melanoma (HR for Q4 vs. Q1: 1.25; 95%CI: 1.06-1.47) and breast cancer (HR for Q4 vs. Q1: 1.13; 95%CI: 1.01-1.25) risk. The meta-analysis showed an inverse association between high levels of STB and risk of lung cancer (Relative risk (RR): 0.69; 95%CI: 0.55-0.86). No associations were seen for colorectal and breast cancer risk. Further studies are required to establish if bilirubin can be used as a biomarker for risk assessment and/or as a novel therapeutic target.

Background: Studies of active surveillance (AS) for prostate cancer (PCa) have focussed predominantly on Caucasian populations. Little is known about the experience of Asian men, while suitability for men of African descent has been questioned., Objective: To compare baseline characteristics, follow-up, and outcomes for men on AS for PCa, according to ethnicity., Design Setting and Participants: The study cohort included 13 centres from the GAP3 consortium that record ethnicity (categorised broadly as Caucasian/white, African/Afro-Caribbean/black, Asian, mixed/other, and unknown). Men with biopsy grade group >2, prostate-specific antigen (PSA) >20 ng/ml, T stage ≥cT3, or age >80 yr were excluded., Outcome Measurements and Statistical Analysis: Clinical characteristics, follow-up schedules, outcome status, and reasons for discontinuation were compared across ethnic groups. Risk of upgrading, potential disease progression (grade group ≥3 or T stage ≥3), suspicious indications (any upgrading, number of positive cores >3, T stage ≥cT3, PSA >20 ng/ml, or PSA density >0.2 ng/ml/cc 2 ), and conversion to treatment were assessed using mixed-effect regression models., Results and Limitations: The eligible cohort ( n = 9158) comprised 83% Caucasian men, 6% men of African descent, 5% Asian men, 2% men of mixed/other ethnicity, and 4% men of unknown ethnicity. Risks of suspicious indicators (hazard ratio = 1.27; 95% confidence interval [CI] 1.12-1.45), upgrading (odds ratio [OR] = 1.40; 95% CI 1.14-1.71), and potential progression (OR = 1.46; 95% CI 1.06-2.01) were higher among African/black than among Caucasian/white men. Risk of transitioning to treatment did not differ by ethnicity. More Asian than Caucasian men converted without progression (42% vs 26%, p < 0.001). Heterogeneity in surveillance protocols and racial makeup limit interpretation., Conclusions: This multinational study found differences in the risk of disease progression and transitioning to treatment without signs of progression between ethnic groups. Further research is required to determine whether differences are due to biology, sociocultural factors, and/or clinical practice., Patient Summary: This international study compared prostate cancer active surveillance outcomes by ethnicity. Risks of upgrading and disease progression were higher among African than among Caucasian men. Transitioning to treatment without progression was highest among Asian men. Understanding of these differences requires further investigation., (© 2021 The Author(s).)

Introduction: The primary objective of the ReIMAGINE Prostate Cancer Screening Study is to explore the uptake of an invitation to prostate cancer screening using MRI., Methods and Analysis: The ReIMAGINE Prostate Cancer Screening Study is a prospective single-centre feasibility study. Eligible men aged 50-75 years with no prior prostate cancer diagnosis or treatment will be identified through general practitioner practices and randomly selected for invitation. Those invited will be offered an MRI scan and a prostate-specific antigen (PSA) blood test. The screening MRI scan consists of T2-weighted, diffusion-weighted and research-specific sequences, without the use of intravenous contrast agents. Men who screen positive on either MRI or PSA density will be recommended to have standard of care (National Health Service) tests for prostate cancer assessment, which includes multiparametric MRI. The study will assess the acceptability of an MRI-based prostate screening assessment and the prevalence of cancer detected in MRI-screened men. Summary statistics will be used to explore baseline characteristics in relation to acceptance rates and prevalence of cancer., Ethics and Dissemination: ReIMAGINE Prostate Cancer Screening is a single-site screening study to assess the feasibility of MRI as a screening tool for prostate cancer. Ethical approval was granted by London-Stanmore Research Ethics Committee Heath Research Authority (reference 19/LO/1129). Study results will be published in peer-reviewed journals after completion of data analysis and used to inform the design of a multicentre screening study in the UK., Trial Registration Number: ClinicalTrials.gov Registry (NCT04063566)., Competing Interests: Competing interests: CMM receives funding from the Prostate Cancer UK, Movember, the Medical Research Council, Cancer Research UK and the NIHR. She receives fees for HIFU proctoring from SonaCare. She has received speaker fees from Astellas and Jannsen. She carries out research into photodynamic therapy supported by Spectracure. ME serves as a consultant/educator/trainer to Sonacare, Exact Imaging, Angiodynamics and Profound Medical., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Background: Although the onset of inflammatory cascades may profoundly influence the nature of antibody responses, the interplay between inflammatory and humoral (antibody) immune markers remains unclear. Thus, we explored the reciprocity between the humoral immune system and inflammation and assessed how external socio-demographic factors may influence these interactions. From the AMORIS cohort, 5513 individuals were identified with baseline measurements of serum humoral immune [immunoglobulin G, A & M (IgG, IgA, IgM)] and inflammation (C-reactive protein (CRP), albumin, haptoglobin, white blood cells (WBC), iron and total iron-binding capacity) markers measured on the same day. Correlation analysis, principal component analysis and hierarchical clustering were used to evaluate biomarkers correlation, variation and associations. Multivariate analysis of variance was used to assess associations between biomarkers and educational level, socio-economic status, sex and age., Results: Frequently used serum markers for inflammation, CRP, haptoglobin and white blood cells, correlated together. Hierarchical clustering and principal component analysis confirmed the interaction between these main biological responses, showing an acute response component (CRP, Haptoglobin, WBC, IgM) and adaptive response component (Albumin, Iron, TIBC, IgA, IgG). A socioeconomic gradient associated with worse health outcomes was observed, specifically low educational level, older age and male sex were associated with serum levels that indicated infection and inflammation., Conclusions: These findings indicate that serum markers of the humoral immune system and inflammation closely interact in response to infection or inflammation. Clustering analysis presented two main immune response components: an acute and an adaptive response, comprising markers of both biological pathways. Future studies should shift from single internal marker assessment to multiple humoral and inflammation serum markers combined, when assessing risk of clinical outcomes such as cancer., (© 2021. The Author(s).)

In breast cancer, humoral immune responses may contribute to clinical outcomes, especially in more immunogenic subtypes. Here, we investigated B lymphocyte subsets, immunoglobulin expression, and clonal features in breast tumors, focusing on aggressive triple-negative breast cancers (TNBC). In samples from patients with TNBC and healthy volunteers, circulating and tumor-infiltrating B lymphocytes (TIL-B) were evaluated. CD20 + CD27 + IgD - isotype-switched B lymphocytes were increased in tumors, compared with matched blood. TIL-B frequently formed stromal clusters with T lymphocytes and engaged in bidirectional functional cross-talk, consistent with gene signatures associated with lymphoid assembly, costimulation, cytokine-cytokine receptor interactions, cytotoxic T-cell activation, and T-cell-dependent B-cell activation. TIL-B-upregulated B-cell receptor (BCR) pathway molecules FOS and JUN, germinal center chemokine regulator RGS1, activation marker CD69, and TNFα signal transduction via NFκB, suggesting BCR-immune complex formation. Expression of genes associated with B lymphocyte recruitment and lymphoid assembly, including CXCL13, CXCR4, and DC-LAMP, was elevated in TNBC compared with other subtypes and normal breast. TIL-B-rich tumors showed expansion of IgG but not IgA isotypes, and IgG isotype switching positively associated with survival outcomes in TNBC. Clonal expansion was biased toward IgG, showing expansive clonal families with specific variable region gene combinations and narrow repertoires. Stronger positive selection pressure was present in the complementarity determining regions of IgG compared with their clonally related IgA in tumor samples. Overall, class-switched B lymphocyte lineage traits were conspicuous in TNBC, associated with improved clinical outcomes, and conferred IgG-biased, clonally expanded, and likely antigen-driven humoral responses. SIGNIFICANCE: Tumor-infiltrating B lymphocytes assemble in clusters, undergoing B-cell receptor-driven activation, proliferation, and isotype switching. Clonally expanded, IgG isotype-biased humoral immunity associates with favorable prognosis primarily in triple-negative breast cancers., (©2021 The Authors; Published by the American Association for Cancer Research.)

Objective: To determine the risk of disease progression and conversion to active treatment following a negative biopsy while on active surveillance (AS) for prostate cancer (PCa)., Patients and Methods: Men on an AS programme at a single tertiary hospital (London, UK) between 2003 and 2018 with confirmed low-intermediate-risk PCa, Gleason Grade Group <3, clinical stage 30% positive cores, magnetic resonance imaging (MRI) Likert score >3/T3 or PSA level of >20 ng/mL. Conversion to treatment included radical or hormonal treatment., Results: Among the 460 eligible patients, 23% had negative follow-up biopsy findings. The median follow-up was 62 months, with one to two repeat biopsies and two MRIs per patient during that period. Negative biopsy findings at first repeat biopsy were associated with decreased risk of converting to active treatment (hazard ration [HR] 0.18, 95% confidence interval [CI] 0.09-0.37; P < 0.001), suspicion of disease progression (HR 0.56, 95% CI: 0.34-0.94; P = 0.029), and upgrading (HR 0.48, 95% CI 0.23-0.99; P = 0.047). Data are limited by fewer men with multiple follow-up biopsies., Conclusion: A negative biopsy finding at the first scheduled follow-up biopsy among men on AS for PCa was strongly associated with decreased risk of subsequent upgrading, clinical or radiological suspicion of disease progression, and conversion to active treatment. A less intense surveillance protocol should be considered for this cohort of patients., (© 2020 The Authors BJU International © 2020 BJU International.)

Background: Experiences of African/Afro-Caribbean men on active surveillance (AS) for prostate cancer (PCa) in the United Kingdom (UK) are not well documented. We compared follow-up appointments, adherence, and clinical outcomes among African/Afro-Caribbean men on AS at a high-volume UK hospital with other ethnicities., Methods: Men with confirmed low-intermediate risk Pca who attended the AS clinic (2005-2016) and had undergone ≥1 follow-up biopsy (n = 458) were included. Non-adherence (defined as >20% missed appointments), suspicion of disease progression (any upgrading, >30% positive cores, cT-stage > 3, PIRADS > 3), any upgrading from diagnostic biopsy and conversion to active treatment (prostatectomy, radiotherapy or hormone therapy) according to ethnicity (African/Afro-Caribbean versus other ethnicities) were assessed using multivariable regression analysis., Results: Twenty-three percent of eligible men were recorded as African/Afro-Caribbean, while the remainder were predominantly Caucasian. African/Afro-Caribbean men had slightly lower PSA at diagnosis (median 5.0 vs. 6.0 ng/mL) and more positive cores at diagnosis (median 2 vs. 1). They had a substantially higher rate of non-attendance at scheduled follow-up visits (24% vs. 10%, p < 0.001). Adjusted analyses suggest African/Afro-Caribbean men may be at increased risk of disease progression (hazard ratio [HR]: 1.38; 95% confidence interval [CI] 0.99-1.91, P = 0.054) and upgrading (HR: 1.29; 95% CI 0.87-1.92, P = 0.305), though neither reached statistical significance. No difference in risk of conversion to treatment was observed between ethnic groups (HR: 1.03; 95% CI 0.64-1.47, P = 0.873)., Conclusions: African/Afro-Caribbean men on AS for PCa in the UK are less likely to adhere to scheduled appointments, suggesting a more tailored service addressing their specific needs may be required. While African/Afro-Caribbean men were no more likely to convert to treatment than Caucasian/other men, findings of a potentially higher risk of disease progression signal the need for careful selection and monitoring of African/Afro-Caribbean men on AS. Larger prospective, multicentre studies with longer follow-up are required to provide more definitive conclusions.

Background: The routine clinical use of serum prostatic specific antigen (PSA) testing has allowed earlier detection of low-grade prostate cancer (PCa) with more favourable characteristics, leading to increased acceptance of management by active surveillance (AS). AS aims to avoid over treatment in men with low and intermediate-risk PCa and multiple governing bodies have described several AS protocols. This study provides a descriptive profile of the Guy's and St Thomas NHS Foundation Trust (GSTT) AS cohort as a platform for future research in AS pathways in PCa., Methods: Demographic and baseline characteristics were retrospectively collected in a database for patients at the GSTT AS clinic with prospective collection of follow-up data from 2012. Seven hundred eighty-eight men being monitored at GSTT with histologically confirmed intermediate-risk PCa, at least 1 follow-up appointment and diagnostic characteristics consistent with AS criteria were included in the profile. Descriptive statistics, Kaplan-Meier survival curves and multivariable Cox proportion hazards regression models were used to characterize the cohort., Discussion: A relatively large proportion of the cohort includes men of African/Afro-Caribbean descent (22%). More frequent use of magnetic resonance imaging and trans-perineal biopsies at diagnosis was observed among patients diagnosed after 2012. Those who underwent trans-rectal ultrasound diagnostic biopsy received their first surveillance biopsy 20 months earlier than those who underwent trans-perineal diagnostic biopsy. At 3 years, 76.1% men remained treatment free. Predictors of treatment progression included Gleason score 3 + 4 (Hazard ratio (HR): 2.41, 95% Confidence interval (CI): 1.79-3.26) and more than 2 positive cores taken at biopsy (HR: 2.65, CI: 1.94-3.62). A decreased risk of progressing to treatment was seen among men diagnosed after 2012 (HR: 0.72, CI: 0.53-0.98)., Conclusion: An organised biopsy surveillance approach, via two different AS pathways according to the patient's diagnostic method, can be seen within the GSTT cohort. Risk of patients progressing to treatment has decreased in the period since 2012 compared with the prior period with more than half of the cohort remaining treatment free at 5 years, highlighting that the fundamental aims of AS at GSTT are being met. Thus, this cohort is a good resource to investigate the AS treatment pathway.

ReIMAGINE Screening is a single-centre study assessing the feasibility of biparametric magnetic resonance imaging as a screening tool for prostate cancer. The study outcomes will take us a step towards more accurate and less harmful prostate cancer screening., (Copyright © 2021. Published by Elsevier B.V.)

Background: The coronavirus disease 2019 (COVID-19) pandemic has had a significant psychological impact on healthcare workers (HCWs)., Aims: There is an urgent need to understand the risk and protective factors associated with poor mental well-being of UK HCWs working during the COVID-19 pandemic., Method: Shortly after the April 2020 UK COVID-19 peak 2773 HCWs completed a survey containing measures of anxiety, depression, post-traumatic stress disorder and stress, as well as questions around potential predictors such as roles, COVID-19 risk perception and workplace-related factors. Respondents were classified as high or low symptomatic on each scale and logistic regression revealed factors associated with severe psychiatric symptoms. Change in well-being from pre- to during COVID-19 was also quantified., Results: Nearlya third of HCWs reported moderate to severe levels of anxiety and depression, and the number reporting very high symptoms was more than quadruple that pre-COVID-19. Several controllable factors were associated with the most severe level of psychiatric symptoms: insufficient personal protective equipment availability, workplace preparation, training and communication, and higher workload. Being female, 'front line', previous psychiatric diagnoses, traumatic events, and being an allied HCW or manager were also significantly associated with severe psychiatric symptoms. Sharing stress, resilience and ethical support for treatment decisions were significantly associated with low psychiatric symptoms. Front-line workers showed greater worsening of mental health compared with non-front-line HCWs., Conclusions: Poor mental well-being was prevalent during the COVID-19 response, however, controllable factors associated with severe psychiatric symptoms are available to be targeted to reduce the detrimental impact of COVID-19 and other pandemics on HCW mental health.

Pancreatic cancer (PCa) is associated with a poor prognosis and high mortality rate. The causes of PCa are not fully elucidated yet, although certain exposome factors have been identified. The exposome is defined as the sum of all environmental factors influencing the occurrence of a disease during a life span. The development of an exposome approach for PCa has the potential to discover new disease-associated factors to better understand the carcinogenesis of PCa and help with early detection strategies. Our systematic review of the literature identified several exposome factors that have been associated with PCa alone and in combination with other exposures. A potential inflammatory signature has been observed among the interaction of several exposures (i.e., smoking, alcohol consumption, diabetes mellitus, obesity, and inflammatory markers) that further increases the incidence and progression of PCa. A large number of exposures have been identified such as genetic, hormonal, microorganism infections and immune responses that warrant further investigation. Future early detection strategies should utilize this information to assess individuals' risk for PCa.

Objectives: To assess the association between vitamin D deficiency and increased morbidity/mortality with COVID-19 respiratory dysfunction., Design: Scoping review., Data Sources: Ovid MEDLINE (1946 to 24 of April 2020) and PubMed (2020 to 17 of September 2020)., Eligibility Criteria for Selecting Studies: A search using the search terms: [(cholecalciferol or ergocalciferol or vitamin D2 or vitamin D3 or vitamin D or 25OHD) and (SARS-CoV-2 or coronavirus or COVID or betacoronavirus or MERS-CoV or SARS-CoV or respiratory infection or acute respiratory distress syndrome or ARDS)]m.p. was conducted on the 24/04/2020 (Search A) and 17/09/2020 (Search B)., Results: 91 studies were identified as being concerned with Acute Respiratory Infection (ARI)/Acute Respiratory Distress Syndrome (ARDS) and vitamin D, and 25 publications specifically explored the role of vitamin D deficiency in the development and progression of SARS-CoV-2/COVID-19 related ARDS. Search "A" identified three main themes of indirect evidence supporting such an association. Consistent epidemiological evidence exists linking low vitamin D levels to increased risk and severity of respiratory tract infections. We also report on plausible biological processes supporting such an association; and present weaker evidence supporting the benefit of vitamin D supplementation in reducing the risk and severity of ARIs. Uncertainty remains about what constitutes an appropriate dosing regimen in relation to reducing risk/severity of ARI/ARDS. More recent evidence (Search B) provided new insights into some direct links between vitamin D and COVID-19; with a number of cohort and ecological studies supporting an association with PCR-positivity for SARS-CoV-2 and vitamin D deficiency. The exact efficacy of the vitamin D supplementation for prevention of, or as an adjunct treatment for COVID-19 remains to be determined; but a number of randomized control trials (RCTs) currently underway are actively investigating these potential benefits., Conclusion: Our rapid review of literature supports the need for observational studies with COVID-19 infected populations to measure and assess vitamin D levels in relation to risk/severity and outcomes; alongside RCTs designed to evaluate the efficacy of supplementation both in preventive and therapeutic contexts. The overlap in the vitamin D associated biological pathways with the dysregulation reported to drive COVID-19 outcomes warrants further investigation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Santaolalla, Beckmann, Kibaru, Josephs, Van Hemelrijck and Irshad.)

Background: Cancer and transplant patients with COVID-19 have a higher risk of developing severe and even fatal respiratory diseases, especially as they may be treated with immune-suppressive or immune-stimulating drugs. This review focuses on the effects of these drugs on host immunity against COVID-19., Methods: Using Ovid MEDLINE, we reviewed current evidence for immune-suppressing or -stimulating drugs: cytotoxic chemotherapy, low-dose steroids, tumour necrosis factorα (TNFα) blockers, interlukin-6 (IL-6) blockade, Janus kinase (JAK) inhibitors, IL-1 blockade, mycophenolate, tacrolimus, anti-CD20 and CTLA4-Ig., Results: 89 studies were included. Cytotoxic chemotherapy has been shown to be a specific inhibitor for severe acute respiratory syndrome coronavirus in in vitro studies, but no specific studies exist as of yet for COVID-19. No conclusive evidence for or against the use of non-steroidal anti-inflammatory drugs (NSAIDs) in the treatment of COVID-19 patients is available, nor is there evidence indicating that TNFα blockade is harmful to patients in the context of COVID-19. COVID-19 has been observed to induce a pro-inflammatory cytokine generation and secretion of cytokines, such as IL-6, but there is no evidence of the beneficial impact of IL-6 inhibitors on the modulation of COVID-19. Although there are potential targets in the JAK-STAT pathway that can be manipulated in treatment for coronaviruses and it is evident that IL-1 is elevated in patients with a coronavirus, there is currently no evidence for a role of these drugs in treatment of COVID-19., Conclusion: The COVID-19 pandemic has led to challenging decision-making about treatment of critically unwell patients. Low-dose prednisolone and tacrolimus may have beneficial impacts on COVID-19. The mycophenolate mofetil picture is less clear, with conflicting data from pre-clinical studies. There is no definitive evidence that specific cytotoxic drugs, low-dose methotrexate for auto-immune disease, NSAIDs, JAK kinase inhibitors or anti-TNFα agents are contraindicated. There is clear evidence that IL-6 peak levels are associated with severity of pulmonary complications., Competing Interests: The authors have no conflicts of interest to declare., (© the authors; licensee ecancermedicalscience.)

Background: Emerging evidence points to potential roles of the humoral immune responses in the development of pancreatic cancer. Epidemiological studies have suggested involvement of viral and bacterial infections in pancreatic carcinogenesis. Experimental studies have reported high expression levels of antigens in pancreatic cancer cells. Therefore, we aimed to investigate the role of different components of humoral immunity in the context of pancreatic cancer. We evaluated associations between pre-diagnostic serum markers of the overall humoral immune system [immunoglobulin A (IgA), immunoglobulin G (IgG) and immunoglobulin M (IgM)], and the risk of pancreatic cancer in the Swedish Apolipoprotein-related MORtality RISk (AMORIS) study. Methods: We selected all participants (≥20 years old) with baseline measurements of IgA, IgG or IgM ( n = 41,900, 136,221, and 29,919, respectively). Participants were excluded if they had a history of chronic pancreatitis and individuals were free from pancreatic cancer at baseline. Multivariate Cox proportional hazards regression was used to estimate risk of pancreatic cancer for medical cut-offs of IgA, IgG, and IgM. Results: Compared to the reference level of 6.10-14.99 g/L, risk of pancreatic cancer was elevated among those with IgG levels <6.10 g/L [HR: 1.69 (95% CI 0.99-2.87)], and an inverse association was observed among those with IgG levels ≥15.00 g/L [0.82 (95% CI 0.64-1.05); P trend = 0.027]. The association appeared to be stronger for women than men [HR: 0.64 (95% CI 0.43-0.97) and 0.95 (95% CI 0.69-1.29), respectively]. No associations were observed with IgA or IgM. Conclusion: An inverse association was observed between pre-diagnostic serum levels of IgG and risk of pancreatic cancer. Our findings highlight the need to further investigate the role of immune response in pancreatic cancer etiology., (Copyright © 2020 Sollie, Santaolalla, Michaud, Sarker, Karagiannis, Josephs, Hammar, Walldius, Garmo, Holmberg, Jungner and Van Hemelrijck.)

Introduction: Given the need for more bladder cancer research and the recently observed advantages of introducing the trials within cohort (TwiCs) design, the set-up of the Graham Roberts Study (Roberts Study) will provide valuable infrastructure to answer a wide variety of research questions of a clinical, mechanistic, as well as supportive care nature in the area of bladder cancer., Methods: Using the TwiCs design, we will recruit patients aged 18 or older who are willing and able to provide signed informed consent and have a diagnosis of new or recurrent bladder cancer into this prospective cohort study. All patients must have a basic understanding of the English language. The following questionnaires will be collected at baseline and every 12 months subsequently: Functional Assessment of Chronic Illness Therapy for Bladder Cancer, the Functional Assessment of Chronic Illness Therapy-Fatigue, the Patient Heath Questionnaire-9, the standardised instrument for a generic health status (EQ-5D-5L), a Short Questionnaire to Assess Health-Enhancing Physical Activity and the Hertfordshire Short Questionnaire to Assess Diet Quality., Ethics and Dissemination: Due to the nature of this study, we obtained full ethical clearance from the London-Fulham Research Ethics Committee (17/LO1975). All participants must provide full informed consent before recruitment onto the study. The results of this study will be published in peer-reviewed journals and data collected as part of the study will be made available to potential collaborators on an application basis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Nested case-control studies examining the association between serum markers of chronic inflammation, focused on three specific biomarkers (CRP, IL-8 and TNF-α), and risk of pancreatic cancer have reported no associations. In this study, we evaluated associations between standard pre-diagnostic serum markers of chronic inflammation (CRP, albumin, haptoglobin and leukocytes) and pancreatic cancer risk in the Swedish Apolipoprotein-related MORtality RISk (AMORIS) prospective cohort study., Methods: We selected all participants (≥20 years old) with baseline measurements of CRP, albumin, haptoglobin and leukocytes between 1985 and 1996 (n = 61,597). Participants were excluded if they had a history of chronic pancreatitis and all individuals were free from pancreatic cancer at baseline. Cox proportional multivariable hazards regression analysis was carried out for medical cut-offs of CRP, albumin, haptoglobin and leukocytes., Results: We observed an increased risk of pancreatic cancer for those individuals with higher levels of serum haptoglobin (≥1.4 g/L), CRP (≥10 mg/L) and leukocytes (≥10 × 10 9 cells/L) compared to those with haptoglobin levels < 1.4 g/L, CRP levels < 10 mg/L and Leukocyte levels < 10 × 10 9 cells/L [haptoglobin HR: 2.23 (95% CI 1.72-2.88), CRP HR: 1.32 (95% CI 1.00-1.74), leukocytes HR: 2.20 (95% CI 1.52-3.18)]. No associations were noted for serum albumin., Conclusions: We found an increased risk of pancreatic cancer associated with pre-diagnostic serum levels of haptoglobin, CRP and leukocytes. Our finding suggests a possible role of chronic inflammation in the aetiology of pancreatic cancer and highlight the need to further investigate this association.

Background: Metabolites are genetically and environmentally determined. Consequently, they can be used to characterize environmental exposures and reveal biochemical mechanisms that link exposure to disease. To explore disease susceptibility and improve population risk stratification, we aimed to identify metabolic profiles linked to carcinogenesis and mortality and their intrinsic associations by characterizing subgroups of individuals based on serum biomarker measurements. We included 13,615 participants from the Swedish Apolipoprotein MOrtality RISk Study who had measurements for 19 biomarkers representative of central metabolic pathways. Latent Class Analysis (LCA) was applied to characterise individuals based on their biomarker values (according to medical cut-offs), which were then examined as predictors of cancer and death using multivariable Cox proportional hazards models., Results: LCA identified four metabolic profiles within the population: (1) normal values for all markers (63% of population); (2) abnormal values for lipids (22%); (3) abnormal values for liver functioning (9%); (4) abnormal values for iron and inflammation metabolism (6%). All metabolic profiles (classes 2-4) increased risk of cancer and mortality, compared to class 1 (e.g. HR for overall death was 1.26 (95% CI: 1.16-1.37), 1.67 (95% CI: 1.47-1.90), and 1.21 (95% CI: 1.05-1.41) for class 2, 3, and 4, respectively)., Conclusion: We present an innovative approach to risk stratify a well-defined population based on LCA metabolic-defined subgroups for cancer and mortality. Our results indicate that standard of care baseline serum markers, when assembled into meaningful metabolic profiles, could help assess long term risk of disease and provide insight in disease susceptibility and etiology.

Purpose: The roles of folate and vitamin B12 in prostate cancer (PCa) or breast cancer (BC) development are unclear. We investigated their roles using the prospective Swedish Apolipoprotein MOrtality RISk (AMORIS) study., Methods: 8,783 men and 19,775 women with vitamin B12 and folate serum measurements were included. Their associations with PCa and BC risk categories were evaluated using Cox proportional hazards regression., Results: During mean follow-up of 13 years, 703 men developed PCa. There was an inverse association between folate > 32 nmol/L and high-risk PCa [hazard ratio (HR) 0.12, 95% confidence interval (CI) 0.02-0.90], and a positive association between folate < 5 nmol/L and metastatic PCa (HR 5.25, 95% CI 1.29-21.41), compared with folate 5-32 nmol/L. No associations with vitamin B12 were found. 795 women developed BC during mean follow-up of 14 years. When restricting to the fasting population, there was a positive association between folate > 32 nmol/L and BC (HR 1.47, 95% CI 1.06-2.04)., Conclusion: High folate levels may protect against PCa and low folate levels may increase risk of metastatic PCa. High fasting folate levels may be associated with an increased BC risk. Vitamin B12 was not found to be linked with risk of PCa or BC. Longitudinal studies with serum and dietary information could help define new prevention targets and add information on the role of folate fortification.

Within the Movember Foundation's Global Action Plan Prostate Cancer Active Surveillance (GAP3) initiative, 25 centers across the globe collaborate to standardize active surveillance (AS) protocols for men with low-risk prostate cancer (PCa). A centralized PCa AS database, comprising data of more than 15000 patients worldwide, was created. Comparability of the histopathology between the different cohorts was assessed by a centralized pathology review of 445 biopsies from 15 GAP3 centers. Grade group 1 (Gleason score 6) in 85% and grade group ≥2 (Gleason score ≥7) in 15% showed 89% concordance at review with moderate agreement (κ=0.56). Average biopsy core length was similar among the analyzed cohorts. Recently established highly adverse pathologies, including cribriform and/or intraductal carcinoma, were observed in 3.6% of the reviewed biopsies. In conclusion, the centralized pathology review of 445 biopsies revealed comparable histopathology among the 15 GAP3 centers with a low frequency of high-risk features. This enables further data analyses-without correction-toward uniform global AS guidelines for men with low-risk PCa. PATIENT SUMMARY: Movember Foundation's Global Action Plan Prostate Cancer Active Surveillance (GAP3) initiative combines data from 15000 men with low-risk prostate cancer (PCa) across the globe to standardize active surveillance protocols. Histopathology review confirmed that the histopathology was consistent with low-risk PCa in most men and comparable between different centers., (Crown Copyright © 2018. Published by Elsevier B.V. All rights reserved.)

Novel approaches for classification, including molecular features, are needed to direct therapy for men with low-grade prostate cancer (PCa), especially men on active surveillance. Risk alleles identified from genome-wide association studies (GWAS) could improve prognostication. Those risk alleles that coincided with genes and somatic copy number aberrations associated with progression of PCa were selected as the most relevant for prognostication. In a systematic literature review, a total of 698 studies were collated. Fifty-three unique SNPs residing in 29 genomic regions, including 8q24, 10q11 and 19q13, were associated with PCa progression. Functional studies implicated 21 of these single nucleotide polymorphisms (SNPs) as modulating the expression of genes in the androgen receptor pathway and several other oncogenes. In particular, 8q24, encompassing MYC , harbours a high density of SNPs conferring unfavourable pathological characteristics in low-grade PCa, while a copy number gain of MYC in low-grade PCa was associated with prostate-specific antigen recurrence after radical prostatectomy. By combining GWAS data with gene expression and structural rearrangements, risk alleles were identified that could provide a new basis for developing a prognostication tool to guide therapy for men with early prostate cancer., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

Since nearly 20% of breast-conserving surgeries (BCS) require re-operation, there is a clear need for developing new techniques to more accurately assess tumor resection margins intraoperatively. This study evaluates the diagnostic accuracy of a handheld terahertz pulsed imaging (TPI) system to discriminate benign from malignant breast tissue ex vivo. Forty six freshly excised breast cancer samples were scanned with a TPI handheld probe system, and histology was obtained for comparison. The image pixels on TPI were classified using (1) parameters in combination with support vector machine (SVM) and (2) Gaussian wavelet deconvolution in combination with Bayesian classification. The results were an accuracy, sensitivity, specificity of 75%, 86%, 66% for method 1, and 69%, 87%, 54% for method 2 respectively. This demonstrates the probe can discriminate invasive breast cancer from benign breast tissue with an encouraging degree of accuracy, warranting further study.

The Swedish Apolipoprotein MOrtality RISk study (AMORIS) contains information on more than 500 biomarkers collected from 397,443 men and 414,630 women from the greater Stockholm area during the period 1985-1996. Using a ten-digit personal identification code, this database has been linked to Swedish national registries, which provide data on socioeconomic status, vital status, cancer diagnosis, comorbidity, and emigration. Within AMORIS, 18 studies assessing risk of overall and site-specific cancers have been published, utilising a range of serum markers representing glucose and lipid metabolism, immune system, iron metabolism, liver metabolism, and bone metabolism. This review briefly summarises these findings in relation to more recently published studies and provides an overview of where we are today and the challenges of observational studies when studying cancer risk prediction. Overall, more recent observational studies supported previous findings obtained in AMORIS, although no new results have been reported for serum fructosamine and inorganic phosphate with respect to cancer risk. A drawback of using serum markers in predicting cancer risk is the potential fluctuations following other pathological conditions, resulting in non-specificity and imprecision of associations observed. Utilisation of multiple combination markers may provide more specificity, as well as give us repeated instead of single measurements. Associations with other diseases may also necessitate further analytical strategies addressing effects of serum markers on competing events in addition to cancer. Finally, delineating the role of serum metabolic markers may generate valuable information to complement emerging clinical studies on preventive effects of drugs and supplements targeting metabolic disorders against cancer.