Pre-diagnostic circulating resistin concentrations and mortality among individuals with colorectal cancer: Results from the European Prospective Investigation into Cancer and Nutrition study.

Resistin is a protein involved in inflammation and angiogenesis processes and may play a role in the progression of colorectal cancer (CRC). However, it remains unclear whether resistin is associated with increased mortality after CRC diagnosis. We examined pre-diagnostic serum resistin concentrations in relation to CRC-specific and all-cause mortality among 1343 incident CRC cases from the European Prospective Investigation into Cancer and Nutrition cohort. For CRC-specific mortality as the primary outcome, hazard ratios (HRs) and 95% confidence intervals (95% CI) were estimated from competing risk analyses based on cause-specific Cox proportional hazards models and further in sensitivity analyses using Fine-Gray proportional subdistribution hazards models. For all-cause mortality as the secondary outcome, Cox proportional hazards models were used. Subgroup analyses were performed by sex, tumor subsite, tumor stage, body mass index and time to CRC diagnosis. Resistin was measured on a median of 4.8 years before CRC diagnosis. During a median follow-up of 8.2 years, 474 deaths from CRC and 147 deaths from other causes were observed. Resistin concentrations were not associated with CRC-specific mortality (HRQ4vsQ1 = 0.95, 95% CI: 0.73-1.23; Ptrend = .97; and HRper doubling of resistin concentration = 1.00; 95% CI: 0.84-1.19; P = .98) or all-cause mortality. Results from competing risk (sensitivity) analysis were similar. No associations were found in any subgroup analyses. These findings suggest no association between pre-diagnostic circulating resistin concentrations and CRC-specific or all-cause mortality among persons with CRC, and the potential insignificance of resistin in CRC progression.

Identifying modifiable risk factors to prevent aggressive colorectal cancer.

It remains unclear if pre-diagnostic factors influence the developmental pathways of colorectal cancer (CRC) that could enhance tumor aggressiveness. This study used prospective data from 205,489 cancer-free US health professionals to investigate the associations of 31 known or putative risk factors with the risk of aggressive CRC. Tumor aggressiveness was characterized by three endpoints: aggressive CRC (cancer that causes death within 5 years of diagnosis), fatal CRC, and tumor stage at diagnosis. The data augmentation method was used to assess the difference in the associations between risk factors and endpoints. We documented 3201 CRC cases, of which 899 were aggressive. The protective associations of undergoing lower endoscopy (hazard ratios [HR] 0.43, 95% confidence interval (CI) 0.37, 0.49 for aggressive versus HR 0.61, 95% CI 0.56, 0.67 for non-aggressive) and regular use of aspirin (HR 0.70, 95% CI 0.61, 0.81 versus HR 0.84, 95% CI 0.77, 0.92) were stronger for aggressive than non-aggressive CRC (pHeterogeneity <0.05). Lower intake of whole grains or cereal fiber and greater dietary inflammatory potential were associated with a higher risk of aggressive but not non-aggressive CRC. The remaining risk factors showed comparable associations with aggressive CRC and non-aggressive CRC. Aggressive cases were more likely to have KRAS-mutated tumors but less likely to have distal or MSI-high tumors (p < .007). Similar results were observed for fatal CRC and advanced tumor stages at diagnosis. These findings provide initial evidence for the role of pre-diagnostic risk factors in the pathogenesis of aggressive CRC and suggest research priorities for preventive interventions.

Prodromal dementia with Lewy bodies in REM sleep behavior disorder: A multicenter study.

INTRODUCTION: Isolated/idiopathic rapid eye movement sleep behavior disorder (iRBD) is a powerful early predictor of dementia with Lewy bodies (DLB) and Parkinson's disease (PD). This provides an opportunity to directly observe the evolution of prodromal DLB and to identify which cognitive variables are the strongest predictors of evolving dementia. METHODS: IRBD participants (n = 754) from 10 centers of the International RBD Study Group underwent annual neuropsychological assessment. Competing risk regression analysis determined optimal predictors of dementia. Linear mixed-effect models determined the annual progression of neuropsychological testing. RESULTS: Reduced attention and executive function, particularly performance on the Trail Making Test Part B, were the strongest identifiers of early DLB. In phenoconverters, the onset of cognitive decline began up to 10 years prior to phenoconversion. Changes in verbal memory best differentiated between DLB and PD subtypes. DISCUSSION: In iRBD, attention and executive dysfunction strongly predict dementia and begin declining several years prior to phenoconversion. HIGHLIGHTS: Cognitive decline in iRBD begins up to 10 years prior to phenoconversion. Attention and executive dysfunction are the strongest predictors of dementia in iRBD. Decline in episodic memory best distinguished dementia-first from parkinsonism-first phenoconversion.

Lipopolysaccharide-binding protein and future Parkinson's disease risk: a European prospective cohort.

INTRODUCTION: Lipopolysaccharide (LPS) is the outer membrane component of Gram-negative bacteria. LPS-binding protein (LBP) is an acute-phase reactant that mediates immune responses triggered by LPS and has been used as a blood marker for LPS. LBP has recently been indicated to be associated with Parkinson's disease (PD) in small-scale retrospective case-control studies. We aimed to investigate the association between LBP blood levels with PD risk in a nested case-control study within a large European prospective cohort. METHODS: A total of 352 incident PD cases (55% males) were identified and one control per case was selected, matched by age at recruitment, sex and study center. LBP levels in plasma collected at recruitment, which was on average 7.8 years before diagnosis of the cases, were analyzed by enzyme linked immunosorbent assay. Odds ratios (ORs) were estimated for one unit increase of the natural log of LBP levels and PD incidence by conditional logistic regression. RESULTS: Plasma LBP levels were higher in prospective PD cases compared to controls (median (interquartile range) 26.9 (18.1-41.0) vs. 24.7 (16.6-38.4) µg/ml). The OR for PD incidence per one unit increase of log LBP was elevated (1.46, 95% CI 0.98-2.19). This association was more pronounced among women (OR 2.68, 95% CI 1.40-5.13) and overweight/obese subjects (OR 1.54, 95% CI 1.09-2.18). CONCLUSION: The findings suggest that higher plasma LBP levels may be associated with an increased risk of PD and may thus pinpoint to a potential role of endotoxemia in the pathogenesis of PD, particularly in women and overweight/obese individuals.

An international multicenter survey reveals health care providers' knowledge gap in childhood central nervous system tumors.

Childhood central nervous system (CNS) tumors have longer delays in diagnosis than do other pediatric malignancies because health care providers (HCPs) lack awareness about clinical presentation of these tumors. To evaluate the knowledge gap among HCPs, we conducted a global cross-sectional survey. The survey consisted of a set of CNS tumor knowledge questions focused on symptoms, signs, and imaging indications. The survey was disseminated to HCPs via email (November 2018-March 2020). Participants had to complete a pre-test survey, attend an education seminar on CNS tumors, and complete a post-test survey. The knowledge gap was evaluated using pre-test and post-test scores. We received 889 pre-test and 392 post-test responses. Most respondents were from Asia (73.1% of pre-test responses; 87.5% of post-test responses). The median pre-test score was 40.0% (range: 13.1-92.9%). A high percentage of correct answers were given in post-test responses (median score: 77.1%, range: 14.9-98.2%). In the pre-test, 18.7% of participants accurately responded that Cushing's triad was a less common symptom, and 15.0% recognized that children aged > 10 years are at risk of late diagnosis. Surprisingly, 21.9% falsely reported that patients with malignancy experienced the longest pre-diagnostic symptom interval, and 54.5% of respondents wrongly selected medulloblastoma as the most common CNS tumor. Overall, pediatricians demonstrated a greater knowledge gap on both surveys than did other specialties.  Conclusion: Pre- and post-test surveys revealed significant knowledge gaps in childhood CNS tumors among HCPs. Thus, raising professional awareness on clinical presentations of CNS tumors through educational strategies is important to address this knowledge deficit. What is Known: • Diagnostic delay in childhood central nervous system (CNS) tumors continues to be a significant problem that negatively impacts the quality of life and treatment sequelae. • Lack of medical education on CNS tumors is a contributing factor to this problem. What is New: • Most health care providers do not realize that low-grade tumors are the most common neoplasm in children. • Health care providers fail to recognize that teenagers and adolescents are a vulnerable age group for diagnostic delays, with the longest pre-diagnostic symptom interval.

Delay in the diagnosis of paediatric brain tumours: a systematic review.

PURPOSE: A delay in obtaining a diagnosis has been associated with inferior outcomes across several cancer types, including paediatric brain tumours. However, no clear evidence exists in this population. We aimed to quantify the reported pre-diagnostic symptom interval (PSI) as the time from onset of first symptoms to diagnosis in the literature, in addition to evaluating the relationship between delay and outcomes, including survival. METHODS: A systematic review of the literature was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. MEDLINE, Wiley Online Library, Web of Science and EMBASE databases were searched. We considered all sources published between 1st January 2010 and 5th November 2022. Children and adolescents aged under 21 years, with new symptomatic primary brain tumour diagnoses, were included. RESULTS: Of 3123 studies identified, 11 were included for analysis. Owing to study heterogeneity, a quantitative meta-analysis was not feasible; however, a narrative synthesis was performed. The median reported PSI varied widely, ranging between 28 and 760.8 days. We failed to identify a significant association between prolonged PSI and inferior overall survival. Few factors were consistently associated with prolonged PSI, amongst them only tumour grade and patient age. CONCLUSION: Delayed diagnosis of paediatric brain tumours was not associated with inferior survival within this review. This 'waiting time' paradox appears to result from several confounding factors including tumour biology, patient population and key systematic factors that were inconsistently reported. Diagnostic interval clearly presents a complex variable, reflected further by disparity in the reporting of delay within the literature. Ultimately diagnostic interval is unlikely to provide a meaningful representation for all tumour types and should not detract from sharp clinical acumen and prompt diagnosis.

Pre-diagnostic cognitive and functional impairment in multiple sporadic neurodegenerative diseases.

INTRODUCTION: The pathophysiological processes of neurodegenerative diseases begin years before diagnosis. However, pre-diagnostic changes in cognition and physical function are poorly understood, especially in sporadic neurodegenerative disease. METHODS: UK Biobank data were extracted. Cognitive and functional measures in individuals who subsequently developed Alzheimer's disease (AD), Parkinson disease, frontotemporal dementia, progressive supranuclear palsy, dementia with Lewy bodies, or multiple system atrophy were compared against individuals without neurodegenerative diagnoses. The same measures were regressed against time to diagnosis, after adjusting for the effects of age. RESULTS: There was evidence for pre-diagnostic cognitive impairment and decline with time, particularly in AD. Pre-diagnostic functional impairment and decline were observed in multiple diseases. DISCUSSION: The scale and longitudinal follow-up of UK Biobank participants provides evidence for cognitive and functional decline years before symptoms become obvious in multiple neurodegenerative diseases. Identifying pre-diagnostic functional and cognitive changes could improve selection for preventive and early disease-modifying treatment trials.

Early Detection of Pancreatic Cancer: Opportunities and Challenges.

Most patients with pancreatic ductal adenocarcinoma (PDAC) present with symptomatic, surgically unresectable disease. Although the goal of early detection of PDAC is laudable and likely to result in significant improvement in overall survival, the relatively low prevalence of PDAC renders general population screening infeasible. The challenges of early detection include identification of at-risk individuals in the general population who would benefit from longitudinal surveillance programs and appropriate biomarker and imaging-based modalities used for PDAC surveillance in such cohorts. In recent years, various subgroups at higher-than-average risk for PDAC have been identified, including those with familial risk due to germline mutations, a history of pancreatitis, patients with mucinous pancreatic cysts, and elderly patients with new-onset diabetes. The last 2 categories are discussed at length in terms of the opportunities and challenges they present for PDAC early detection. We also discuss current and emerging imaging modalities that are critical to identifying early, potentially curable PDAC in high-risk cohorts on surveillance.

Central adiposity at diagnosis may reduce prostate cancer-specific mortality in African-Caribbean men with prostate cancer: 10-year follow-up of participants in a case-control study.

PURPOSE: General and central adiposity are associated with the risk of developing prostate cancer (PCa), but the role of these exposures on PCa survival among men of African ancestry are less studied. This study aimed to investigate the association of anthropometry at diagnosis with all-cause and PCa-specific mortality and evaluate whether androgen deprivation therapy (ADT) modulated this risk. METHODS: Associations between body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR) at diagnosis and mortality were examined in 242 men with newly diagnosed PCa enrolled between 2005 and 2007 and re-evaluated 10.9 years later. Multi-variable Cox proportional hazard models were used to examine associations of body size variables (using standard WHO cut-points and as continuous variables) with mortality, adjusted for sociodemographic characteristics, Gleason score, smoking, diabetes, primary treatment, and ADT therapy. RESULTS: A total of 139 deaths (all-cause mortality 6.98/100 person-years) occurred (PCa-specific deaths, 56; other causes, 66; causes unknown, 17). In multi-variable analysis BMI, WC and WHR categories at diagnosis were not associated with all-cause mortality even after adjusting for ADT. While WHR (but not BMI or WC) when included as a continuous variable predicted lower PCa-specific mortality (multi-variable adjusted WHR per 0.1 difference: HR, 0.50; 95%CI 0.28, 0.93), the effect disappeared with ADT covariance and excluding deaths within the first 2 years. CONCLUSION: Our study suggests that central adiposity as measured by WHR may improve long-term survival among men of African ancestry. Metabolic studies to understand the mechanism for this association are needed.

Time to diagnosis and clinical characteristics in pediatric brain tumor patients.

PURPOSE: We aimed to identify factors that affect the time to diagnosis in pediatric brain tumors and investigate the effect of time to diagnosis on clinical outcome. METHODS: A retrospective study of children with brain tumors aged less than 18 years diagnosed at the University of Tsukuba Hospital over a period of 7 years was conducted. RESULTS: Eighty-five consecutive patients, with a mean age of 9.1 years, were included in the study. The median interval from symptom onset to diagnosis was 45 days (range 0-1673); median interval from symptom onset to first presentation was 31.0 days; and median interval from first presentation to diagnosis was 13.5 days. Germinoma had the longest interval from symptom onset to first presentation, and from first presentation to diagnosis. Patients presenting with endocrine disorder had a significantly longer interval from symptom onset to first presentation (p = 0.019); those with visual disturbance (p = 0.016) or endocrine disorder (p = 0.030) had significantly longer intervals from first presentation to diagnosis. CONCLUSION: Pediatric brain tumor patients with germinoma and presenting symptoms of endocrine disorder or visual disturbance have a longer time to diagnosis. Although improved prognosis is not clearly related to a shorter time to diagnosis, we believe that early diagnosis can lead to improved treatment and better quality of life. A detailed medical history and neuroimaging studies at the earliest time possible are important for early diagnosis.

Pre-diagnostic serum levels of EGFR and ErbB2 and genetic glioma risk variants: a nested case-control study.

Genetic variants have been associated with the risk of developing glioma, but functional mechanisms on disease phenotypic traits remain to be investigated. One phenotypic trait of glioblastoma is the mutation and amplification of the epidermal growth factor receptor (EGFR) gene. We investigated associations between pre-diagnostic serum protein concentrations of EGFR and ErbB2, both members of the EGFR family, and future risk of glioma. Further, we studied if EGFR glioma risk variants were associated with EGFR and ErbB2 serum levels. We assessed the associations between genetic glioma risk variants and serum concentrations of EGFR and ErbB2, as measured in pre-diagnostic cohort serum samples of 593 glioma patients and 590 matched cancer-free controls. High serum EGFR and ErbB2 levels were associated with risk of developing glioblastoma (P = 0.008; OR = 1.58, 95 % CI = 1.13-2.22 and P = 0.017, OR = 1.63, 95 % CI = 1.09-2.44, respectively). High serum ErbB2 concentration was also associated with glioma risk overall (P = 0.049; OR = 1.39, 95 % CI = 1.00-1.93). Glioma risk variants were not associated with high serum protein abundance. In contrast, the EGFR risk variant rs4947986 (T) was correlated with decreased EGFR serum levels (study cohort P = 0.024 and controls P = 0.009). To our knowledge, this is the first study showing an association of EGFR and ErbB2 serum levels with glioma more than a decade before diagnosis, indicating that EGFR and ErbB2 serum proteins are important in early gliomagenesis. However, we did not find evidence that glioma risk variants were associated with high pre-diagnostic serum concentrations of EGFR and ErbB2.

Prospective study of DNA methylation at LINE-1 and Alu in peripheral blood and the risk of prostate cancer.

BACKGROUND: Evidence suggests that global blood DNA methylation levels may be associated with the risk of various cancers, but no studies have evaluated this relationship for prostate cancer. METHODS: We used pyrosequencing to quantify DNA methylation levels at the long interspersed nuclear element 1 (LINE-1) and Alu repetitive elements in pre-diagnostic blood samples from 694 prostate cancer cases and 703 controls from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. We evaluated prostate cancer risk associated with the mean methylation level for each element using logistic regression, adjusting for potential confounders. RESULTS: We did not observe a significant association with prostate cancer for LINE-1 [odds ratio (OR) for the highest compared to the lowest quartile = 1.01, 95% confidence interval (CI): 0.73-1.39, Ptrend = 0.99] or Alu (OR = 0.94, 95% CI: 0.68-1.29, Ptrend = 0.69) methylation levels overall. However, for Alu, we observed that higher DNA methylation levels were associated with a significant increased risk for those diagnosed 4 or more years after blood draw (OR = 2.26, 95% CI: 1.27-4.00, Ptrend = 4.4 × 10(-3) ). In contrast, there was no association for those diagnosed 2 (OR = 1.13, 95% CI: 0.67-1.90, Ptrend = 0.64) or 3 years after draw (OR = 1.22, 95% CI: 0.71-2.07, Ptrend = 0.32), and a decreased risk for those diagnosed less than 2 years after draw (OR = 0.40, 95% CI: 0.25-0.65, Ptrend = 3.8 × 10(-5) ; Pheterogeneity = 5.3 × 10(-6) ). CONCLUSIONS: Although LINE-1 DNA methylation levels were not associated with prostate cancer, we observed an association for Alu that varied by time from blood draw to diagnosis. Our study suggests that elevated Alu blood DNA methylation levels several years before diagnosis may be associated with an increased prostate cancer risk.

Pre-diagnostic serum levels of inflammation markers and risk of ovarian cancer in the prostate, lung, colorectal and ovarian cancer (PLCO) screening trial.

OBJECTIVE: Pro-inflammatory mechanisms may explain the increased ovarian cancer risk linked to more lifetime ovulations, endometriosis, and exposure to talc and asbestos, as well as decreased risk with non-steroidal anti-inflammatory drugs. Limited data are available to estimate ovarian cancer risk associated with levels of circulating inflammatory markers. METHODS: We conducted a nested case-control study within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Pre-diagnostic serum levels of 46 inflammation-related biomarkers (11 with a priori hypotheses; 35 agnostic) were measured in 149 incident ovarian cancer cases and 149 matched controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression and adjusted for identified covariates. RESULTS: Increased ovarian cancer risk was associated with elevated levels of C-reactive protein (CRP) [tertile (T)3 vs. T1: OR (95% CI) 2.04 (1.06-3.93), p-trend=0.03], interleukin (IL)-1α [detectable vs. undetectable: 2.23 (1.14-4.34)] and tumor necrosis factor alpha (TNF-α) [T3 vs. T1: 2.21 (1.06-4.63), p-trend=0.04]. Elevated IL-8 was non-significantly associated with risk [T3 vs. T1: 1.86 (0.96-3.61), p-trend=0.05]. In analyses restricted to serous ovarian cancer (n=83), the associations with CRP and IL-8 remained or strengthened [CRP T3 vs. T1: 3.96 (1.14-11.14), p-trend=0.008; IL-8 T3 vs. T1: 3.05 (1.09-8.51), p-trend=0.03]. Elevated levels of CRP and TNF-α remained positively associated with ovarian cancer risk in analysis restricted to specimens collected at least 5years before diagnosis (n=56). CONCLUSION: These results suggest that CRP, IL-1α, IL-8, and TNF-α are associated with increased risk of subsequently developing ovarian cancer.

Duration of the pre-diagnostic interval in medulloblastoma is subgroup dependent.

BACKGROUND: Children presenting with medulloblastoma have a wide range of initial presenting symptoms. However, the influence of underlying tumor biology on the initial presentation of medulloblastoma is currently unknown. In light of the recent discovery of distinct medulloblastoma subgroups, we sought to define the initial presentation of childhood medulloblastoma in a subgroup specific manner. PROCEDURE: We assembled a cohort of 126 medulloblastoma cases at the Hospital for Sick Children between 1994 and 2012 and determined subgroup affiliation using nanoString. Clinical details pertaining to the initial presentation were determined through a retrospective chart review. RESULTS: The median pre-diagnostic interval across all medulloblastoma cases was 4 weeks (IQR: 4-12 weeks). Strikingly, when the pre-diagnostic interval was then determined in a subgroup specific manner, cases with WNT and Group 4 tumors showed significantly longer median pre-diagnostic intervals of 8 weeks compared to 2 weeks for SHH and 4 weeks for Group 3 (P = 0.0001). Younger age was significantly associated with a prolonged pre-diagnostic interval (P = 0.02 for all). When stratifying by subgroup the association with age was only significant in Group 4 (P = 0.04 for Group 4). Improved survival was significantly associated with a longer pre-diagnostic interval (P = 0.02), however is no longer significant when controlling for subgroup (P = 0.07). CONCLUSIONS: The duration of the pre-diagnostic interval in childhood medulloblastoma is highly subgroup dependent, further highlighting the clinical heterogeneity and biological relevance of the four principle subgroups of medulloblastoma.

Caregiver Perspectives on Telehealth Assessment and Other Supports for Infants with Early Developmental Concerns.

This study examined the experiences of families of children with developmental concerns in the first year of life, before formal diagnostic evaluations are typically conducted. We aimed to understand the impact of participation in a telehealth-based research evaluation in infancy, identify existing community-based supports perceived favorably by caregivers, and identify suggestions for future directions. Participants were recruited from an prior study evaluating a telehealth assessment for infants with early social communication delays. Here, we interviewed caregivers (n = 19) who participated in follow-up study in toddlerhood. Transcripts from the semi-structured interviews were transcribed and analyzed using both inductive thematic and content coding approaches. Analysis of these interviews resulted in four core themes describing caregiving during this time: (1) Caregivers felt lonely, overwhelmed, and dismissed by providers, leading to feelings of uncertainty about their child's development and future; (2) Telehealth assessments were appreciated because external supports are minimal, complex to navigate, and do not address all areas of need; (3) Desire for additional community and connection; and (4) Information is power. Caregivers reported participating in the telehealth assessments helped them to feel reassured, validated and supported. Outside the study, they sought a wide variety of services and resources. The most frequent requests were for parent coaching sessions and family navigation. Caregivers experienced uncertainty and disempowerment during the pre-diagnostic period and sought education and guidance during this time. Findings reflect the importance of centering family priorities when developing early intervention services for infants with elevated likelihood of autism.

Novel DNA methylation-based epigenetic signatures in colorectal cancer from peripheral blood leukocytes.

Colorectal cancer (CRC) is a multifactorial disease characterized by accumulation of multiple genetic and epigenetic alterations, transforming colonic epithelial cells into adenocarcinomas. Alteration of DNA methylation (DNAm) is a promising biomarker for predicting cancer risk and prognosis, but its role in CRC tumorigenesis is inconclusive. Notably, few DNAm studies have used pre-diagnostic peripheral blood (PB) DNA, causing difficulty in postulating the underlying biologic mechanism of CRC initiation. We conducted epigenome-wide association (EWA) scans in postmenopausal women from Women's Health Initiative (WHI) with their pre-diagnostic DNAm in PB leukocytes (PBLs) to prospectively evaluate CRC development. Our site-specific DNAm analyses across the genome adjusted for DNAm-age, leukocyte heterogeneities, as well as body mass index, diabetes, and insulin resistance. We validated 20 top EWA-CpGs in 2 independent CRC tissue datasets. Also, we detected differentially methylated regions (DMRs) associated with CRC, further mapped to transcriptomic profile, and finally conducted a Gene Set Enrichment Analysis. We detected multiple novel CpGs validated across WHI and tissue datasets. In particular, 2 CpGs (B4GALNT4cg10321339, SV2Bcg18144285) had the strongest effect on CRC risk. Results from our DMR scans contained MIR663cg06007966, which was also validated in EWA analyses. Also, we detected 1 methylome region in PEG10 of Chr7 shared across datasets. Our findings reflect both novel and well-established epigenomic and transcriptomic sites in CRC, warranting further functional validations. Our study contributes to better understanding of the complex interrelated mechanisms on the methylome underlying CRC tumorigenesis and suggests novel preventive DNAm-targets in PBLs for detecting at-risk individuals for CRC development.

Temporal progression of pancreatic cancer computed tomography findings until diagnosis: A large-scale multicenter study.

BACKGROUND: Focal parenchymal atrophy and main pancreatic duct (MPD) dilatation have been identified as early signs of pancreatic ductal adenocarcinoma. However, limited evidence exists regarding their temporal progression due to previous study limitations with restricted case numbers. OBJECTIVE: To ascertain a more precise frequency assessment of suspicious pancreatic ductal adenocarcinoma findings as well as delineate the temporal progression of them. METHODS: A multicenter retrospective study was conducted on patients diagnosed with pancreatic ductal adenocarcinoma between 2015 and 2021. We included patients who had undergone at least one computed tomography (CT) scan ≥6 months before diagnosing pancreatic ductal adenocarcinoma. The temporal progression of suspicious pancreatic ductal adenocarcinoma findings on CT was investigated. RESULTS: Out of 1832 patients diagnosed with pancreatic ductal adenocarcinoma, 320 had a previous CT before their diagnosis. Suspicious pancreatic ductal adenocarcinoma findings were detected in 153 cases (47.8%), with focal parenchymal atrophy (26.6%) being the most common followed by MPD dilatation (11.3%). Focal parenchymal atrophy was the earliest detectable sign among all suspicious findings and became visible on average 2.7 years before diagnosis, and the next most common, MPD dilatation, 1.1 years before diagnosis. Other findings, such as retention cysts, were less frequent and appeared around 1 year before diagnosis. Focal parenchymal atrophy followed by MPD dilatation was observed in 10 patients but not in reverse order. Focal parenchymal atrophy was more frequently detected in the pancreatic body/tail. No significant relationship was found between the pathological pancreatic ductal adenocarcinoma differentiation or tumor stage and the time course of the CT findings. All cases of focal parenchymal atrophy progressed just prior to diagnosis, and the atrophic area was occupied by tumor at diagnosis. Main pancreatic duct dilatation continued to progress until diagnosis. CONCLUSION: This large-scale study revealed that the temporal progression of focal parenchymal atrophy is the earliest detectable sign indicating pancreatic ductal adenocarcinoma. These results provide crucial insights for early pancreatic ductal adenocarcinoma detection.

Pre-diagnostic blood biomarkers for adult glioma.

Glioma is one of the most common malignant primary brain tumours in adults, of which, glioblastoma is the most prevalent and malignant entity. Glioma is often diagnosed at a later stage of disease progression, which means it is associated with significant mortality and morbidity. Therefore, there is a need for earlier diagnosis of these tumours, which would require sensitive and specific biomarkers. These biomarkers could better predict glioma onset to improve diagnosis and therapeutic options for patients. While liquid biopsies could provide a cheap and non-invasive test to improve the earlier detection of glioma, there is little known on pre-diagnostic biomarkers which predate disease detection. In this review, we examine the evidence in the literature for pre-diagnostic biomarkers in glioma, including metabolomics and proteomics. We also consider the limitations of these approaches and future research directions of pre-diagnostic biomarkers for glioma.

Pre-diagnostic prescribing patterns in dyspnoea patients with as-yet-undiagnosed lung cancer: A longitudinal study of linked primary care and cancer registry data.

INTRODUCTION: Patients with as-yet undiagnosed lung cancer (LC) can present to primary care with non-specific symptoms such as dyspnoea, often in the context of pre-existing chronic obstructive pulmonary disease (COPD). Related medication prescriptions pre-diagnosis might represent opportunities for earlier diagnosis, but UK evidence is limited. Consequently, we explored prescribing patterns of relevant medications in patients who presented with dyspnoea in primary care and were subsequently diagnosed with LC. METHOD: Linked primary care (Clinical Practice Research Datalink) and National Cancer Registry data were used to identify 5434 patients with incident LC within a year of a dyspnoea presentation in primary care between 2006 and 2016. Primary care prescriptions relevant to dyspnoea management were examined: antibiotics, inhaled medications, oral steroids, and opioid analgesics. Poisson regression models estimated monthly prescribing rates during the year pre-diagnosis. Variation by COPD status (52 % pre-existing, 36 % COPD-free, 12 % new-onset) was examined. Inflection points were identified indicating when prescribing rates changed from the background rate. RESULTS: 63 % of patients received 1 or more relevant prescriptions 1-12 months pre-diagnosis. Pre-existing COPD patients were most prescribed inhaled medications. COPD-free and new-onset COPD patients were most prescribed antibiotics. Most patients received 2 or more relevant prescriptions. Monthly prescribing rates of all medications increased towards time of diagnosis in all patient groups and were highest in pre-existing COPD patients. Increases in prescribing activity were observed earliest in pre-existing COPD patients 5 months pre-diagnosis for inhaled medications, antibiotics, and steroids, CONCLUSION: Results indicate that a diagnostic window of appreciable length exists for potential earlier LC diagnosis in some patients. Lung cancer diagnosis may be delayed if early symptoms are misattributed to COPD or other benign conditions.

Increased levels of microRNA-320 in blood serum and plasma is associated with imminent and advanced lung cancer.

Lung cancer (LC) incidence is increasing globally and altered levels of microRNAs (miRNAs) in blood may contribute to identification of individuals with LC. We identified miRNAs differentially expressed in peripheral blood at LC diagnosis and evaluated, in pre-diagnostic blood specimens, how long before diagnosis expression changes in such candidate miRNAs could be detected. We identified upregulated candidate miRNAs in plasma specimens from a hospital-based study sample of 128 patients with confirmed LC and 62 individuals with suspected but confirmed negative LC (FalsePos). We then evaluated the expression of candidate miRNAs in pre-diagnostic plasma or serum specimens of 360 future LC cases and 375 matched controls. There were 1663 miRNAs detected in diagnostic specimens, nine of which met our criteria for candidate miRNAs. Higher expression of three candidates, miR-320b, 320c, and 320d, was associated with poor survival, independent of LC stage and subtype. Moreover, miR-320c and miR-320d expression was higher in pre-diagnostic specimens collected within 2 years of LC diagnosis. Our results indicated that elevated levels of miR-320c and miR-320d may be early indications of imminent and advanced LC.