PC Risk Research Articles

Finding the PSA-based screening stopping age using prostate cancer risk

BackgroundProstate Cancer screening was not rational for people who were suffered from other serious diseases and had a low quality of life. Biopsy and Prostate-Specific Antigen based screening also had imperfect information, pain, and costs. Finding the Prostate Cancer screening stopping age was important because after an age, Prostate-Specific Antigen test was not recommended and patients should not perform subsequent procedures. It could reduce the economic burden of Prostate Cancer. In this study, we modeled the effects of Prostate Cancer risk and comorbidities on the Prostate Cancer screening stopping age. Methodsfirst, using a Markov model for PC progression, we provided a model for optimal Prostate Cancer screening stopping age. Second, we explored the relationship between comorbidities effects, Prostate Cancer risk and the stopping age. ResultsOur results suggest that the stopping age was an increasing function of PC risk and comorbidities effects. Screening should be stopped before 70 years. Finding showed that for men with diseases such as stroke or heart diseases, screening should not be performed at any age. ConclusionsPersonalizing PC screening through paying more attention to PC risk can improve efficiency of screening. The role of personal characteristics such as race, family history, and previous PSA in PC screening decision-making was highlighted by stratifying men in different PC risk groups to find their stopping age. Incorporating comorbidity effects shows that severity of comorbidity was a crucial factor in PC screening stopping age decision-making process.

Genetic Susceptibility to Nonalcoholic Fatty Liver Disease and Risk for Pancreatic Cancer: Mendelian Randomization.

There are conflicting data on whether nonalcoholic fatty liver disease (NAFLD) is associated with susceptibility to pancreatic cancer. Using Mendelian randomization (MR), we investigated the relationship between genetic predisposition to NAFLD and risk for pancreatic cancer. Data from genome-wide association studies (GWAS) within the Pancreatic Cancer Cohort Consortium (PanScan; cases n = 5,090, controls n = 8,733) and the Pancreatic Cancer Case Control Consortium (PanC4; cases n = 4,163, controls n = 3,792) were analyzed. We used data on 68 genetic variants with four different MR methods [inverse variance weighting (IVW), MR-Egger, simple median, and penalized weighted median] separately to predict genetic heritability of NAFLD. We then assessed the relationship between each of the four MR methods and pancreatic cancer risk, using logistic regression to calculate ORs and 95% confidence intervals (CI), adjusting for PC risk factors, including obesity and diabetes. No association was found between genetically predicted NAFLD and pancreatic cancer risk in the PanScan or PanC4 samples [e.g., PanScan, IVW OR, 1.04; 95% confidence interval (CI), 0.88-1.22; MR-Egger OR, 0.89; 95% CI, 0.65-1.21; PanC4, IVW OR, 1.07; 95% CI, 0.90-1.27; MR-Egger OR, 0.93; 95% CI, 0.67-1.28]. None of the four MR methods indicated an association between genetically predicted NAFLD and pancreatic cancer risk in either sample. Genetic predisposition to NAFLD is not associated with pancreatic cancer risk. Given the close relationship between NAFLD and metabolic conditions, it is plausible that any association between NAFLD and pancreatic cancer might reflect host metabolic perturbations (e.g., obesity, diabetes, or metabolic syndrome) and does not necessarily reflect a causal relationship between NAFLD and pancreatic cancer.

Abstract B082: Autoimmune conditions and pancreatic cancer risk in older American adults

Abstract Pancreatic cancer (PC) is highly fatal, and its incidence is increasing in the United States. Population-based registry studies suggest associations between a few autoimmune conditions and PC risk, albeit based on a relatively small number of cases. We hypothesize that autoimmune conditions are associated with risk of PC. We conducted a population-based, nested case-control study to examine the association between autoimmune conditions and PC risk within the Surveillance, Epidemiology, and End Results Program (SEER)-Medicare population. Incident primary malignant PC cases (n=80,074) were adults > 66 years and diagnosed between 1992 and 2015. Controls (n=320,296) were alive at the time cases were diagnosed and frequency-matched to cases (4:1 ratio) by age, sex, and year of diagnosis. We used multivariable-adjusted, unconditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for 45 autoimmune conditions identified from Medicare claims. Eight autoimmune conditions including ankylosing spondylitis (OR = 1.45; 95% CI: 1.14-1.84), Graves’ disease (OR = 1.18; 95% CI: 1.03-1.34), localized scleroderma (OR = 1.27; 95% CI: 1.06-1.52), pernicious anemia (OR = 1.08; 95% CI: 1.02-1.14), primary sclerosing cholangitis (OR = 1.37; 95% CI: 1.18-1.59), pure red cell aplasia (OR = 1.31; 95% CI: 1.16-1.47), type 1 diabetes (OR = 1.11; 95% CI: 1.07-1.15), and ulcerative colitis (OR = 1.18; 95% CI: 1.07-1.31) were associated with increased PC risk (false discovery rate-adjusted P values < 0.10). In subtype analyses, these conditions were associated with pancreatic ductal adenocarcinoma, whereas only ulcerative colitis was associated with pancreatic neuroendocrine tumors. Our results support the hypothesis that autoimmune conditions may play a role in PC development. Citation Format: Fancheng Yuan, Ruth M. Pfeiffer, Sachelly Julian-Serrano, Simran Arjani, Michael J. Barrett, Jill Koshiol, Rachael Z. Stolzenberg-Solomon. Autoimmune conditions and pancreatic cancer risk in older American adults [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B082.

Family history, obesity, urological factors and diabetic medications and their associations with risk of prostate cancer diagnosis in a large prospective study

BackgroundProstate cancer (PC) aetiology is unclear. PC risk was examined in relation to several factors in a large population-based prospective study.MethodsMale participants were from Sax Institute’s 45 and Up Study (Australia) recruited between 2006 and 2009. Questionnaire and linked administrative health data from the Centre for Health Record Linkage and Services Australia were used to identify incident PC, healthcare utilisations, Prostate Specific Antigen (PSA) testing reimbursements and dispensing of metformin and benign prostatic hyperplasia (BPH) prescriptions. Multivariable Cox and Joint Cox regression analyses were used to examine associations by cancer spread, adjusting for various confounders.ResultsOf 107,706 eligible men, 4257 developed incident PC up to end 2013. Risk of PC diagnosis increased with: PC family history (versus no family history of cancer; HRadjusted = 1.36; 95% CI:1.21–1.52); father and brother(s) diagnosed with PC (versus cancer-free family history; HRadjusted = 2.20; 95% CI:1.61–2.99); severe lower-urinary-tract symptoms (versus mild; HRadjusted = 1.77; 95% CI:1.53–2.04) and vasectomy (versus none; HRadjusted = 1.08; 95% CI:1.00–1.16). PC risk decreased with dispensed prescriptions (versus none) for BPH (HRadjusted = 0.76; 95% CI:0.69–0.85) and metformin (HRadjusted = 0.57; 95% CI:0.48–0.68). Advanced PC risk increased with vasectomy (HRadjusted = 1.28; 95% CI:1.06–1.55) and being obese (versus normal weight; HRadjusted = 1.31; 95% CI:1.01–1.69).ConclusionVasectomy and obesity are associated with an increased risk of advanced PC. The reduced risk of localised and advanced PC associated with BPH, and diabetes prescriptions warrants investigation.

Pancreatic cancer risk: alcoholic and non-alcoholic beverages

This article provides an overview of the metaanalyzes (PubMed, 19952019) of alcohol and non-alcoholic (coffee, tea, dairy products) beverage consumption in relation to risk of pancreatic cancer PC (PubMed, 19952019). Increased the PC risk was associated with high alcohol intake. The increased risk for heavy drinking did not explained by residual confounding by history of pancreatitis or tobacco smoking or diabetes. Light-moderate alcohol intake may reduced the PC risk, probably due to the fasting insulin levels decrement, which leads to the diminished the РС risk. The association between alcohol and the PC was stronger in men than in women. Some metaanalyzes demonstrated that a small amount of coffee may reduce PC risk, and a large amount to increase PC risk. Another meta-analyzes have not confirmed any association between the PC risk and coffee or tea consumption. One meta-analysis revealed a direct association of the PC risk with the dairy products consumption, but most research showed no such connection. Nutrition is considered to be associated with the PC risk, but the degree of risk due to structure of beverages consumption (dose, duration, alcohol, coffee, tea, dairy products pattern) is still not clear.

Sustained Weight Loss, Weight Cycling, and Weight Gain During Adulthood and Pancreatic Cancer Incidence in the Women's Health Initiative.

Pancreatic cancer (PC) is the fourth leading cause of cancer mortality among women in the United States. Obesity is positively associated with PC risk. Current health recommendations focus on weight maintenance for healthy-weight individuals and weight loss for overweight/obese individuals; however, little research has assessed associations between PC risk and changes in weight throughout the life course. Using prospective cohort study data, we examined the relationship between baseline adulthood weight patterns self-reported between 1993 and 1998 and PC risk in 136,834 postmenopausal women with 873 incident PC cases through September 30, 2015, in the Women's Health Initiative. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox proportional hazards models, adjusting for age, smoking habits, heavy alcohol consumption, and body mass index. Compared with women with stable weight, no significant associations were found between steady weight gain (HR=1.01, 95% CI: 0.83, 1.22), sustained weight loss (HR=1.26, 95% CI: 0.85, 1.87), or weight cycling patterns (HR=1.08, 95% CI: 0.89, 1.30) and PC. Results were similar when the outcome definition was restricted to pancreatic adenocarcinoma cases. Overall, we did not find evidence to suggest that weight changes in adulthood significantly impact PC risk among postmenopausal women.

Abstract 2581: Dietary fat influences pancreatic cancer progression by altering cell membrane lipid content to impact the PI3K/AKT pathway

Abstract Pancreatic cancer (PC) is one of the few cancers for which incidence and mortality continue to rise despite increasing knowledge of its etiology and risk factors. Amongst the latter, dietary patterns are significantly associated with PC risk. Due to its relatively slow progression, preventive strategies represent a simple means to improve outcomes. We are interested in understanding the influence of diet on PC prevention and have studied the effects of polyunsaturated fatty acids (PUFAs) in the progression of the disease both in vitro (via PC cell lines) and in vivo (via EL-KrasG12D and p48Cre/LSL-KrasG12D mouse models that recapitulate IPMN- and PanIN-like lesions, respectively). Our data demonstrate that dietary PUFAs are incorporated into plasma membrane phospholipids (PL) affecting signal transduction, particularly PI3K/AKT signaling, supporting the emergence of membrane-targeted therapies. We evaluated the effects of diets supplemented with omega-3 (ω-3) or omega-6 (ω-6) PUFAs on neoplastic lesion development. This work supports that ω-3 reduces while ω-6 accelerates lesion penetrance, tumor formation and proliferation associated with changes in pAKT. These results were also recapitulated in vitro to confirm that reduced activity of the PI3K/AKT pathway when incubated with Docosahexaenoic Acid (DHA), the primary component of the ω-3 enriched diet. This effect was abrogated by over-activation of the pathway when dosed with the main component of the ω-6 enriched diet, Linoleic Acid (LA). Since PI3K depends on its binding to PIP2 in the membrane for its activity, we next aimed to study if PUFAs were altering PL composition. By using IF and stably-transfected PC cells with a fluorescent translocation biosensor to monitor PIP2 and PIP3 lipids in the membrane, we discovered an effect of exogenous fatty acids expressed as a ratio of PIP2 to PIP3 in the plasma membrane. Enriched areas of membrane GFP staining (or PIP3) were observed in LA-treated Panc-1 cells. DHA treatment prevented PIP3 localization in the membrane of tumor cells, keeping the GFP signal diffuse in the cytoplasm. Using the PIP2 biosensor we sought to study the affinity of PI3K for PIP2 depending on the incorporation of DHA or LA in PIP2. DHA treatment reduced PI3K interaction (not total PI3K) with PIP2 resulting in lower levels of PIP3 in the membrane and reduced pAKT activation. Our results are encouraging because these PUFAs impinge on AKT, a downstream target of Kras which serves as a logical alternative to the elusive therapies for Kras and often toxic effects of PI3K/AKT pathway inhibition. Citation Format: Carolina Torres, Georgina Mancinelli, Emily Chen, Jose Cordoba-Chacon, Danielle Pins, Ronald McKinney, Sara Saeed, Karla Castellanos, Giulia Orsi, Megha Singhal, Sam Grimaldo, Poorna Chandra Rao Yalagala, Papasani Subbaiah, Cecilia Leal, Paul Grippo. Dietary fat influences pancreatic cancer progression by altering cell membrane lipid content to impact the PI3K/AKT pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2581.

The Role of Ga-68-PSMA PET/CT in the Initial Staging of Prostate Cancer - A Single Center 4 Year Experience.

BackgroundRecommended imaging modalities for prostate cancer staging have disappointing sensitivities, whereas [68Ga]-PSMA PET/CT (PET-PSMA) shows promising sensitivities and specificities in the initial management of prostate cancer. Recent studies have revealed that a significant change of management when PET-PSMA was used, with favorable negative predictive values.MethodsIn this retrospective study, we analyzed every PET-PSMA performed in our center for initial staging of intermediate and high-risk prostate cancer. Patients were divided into two groups based on whether imaging modalities other than PET-PSMA were performed. In patients submitted to radical prostatectomy, PET-PSMA findings were compared to histological analysis of the specimen.ResultsPET-PSMA results of 57 patients were gathered, with 77.2% (n=44) having performed CT scan or bone scan (BS) prior to PET-PSMA. Prostate cancer management strategy was changed in 61.4% (n=27), when PET-PSMA was performed following CT and BS. BS and CT results were consistent with PET-PSMA in 43.2% and 44.8%, respectively. In 30 cases, a curative strategy was used based on PET-PSMA findings. PET-PSMA revealed a negative predictive value of 95.2% in 23 patients submitted to radical prostatectomy with bilateral pelvic lymphadenectomy. Prostate SUV values on preoperative PET-PSMA correlated with initial PSA, ISUP grade, PC risk staging and presence of extraprostatic lesions.ConclusionsPET-PSMA is a key element for prostate cancer staging and management, with high diagnostic accuracy. More prospective studies need to be implemented to determine its role as a first-line staging tool.

Impact of changing guidelines on genetic testing and surveillance recommendations in a contemporary cohort of breast cancer survivors with family history of pancreatic cancer

Changing practice guidelines and recommendations have important implications for cancer survivors. This study investigated genetic testing patterns and outcomes and reported family history of pancreatic cancer (FHPC) in a large registry population of breast cancer (BC) patients. Variables including clinical and demographic characteristics, FHPC in a first or second-degree relative, and genetic testing outcomes were analyzed for BC patients diagnosed between 2010 and 2018 in the NYU Langone Health Breast Cancer Database. Among 3334 BC patients, 232 (7%) had a positive FHPC. BC patients with FHPC were 1.68 times more likely to have undergone genetic testing (p < 0.001), but 33% had testing for BRCA1/2 only and 44% had no genetic testing. Pathogenic germline variants (PGV) were identified in 15/129 (11.6%) BC patients with FHPC, and in 145/1315 (11.0%) BC patients without FHPC. Across both groups, updates in genetic testing criteria and recommendations could impact up to 80% of this cohort. Within a contemporary cohort of BC patients, 7% had a positive FHPC. The majority of these patients (56%) had no genetic testing, or incomplete testing by current standards, suggesting under-diagnosis of PC risk. This study supports recommendations for survivorship care that incorporate ongoing genetic risk assessment and counseling.

A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer

BackgroundPancreatic cancer (PC) is a complex disease in which both non-genetic and genetic factors interplay. To date, 40 GWAS hits have been associated with PC risk in individuals of European descent, explaining 4.1% of the phenotypic variance.MethodsWe complemented a new conventional PC GWAS (1D) with genome spatial autocorrelation analysis (2D) permitting to prioritize low frequency variants not detected by GWAS. These were further expanded via Hi-C map (3D) interactions to gain additional insight into the inherited basis of PC. In silico functional analysis of public genomic information allowed prioritization of potentially relevant candidate variants.ResultsWe identified several new variants located in genes for which there is experimental evidence of their implication in the biology and function of pancreatic acinar cells. Among them is a novel independent variant in NR5A2 (rs3790840) with a meta-analysis p value = 5.91E−06 in 1D approach and a Local Moran’s Index (LMI) = 7.76 in 2D approach. We also identified a multi-hit region in CASC8—a lncRNA associated with pancreatic carcinogenesis—with a lowest p value = 6.91E−05. Importantly, two new PC loci were identified both by 2D and 3D approaches: SIAH3 (LMI = 18.24), CTRB2/BCAR1 (LMI = 6.03), in addition to a chromatin interacting region in XBP1—a major regulator of the ER stress and unfolded protein responses in acinar cells—identified by 3D; all of them with a strong in silico functional support.ConclusionsThis multi-step strategy, combined with an in-depth in silico functional analysis, offers a comprehensive approach to advance the study of PC genetic susceptibility and could be applied to other diseases.

Saturation excess overland flow accelerates the spread of a generalist soil-borne pathogen

Plant pathogens are a major agent of disturbance in ecosystems worldwide. Disturbance by diseases which inhibit plant water uptake can alter the hydrological function of affected ecosystems. However, many plant pathogens are also sensitive to soil moisture and can be propagated by the transport of infectious tissue or reproductive structures in surface flow, so that hydrological processes can drive pathogen infection. These feed-forward and feed-back processes set up the possibility of complex ecohydrological dynamics relating plant disease and the water cycle. Here the generalist root pathogen Phytophthora cinnamomi (Pc) is used as a case study to examine the potential importance of hydrological dynamics on disease spread. A numerical model of Pc growth and dispersal is used to investigate the importance of Pc transport in intermittent surface runoff compared to more continuous rhizosphere Pc spread via diffusion-like hyphal growth. We apply and test this model at two well-studied sites of Pc infection with contrasting hydrology: a Banksia woodland in Western Australia where deep sandy soils inhibit surface runoff, and an Erica heathland in the Spanish Central Plateau where relatively shallow soils on steep slopes generate intermittent saturation excess overland flow. Predictions of Pc spatial spread at the Spanish site improve when Pc transport in runoff is incorporated into the model, while no such improvements arise at the Australian site. Omitting transport in overland flow from model predictions at the Spanish site results in an average under-prediction of final pathogen patch areas by 350 m2 for each year of growth between observations, highlighting the importance of surface hydrological transport to Pc growth and spread and need for further studies. Hydrological theories that predict the occurrence of overland flow based on soil, topographic, and climate properties can be used to better incorporate this transport pathway and the influence of local hydrological processes in existing Pc risk assessment methods.

Biomarker discrimination and calibration with MRI-targeted biopsies: an analysis with the Stockholm3 test.

The validated Stockholm3 test is used to improve PC detection. Stockholm3, however, was developed using systematic biopsies. We aimed to assess Stockholm3 operating performance when using MRI-targeted biopsies for PC detection. A prospective cohort of 532 men was considered for prostate biopsy during 2016-2017. All men underwent Stockholm3 testing and MRI before biopsy. All PIRADs ≥3 lesion underwent targeted biopsy; all men underwent systematic biopsy. The primary outcome was ISUP Grade Group ≥2 (GG ≥ 2) PC. Detection strategies included: (1) systematic biopsies alone, (2) targeted biopsies alone, (3) targeted with associated systematic biopsies for MRI+, and (4) all biopsies in all men. For each strategy, the Stockholm3 operating characteristics were assessed with discrimination, calibration, and decision curve analysis (DCA). Median age was 65 years, median PSA was 6.2 ng/mL, median Stockholm3 score was 16.5%, and overall detection of GG ≥ 2 PC was 36% (193/532). Stockholm3 showed accurate discrimination for separating GG ≥ 2 cancer from benign and GG1, with an area under the curve of 0.84-0.86 depending on the biopsy strategy. Calibration analysis showed that Stockholm3 underestimated risks for GG ≥ 2 PC risk using MRI-targeted biopsies: there was a net benefit over biopsies in all men for Stockholm3 at risk thresholds varying from >3% in systematic biopsies to >15% in targeted with systematic biopsies in MRI+ men. When using a Stockholm3 score of >10% cutoff, a range of 32-38% of biopsies could be avoided while missing 5-11% of GG ≥ 2 PC and 0-3% of GG ≥ 3 PC. Stockholm3 shows high discriminatory performance in an MRI-targeted biopsy setting, however risks are underpredicted due to MRI-targeted biopsies being more sensitive than the systematic biopsies for which Stockholm3 was developed. Stockholm3, along with any risk prediction model developed for systematic prostate biopsy decisions, will need recalibration for optimal use in an MRI-driven biopsy setting.

Screening for pancreatic cancer: a review for general clinicians.

Pancreatic cancer (PC) is an exceptionally lethal malignancy with increasing incidence and mortality worldwide. One of the principal challenges in the treatment of PC is that the diagnosis is usually made at a late stage when potentially curative surgical resection is no longer an option. General clinicians including internists and family physicians are well positioned to identify high-risk individuals and refer them to centers with expertise in PC screening and treatment where screening modalities can be employed. Here, we provide an up-to-date review of PC precursor lesions, epidemiology, and risk factors to empower the general clinician to recognize high-risk patients and employ risk reduction strategies. We also review current screening guidelines and modalities and preview progress that is being made to improve screening tests and biomarkers. It is our hope that this review article will empower the general clinician to understand which patients need to be screened for PC, strategies that may be used to reduce PC risk, and which screening modalities are available in order to diminish the lethality of PC.

Clinical significance of PON1 L55M, Q192R and I102V polymorphisms and their association with prostate cancer risk in Polish men.

We tested the association between PON1 L55M, Q192R and I102V polymorphic variants and PC risk in Polish men. DNA from 110 consecutive, newly diagnosed patients hospitalized because of PC and DNA from 110 men - volunteers, healthy at the time of the study. PCR-RFLP method. In our study the average age at PC diagnosis of 55MM genotype carriers from families fulfilling Hereditary Prostate Criteria (HPC) was statistically significantly lower (by 7 years) than the average age at the disease diagnosis of 55MM carriers from families without HPC (54.6 ±6.7 vs. 61.9 ±5.4, respectively, p = 0.03). The probability of 5-year survival for the 55MM carriers was 81.3%, compared to 95.7% for non-carriers (p = 0.08, tendency). This is the first study in Polish men evaluating the impact of PON1 genetic polymorphisms on prostate cancer development and its clinical course. PON1 55MM variant may be probably associated with younger age at PC onset in men from families with HPC and with a shorter survival. However, more extensive studies on a larger number of PC patients, possibly from various populations, are necessary to confirm, and extend our findings.

Genetic counselling and personalised risk assessment in the Australian pancreatic cancer screening program

BackgroundPancreatic cancer (PC) is an aggressive disease with a dismal 5-year survival rate. Surveillance of high-risk individuals is hoped to improve survival outcomes by detection of precursor lesions or early-stage malignancy.MethodsSince 2011, a national high-risk cohort recruited through St Vincent’s Hospital, Sydney, has undergone prospective PC screening incorporating annual endoscopic ultrasound, formal genetic counselling and mutation analysis as appropriate. PancPRO, a Bayesian PC risk assessment model, was used to estimate 5-year and lifetime PC risks for familial pancreatic cancer (FPC) participants and this was compared to their perceived chance of pancreatic and other cancers. Genetic counselling guidelines were developed to improve consistency. Follow-up questionnaires were used to assess the role of genetic counselling and testing.ResultsWe describe the Australian PC screening program design and recruitment strategy and the results of the first 102 individuals who have completed at least one-year of follow-up. Seventy-nine participants met the FPC criteria (≥ two first-degree relatives affected), 22 individuals had both a BRCA2 pathogenic variant and a close relative with PC and one had a clinical diagnosis of Peutz-Jeghers syndrome. Participants reported a high perceived chance of developing PC regardless of their genetic testing status. PancPRO reported FPC participants’ mean 5-year and lifetime PC risks as 1.81% (range 0.2–3.2%) and 10.17% (range 2.4–14.4%), respectively. Participants’ perceived PC chance did not correlate with their PancPRO 5-year (r = − 0.17, p = 0.128) and lifetime PC risks (r = 0.19, p = 0.091). Two-thirds felt that current genetic testing would help them, and 91% of tested participants were glad to have undergone genetic testing. Overall, 79% of participants found genetic counselling to be helpful, and 88% reported they would recommend counselling to their relatives.ConclusionsParticipants reported multiple benefits of genetic counselling and testing but continue to seek greater clarification about their individual PC risk. Extension of PancPRO is required to enable personalised PC risk assessment for all high-risk sub-groups. More detailed discussion of PC risk for BRCA2 pathogenic variant carriers, providing a written summary in all cases and a plan for genetics review were identified as areas for improvement.

Functional polymorphisms in LncRNA HOTAIR contribute to susceptibility of pancreatic cancer

BackgroundPancreatic cancer (PC) remains one of the most aggressive cancers worldwide. However, genetic factors underlying PC susceptibility remain largely unclear. Long noncoding RNA (lncRNA) HOX transcript antisense RNA (HOTAIR) acts as an oncogene and its genetic variation has been linked to many cancers. However, the associations between genetic variants in HOTAIR gene and PC risk has not yet been reported.MethodsA two-stage, case–control study was conducted to investigate the associations between HOTAIR SNPs and the PC risk. Dual luciferase reporter assay and real-time -PCR (RT-PCR) was conducted to evaluate the potential regulatory function of HOTAIR rs4759314 and rs200349340.ResultsWe found the minor alleles of rs4759314 (OR = 1.76; 95 CI 1.37–2.25; P = 0.001) and rs200349340 (OR = 1.32; 95 CI 1.12–1.56; P = 0.001) were significantly associated with PC susceptibility. In functional experiments, we found subjects carrying the minor alleles of rs4759314 and rs200349340 had significantly higher HOTAIR RNA levels (mean ± SD) than those carrying the major alleles in PC tissues. For rs4759314, cells transfected with rs4759314 -G allele construct showed higher relative luciferase activity; while for rs200349340, cells transfected with rs200349340 -G allele construct showed more sensitive change of the relative luciferase activity.ConclusionOur studies revealed that functional SNP rs4759314 and rs200349340 of HOTAIR had strong associations with PC susceptibility. These findings elucidate that functional genetic variants influencing lncRNA expression may explain a portion of PC genetic basis.

G84E germline mutation in HOXB13 gene is associated with increased prostate cancer risk in Polish men.

We tested the association between HOXB13 G84E (rs138213197) germline mutation and PC risk in Polish men. DNA from 103 consecutive, newly diagnosed patients hospitalised because of PC and DNA from 103 men: volunteers, healthy at the time of the study. The G84E mutation was genotyped using Sanger sequencing. The HOXB13 G84E germline mutation was detected in 2.9% of PC men (3/103) and not detected in any healthy man. Two mutation carriers originated from two of 25 families fulfilling hereditary prostate cancer criteria (HPC) and one mutation carrier from one family among 78 families without HPC (PC frequency: 8% vs. 1.3%, OR=6.70, p=0.13). In two of three mutation carriers, disease was detected above 60 years of age. There was atrend for alower probability of 5-year survival in patients with G84E than in patients without it (66.7% vs. 94.0%, p=0.08). The HOXB13 G84E germline mutation is associated with increased prostate cancer risk in Polish men, with hereditary form of the disease, and probably with older age at PC onset (> 60 years of age) and shorter survival. However, it is not associated with PSA level, or PC stage or grade at the time of diagnosis.

Development of MR quantified pancreatic fat deposition as a cancer risk biomarker

BackgroundExcess body adiposity is associated with increased risk of pancreatic cancer, and in animal models excess intra-pancreatic fat is a driver of pancreatic carcinogenesis. Within a programme to evaluate pancreatic fat and PC risk in humans, we assessed whether MR-quantified pancreatic fat fraction (PFF) was ‘fit for purpose’ as an imaging biomarker. MethodsWe determined PFF using MR spectroscopy (MRS) and MR chemical shift imaging (CS-MR), in two groups. In Group I, we determined accuracy of MR-derived PFF with histological digital fat quantification in 12 patients undergoing pancreatic resection. In a second study, we assessed reproducibility in 15 volunteers (Group IIa), and extended to 43 volunteers (Group IIa & IIb) to relate PFF with MR-derived hepatic fat fraction (HFF), body mass index (BMI), and waist circumference (WC) using linear regression models. We assessed intra- and inter-observer, and between imaging modality levels of agreement using Bland-Altman plots. ResultsIn Group I patients, we found strong levels of agreement between MRS and CS-MR derived PFF and digitally quantified fat on histology (rho: 0.781 and 0.672 respectively). In Group IIa, there was poor reproducibility in initial assessments. We refined our protocols to account for 3D dimensionality of the pancreas, and found substantially improved intra-observer agreements. In Group II, HFF and WC were significantly correlated with PFF (p values < 0.05). InterpretationBoth CS-MR and MRS (after accounting for pancreatic 3D dimensionality) were ‘fit for purpose’ to determine PFF and might add information on cancer prediction independent from measures of general body adiposity.

A prospective study of Trichomonas vaginalis and prostate cancer risk among African American men.

BackgroundAfrican Americans (AA) have a higher prevalence of Trichomonas vaginalis (Tv) infection and a higher prostate (PC) risk. Past studies suggest an association between Tv seropositivity and PC, and therefore we prospectively investigated this association among AA men.ResultsIncident PC cases were individually matched to controls in a nested case–control study within the Southern Community Cohort Study (SCCS). Primary analysis included 296 PC cases and 497 race-matched controls. Levels of Tv antibody response were measured by ELISA in serum collected at baseline. Tv antibody response did not significantly differ between cases and controls overall or within AA participants (253 AA cases). There were no significant associations or trends between levels of Tv response and PC risk or the diagnosis of aggressive PC.ConclusionWe found no evidence of a prospective association between baseline Tv infection and PC risk in AA men. Tv infection in men may have substantial health implications in HIV transmission and reproductive outcomes, but may not impact future PC risk in AA men at high-risk for PC. Further efforts need to define past vs. present Tv infection and to separate pathophysiology from PC detection.

PD15-10 COMBINED ERSPC RISK CALCULATOR AND MULTIPARAMETRIC MRI FOR ADVANCED RISK MODELING OF PROSTATE CANCER

You have accessJournal of UrologyProstate Cancer: Detection & Screening IV1 Apr 2016PD15-10 COMBINED ERSPC RISK CALCULATOR AND MULTIPARAMETRIC MRI FOR ADVANCED RISK MODELING OF PROSTATE CANCER Jan Philipp Radtke, David Bonekamp, Martin Freitag, Claudia Verena Kesch, Celine Alt, Kamil Celik, Florian Distler, Kathrin Wieczorek, Matthias Claudius Roethke, Heinz-Peter Schlemmer, Markus Hohenfellner, and Boris Hadaschik Jan Philipp RadtkeJan Philipp Radtke More articles by this author , David BonekampDavid Bonekamp More articles by this author , Martin FreitagMartin Freitag More articles by this author , Claudia Verena KeschClaudia Verena Kesch More articles by this author , Celine AltCeline Alt More articles by this author , Kamil CelikKamil Celik More articles by this author , Florian DistlerFlorian Distler More articles by this author , Kathrin WieczorekKathrin Wieczorek More articles by this author , Matthias Claudius RoethkeMatthias Claudius Roethke More articles by this author , Heinz-Peter SchlemmerHeinz-Peter Schlemmer More articles by this author , Markus HohenfellnerMarkus Hohenfellner More articles by this author , and Boris HadaschikBoris Hadaschik More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.1136AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Multiparametric MRI (mpMRI) gains widespread acceptance in PC diagnosis and improves detection of significant PC (sPC). We added pre-biopsy mpMRI data to a European Randomised study of Screening for PC (ERSPC) risk calculator 4 (RC4) and developed a nomogram to predict individual sPC risk. METHODS First, clinical parameters of 755 men who underwent mpMRI prior to transperineal MRI/TRUS-fusion-biopsy between 2012 and 2014 were retrospectively analyzed as training sample. SPC was defined according to NCCN criteria (GS=3+3 and PSA>=10 ng/ml or GS>=3+4). A multivariate regression model was used to determine significant predictors of sPC in the training set and to develop a nomogram. The accuracy was compared to ERSPC RC4 and mpMRI alone (PI-RADS Likert score) by Receiver operating characteristics (ROC) curve. Based on the difference in accuracy, a sample size calculation was performed for a validation set. Subsequently, accuracy, discrimination and calibration of the nomogram were prospectively analyzed in 404 men. RESULTS Overall, PC occurred in 732 (63%) and sPC in 560 (48%) men. In the trainings set, 50% of men harbored PC and 78% of them sPC. In multivariate analysis, PSA, PSA-density, Likert score and ERSPC RC4 (each p<0.001) were significant predictors of sPC and used for the prediction model. In ROC analysis, Area under the curve (AUC) was highest for the novel nomogram (0.82), compared to 0.74 for ERSPC RC4 and 0.76 for Likert scoring. Based on the 0.08 benefit of the nomogram, 404 men were enrolled as prospective validation sample. In that subgroup, accuracy of the nomogram was best (0.79), compared to Likert scoring (0.78) and ERSPC RC4 (0.60). Calibration was analyzed using a calibration plot, demonstrating a good slope (0.94). However, the plot demonstrates slight overestimation of the prediction model. CONCLUSIONS We provide a new prostate cancer prediction model. This model incorporates both ERSPC RC4 and mpMRI data. Compared to clinical and MRI parameters alone, the model provides significantly more reliable non-invasive risk prediction of sPC. Thus, it can help to avoid unnecessary prostate biopsies. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e392-e393 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Jan Philipp Radtke More articles by this author David Bonekamp More articles by this author Martin Freitag More articles by this author Claudia Verena Kesch More articles by this author Celine Alt More articles by this author Kamil Celik More articles by this author Florian Distler More articles by this author Kathrin Wieczorek More articles by this author Matthias Claudius Roethke More articles by this author Heinz-Peter Schlemmer More articles by this author Markus Hohenfellner More articles by this author Boris Hadaschik More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...