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Introduction: The localization, density but mostly the phenotype of tumor infiltrating lymphocytes (TIL) provide important information on the initial interaction between the host immune system and the tumor. Our objective was to assess the prognostic significance of T (CD3 + ), T regulatory (T reg ) (FoxP3 + ) and T memory (T mem ) (CD45RO + ) infiltrating lymphocytes and of genes associated with TIL in prostate cancer (PCa)., Methods: Immunohistochemistry (IHC) was used to assess the infiltration of CD3 + , FoxP3 + and CD45RO + cells in the tumor area, tumor margin and adjacent normal-like epithelium of a series of 98 PCa samples with long clinical follow-up. Expression of a panel of 31 TIL-associated genes was analyzed by Taqman Low-Density Array (TLDA) technology in another series of 50 tumors with long clinical follow-up. Kaplan-Meier and Cox proportional hazards regression analyses were performed to determine association of these markers with biochemical recurrence (BCR), need for definitive androgen deprivation therapy (ADT) or lethal PCa., Results: TIL subtypes were present at different densities in the tumor, tumor margin and adjacent normal-like epithelium, but their density and phenotype in the tumor area were the most predictive of clinical outcomes. In multivariate analyses, a high density of T reg (high FoxP3 + /CD3 + cell ratio) predicted a higher risk for need of definitive ADT (HR=7.69, p=0.001) and lethal PCa (HR=4.37, p=0.04). Conversely, a high density of T mem (high CD45RO + /CD3 + cell ratio) predicted a reduced risk of lethal PCa (HR=0.06, p=0.04). TLDA analyses showed that a high expression of FoxP3 was associated with a higher risk of lethal PCa (HR=5.26, p=0.02). Expression of CTLA-4, PD-1, TIM-3 and LAG-3 were correlated with that of FoxP3. Amongst these, only a high expression of TIM-3 was associated with a significant higher risk for definitive ADT in univariate Cox regression analysis (HR=3.11, p=0.01)., Conclusion: These results show that the proportion of T reg and T mem found within the tumor area is a strong and independent predictor of late systemic progression of PCa. Our results also suggest that inhibition of TIM-3 might be a potential approach to counter the immunosuppressive functions of T reg in order to improve the anti-tumor immune response against PCa., 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 Molina, LaRue, Simonyan, Hovington, Vittrant, Têtu, Fradet, Lacombe, Bergeron and Fradet.)

Objectives: To evaluate the International Society of Urological Pathology (ISUP) 5-tier grade grouping (GG) system of prostate cancers as well as previously proposed optimizations., Patients and Methods: The PROCURE biobank is a prospective cohort study of patients with localized prostate cancer who underwent radical prostatectomy in Quebec province between 2005 and 2013. Surgical specimens were graded by experienced genitourinary pathologists using 2019 ISUP criteria. Follow-up was conducted until November 2021. The current 5-tier and a proposed 6-tier GG system were evaluated, the latter having two changes: 1) Gleason 3 + 4 and 4 + 3 tumors with minor/tertiary Gleason 5 patterns were upgraded to GG 3 and 4, respectively; and 2) patients in GG5 were separated based on primary Gleason pattern (4 or 5). Cox proportional hazards models and Harrell's concordance (C) indices were used for statistical analyses., Results: 2003 patients were included (median follow-up: 8.7 years). The current 5-tier GG system predicted time to recurrence (hazard ratio [HR] 2.12, 95% confidence interval [95%CI] 1.99-2.25, C 0.717), androgen-deprivation therapy (HR 2.58, 95%CI 2.38-2.80, C 0.790), metastasis (HR 2.48, 95%CI 2.17-2.83, C 0.806), castration-resistant prostate cancer (HR 2.67, 95%CI 2.28-3.13, C 0.829), and cancer-specific mortality (HR 2.80, 95%CI 2.27-3.44, C 0.835). Goodness-of-fit further improved with the proposed 6-tier GG system, with Harrell's C of 0.733, 0.807, 0.827, 0.853, and 0.853, respectively., Conclusions: The 5-tier GG system predicted short- and long-term outcomes for patients with localized prostate cancer, and the proposed 6-tier GG system further improved its accuracy., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Prostate cancer (PCa) shows considerable variation in clinical outcomes between individuals with similar diseases. The initial host-tumor interaction as assessed by detailed analysis of tumor infiltrating immune cells within the primary tumor may dictate tumor evolution and late clinical outcomes. In this study, we assessed the association between clinical outcomes and dendritic cell (DC) or macrophage (MΦ) tumor infiltration as well as with expression of genes related to their functions., Methods: Infiltration and localization of immature DC, mature DC, total MΦ and M2-type MΦ was analyzed by immunohistochemistry in 99 radical prostatectomy specimens from patients with 15.5 years median clinical follow-up using antibodies against CD209, CD83, CD68 and CD163, respectively. The density of positive cells for each marker in various tumor areas was determined. In addition, expression of immune genes associated with DC and MΦ was tested in a series of 50 radical prostatectomy specimens by Taqman Low-Density Array with similarly long follow-up. Gene expression was classified as low and high after unsupervised hierarchical clustering. Numbers and ratio of positive cells and levels of gene expression were correlated with endpoints such as biochemical recurrence (BCR), need for definitive androgen deprivation therapy (ADT) or lethal PCa using Cox regression analyses and/or Kaplan-Meier curves., Results: Positive immune cells were observed in tumor, tumor margin, and normal-like adjacent epithelium areas. CD209 + and CD163 + cells were more abundant at the tumor margin. Higher CD209 + /CD83 + cell density ratio at the tumor margin was associated with higher risk of ADT and lethal PCa while higher density of CD163 + cells in the normal-like adjacent epithelium was associated with a higher risk of lethal PCa. A combination of 5 genes expressed at high levels correlated with a shorter survival without ADT and lethal PCa. Among these five genes, expression of IL12A and CD163 was correlated to each other and was associated with shorter survival without BCR and ADT/lethal PCa, respectively., Conclusion: A higher level of infiltration of CD209 + immature DC and CD163 + M2-type MΦ in the peritumor area was associated with late adverse clinical outcomes., 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 © 2023 Molina, LaRue, Simonyan, Hovington, Têtu, Fradet, Lacombe, Toren, Bergeron and Fradet.)

The COVID-19 pandemic has accelerated the deployment of telehealth services in many countries around the world. It also revealed many barriers and challenges to the use of digital health technologies in health organisations and systems that have persisted for decades. One of these barriers is what is known as the 'wrong pocket' problem - where an organisation or sector makes expenditures and investments to address a given problem, but the benefits (return on investment) are captured by another organisation or sector (the wrong pocket). This problem is the origin of many difficulties in public policies and programmes (e.g. education, environment, justice and public health), especially in terms of sustainability and scaling-up of technology and innovation. In this essay/perspective, we address the wrong pocket problem in the context of a major telehealth project in Canada. We show how the problem of sharing investments and expenses, as well as the redistribution of economies among the different stakeholders involved, may have threatened the sustainability and scaling-up of this project, even though it has demonstrated the clinical utility and contributed to improving the health of populations. In conclusion, the wrong pocket problem may be decisive in the reduced take-up, and potential failure, of certain telehealth programmes and policies. It is not enough for a telehealth service to be clinically relevant and 'efficient', it must also be mutually beneficial to the various stakeholders involved, particularly in terms of the equitable sharing of costs and benefits (return on investment) associated with the implementation of this new service model. Finally, the wrong pocket concept offers a helpful lens for studying the success, sustainability, and scale-up of digital transformations in health organisations and systems. This needs to be considered in future research and evaluations in the field., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Intraductal carcinoma of the prostate (IDC-P) is an aggressive histological subtype of prostate cancer (PCa) detected in approximately 20% of radical prostatectomy (RP) specimens. As IDC-P has been associated with PCa-related death and poor responses to standard treatment, the purpose of this study was to explore the immune infiltrate of IDC-P. Hematoxylin- and eosin-stained slides from 96 patients with locally advanced PCa who underwent RP were reviewed to identify IDC-P. Immunohistochemical staining of CD3, CD8, CD45RO, FoxP3, CD68, CD163, CD209 and CD83 was performed. For each slide, the number of positive cells per mm 2 in the benign tissues, tumor margins, cancer and IDC-P was calculated. Consequently, IDC-P was found in a total of 33 patients (34%). Overall, the immune infiltrate was similar in the IDC-P-positive and the IDC-P-negative patients. However, FoxP3 + regulatory T cells ( p < 0.001), CD68 + and CD163 + macrophages ( p < 0.001 for both) and CD209 + and CD83 + dendritic cells ( p = 0.002 and p = 0.013, respectively) were less abundant in the IDC-P tissues compared to the adjacent PCa. Moreover, the patients were classified as having immunologically "cold" or "hot" IDC-P, according to the immune-cell densities averaged in the total IDC-P or in the immune hotspots. The CD68/CD163/CD209-immune hotspots predicted metastatic dissemination ( p = 0.014) and PCa-related death ( p = 0.009) in a Kaplan-Meier survival analysis. Further studies on larger cohorts are necessary to evaluate the clinical utility of assessing the immune infiltrate of IDC-P with regards to patient prognosis and the use of immunotherapy for lethal PCa.

Objective: The accuracy of artificial intelligence (AI) in medicine and in pathology in particular has made major progress but little is known on how much these algorithms will influence pathologists' decisions in practice. The objective of this paper is to determine the reliance of pathologists on AI and to investigate whether providing information on AI impacts this reliance., Materials and Methods: The experiment using an online survey design. Under 3 conditions, 116 pathologists and pathology students were tasked with assessing the Gleason grade for a series of 12 prostate biopsies: (1) without AI recommendations, (2) with AI recommendations, and (3) with AI recommendations accompanied by information about the algorithm itself, specifically algorithm accuracy rate and algorithm decision-making process., Results: Participant responses were significantly more accurate with the AI decision aids than without (92% vs 87%, odds ratio 13.30, P &lt; .01). Unexpectedly, the provision of information on the algorithm made no significant difference compared to AI without information. The reliance on AI correlated with general beliefs on AI's usefulness but not with particular assessments of the AI tool offered. Decisions were made faster when AI was provided., Discussion: These results suggest that pathologists are willing to rely on AI regardless of accuracy or explanations. Generalization beyond the specific tasks and explanations provided will require further studies., Conclusion: This study suggests that the factors that influence the reliance on AI differ in practice from beliefs expressed by clinicians in surveys. Implementation of AI in prospective settings should take individual behaviors into account., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Significance: Prostate cancer is the most common cancer among men. An accurate diagnosis of its severity at detection plays a major role in improving their survival. Recently, machine learning models using biomarkers identified from Raman micro-spectroscopy discriminated intraductal carcinoma of the prostate (IDC-P) from cancer tissue with a ≥85  %   detection accuracy and differentiated high-grade prostatic intraepithelial neoplasia (HGPIN) from IDC-P with a ≥97.8  %   accuracy., Aim: To improve the classification performance of machine learning models identifying different types of prostate cancer tissue using a new dimensional reduction technique., Approach: A radial basis function (RBF) kernel support vector machine (SVM) model was trained on Raman spectra of prostate tissue from a 272-patient cohort (Centre hospitalier de l'Université de Montréal, CHUM) and tested on two independent cohorts of 76 patients [University Health Network (UHN)] and 135 patients (Centre hospitalier universitaire de Québec-Université Laval, CHUQc-UL). Two types of engineered features were used. Individual intensity features, i.e., Raman signal intensity measured at particular wavelengths and novel Raman spectra fitted peak features consisting of peak heights and widths., Results: Combining engineered features improved classification performance for the three aforementioned classification tasks. The improvements for IDC-P/cancer classification for the UHN and CHUQc-UL testing sets in accuracy, sensitivity, specificity, and area under the curve (AUC) are (numbers in parenthesis are associated with the CHUQc-UL testing set): +4  %   (+8  %  ), +7  %   (+9  %  ), +2  %   (6%), +9 (+9) with respect to the current best models. Discrimination between HGPIN and IDC-P was also improved in both testing cohorts: +2.2  %   (+1.7  %  ), +4.5  %   (+3.6  %  ), +0  %   (+0  %  ), +2.3 (+0). While no global improvements were obtained for the normal versus cancer classification task [+0  %   (-2  %  ), +0  %   (-3  %  ), +2  %   (-2  %  ), +4 (+3)], the AUC was improved in both testing sets., Conclusions: Combining individual intensity features and novel Raman fitted peak features, improved the classification performance on two independent and multicenter testing sets in comparison to using only individual intensity features.

Using a modified RNA-sequencing (RNA-seq) approach, we discovered a new family of unusually short RNAs mapping to ribosomal RNA 5.8S, which we named dodecaRNAs (doRNAs), according to the number of core nucleotides (12 nt) their members contain. Using a new quantitative detection method that we developed, we confirmed our RNA-seq data and determined that the minimal core doRNA sequence and its 13-nt variant C-doRNA (doRNA with a 5' Cytosine) are the two most abundant doRNAs, which, together, may outnumber microRNAs. The C-doRNA/doRNA ratio is stable within species but differed between species. doRNA and C-doRNA are mainly cytoplasmic and interact with heterogeneous nuclear ribonucleoproteins (hnRNP) A0, A1 and A2B1, but not Argonaute 2. Reporter gene activity assays suggest that C-doRNA may function as a regulator of Annexin II receptor (AXIIR) expression. doRNAs are differentially expressed in prostate cancer cells/tissues and may control cell migration. These findings suggest that unusually short RNAs may be more abundant and important than previously thought.

Background: Prostate cancer (PC) is the most frequently diagnosed cancer in North American men. Pathologists are in critical need of accurate biomarkers to characterize PC, particularly to confirm the presence of intraductal carcinoma of the prostate (IDC-P), an aggressive histopathological variant for which therapeutic options are now available. Our aim was to identify IDC-P with Raman micro-spectroscopy (RμS) and machine learning technology following a protocol suitable for routine clinical histopathology laboratories., Methods and Findings: We used RμS to differentiate IDC-P from PC, as well as PC and IDC-P from benign tissue on formalin-fixed paraffin-embedded first-line radical prostatectomy specimens (embedded in tissue microarrays [TMAs]) from 483 patients treated in 3 Canadian institutions between 1993 and 2013. The main measures were the presence or absence of IDC-P and of PC, regardless of the clinical outcomes. The median age at radical prostatectomy was 62 years. Most of the specimens from the first cohort (Centre hospitalier de l'Université de Montréal) were of Gleason score 3 + 3 = 6 (51%) while most of the specimens from the 2 other cohorts (University Health Network and Centre hospitalier universitaire de Québec-Université Laval) were of Gleason score 3 + 4 = 7 (51% and 52%, respectively). Most of the 483 patients were pT2 stage (44%-69%), and pT3a (22%-49%) was more frequent than pT3b (9%-12%). To investigate the prostate tissue of each patient, 2 consecutive sections of each TMA block were cut. The first section was transferred onto a glass slide to perform immunohistochemistry with H&E counterstaining for cell identification. The second section was placed on an aluminum slide, dewaxed, and then used to acquire an average of 7 Raman spectra per specimen (between 4 and 24 Raman spectra, 4 acquisitions/TMA core). Raman spectra of each cell type were then analyzed to retrieve tissue-specific molecular information and to generate classification models using machine learning technology. Models were trained and cross-validated using data from 1 institution. Accuracy, sensitivity, and specificity were 87% ± 5%, 86% ± 6%, and 89% ± 8%, respectively, to differentiate PC from benign tissue, and 95% ± 2%, 96% ± 4%, and 94% ± 2%, respectively, to differentiate IDC-P from PC. The trained models were then tested on Raman spectra from 2 independent institutions, reaching accuracies, sensitivities, and specificities of 84% and 86%, 84% and 87%, and 81% and 82%, respectively, to diagnose PC, and of 85% and 91%, 85% and 88%, and 86% and 93%, respectively, for the identification of IDC-P. IDC-P could further be differentiated from high-grade prostatic intraepithelial neoplasia (HGPIN), a pre-malignant intraductal proliferation that can be mistaken as IDC-P, with accuracies, sensitivities, and specificities > 95% in both training and testing cohorts. As we used stringent criteria to diagnose IDC-P, the main limitation of our study is the exclusion of borderline, difficult-to-classify lesions from our datasets., Conclusions: In this study, we developed classification models for the analysis of RμS data to differentiate IDC-P, PC, and benign tissue, including HGPIN. RμS could be a next-generation histopathological technique used to reinforce the identification of high-risk PC patients and lead to more precise diagnosis of IDC-P., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: F.D. holds a fellowship co-sponsored by Mitacs and ODS Medical. ODS Medical is a medical device company. A.B. reports grant from Astellas Pharma Canada, Merck and IMV, personal fees from Merck, outside the submitted work; In addition, A.B. has an issued patent on MAGE antigen binding proteins with GSK biologicals.

Oncogenesis is driven by germline, environmental and stochastic factors. It is unknown how these interact to produce the molecular phenotypes of tumors. We therefore quantified the influence of germline polymorphisms on the somatic epigenome of 589 localized prostate tumors. Predisposition risk loci influence a tumor's epigenome, uncovering a mechanism for cancer susceptibility. We identified and validated 1,178 loci associated with altered methylation in tumoral but not nonmalignant tissue. These tumor methylation quantitative trait loci influence chromatin structure, as well as RNA and protein abundance. One prominent tumor methylation quantitative trait locus is associated with AKT1 expression and is predictive of relapse after definitive local therapy in both discovery and validation cohorts. These data reveal intricate crosstalk between the germ line and the epigenome of primary tumors, which may help identify germline biomarkers of aggressive disease to aid patient triage and optimize the use of more invasive or expensive diagnostic assays.

Dietary omega-3 fatty acids (ω3), particularly long-chain ω3 (LCω3), have protective effects against prostate cancer (PCa) in experimental studies. Observational studies are conflicting, possibly because of the biomarker used. This study aimed at evaluating associations between grade reclassification and ω3 levels assessed in prostatic tissue, red blood cells (RBC), and diet. We conducted a validation cross-sectional study nested within a phase II clinical trial. We identified 157 men diagnosed with low-risk PCa who underwent a first active surveillance repeat prostate biopsy session. Fatty acid (FA) intake was assessed using a food frequency questionnaire and their levels measured in prostate tissue and RBC. Associations were evaluated using logistic regression. At first repeat biopsy session, 39 (25%) men had high-grade PCa (grade group ≥2). We found that high LCω3-eicosapentaenoic acid (EPA) level in prostate tissue (odds ratio (OR) 0.25; 95% (confidence interval (CI) 0.08-0.79; p -trend = 0.03) was associated with lower odds of high-grade PCa. Similar results were observed for LCω3 dietary intake (OR 0.30; 95% CI 0.11-0.83; p -trend = 0.02) but no association for RBC. LCω3-EPA levels in the target prostate tissue are inversely associated with high-grade PCa in men with low-risk PCa, supporting that prostate tissue FA, but not RBC FA, is a reliable biomarker of PCa risk.

Clinical utility of new biomarkers often requires the identification of their optimal threshold. This external validation study was conducted to assess the performance of the preoperative plasma tumor markers HE4 and CA125 optimal cut-offs to predict cancer mortality in women with epithelial ovarian cancer (EOC). Participating women had upfront debulking surgery in the University Hospital of Quebec City (Canada) between 1998 and 2013. A total of 136 women participated in the training cohort (cohort 1) and 177 in the validation cohort (cohort 2). Preoperative plasma HE4 and CA125 levels were measured by Elecsys. Optimal thresholds were identified in the cohort 1 using time-dependent receiver operating characteristic (ROC) curves. Multivariate Cox models were used to validate the biomarkers using their optimal cut-offs in the cohort 2. The likelihood ratio (LR) test was done to test whether the biomarkers added prognostic information beyond that provided by standard prognostic factors. The Areas Under the Curves (AUC) for HE4 and CA125 were respectively 64.2 (95% CI: 54.7-73.6) and 63.1 (95%CI: 53.6-72.6). The optimal thresholds were 277 pmol/L for HE4 and 282 U/ml for CA125. Preoperative plasma HE4 (≥277 pmol/L) was significantly associated with EOC mortality (adjusted hazard ratio (aHR): 1.90; 95% CI:1.09-3.29). The prognostic effect of HE4 was strongest in the subgroup of women with serous ovarian cancer (aHR: 2.42; 95% CI: 1.25-4.68). Using a multivariate model including all standard prognostic factors, this association was maintained (aHR: 2.21; 95% CI: 1.15-4.23). In addition, preoperative plasma HE4 added prediction for death over the standard prognostic markers in women with serous tumors (p-value for LR-test: 0.01). Preoperative CA125 was not associated with cancer mortality, both in women with EOC and in those with serous tumors. Preoperative HE4 is a promising prognostic biomarker in EOC, especially in serous tumor., Competing Interests: Doctor Isabelle Bairati received a grant from Roche Diagnostics, Canada, for conducting this study. Roche Diagnostics approved the study protocol without any change. Roche Diagnostics was informed of the study results, as well as the interpretations done by the research team. They did not interfere in the writing of this manuscript. This funding does not alter our adherence to PLOS ONE policies on sharing data and materials.

Ovarian carcinoma is one of the most lethal malignancies, but only very few prognostic biomarkers are known. The degradome, comprising proteases, protease non-proteolytic homologues and inhibitors, have been involved in the prognosis of many cancer types, including ovarian carcinoma. The prognostic significance of the whole degradome family has not been specifically studied in high-grade serous ovarian cancer. A targeted DNA microarray known as the CLIP-CHIP microarray was used to identify potential prognostic factors in ten high-grade serous ovarian cancer women who had early recurrence (<1.6 years) or late/no recurrence after first line surgery and chemotherapy. In women with early recurrence, we identified seven upregulated genes (TMPRSS4, MASP1/3, SPC18, PSMB1, IGFBP2, CFI - encoding Complement Factor I - and MMP9) and one down-regulated gene (ADAM-10). Using immunohistochemistry, we evaluated the prognostic effect of these 8 candidate genes in an independent cohort of 112 high-grade serous ovarian cancer women. Outcomes were progression, defined according to CA-125 criteria, and death. Multivariate Cox proportional hazard regression models were done to estimate the associations between each protein and each outcome. High ADAM-10 expression (intensity of 2-3) was associated with a lower risk of progression (adjusted hazard ratio (HR): 0.51; 95% confidence interval (CI): 0.29-0.87). High complement factor I expression (intensity 2-3) was associated with a higher risk of progression (adjusted HR: 2.30, 95% CI: 1.17-4.53) and death (adjusted HR: 3.42; 95% CI: 1.72-6.79). Overall, we identified the prognostic value of two proteases, ADAM-10 and complement factor I, for high-grade serous ovarian cancer which could have clinical significance., (Crown Copyright © 2019. Published by Elsevier GmbH. All rights reserved.)

Purpose: We evaluated whether an increased body-mass index (BMI) and decreased physical activity increase the risk of locally advanced or high-risk prostate cancer (PCa) at radical prostatectomy (RP), and treatment failure after surgery., Methods: Data were collected from the PROCURE Biobank, a prospective cohort of patients with localized PCa undergoing RP in four academic centers in Québec between 2006 and 2013. Treatment failure was defined as biochemical recurrence and/or initiation of secondary, non-adjuvant therapy, and analyzed using the Kaplan-Meier method, log-rank tests, and Cox proportional-hazards models. Uni- and multivariate (ordered) logistic regression was used for time-independent variables., Results: 1813 patients were included. Median follow-up time was 69 months. Patients who reported a lower BMI were generally older, of Asian descent, and physically more active (p < 0.05). Younger, black, and overweight/obese patients reported less physical activity (p < 0.05). In multivariate analyses, a higher BMI increased the risk for locally advanced, high-risk PCa (defined as a pT3, N1 and/or Gleason 8-10 tumor; odds ratio 1.33, p < 0.001), but increased physical activity did not predict high-risk disease (odds ratio 0.84, p = 0.39). Patients with a higher BMI also had a larger prostate at surgery (odds ratio 1.13, p = 0.03). BMI and physical activity were not associated with positive surgical margins or time to treatment failure (p > 0.05)., Conclusions: BMI was an independent predictor for locally advanced, high-risk disease in this cohort of PCa patients undergoing RP, but was unrelated to treatment failure. Physical activity was not related to locally advanced, high-risk PCa or treatment failure.

Accurate quantification of the metabolic enzyme uridine diphospho-glucuronosyltransferase (UGT) UGT2B17 has been hampered by the high sequence identity with other UGT2B enzymes (as high as 94%) and by the lack of a specific antibody. Knowing the significance of the UGT2B17 pathway in drug and hormone metabolism and cancer, we developed a specific monoclonal antibody (EL-2B17mAb), initially validated by the lack of detection in liver microsomes of an individual carrying no UGT2B17 gene copy and in supersomes expressing UGT2B enzymes. Immunohistochemical detection in livers revealed strong labeling of bile ducts and variable labeling of hepatocytes. Expression levels assessed by immunoblotting were highly correlated to mass spectrometry-based quantification ( r = 0.93), and three major expression patterns (absent, low, or high) were evidenced. Livers with very low expression were carriers of the functional rs59678213 G variant, located in the binding site for the transcription factor forkhead box A1 (FOXA1) of the UGT2B17 promoter. The highest level of expression was observed for individuals carrying at least one rs59678213 A allele. Multiple regression analysis indicated that the number of gene copies explained only 8% of UGT2B17 protein expression, 49% when adding rs59678213, reaching 54% when including sex. The novel EL-2B17mAb antibody allowed specific UGT2B17 quantification and exposed different patterns of hepatic expression. It further suggests that FOXA1 is a key driver of UGT2B17 expression in the liver. The availability of this molecular tool will help characterize the UGT2B17 level in various disease states and establish more precisely the contribution of the UGT2B17 enzyme to drug and hormone metabolism., (Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.)

Objectives: To evaluate the five-tier Gleason grade group (GG) scoring of prostate cancers adopted by the International Society of Urology Pathology (ISUP) in 2014, and to propose modifications to optimize its performance., Patients and Methods: Data were obtained from PROCURE, a prospective cohort of patients with localized prostate cancer undergoing radical prostatectomy in Québec, 2006-2013. Surgical specimens were evaluated by genitourinary pathologists using 2014 ISUP criteria. Treatment failure was defined as biochemical recurrence and/or initiation of secondary, non-adjuvant therapy. Analyses were conducted using Kaplan-Meier methods, log-rank tests, Cox proportional hazards models and Harrell's concordance indices., Results: A total of 1 917 patients were included, with a median follow-up of 69 months. The 5-year treatment failure rates were 9.6%, 23.5%, 43.1%, 52.6% and 84.3% in GG1-5, respectively (P < 0.001 when comparing GG2 with GG3). Treatment failure rates for patients in GG2 and GG3 with tertiary Gleason 5 pattern were higher than patients in the same group without a tertiary pattern (P < 0.001), but were similar to rates for patients in GGs 3 or 4 without a tertiary pattern (P > 0.3). Primary Gleason pattern (4/5) predicted treatment failure in GG5 (5-year failure rates 82.3% vs 97.1%, respectively; P = 0.001). The five-tier GG system had greater accuracy as a prognostic indicator compared with the four-tier system (Harrell's concordance index 0.716 vs 0.676). When upgrading patients in GG2/3 with tertiary Gleason 5 pattern to patients in GG3/4, and separating patients in GG5 by primary Gleason pattern, the Harrell's concordance index increased to 0.730., Conclusion: The five-tier GG system increased accuracy for predicting treatment failure compared with the previous grading systems, but can be further improved., (© 2018 The Authors BJU International © 2018 BJU International Published by John Wiley & Sons Ltd.)

The cancer transcriptome is remarkably complex, including low-abundance transcripts, many not polyadenylated. To fully characterize the transcriptome of localized prostate cancer, we performed ultra-deep total RNA-seq on 144 tumors with rich clinical annotation. This revealed a linear transcriptomic subtype associated with the aggressive intraductal carcinoma sub-histology and a fusion profile that differentiates localized from metastatic disease. Analysis of back-splicing events showed widespread RNA circularization, with the average tumor expressing 7,232 circular RNAs (circRNAs). The degree of circRNA production was correlated to disease progression in multiple patient cohorts. Loss-of-function screening identified 11.3% of highly abundant circRNAs as essential for cell proliferation; for ∼90% of these, their parental linear transcripts were not essential. Individual circRNAs can have distinct functions, with circCSNK1G3 promoting cell growth by interacting with miR-181. These data advocate for adoption of ultra-deep RNA-seq without poly-A selection to interrogate both linear and circular transcriptomes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

It has been highlighted that the original article [1] contained a typesetting mistake in the family name of Dominique Trudel.

Background: The expression of high temperature requirement factor A1 (Htra1) has been reported to be decreased in ovarian carcinoma, but its prognostic effect remains undetermined., Methods: We evaluated the impact of HtrA1 downregulation in tumoral tissues on cancer progression and death in women with serous ovarian carcinoma. HtrA1 staining was performed on tissue microarrays (TMA) comprised of tumor samples from a cohort of 106 women who were diagnosed with primary high-grade serous ovarian carcinoma and receiving standard treatment at the Québec University Hospital between 1993 and 2006. HtrA1 expression was assessed visually (percentage of positive nuclei) and by digital image analysis (percentage of positive area). Cox regression multivariate models included standard prognostic factors and were used to estimate adjusted hazard ratios (aHR) for progression or death in the cohort., Results: By visual analysis, a low percentage of HtrA1-positive nuclei (< 10% vs ≥10%) tend to be associated with a lower risk of progression (aHR = 0.71; 95% Confidence interval (CI) = 0.46-1.09; P = 0.11) and mortality (aHR = 0.65; 95% CI = 0.41-1.04; P = 0.07). Low nuclear HtrA1 expression assessed by digital image analysis (< median % vs ≥ median %) showed a significant association with lower risk of progression (aHR = 0.62; 95% CI = 0.40-0.95; p = 0.03) and death (aHR = 0.60; 95% CI = 0.38-0.95; p = 0.03)., Conclusion: Altogether, our results demonstrate that nuclear downregulation of HtrA1 is associated with a better prognosis in women with high grade serous ovarian carcinoma.

Background: The Eastern Quebec Telepathology Network (EQTN) has been implemented in the province of Quebec (Canada) to support pathology and surgery practices in hospitals that are lack of pathologists, especially in rural and remote areas. This network includes 22 hospitals and serves a population of 1.7 million inhabitants spread over a vast territory. An evaluation of this network was conducted in order to identify and analyze the factors and issues associated with its implementation and deployment, as well as those related to its sustainability and expansion., Methods: Qualitative evaluative research based on a case study using: (1) historical analysis of the project documentation (newsletters, minutes of meetings, articles, ministerial documents, etc); (2) participation in meetings of the committee in charge of telehealth programs and the project; and (3) interviews, focus groups, and discussions with different stakeholders, including decision-makers, clinical and administrative project managers, clinicians (pathologists and surgeons), and technologists. Data from all these sources were cross-checked and synthesized through an integrative and interpretative process., Results: The evaluation revealed numerous socio-political, regulatory, organizational, governance, clinical, professional, economic, legal and technological challenges related to the emergence and implementation of the project. In addition to technical considerations, the development of this network was associated with major changes and transformations of production procedures, delivery and organization of services, clinical practices, working methods, and clinicaladministrative processes and cultures (professional/organizational)., Conclusion: The EQTN reflects the complex, structuring, and innovative projects that organizations and health systems are required to implement today. Future works should be more sensitive to the complexity associated with the emergence of telehealth networks and no longer reduce them to technological considerations., (© 2018 The Author(s); Published by Kerman University of Medical Sciences. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.)

Physical activity is associated with decreased breast cancer risk. The underlying biological mechanisms could include the reduction of the local inflammation in the breast tissue. We conducted a cross-sectional study to assess the association between the physical activity and the protein expression levels of eleven mediators of inflammation in normal breast tissue of 164 women having breast cancer. Information on total physical activity (household, occupational and recreational) performed during a one-year period was collected using a questionnaire. Normal breast tissue was obtained from mastectomy blocks distant from the tumor. The expression of the mediators of inflammation in normal breast tissue was visually evaluated by immunohistochemistry. Multivariate linear regression analyses were used to assess the prevalence ratios (PR) and 95% confidence intervals (CI) for higher protein expression levels of the mediators of inflammation in normal breast tissue across quartiles of physical activity. Higher total physical activity was associated with lower expression levels of the pro-inflammatory mediator TNF-α in normal breast epithelial tissue among all (PR=0.64, 95% CI=0.44-0.93 for the fourth quartile; P trend =0.013), premenopausal (PR=0.61, 95% CI=0.41-0.91 for the fourth quartile; P trend =0.014) and postmenopausal women (PR=0.45, 95% CI=0.21-0.96 for the fourth quartile; P trend =0.022). Conversely, higher total physical activity was associated with higher expression levels of the anti-inflammatory mediator IL-10 in normal breast epithelial tissue among all (PR=1.66, 95% CI=0.97-2.85 for the fourth quartile; P trend =0.071) and postmenopausal women (PR=4.69, 95% CI=1.26-17.43 for the fourth quartile; P trend =0.010). Our findings suggest a beneficial effect of physical activity on the local inflammatory profile in the breast tissue., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Chronic inflammation may be a causative factor in breast cancer. One possible underlying mechanism is the generation of oxidative stress, which may favor tumorigenic processes. Antioxidant consumption may, therefore, help reduce tissue inflammation levels. However, few studies have explored this relation in breast tissue. We aimed to evaluate correlations between antioxidant (vitamin A/retinol, vitamin C, vitamin E, β-carotene, α-carotene, lycopene, lutein/zeaxanthin, β-cryptoxanthin, selenium, and zinc) intakes and protein expression levels of interleukin (IL)-6, tumor necrosis factor-α, C-reactive protein, cyclooxygenase-2, leptin, serum amyloid A1, signal transducer and activator of transcription 3, IL-8, IL-10, lactoferrin, and transforming growth factor-β measured in the normal breast tissue of 160 women diagnosed with breast cancer. Antioxidant intakes were collected using a self-administered food frequency questionnaire. Inflammation marker expression was assessed by immunohistochemistry. Correlations between antioxidant intakes and inflammatory marker expression were evaluated using Spearman's partial correlation coefficients ( r) for all women and for premenopausal and postmenopausal women separately. After Bonferroni correction, negative correlations were observed between dietary β-tocopherol and IL-10 expression in all women combined ( r = -0.26, P = .003) and among postmenopausal women ( r = -0.39, P = .003). For all women, a negative correlation was found between total zinc intakes and IL-10 ( r = -0.26, P = .002). Among postmenopausal women, dietary selenium intake was negatively correlated with the expression of lactoferrin ( r = -0.39, P = .003). No associations were observed in premenopausal women. Our findings suggest that consumption of specific antioxidants, including β-tocopherol, zinc, and selenium, may act on the breast tissue through mechanisms affecting the expression of some inflammation markers, particularly among postmenopausal women.

Background: Intraductal carcinoma (IDC) and cribriform architecture (CA) represent unfavorable subpathologies in localized prostate cancer. We recently showed that IDC shares a clonal ancestry with the adjacent glandular adenocarcinoma., Objective: We investigated for the co-occurrence of "aggression" factors, genomic instability and hypoxia, and performed gene expression profiling of these tumors., Design, Setting, and Participants: A total of 1325 men were treated for localized prostate cancer from four academic institutions (University Health Network, CHU de Québec-Université Laval, Memorial Sloan Kettering Cancer Center [MSKCC], and Erasmus Medical Center). Pathological specimens were centrally reviewed. Gene copy number and expression, and intraprostatic oxygenation were assessed., Outcome Measurements and Statistical Analysis: IDC/CA was separately assessed for biochemical relapse risk in the Canadian and MSKCC cohorts. Both cohorts were pooled for analyses on metastasis., Results and Limitation: Presence of IDC/CA independently predicted for increased risks of biochemical relapse (HR Canadian 2.17, p<0.001; HR MSKCC 2.32, p=0.0035) and metastasis (HR pooled 3.31, p<0.001). IDC/CA+ cancers were associated with an increased percentage of genome alteration (PGA [median] 7.2 vs 3.0, p<0.001), and hypoxia (64.0% vs 45.5%, p=0.17). Combinatorial genomic-pathological indices offered the strongest discrimination for metastasis (C-index 0.805 [clinical+IDC/CA+PGA] vs 0.786 [clinical+IDC/CA] vs 0.761 [clinical]). Profiling of mRNA abundance revealed that long noncoding RNA, SChLAP1, was the only gene expressed at >3-fold higher (p<0.0001) in IDC/CA+ than in IDC/CA- tumors, independently corroborated by increased SChLAP1 RNA in situ hybridization signal. Optimal treatment intensification for IDC/CA+ prostate cancer requires prospective testing., Conclusions: The poor outcome associated with IDC and CA subpathologies is associated with a constellation of genomic instability, SChLAP1 expression, and hypoxia. We posit a novel concept in IDC/CA+ prostate cancer, "nimbosus" (gathering of stormy clouds, Latin), which manifests as increased metastatic capacity and lethality., Patient Summary: A constellation of unfavorable molecular characteristics co-occur with intraductal and cribriform subpathologies in prostate cancer. Modern imaging for surveillance and treatment intensification trials should be considered in this adverse subgroup., (Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Increased levels of pro-inflammatory markers and decreased levels of anti-inflammatory markers in the breast tissue can result in local inflammation. We aimed to investigate whether local inflammation in the breast tissue is associated with age-related lobular involution, a process inversely related to breast cancer risk. Levels of eleven pro- and anti-inflammatory markers were assessed by immunohistochemistry in normal breast tissue obtained from 164 pre- and postmenopausal breast cancer patients. Involution status of the breast (degree of lobular involution and the predominant lobule type) was microscopically assessed in normal breast tissue on hematoxylin-eosin stained mastectomy slides. Multivariate generalized linear models were used to assess the associations. In age-adjusted analyses, higher levels of pro-inflammatory markers IL-6, TNF-α, CRP, COX-2, leptin, SAA1 and IL-8; and anti-inflammatory marker IL-10, were inversely associated with the prevalence of complete lobular involution (all P≤0.04). Higher levels of the pro-inflammatory marker COX-2 were also associated with lower prevalence of predominant type 1/no type 3 lobules in the breast, an indicator of complete involution, in age-adjusted analysis (P = 0.017). Higher tissue levels of inflammatory markers, mainly the pro-inflammatory ones, are associated with less involuted breasts and may consequently be associated with an increased risk of developing breast cancer.

Background: Localized prostate cancer is clinically heterogeneous, despite clinical risk groups that represent relative prostate cancer-specific mortality. We previously developed a 100-locus DNA classifier capable of substratifying patients at risk of biochemical relapse within clinical risk groups., Objective: The 100-locus genomic classifier was refined to 31 functional loci and tested with standard clinical variables for the ability to predict biochemical recurrence (BCR) and metastasis., Design, Setting, and Participants: Four retrospective cohorts of radical prostatectomy specimens from patients with localized disease were pooled, and an additional 102-patient cohort used to measure the 31-locus genomic classifier with the NanoString platform., Outcome Measurements and Statistical Analysis: The genomic classifier scores were tested for their ability to predict BCR (n=563) and metastasis (n=154), and compared with clinical risk stratification schemes., Results and Limitations: The 31-locus genomic classifier performs similarly to the 100-locus classifier. It identifies patients with elevated BCR rates (hazard ratio=2.73, p<0.001) and patients that eventually develop metastasis (hazard ratio=7.79, p<0.001). Combining the genomic classifier with standard clinical variables outperforms clinical models. Finally, the 31-locus genomic classifier was implemented using a NanoString assay. The study is limited to retrospective cohorts., Conclusions: The 100-locus and 31-locus genomic classifiers reliably identify a cohort of men with localized disease who have an elevated risk of failure. The NanoString assay will be useful for selecting patients for treatment deescalation or escalation in prospective clinical trials based on clinico-genomic scores from pretreatment biopsies., Patient Summary: It is challenging to determine whether tumors confined to the prostate are aggressive, leading to significant undertreatment and overtreatment. We validated a test based on prostate tumor DNA that improves estimations of relapse risk, and that can help guide treatment planning., (Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objective: Inflammatory markers may be associated with breast cancer risk. We assessed the association between expression levels of proinflammatory (interleukin 6, tumor necrosis factor-α, C-reactive protein, cyclooxygenase 2, leptin, serum amyloid A1, interleukin 8, and signal transducer and activator of transcription 3) and anti-inflammatory markers (transforming growth factor-β, interleukin 10, and lactoferrin) in normal breast tissue with mammographic density, a strong breast cancer risk indicator, among 163 breast cancer patients., Methods: The expression of inflammatory markers was visually evaluated on immunohistochemistry stained slides. The percent mammographic density (PMD) was estimated by a computer-assisted method in the contralateral cancer-free breast. We used generalized linear models to estimate means of PMD by median expression levels of the inflammatory markers while adjusting for age and waist circumference., Results: Higher expression levels (above median) of the proinflammatory marker interleukin 6 were associated with higher PMD among all women (24.1% vs 18.5%, P = 0.007). Similarly, higher expression levels (above median) of the proinflammatory markers (interleukin 6, tumor necrosis factor-α, C-reactive protein, and interleukin 8) were associated with higher PMD among premenopausal women (absolute difference in the PMD of 8.8% [P = 0.006], 7.7% [P = 0.022], 6.7% [P = 0.037], and 16.5% [P = 0.032], respectively). Higher expression levels (above median) of the anti-inflammatory marker transforming growth factor-β were associated with lower PMD among all (18.8% vs 24.3%, P = 0.005) and postmenopausal women (14.5% vs 20.7%, P = 0.013)., Conclusions: Our results provide support for the hypothesized role of inflammatory markers in breast carcinogenesis through their effects on mammographic density. Inflammatory markers could be targeted in future breast cancer prevention interventions.

Alternative splicing at the human glucuronosyltransferase 1 gene locus (UGT1) produces alternate isoforms UGT1A&#95;i2s that control glucuronidation activity through protein-protein interactions. Here, we hypothesized that UGT1A&#95;i2s function as a complex protein network connecting other metabolic pathways with an influence on cancer cell metabolism. This is based on a pathway enrichment analysis of proteomic data that identified several high-confidence candidate interaction proteins of UGT1A&#95;i2 proteins in human tissues-namely, the rate-limiting enzyme of glycolysis pyruvate kinase (PKM), which plays a critical role in cancer cell metabolism and tumor growth. The partnership of UGT1A&#95;i2 and PKM2 was confirmed by coimmunoprecipitation in the HT115 colon cancer cells and was supported by a partial colocalization of these two proteins. In support of a functional role for this partnership, depletion of UGT1A&#95;i2 proteins in HT115 cells enforced the Warburg effect, with a higher glycolytic rate at the expense of mitochondrial respiration, and led to lactate accumulation. Untargeted metabolomics further revealed a significantly altered cellular content of 58 metabolites, including many intermediates derived from the glycolysis and tricarboxylic acid cycle pathways. These metabolic changes were associated with a greater migration potential. The potential relevance of our observations is supported by the down-regulation of UGT1A&#95;i2 mRNA in colon tumors compared with normal tissues. Alternate UGT1A variants may thus be part of the expanding compendium of metabolic pathways involved in cancer biology directly contributing to the oncogenic phenotype of colon cancer cells. Findings uncover new aspects of UGT functions diverging from their transferase activity., (Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.)

Introduction: Telomere length, a marker of cell aging, seems to be affected by the same factors thought to be associated with breast cancer prognosis., Objective: To examine associations of peripheral blood cell-measured telomere length with traditional and potential prognostic factors in breast cancer patients., Methods: We conducted a cross-sectional analysis of data collected before surgery from 162 breast cancer patients recruited consecutively between 01/2011 and 05/2012, at a breast cancer reference center. Data on the main lifestyle factors (smoking, alcohol consumption, physical activity) were collected using standardized questionnaires. Anthropometric factors were measured. Tumor biological characteristics were extracted from pathology reports. Telomere length was measured using a highly reproducible quantitative PCR method in peripheral white blood cells. Spearman partial rank-order correlations and multivariate general linear models were used to evaluate relationships between telomere length and prognostic factors., Results: Telomere length was positively associated with total physical activity (rs = 0.17, P = 0.033; Ptrend = 0.069), occupational physical activity (rs = 0.15, P = 0.054; Ptrend = 0.054) and transportation-related physical activity (rs = 0.19, P = 0.019; P = 0.005). Among post-menopausal women, telomere length remained positively associated with total physical activity (rs = 0.27, P = 0.016; Ptrend = 0.054) and occupational physical activity (rs = 0.26, P = 0.021; Ptrend = 0.056) and was only associated with transportation-related physical activity among pre-menopausal women (rs = 0.27, P = 0.015; P = 0.004). No association was observed between telomere length and recreational or household activities, other lifestyle factors or traditional prognostic factors., Conclusions: Telomeres are longer in more active breast cancer patients. Since white blood cells are involved in anticancer immune responses, these findings suggest that even regular low-intensity physical activity, such as that related to transportation or occupation, could be recommended to breast cancer patients., Competing Interests: The authors have declared that no competing interests exist.

Background: Androgen inactivation occurs mainly through the glucuronidation conjugative reaction mediated by UDP-glucuronosyltransferases (UGTs). This metabolic process is involved in the control of systemic and local androgen bioavailability., Objective: To examine the relationship among expression of the androgen-inactivating UGT2B28 enzyme, circulating steroid hormone levels, and clinical phenotype in prostate cancer (PCa)., Design, Setting, and Participants: We conducted an analysis of a high-density prostate tumor tissue microarray consisting of 239 localized PCa cases. The study of 51 additional PCa patients with no copies of UDP glucuronosyltransferase 2B subfamily, polypeptide B28 (UGT2B28) in their genomes was performed to confirm the importance of the enzyme on circulating hormone levels., Outcome Measurements and Statistical Analysis: Steroid hormones were measured by mass spectrometry. Multivariate Cox proportional hazard models assessed the influence of UGT2B28 on progression, and general linear model regression evaluated variations in hormone levels., Results and Limitations: Tumor overexpression of UGT2B28 was associated with lower prostate-specific antigen levels at diagnosis, higher Gleason scores, margin and nodal invasion status, and it was shown to be an independent prognostic factor associated with progression. Enzyme overexpression correlated with 30% higher circulating levels of testosterone (T) and dihydrotestosterone (DHT). Patients with no copies of UGT2B28 in their genomes have lower levels of T (19%), DHT (17%), its glucuronide metabolites (18-38%), and enhanced levels of the adrenal precursor androstenedione (36%)., Conclusions: The UGT2B28 steroid-inactivating pathway modifies circulating T and DHT levels, and UGT2B28 overexpression is associated with high-grade PCa. Our work has uncovered the role of UGT2B28 as a regulator of steroidogenesis and underscores the interconnectivity among the steroid-inactivation capacity of cancer cells, hormone levels, disease characteristics, and the risk of cancer progression., Patient Summary: The androgen-inactivating UGT2B28 enzyme influences hormone levels, clinical and pathologic factors, and the risk of cancer progression., (Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Targeting specifically primary prostate cancer (PCa) cells for immune therapy, gene therapy or molecular imaging is of high importance. The PCA3 long non-coding RNA is a unique PCa biomarker and oncogene that has been widely studied. This gene has been mainly exploited as an accurate diagnostic urine biomarker for PCa detection. In this study, the PCA3 promoter was introduced into a new transcriptional amplification system named the 3-Step Transcriptional Amplification System (PCA3-3STA) and cloned into type 5 adenovirus. PCA3-3STA activity was highly specific for PCa cells, ranging between 98.7- and 108.0-fold higher than that for benign primary prostate epithelial or non-PCa cells, respectively. In human PCa xenografts, PCA3-3STA displayed robust bioluminescent signals at levels that are sufficient to translate to positron emission tomography (PET)-based reporter imaging. Remarkably, when freshly isolated benign or cancerous prostate biopsies were infected with PCA3-3STA, the optical signal produced from primary PCa biopsies was significantly higher than from benign prostate biopsies (4.4-fold, p < 0.0001). PCA3-3STA therefore represents a PCa-specific expression system with the potential to target, with high accuracy, primary or metastatic PCa epithelial cells for imaging, vaccines, or gene therapy.

Objective: Physical activity may protect against breast cancer by modulating breast tissue composition. We evaluated the association of physical activity with two visual assessments of breast tissue composition-percentage of mammographic density (a radiologic observation) and age-related lobular involution (a histologic assessment)., Methods: Among 164 premenopausal and postmenopausal women with breast cancer, physical activity (household, occupational, and recreational) performed during the year preceding the diagnosis was evaluated using a validated questionnaire. Percentage of mammographic density was assessed in the contralateral breast by a computer-assisted method. Age-related lobular involution was assessed in normal breast tissue on H&E-stained slides. Multivariate generalized linear models were used to assess associations by quartiles of physical activity., Results: Overall, we observed no significant association between total physical activity and percentage of mammographic density or degree of lobular involution. However, occupational physical activity was significantly positively associated with the predominant type I/no type III lobules among premenopausal women (last quartile: prevalence ratio [PR], 5.92; P(trend )= 0.04). Although total physical activity was positively associated with the predominant type I/no type III lobules among premenopausal women (last quartile: PR, 2.61; P(trend) = 0.08), an inverse association was observed among postmenopausal women (last quartile: PR, 0.44; P(trend) = 0.01). Higher levels of household physical activity were significantly associated with higher prevalence of lower mammographic density and complete involution among postmenopausal women (last quartile: PR, 1.21; P(trend) = 0.01)., Conclusions: Physical activity may be associated with less dense and more involuted breasts. Physical activity's effect on mammographic density or age-related lobular involution may mediate, in part, its protective effect against breast cancer.

Background: The tumor proliferative index marker Ki-67 was shown to be associated with clinically significant outcomes in prostate cancer, but its clinical application has limitations due to lack of uniformity and consistency in quantification. Our objective was to compare the measurements obtained with digital image analysis (DIA) versus virtual microscopy (visual scoring (VS))., Methods: To do so, we compared the measurement distributions of each technique and their ability to predict clinically useful endpoints. A tissue microarray series from a cohort of 225 men who underwent radical prostatectomy was immunostained for Ki-67. The percentage of Ki-67 positive nuclei in malignant cells was assessed both by VS and DIA, and a H-score was calculated. The distribution and predictive ability of these scoring methods to predict biochemical recurrence (BCR) and death from prostate cancer (DPCa) were compared using Mann-Whitney test and C-index., Results: The measurements obtained with VS were similar to the DIA measurements (p = 0.73) but dissimilar to the H-score (p < 0.001). Cox regression models showed that Ki-67 was associated with BCR (HR 1.46, 95 % CI 1.10-1.94) and DPCa (HR 1.26, 95 % CI 1.06-1.50). C-indexes revealed that Ki-67 was a better predictor of DPCa (0.803, 0.8059 and 0.789; VS, DIA and H-score, respectively) than of BCR (0.625, 0.632 and 0.604; VS, DIA and H-score, respectively)., Conclusion: The measurement distributions and the predictive abilities of VS and DIA were similar and presented the same predictive behaviour in our cohort, supporting the role of Ki-67 proliferative index as an important prognostic factor of BCR and DPCa in prostate cancer post RP., Virtual Slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/6656878501536663.

The objective of this cohort study was to evaluate whether the immunohistochemical expression of tissue inhibitor of metalloprotease 2, matrix metalloproteinase (MMP) 2, and MMP-9 could predict the occurrence of death and progression in women with ovarian high-grade serous carcinoma (HGSC). A total of 100 women with primary HGSC who were treated by cytoreductive surgery and adjuvant chemotherapy at the Centre Hospitalier Universitaire de Québec (Canada) were included. Biomarker expression was evaluated by immunohistochemistry on tissue microarrays constructed from primary tumors. Immunostaining quantification was performed using digital image analysis, from algorithms created with Calopix software, and continuous H-score data were obtained. The cancer antigen-125 and/or the Response Evaluation Criteria In Solid Tumors criteria were used to define progression. Dates of death were obtained by record linkage with the Québec mortality files. Hazard ratios (HRs) of death and progression with their 95% confidence intervals (CIs) were estimated using the Cox proportional hazards regression model. Overall, a low variability of expression was observed for each marker. No association was found between the level of expression and standard prognostic factors. When assessed as a continuous variable, increased MMP-9 expression (10 units of H-score) was associated with death (HR, 1.08; 95% CI, 1.01-1.16; P = .02), but not with progression (HR, 1.03; 95% CI, 0.97-1.10; P = .29). There was no association between the expression of MMP-2 or tissue inhibitor of metalloprotease 2 and death or progression. In conclusion, in a homogeneous cohort of women with HGSC, increased MMP-9 tissue expression, as assessed by automated immunostaining quantification, was associated with a higher risk of death., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Aim: We determined whether the Y-box binding protein-1 (YB-1) and its binding partner, the X-linked ribosomal protein S4 (RPS4X), are associated with clinical outcome in bladder cancer., Materials & Methods: A population of 167 patients with muscle-invasive bladder tumor without evidence of metastasis at time of cystectomy was analyzed retrospectively. YB-1 and RPS4X expressions were evaluated immunohistochemically in tumors and analyzed for association with clinical variables and survival., Results: Kaplan-Meier and multivariate Cox regression analyses indicated that low expression of RPS4X was associated with a higher risk of death or disease recurrence. In contrast, YB-1 was not significantly associated with either recurrence-free or overall survival., Conclusion: Low RPS4X expression is associated with poor disease-specific and recurrence-free survival in bladder cancer.