Stage Shifting by Modifying the Determinants of Breast Cancer Stage at Diagnosis: A Simulation Study.

BACKGROUND: Breast cancer is the most common cancer in Canadian women; nearly 25% of women diagnosed with cancer have breast cancer. The early detection of breast cancer is a major challenge because tumours often grow without causing symptom. The diagnosis of breast cancer at an early stage (stages I and II) improves survival outcomes because treatments are more effective and better tolerated. To better inform the prevention of and screening for breast cancer, simulations using modifiable rather than non-modifiable risk factors may be helpful in shifting the stage at diagnosis downward. METHODS: Breast cancer stages were simulated using the data distributions from Alberta's Tomorrow Project participants who developed breast cancer. Using multivariable partial proportional odds regression models, modifiable lifestyle factors associated with the stage of cancer at diagnosis were evaluated. The proportions or mean levels of these lifestyle factors in the simulated population were systematically changed, then multiplied by their corresponding estimated odds ratios from the real data example. The effects of these changes were evaluated singly as well as cumulatively. RESULTS: Increasing total dietary protein (g/day) intake was the single most important lifestyle factor in shifting the breast cancer stage downwards followed by decreasing total dietary energy intake (kcal/day). Increasing the proportion of women who spend time in the sun between 11 am and 4 pm in the summer months, who have had a mammogram, who have been pregnant or reducing the proportion who are in stressful situations had much smaller effects. The percentage of Stage I diagnoses could be increased by approximately 12% with small modifications of these lifestyle factors. CONCLUSION: Shifting the breast cancer stage at diagnosis of a population may be achieved through changes to lifestyle factors. This proof of principle study that evaluated multiple factors associated with the stage at diagnosis in a population can be expanded to other cancers as well, providing opportunities for cancer prevention programs to target specific factors and identify populations at higher risk.

Assessing Breast Cancer Screening and Outcomes Among First Nations Women in Alberta.

BACKGROUND: Breast cancer (BC) incidence rates for First Nations (FN) women in Canada have been steadily increasing and are often diagnosed at a later stage. Despite efforts to expand the reach of BC screening programs for FN populations in Alberta (AB), gaps in screening and outcomes exist. METHODS: Existing population-based administrative databases including the AB BC Screening Program, the AB Cancer Registry, and an AB-specific FN registry data were linked to evaluate BC screening participation, detection, and timeliness of outcomes in this retrospective study. Tests of proportions and trends compared the findings between FN and non-FN women, aged 50-74 years, beginning in 2008. Incorporation of FN principles of ownership, control, access, and possession (OCAP®) managed respectful sharing and utilization of FN data and findings. RESULTS: The average age-standardized participation (2013-8) and retention rates (2015-6) for FN women compared to non-FN women in AB were 23.8% (P < .0001) and 10.3% (P = .059) lower per year, respectively. FN women were diagnosed with an invasive cancer more often in Stage II (P-value = .02). Following 90% completion of diagnostic assessments, it took 2-4 weeks longer for FN women to receive their first diagnosis as well as definitive diagnoses than non-FN women. CONCLUSION: Collectively, these findings suggest that access to and provision of screening services for FN women may not be equitable and may contribute to higher BC incidence and mortality rates. Collaborations between FN groups and screening programs are needed to eliminate these inequities to prevent more cancers in FN women.

Creation of a Métis-Specific Instrument for Cancer Screening: A Scoping Review of Cancer-Screening Programs and Instruments.

Understanding the barriers to and facilitators of cancer screening programs among Indigenous populations remains limited. In the spirit of mutual respect, this co-led, collaborative project was carried out between the Métis Nation of Alberta and Screening Programs from Alberta Health Services (AHS). This scoping review assessed the cancer screening literature for available questionnaires and then identified themes and suitable questions for a Métis-specific cancer screening questionnaire. Literature searches on cervical, breast, and colorectal cancer screening programs and related concepts were conducted in electronic databases, including the Native Health Database, MEDLINE (Ovid), PsycINFO, PubMed, PubMed Central, CINAHL, MEDLINE (Ebsco), Psychology & Behavioral Sciences Collection, and Web of Science. Grey literature was collected from AHS Insite, Open Archives Initiative repository, American Society of Clinical Oncology, European Society of Medical Oncology, Google, and Google Scholar. 135 articles were screened based on the eligibility criteria with 114 articles selected, including 14 Indigenous-specific ones. Knowledge, attitude, belief, behaviour, barrier, and facilitator themes emerged from the review, but no Métis-specific cancer screening instruments were found. Thus, one was developed using existing cancer screening instruments, with additional questions created by the project team. A survey of the Métis population in Alberta will use this questionnaire and provide data to address the burden of cancer among Métis people.

Health-Related and Psychosocial Factors Associated with Prostate Cancer Stage at Diagnosis among Males Participating in Alberta's Tomorrow Project.

Prostate cancer (PCa) stage at diagnosis is an important predictor of cancer prognosis. In Canada, over one-quarter of males are diagnosed with advanced-stage PCa. Studies have identified several factors associated with PCa stage at diagnosis; however, evidence from Canada is limited. This study aimed to examine associations between sociodemographic characteristics, health history, health practices, and psychosocial factors and PCa stage at diagnosis among males participating in Alberta's Tomorrow Project (ATP), a prospective cohort in Alberta, Canada. The study included males aged 35-69 years who developed PCa until January 2018. Factors associated with PCa stage at diagnosis were examined using partial proportional odds (PPO) ordinal regression models. A total of 410 males were diagnosed with PCa over the study period. A higher number of lifetime prostate-specific antigen tests were associated with earlier-stage PCa (OR 0.91, p = 0.02, 95% CI 0.83-0.99), while higher abdominal circumference (OR 1.02, p = 0.05, 95% CI 1.00-1.03), lower social support (OR 2.34, p < 0.01, 95% CI 1.31-4.17), and having children (OR 2.67, p < 0.01, 95% CI 1.38-5.16) were associated with later-stage disease. This study identified factors previously found in the literature as well as novel factors associated with PCa stage at diagnosis, which can help inform targets for cancer prevention programs to improve PCa prognosis.

Development and External Validation of Partial Proportional Odds Risk Prediction Models for Cancer Stage at Diagnosis among Males and Females in Canada.

Risk prediction models for cancer stage at diagnosis may identify individuals at higher risk of late-stage cancer diagnoses. Partial proportional odds risk prediction models for cancer stage at diagnosis for males and females were developed using data from Alberta's Tomorrow Project (ATP). Prediction models were validated on the British Columbia Generations Project (BCGP) cohort using discrimination and calibration measures. Among ATP males, older age at diagnosis was associated with an earlier stage at diagnosis, while full- or part-time employment, prostate-specific antigen testing, and former/current smoking were associated with a later stage at diagnosis. Among ATP females, mammogram and sigmoidoscopy or colonoscopy were associated with an earlier stage at diagnosis, while older age at diagnosis, number of pregnancies, and hysterectomy were associated with a later stage at diagnosis. On external validation, discrimination results were poor for both males and females while calibration results indicated that the models did not over- or under-fit to derivation data or over- or under-predict risk. Multiple factors associated with cancer stage at diagnosis were identified among ATP participants. While the prediction model calibration was acceptable, discrimination was poor when applied to BCGP data. Updating our models with additional predictors may help improve predictive performance.

Clinical and metabolomic characterization of Brivanib-Induced hypertension in metastatic colorectal cancer.

BACKGROUND: Trials of tyrosine kinase inhibitors (TKI) have not demonstrated dramatic benefits in advanced colorectal cancer (CRC), and this may be a function of poor patient selection. TKI-induced hypertension is reportedly a surrogate marker for treatment benefit for some tumor types. Our objective was to determine whether hypertension was associated with benefit in the context of CRC treatment, and also to gain insight on the pathogenesis of TKI-induced hypertension by monitoring associated changes in the circulating metabolome. PATIENTS AND METHODS: Clinical data were acquired from clinical trial patients with metastatic CRC randomized to cetuximab ± the TKI brivanib (N = 750). Outcomes were evaluated as a function of treatment-induced hypertension. For metabolomic studies, plasma samples were taken at baseline, as well as at 1, 4, and 12 weeks after treatment initiation. Samples were submitted to gas chromatography-mass spectrometry to identify treatment-related metabolomic changes associated with TKI-induced hypertension, compared to pre-treatment baseline. A model based on changes in metabolite concentrations was generated using orthogonal partial least squares discriminant analysis (OPLS-DA). RESULTS: In the brivanib treated group, 95 patients had treatment-related hypertension within 12 weeks of initiating treatment. TKI-induced hypertension was not associated with a significantly higher response rate, nor was it associated with improved progression-free or overall survival. In metabolomic studies, 386 metabolites were identified. There were 29 metabolites that changed with treatment and distinguished patients with and without TKI-induced hypertension. The OPLS-DA model for brivanib-induced hypertension was significant and robust (R2 Y score = 0.89, Q2 Y score = 0.70, CV-ANOVA = 2.01 e-7). Notable metabolomic features previously reported in pre-eclampsia and associated with vasoconstriction were found. CONCLUSION: TKI-induced hypertension was not associated with clinical benefit in metastatic CRC. We have identified changes in the metabolome that are associated with the development of worsening brivanib-induced hypertension that may be useful in future efforts of characterizing this toxicity.

Low Serum Vitamin D Associated With Increased Tumor Size and Higher Grade in Premenopausal Canadian Women With Breast Cancer.

INTRODUCTION: This study investigated the association of Vitamin D with tumor characteristics in pre and postmenopausal women. PATIENTS AND METHODS: A prospective cohort of 476 women with incident stage I-III breast cancer (BC) in Alberta, Canada comprised the study population. Vitamin D was measured as 25(OH)D concentration in serum samples collected at diagnosis (presurgery and prior to treatment initiation). Tumor characteristics including size, grade, receptor status, stage and nodal status were evaluated in regression models for association with Vitamin D and measured cytokines in models adjusted for menopausal status. RESULTS: More than half of the women were diagnosed as stage I and Luminal A/B, most were postmenopausal, had sufficient Vitamin D levels, and were 56.6 years of age on average. Higher vitamin D levels were associated with decreased tumor size for all women with larger effect seen in premenopausal status. Insufficient vitamin D levels were significantly associated with increased risk of higher grade, but only in premenopausal women. Elevated human granulocyte macrophage colony-stimulating factor was an independent risk factor associated with increased risk of higher-grade tumors. CONCLUSION: Women with sufficient Vitamin D levels at BC diagnosis had smaller and lower grade tumors compared to women with insufficient vitamin D, especially among premenopausal women. Maintaining adequate vitamin D levels in premenopausal women could improve prognostically important BC characteristics at diagnosis.

Health-Related and Behavioral Factors Associated With Lung Cancer Stage at Diagnosis: Observations From Alberta's Tomorrow Project.

BACKGROUND: Lung cancer is the leading cause of cancer death in Canada, with stage at diagnosis among the top predictors of lung cancer survival. Identifying factors associated with stage at diagnosis can help reduce lung cancer morbidity and mortality. This study used data from a prospective cohort study of adults living in Alberta, Canada to examine factors associated with lung cancer stage at diagnosis. METHODS: This cohort study used data from adults aged 35-69 years enrolled in Alberta's Tomorrow Project. Partial Proportional Odds models were used to examine associations between sociodemographic characteristics and health-related factors and subsequent lung cancer stage at diagnosis. RESULTS: A total of 221 participants (88 males and 133 females) developed lung cancer over the study period. Nearly half (48.0%) of lung cancers were diagnosed at a late stage (stage IV), whereas 30.8 % and 21.3% were diagnosed at stage I/II and III, respectively. History of sunburn in the past year was protective against late-stage lung cancer diagnosis (odds ratio (OR) .40, P=.005). In males, a higher number of lifetime prostate specific antigen tests was associated with reduced odds of late-stage lung cancer diagnosis (odds ratio .66, P=.02). Total recreational physical activity was associated with increased odds of late-stage lung cancer diagnosis (OR 1.08, P=.01). DISCUSSION: Lung cancer stage at diagnosis remains a crucial determinant of prognosis. This study identified important factors associated with lung cancer stage at diagnosis. Study findings can inform targeted cancer prevention initiatives towards improving early detection of lung cancer and lung cancer survival.

Pre-diagnosis lifestyle, health history and psychosocial factors associated with stage at breast cancer diagnosis - Potential targets to shift stage earlier.

BACKGROUND: Early detection of breast cancer improves survival, so identifying factors associated with stage at diagnosis may help formulate cancer prevention messages tailored for higher risk women. The goal of this study was to evaluate associations between multiple potential risk factors, including novel ones, measured before a breast cancer diagnosis and stage at diagnosis in women from Alberta, Canada. METHODS: Women enrolled in Alberta's Tomorrow Project completed health and lifestyle questionnaires on average 7 years before their breast cancer diagnosis. The association of previously identified and novel predictors with stage (I, II and III + IV) at diagnosis were simultaneously evaluated in partial proportional odds ordinal (PPO) regression models. RESULTS: The 492 women in this study were predominantly diagnosed in Stage 1 (51.4%), had college or university education (75.4%), were married or had a partner (74.6%), had been pregnant (90.2%), had taken birth control pills for any reason (86.8%), and had an average body mass index of 26.6. Most had at least one mammogram (83%) with five mammograms the average number. Nearly all reported previously having a breast health examination from a medical practitioner (92.5%). Statistically significant factors identified in the PPO model included protective ones (older age at diagnosis, high household income, parity, smoking, spending time in the sun during high ultraviolet times, having a mammogram and high daily protein intake) and ones that increased risk of later stage at diagnosis (a comorbidity, current stressful situations and high daily caloric intake). CONCLUSION: Shifting breast cancer stage at diagnosis downwards may potentially be achieved through cancer prevention programs that target higher risk groups such as women with co-morbidities, non-smokers and younger women who may be eligible for breast cancer screening.

Comparison of Two Automated Targeted Metabolomics Programs to Manual Profiling by an Experienced Spectroscopist for 1H-NMR Spectra.

Automated programs that carry out targeted metabolite identification and quantification using proton nuclear magnetic resonance spectra can overcome time and cost barriers that limit metabolomics use. However, their performance needs to be comparable to that of an experienced spectroscopist. A previously analyzed pediatric sepsis data set of serum samples was used to compare results generated by the automated programs rDolphin and BATMAN with the results obtained by manual profiling for 58 identified metabolites. Metabolites were selected using Student's t-tests and evaluated with several performance metrics. The manual profiling results had the highest performance metrics values, especially for sensitivity (76.9%), area under the receiver operating characteristic curve (0.90), precision (62.5%), and testing accuracy based on a neural net (88.6%). All three approaches had high specificity values (77.7-86.7%). Manual profiling by an expert spectroscopist outperformed two open-source automated programs, indicating that further development is needed to achieve acceptable performance levels.

Early detection of treatment futility in patients with metastatic colorectal cancer.

PURPOSE: Chemotherapy options for treating CRC have rapidly expanded in recent years, and few have predictive biomarkers. Oncologists are challenged with evidence-based selection of treatments, and response is evaluated retrospectively based on serial imaging beginning after 2-3 months. As a result, cumulative toxicities may appear in patients who will not benefit. Early recognition of non-benefit would reduce cumulative toxicities. Our objective was to determine treatment-related changes in the circulating metabolome corresponding to treatment futility. METHODS: Metabolomic studies were performed on serial plasma samples from patients with CRC in a randomized controlled trial of cetuximab vs. cetuximab + brivanib (N = 188). GC-MS quantified named 94 metabolites and concentrations were evaluated at baseline, Weeks 1, 4 and 12 after treatment initiation. In a discovery cohort (N = 68), a model distinguishing changes in metabolites associated with radiographic disease progression and response was generated using OPLS-DA. A cohort of 120 patients was used for validation of the model. RESULTS: By one week after treatment, a stable model of 21 metabolites could distinguish between progression and partial response (R2Y = 0.859; Q2Y = 0.605; P = 5e-4). In the validation cohort, patients with the biomarker had a significantly shorter OS (P < 0.0001). In a separate cohort of patients with HCC on axitinib, appearance of the biomarker also signified a shorter PFS (1.7 months vs. 9.2 months, P = 0.001). CONCLUSION: We have identified changes in the metabolome that appear within 1 week of starting treatment associated with treatment futility. The novel approach described is applicable to future efforts in developing a biomarker for early assessment of treatment efficacy.

The Alberta moving beyond breast cancer (AMBER) cohort study: baseline description of the full cohort.

PURPOSE: The Alberta Moving Beyond Breast Cancer (AMBER) Study is an ongoing prospective cohort study investigating how direct measures of physical activity (PA), sedentary behavior (SB), and health-related fitness (HRF) are associated with survival after breast cancer. METHODS: Women in Alberta with newly diagnosed stage I (≥ T1c) to IIIc breast cancer were recruited between 2012 and 2019. Baseline assessments were completed within 90 days of surgery. Measurements included accelerometers to measure PA and SB; a graded treadmill test with gas exchange analysis to measure cardiorespiratory fitness (VO2peak); upper and lower body muscular strength and endurance; dual-X-ray absorptiometry to measure body composition; and questionnaires to measure self-reported PA and SB. RESULTS: At baseline, the 1528 participants' mean age was 56 ± 11 years, 59% were post-menopausal, 62% had overweight/obesity, and 55% were diagnosed with stage II or III disease. Based on device measurements, study participants spent 8.9 ± 1.7 h/day sedentary, 4.4 ± 1.2 h/day in light-intensity activity, 0.9 ± 0.5 h/day in moderate-intensity activity, and 0.2 ± 0.2 h/day in vigorous-intensity activity. For those participants who reached VO2peak, the average aerobic fitness level was 26.6 ± 6 ml/kg/min. Average body fat was 43 ± 7.1%. CONCLUSION: We have established a unique cohort of breast cancer survivors with a wealth of data on PA, SB, and HRF obtained through both direct and self-reported measurements. Study participants are being followed for at least ten years to assess all outcomes after breast cancer. These data will inform clinical and public health guidelines on PA, SB, and HRF for improving breast cancer outcomes.

Predictors of CRC Stage at Diagnosis among Male and Female Adults Participating in a Prospective Cohort Study: Findings from Alberta's Tomorrow Project.

Colorectal cancer (CRC) is a leading cause of morbidity and mortality in Canada. CRC screening and other factors associated with early-stage disease can improve CRC treatment efficacy and survival. This study examined factors associated with CRC stage at diagnosis among male and female adults using data from a large prospective cohort study in Alberta, Canada. Baseline data were obtained from healthy adults aged 35-69 years participating in Alberta's Tomorrow Project. Factors associated with CRC stage at diagnosis were evaluated using Partial Proportional Odds models. Analyses were stratified to examine sex-specific associations. A total of 267 participants (128 males and 139 females) developed CRC over the study period. Among participants, 43.0% of males and 43.2% of females were diagnosed with late-stage CRC. Social support, having children, and caffeine intake were predictors of CRC stage at diagnosis among males, while family history of CRC, pregnancy, hysterectomy, menopausal hormone therapy, lifetime number of Pap tests, and household physical activity were predictive of CRC stage at diagnosis among females. These findings highlight the importance of sex differences in susceptibility to advanced CRC diagnosis and can help inform targets for cancer prevention programs to effectively reduce advanced CRC and thus improve survival.

Dipeptidase-1 Is an Adhesion Receptor for Neutrophil Recruitment in Lungs and Liver.

A hallmark feature of inflammation is the orchestrated recruitment of neutrophils from the bloodstream into inflamed tissue. Although selectins and integrins mediate recruitment in many tissues, they have a minimal role in the lungs and liver. Exploiting an unbiased in vivo functional screen, we identified a lung and liver homing peptide that functionally abrogates neutrophil recruitment to these organs. Using biochemical, genetic, and confocal intravital imaging approaches, we identified dipeptidase-1 (DPEP1) as the target and established its role as a physical adhesion receptor for neutrophil sequestration independent of its enzymatic activity. Importantly, genetic ablation or functional peptide blocking of DPEP1 significantly reduced neutrophil recruitment to the lungs and liver and provided improved survival in models of endotoxemia. Our data establish DPEP1 as a major adhesion receptor on the lung and liver endothelium and identify a therapeutic target for neutrophil-driven inflammatory diseases of the lungs.

Oncolytic immunotherapy and bortezomib synergy improves survival of refractory multiple myeloma in a preclinical model.

The oncolytic reovirus (RV) has demonstrated clinical efficacy and minimal toxicity in a variety of cancers, including multiple myeloma (MM). MM is a malignancy of plasma cells that is considered treatable but incurable because of the 90% relapse rate that is primarily from drug resistance. The systemic nature of MM and the antitumor immunosuppression by its tumor microenvironment presents an ongoing therapeutic challenge. In the present study, we demonstrate that RV synergizes with the standard-of-care MM drug bortezomib (BTZ) and, importantly, enhances its therapeutic potential in therapy-resistant human MM cell lines in vitro. Using the syngeneic Vk*MYC BTZ-resistant immunocompetent transplantable MM murine model, we also demonstrate that mice harboring BTZ-insensitive MM tumors respond to the RV/BTZ combination treatment in terms of decreased tumor burden and improved overall survival (P < .00001). We demonstrate that BTZ augments RV replication in tumor-associated endothelial cells and myeloma cells, leading to enhanced viral delivery and thereby stimulating cytokine release, immune activity, apoptosis, and reduction of the MM-associated immune suppression. We conclude that combined RV/BTZ is an attractive therapeutic strategy with no safety signals for the treatment of MM.

Serum Metabolomics of Activity Energy Expenditure and its Relation to Metabolic Syndrome and Obesity.

Modifiable lifestyle factors, including exercise and activity energy expenditure (AEE), may attenuate the unfavorable health effects of obesity, such as risk factors of metabolic syndrome (MetS). However, the underlying mechanisms are not clear. In this study we sought to investigate whether the metabolite profiles of MetS and adiposity assessed by body mass index (BMI) and central obesity are inversely correlated with AEE and physical activity. We studied 35 men and 47 women, aged 30-60 years, using doubly labeled water to derive AEE and the Sedentary Time and Activity Reporting Questionnaire (STAR-Q) to determine the time spent in moderate and vigorous physical activity. Proton nuclear magnetic resonance spectroscopy was used for serum metabolomics analysis. Serine and glycine were found in lower concentrations in participants with more MetS risk factors and greater adiposity. However, serine and glycine concentrations were higher with increasing activity measures. Metabolic pathway analysis and recent literature suggests that the lower serine and glycine concentrations in the overweight/obese state could be a consequence of serine entering de novo sphingolipid synthesis. Taken together, higher levels of AEE and physical activity may play a crucial part in improving metabolic health in men and women with and without MetS risk factors.

Post-diagnosis alcohol intake and prostate cancer survival: A population-based cohort study.

Alcohol consumption has been declared a Group 1 carcinogen by the International Agency for Research on Cancer (IARC) and is a potential risk factor for several types of cancer mortality. However, evidence for an association with prostate cancer survival remains inconsistent. We examined how alcohol consumption post-diagnosis was associated with survival after prostate cancer diagnosis. Men diagnosed with prostate cancer (n = 829) in Alberta, Canada between the years 1997 and 2000 were recruited into a population-based case-control study and then followed for up to 19 years for survival outcomes. Pre- and post-diagnosis alcohol consumption, clinical characteristics and lifestyle factors were collected through in-person interviews shortly after diagnosis and again 2-3 years post-diagnosis. Cox proportional hazards were used to examine how post-diagnosis alcohol consumption was associated with all-cause and prostate cancer-specific mortality (competing risk analysis too), in addition to first recurrence/progression or new primary cancer. Most participants reported drinking alcohol (≥once a month for 6 months) post-diagnosis (n = 589, 71.0%). Exceeding Canadian Cancer Society (CCS) alcohol consumption recommendations (≥2 drinks/day) post-diagnosis was associated with prostate cancer-specific mortality relative to non-drinkers (aHR: 1.82, 95% CI: 1.07-3.10) with borderline evidence of a linear trend. Interestingly, those in the highest quartile of drinks/week pre- and post-diagnosis also had a twofold increase for prostate-specific mortality (aHR: 2.67, 95% CI: 1.28-5.56) while controlling for competing risks. Our results support post-diagnosis alcohol consumption was associated with increased mortality after prostate cancer diagnosis, specifically for prostate cancer-related death. Future studies focused on confirming this burden of disease are warranted.

A quantitative multimodal metabolomic assay for colorectal cancer.

BACKGROUND: Early diagnosis of colorectal cancer (CRC) simplifies treatment and improves treatment outcomes. We previously described a diagnostic metabolomic biomarker derived from semi-quantitative gas chromatography-mass spectrometry. Our objective was to determine whether a quantitative assay of additional metabolomic features, including parts of the lipidome could enhance diagnostic power; and whether there was an advantage to deriving a combined diagnostic signature with a broader metabolomic representation. METHODS: The well-characterized Biocrates P150 kit was used to quantify 163 metabolites in patients with CRC (N = 62), adenoma (N = 31), and age- and gender-matched disease-free controls (N = 81). Metabolites included in the analysis included phosphatidylcholines, sphingomyelins, acylcarnitines, and amino acids. Using a training set of 32 CRC and 21 disease-free controls, a multivariate metabolomic orthogonal partial least squares (OPLS) classifier was developed. An independent set of 28 CRC and 20 matched healthy controls was used for validation. Features characterizing 31 colorectal adenomas from their healthy matched controls were also explored, and a multivariate OPLS classifier for colorectal adenoma could be proposed. RESULTS: The metabolomic profile that distinguished CRC from controls consisted of 48 metabolites (R2Y = 0.83, Q2Y = 0.75, CV-ANOVA p-value < 0.00001). In this quantitative assay, the coefficient of variance for each metabolite was <10%, and this dramatically enhanced the separation of these groups. Independent validation resulted in AUROC of 0.98 (95% CI, 0.93-1.00) and sensitivity and specificity of 93% and 95%. Similarly, we were able to distinguish adenoma from controls (R2Y = 0.30, Q2Y = 0.20, CV-ANOVA p-value = 0.01; internal AUROC = 0.82 (95% CI, 0.72-0.93)). When combined with the previously generated GC-MS signatures for CRC and adenoma, the candidate biomarker performance improved slightly. CONCLUSION: The diagnostic power for metabolomic tests for colorectal neoplasia can be improved by utilizing a multimodal approach and combining metabolites from diverse chemical classes. In addition, quantification of metabolites enhances separation of disease-specific metabolomic profiles. Our future efforts will be focused on developing a quantitative assay for the metabolites comprising the optimal diagnostic biomarker.

Anthropometric measurements and survival after a prostate cancer diagnosis.

BACKGROUND: Evidence regarding the role of anthropometrics in prostate cancer survival is inconsistent. We examined the associations between anthropometric measures and survival outcomes. METHODS: Men diagnosed with prostate cancer (n=987) were recruited into a population-based case-control study between 1997 and 2000 then a prospective cohort study between 2000 and 2002 where anthropometric measurements (weight, height, body mass index, waist circumference, waist-hip ratio) were taken and participants were followed up to 19 years for survival outcomes. Cox proportional hazards were used to examine these associations. RESULTS: Survival analyses suggested no clear pattern of associations between post-diagnosis anthropometric measurements and all-cause mortality, prostate-specific mortality, first recurrence/progression or new primary cancer. CONCLUSIONS: We did not find a significant trend relating anthropometrics to survival outcomes after prostate cancer diagnosis. Continued assessment of objective measurements of body composition over the life-course is warranted to determine true associations between anthropometrics and survival after prostate cancer.