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2.  Association between duration and type of androgen deprivation therapy and risk of diabetes in men with prostate cancer 
International Journal of Cancer  2016;139(12):2698-2704.
Androgen deprivation therapy (ADT) for prostate cancer (PCa) increases risk of type 2 diabetes (T2DM); however the association between types and duration of ADT has not been fully elucidated. We examined how type and duration of ADT affects risk of T2DM. Using data from Prostate Cancer database Sweden (PCBaSe) we investigated risk of T2DM in a cohort of 34,031 men with PCa on ADT; i.e., anti‐androgens (AA), orchiectomy, or gonadotropin‐releasing hormone (GnRH) agonists compared to an age‐matched, PCa‐free comparison cohort (n = 167,205) using multivariate Cox proportional hazard regression. T2DM was defined as a newly filled prescription for metformin, sulphonylurea, or insulin in the Prescribed Drug Register. A total of 21,874 men with PCa received GnRH agonists, 9,143 AA and 3,014 underwent orchiectomy. Risk of T2DM was increased in men in the GnRH agonists/orchiectomy group during the first 3 years of ADT [i.e., 1 − 1.5 years HR: 1.61 (95%CI: 1.36 − 1.91)], compared to PCa‐free men. The risk decreased thereafter (e.g., 3 − 4 years HR: 1.17 (95% CI: 0.98 − 1.40)). Conversely, no increased risk was seen in men on AA (HR: 0.74 (95%CI: 0.65 − 0.84). The incidence of T2DM per 1,000 person‐years was 10 for PCa‐free men, 8 for men on AA, and 13 for men on GnRH agonists/orchiectomy. Duration of ADT has a significant impact on risk of T2DM. With the peak after three years of treatment, our data indicates that men on ADT, even for a limited period of time, such as adjuvant to radiotherapy, are at increased risk of T2DM.
What's new?
All treatments involve tradeoffs. For patients with prostate cancer, treatment with androgen deprivation therapy (ADT) can lead to an increased risk of type II diabetes. These authors set out to analyze how the duration of treatment, and the type of ADT, affect diabetes risk. They collected data on patients receiving three types of ADT: anti‐androgens, gonadotropin releasing hormone agonists, and orchiectomy, and compared them with age‐matched, cancer‐free controls. The risk of diabetes peaked after 3 years of treatment with GnRH agonists or orchiectomy. By contrast, patients receiving anti‐androgens showed no increase in diabetes risk relative to cancer‐free controls.
doi:10.1002/ijc.30403
PMCID: PMC5095878  PMID: 27557616
prostate cancer; type two diabetes; androgen deprivation therapy
3.  Serum lactate dehydrogenase and survival following cancer diagnosis 
British Journal of Cancer  2015;113(9):1389-1396.
Background:
There is evidence that high level of serum lactate dehydrogenase (LDH) is associated with poorer overall survival in several malignancies, but its link to cancer-specific survival is unclear.
Methods:
A total of 7895 individuals diagnosed with cancer between 1986 and 1999 were selected for this study. Multivariable Cox proportional hazards regression was used to assess overall and cancer-specific death by the z-score and clinical categories of serum LDH prospectively collected within 3 years before diagnosis. Site-specific analysis was performed for major cancers. Analysis was repeated by different lag times between LDH measurements and diagnosis.
Results:
At the end of follow-up, 5799 participants were deceased. Hazard ratios (HRs) and 95% confidence intervals (CIs) for overall and cancer-specific death in the multivariable model were 1.43 (1.31–1.56) and 1.46 (1.32–1.61), respectively, for high compared with low prediagnostic LDH. Site-specific analysis showed high LDH to correlate with an increased risk of death from prostate, pulmonary, colorectal, gastro-oesophageal, gynaecological and haematological cancers. Serum LDH assessed within intervals closer to diagnosis was more strongly associated with overall and cancer-specific death.
Conclusions:
Our findings demonstrated an inverse association of baseline serum LDH with cancer-specific survival, corroborating its role in cancer progression.
doi:10.1038/bjc.2015.361
PMCID: PMC4815785  PMID: 26469834
LDH; the Warburg effect; survival; prospective study
4.  Long-term outcome in young women with breast cancer: a population-based study 
Purpose
Whether young age at diagnosis of breast cancer is an independent risk factor for death remains controversial, and the question whether young age should be considered in treatment decisions is still to be answered.
Methods
From a population-based cohort of 22,017 women with breast cancer, all women <35 years (n = 471) were compared to a random sample of 700 women aged 35–69 years from the same cohort. Information on patient and tumor characteristics, treatment, and follow-up was collected from the medical records. Tissue microarrays were produced for analysis of classical biomarkers. Breast cancer-specific survival (BCSS), distant disease-free survival (DDFS), and locoregional recurrence-free survival (LRFS) by age were compared using women 50–69 years as reference.
Results
At 10 years follow-up, women <35 years and 35–39 years had a worse BCSS [age <35 years 69 % (HR 2.75, 95 % CI 1.93–3.94), age 35–39 years 76 % (HR 2.33, 95 % CI 1.54–3.52), age 40–49 years 84 % (HR 1.53, 95 % CI 0.97–2.39), and age 50–69 years 89 % (reference)]. The worse BCSS was statistically significant in stages I–IIa and Luminal B tumors. At multivariate analysis age <35 years and 35–39 years confined a risk in LRFS (HR 2.13, 95 % CI 1.21–3.76 and HR 1.97, 95 % CI 1.06–3.68) but not in DDFS and BCSS. In the subgroup of women <40 years with luminal tumors stage I–IIa, low age remained an independent risk factor also in DDFS (HR 1.87, 95 % CI 1.03–3.44).
Conclusion
Young women have a high risk of systemic disease even when diagnosed in an early stage. The excess risk of relapse is most pronounced in Luminal B tumors, where low age is an independent prognostic factor of DDFS and LRFS.
Electronic supplementary material
The online version of this article (doi:10.1007/s10549-016-3983-9) contains supplementary material, which is available to authorized users.
doi:10.1007/s10549-016-3983-9
PMCID: PMC5050247  PMID: 27624330
Breast cancer; Young age; Subtype; Luminal B; Early stage; Prognosis; Population-based
5.  Serum Calcium and the Risk of Breast Cancer: Findings from the Swedish AMORIS Study and a Meta-Analysis of Prospective Studies 
To investigate the association between serum calcium and risk of breast cancer using a large cohort and a systematic review with meta-analysis. From the Swedish Apolipoprotein Mortality Risk (AMORIS) Study we included 229,674 women who had baseline measurements of serum total calcium and albumin. Multivariable Cox regression was used to assess the association between total and albumin-corrected calcium and breast cancer risk. For the systematic review, an electronic search of MEDLINE and EMBASE databases was performed to identify other prospective cohorts assessing the relationship between serum calcium and breast cancer risk. We pooled the results of our AMORIS cohort with other eligible studies in a meta-analysis using a random effects model. I2 test was used to assess heterogeneity. In the AMORIS study, 10,863 women were diagnosed with breast cancer (mean follow-up: 19 years). We found an inverse association between total serum calcium and breast cancer when comparing the fourth quartile to the first quartile (HR: 0.94, 95% CI: 0.88–0.99, p value for trend 0.04) and similar results using albumin-corrected calcium. In the systematic review, we identified another two prospective cohorts evaluating pre-diagnostic serum total calcium and breast cancer. Combining these studies and our findings in AMORIS in a meta-analysis showed a protective effect of serum calcium against breast cancer, with a summary RR of 0.80 (95% CI: 0.66–0.97). No substantial heterogeneity was observed. Our findings in AMORIS and the meta-analysis support an inverse association between serum calcium and breast cancer risk, which warrants mechanistic investigations.
doi:10.3390/ijms17091487
PMCID: PMC5037765  PMID: 27608013
calcium; breast cancer; albumin; prospective study
7.  Effect of selective serotonin reuptake inhibitors use on endocrine therapy adherence and breast cancer mortality: a population-based study 
The purpose of the study was to investigate whether the concomitant use of selective serotonin reuptake inhibitors (SSRI) with tamoxifen influences the risk of death due to breast cancer, and we also investigated the association between SSRI use and adherence to oral endocrine therapy (ET). We analyzed data from BCBaSe Sweden, which is a database created by the data linkage of Registries from three different regions of Sweden. To investigate the association between ET adherence and SSRI use, we included all women who were diagnosed with non-distant metastatic ER-positive invasive breast cancer from July 2007 to July 2011 and had at least one dispensed prescription of oral tamoxifen or aromatase inhibitor. To investigate the role of concurrent administration of SSRI and tamoxifen on breast cancer prognosis, we performed a nested case–control study. In the adherence cohort, 9104 women were included in the analyses. Women who received SSRI, either before or after breast cancer diagnosis, were at higher risk for low adherence to ET. However, when the overlapping period between SSRI use and ET was >50 %, no excess risk for low adherence was observed. Non-adherence (<80 %) to ET was significantly associated with worse breast cancer survival (OR 4.07; 95 % CI 3.27–5.06). In the case–control study, 445 cases and 11125 controls were included. The concomitant administration of SSRI and tamoxifen did not influence breast cancer survival, neither in short-term (OR 1.41; 95 % CI 0.74–2.68) nor in long-term SSRI users (OR 0.85; 95 % CI 0.35–2.08). Concomitant SSRI and tamoxifen use does not seem to increase risk for death due to breast cancer. Given the positive association between continuing antidepressive pharmacotherapy for a longer period of time and adherence to ET, it is essential to capture and treat depression in breast cancer patients to secure adherence to ET.
doi:10.1007/s10549-016-3928-3
PMCID: PMC5012147  PMID: 27492739
Breast cancer; SSRI; Adherence; Endocrine therapy; Prognosis; Tamoxifen
8.  Associations of C-Reactive Protein, Granulocytes and Granulocyte-to-Lymphocyte Ratio with Mortality from Breast Cancer in Non-Institutionalized American Women 
PLoS ONE  2016;11(6):e0157482.
Inflammation may play a role in breast cancer, but evidence in the general population is lacking. We investigated the association between serum inflammatory markers (C-reactive protein (CRP), absolute granulocyte count (AGC) and granulocyte-to-lymphocyte (G/L) ratio) and breast cancer (BCa) mortality in American women while accounting for adiposity. From the Third National Health and Nutrition Examination Survey (NHANES III) we selected all women aged 20+ without any known history of cancer (n = 7,780). Multivariable Cox regression models were used to assess CRP, AGC and G/L ratio in relation to mortality from BCa, all cancer, cardiovascular disease and all causes. Stratification analyses by body mass index (BMI) and waist circumference were performed to investigate the effect of adiposity on this association. During a mean follow-up of 167 months, 44 women died from BCa. After adjustments for BMI and waist circumference, only G/L ratio was associated to risk of BCa death (e.g. HR: 2.35, 95% CI: 1.36–4.06 for the 3rd compared to the 1st tertile, Ptrend = 0.01). Except for a borderline interaction between CRP categories and obesity by BMI, no statistically significant interaction between markers and categories of BMI or waist circumference was observed. All three markers were associated with mortality from cardiovascular disease and all causes. Our findings support a role of inflammation in BCa mortality which may involve mechanisms apart from obesity, and potential usefulness of GLR as a marker in assessing inflammation and cancer.
doi:10.1371/journal.pone.0157482
PMCID: PMC4905698  PMID: 27294662
9.  Causes of death in men with localized prostate cancer: a nationwide, population‐based study 
Bju International  2015;117(3):507-514.
Objective
To detail the distribution of causes of death from localized prostate cancer (PCa).
Patients and Methods
The database PCBase Sweden links the Swedish National Prostate Cancer Register with other nationwide population‐based healthcare registers. We selected all 57 187 men diagnosed with localized PCa between 1997 and 2009 and their 114 374 PCa‐free control subjects, matched according to age and county of residence. Mortality was calculated using competing risk regression analyses, taking into account PCa risk category, age and Charlson comorbidity index (CCI).
Results
In men with low‐risk PCa, all‐cause mortality was lower compared with that in corresponding PCa‐free men: 10‐year all‐cause mortality was 18% for men diagnosed at age 70 years, with a CCI score of 0, and 21% among corresponding control subjects. Of these cases, 31% died from cardiovascular disease (CVD) compared with 37% of the corresponding control subjects. For men with low‐risk PCa, 10‐year PCa‐mortality was 0.4, 1 and 3% when diagnosed at age 50, 60 and 70 years, respectively. PCa was the third most common cause of death (18%), after CVD (31%) and other cancers (30%). By contrast, PCa was the most common cause of death in men with intermediate‐ and high‐risk localized PCa.
Conclusions
Men with low‐risk PCa had lower all‐cause mortality than PCa‐free men because of lower CVD mortality, driven by early detection selection; however, for men with intermediate‐ or high‐risk disease, the rate of PCa death was substantial, irrespective of CCI score, and this was even more pronounced for those diagnosed at age 50 or 60 years.
doi:10.1111/bju.13059
PMCID: PMC4832314  PMID: 25604807
comorbidities; prostate cancer death; curative treatment; localized disease
10.  Investigating the association between allergen-specific immunoglobulin E, cancer risk and survival 
Oncoimmunology  2016;5(6):e1154250.
ABSTRACT
Prior findings linking allergy and cancer have been inconsistent, which may be driven by diverse assessment methods. We used serum specific immunoglobulin E (IgE) against common inhalant allergens that was assessed prior to cancer diagnosis in studying this association. We selected 8,727 Swedish men and women who had measurements of serum allergen-specific IgE and total IgE between 1992 and 1996. Multivariable Cox regression using age as a timescale was performed to assess the associations of IgE sensitization, defined by any levels of serum specific IgE ≥35 kU/L, with risk of overall and specific cancers. A test for trend was performed by assigning scores derived from allergen-specific IgE levels at baseline as an ordinal scale. Kaplan–Meier curves and log-rank test were used to assess cancer survival by IgE sensitization status. During a mean follow-up of 16 year, 689 persons were diagnosed with cancer. We found an inverse association between IgE sensitization and cancer risk, with a hazard ratio (HR) of 0.83 and 95% confidence intervals (CI) of 0.70–0.99. A similar trend was seen with specific IgE scores overall (Ptrend = 0.007) and in women (Ptrend = 0.01). Although IgE sensitization was not associated with risk of common site-specific cancers, serum specific IgE scores were inversely associated with melanoma risk in men and women combined, and with risk of female breast and gynecological cancers combined. No association with survival was observed. The association between circulating IgE levels and incident cancer may point toward a role of T-helper 2 (TH2)-biased response in development of some cancers.
doi:10.1080/2162402X.2016.1154250
PMCID: PMC4938379  PMID: 27471625
Allergy; atopy; cancer; immunoglobulin E; cohort
11.  Association between baseline serum glucose, triglycerides and total cholesterol, and prostate cancer risk categories 
Cancer Medicine  2016;5(6):1307-1318.
Abstract
Lifestyle‐related risk factors such as hyperglycemia and dyslipidemia have been associated with several cancers. However, studies exploring their link with prostate cancer (PCa) clinicopathological characteristics are sparse and inconclusive. Here, we investigated the associations between serum metabolic markers and PCa clinicopathological characteristics. The study comprised 14,294 men from the Swedish Apolipoprotein MOrtality RISk (AMORIS) cohort who were diagnosed with PCa between 1996 and 2011. Univariate and multivariable logistic regression were used to investigate the relation between glucose, triglycerides and total cholesterol and PCa risk categories, PSA, Gleason score, and T‐stage. Mean age at time of PCa diagnosis was 69 years. Men with glucose levels >6.9 mmol/L tend to have PSA<4 μg/L, while those with glucose levels of 5.6–6.9 mmol/L had a greater odds of PSA>20 μg/L compared to PSA 4.0–9.9 μg/L. Hypertriglyceridemia was also positively associated with PSA>20 μg/L. Hyperglycemic men had a greater odds of intermediate‐ and high‐grade PCa and advanced stage or metastatic PCa. Similarly, hypertriglyceridemia was positively associated with high‐grade PCa. There was also a trend toward an increased odds of intermediate risk localized PCa and advanced stage PCa among men with hypertriglyceridemia. Total cholesterol did not have any statistically significant association with any of the outcomes studied. Our findings suggest that high serum levels of glucose and triglycerides may influence PCa aggressiveness and severity. Further investigation on the role of markers of glucose and lipid metabolism in influencing PCa aggressiveness and severity is needed as this may help define important targets for intervention.
doi:10.1002/cam4.665
PMCID: PMC4924389  PMID: 26923095
Glucose; prostate cancer; total cholesterol; triglycerides
12.  Family history of breast cancer and its association with disease severity and mortality 
Cancer Medicine  2016;5(5):942-949.
Abstract
A family history (FH) of breast cancer (BC) is known to increase an individual's risk of disease onset. However, its role in disease severity and mortality is less clear. We aimed to ascertain associations between FH of BC, severity and BC‐specific mortality in a hospital‐based cohort of 5354 women with prospective information on FH. We included women diagnosed at Guy's and St Thomas’ NHS Foundation Trust between 1975 and 2012 (n = 5354). BC severity was defined and categorized as good, moderate, and poor prognosis. Data on BC‐specific mortality was obtained from the National Cancer Registry and medical records. Associations between FH and disease severity or BC‐specific mortality were evaluated using proportional odds models and Cox proportional hazard regression models, respectively. Available data allowed adjustment for potential confounders (e.g., treatment, socioeconomic status, and ethnicity). FH of any degree was not associated with disease severity at time of diagnosis (adjusted proportional OR: 1.00 [95% CI: 0.85 to 1.17]), which remained true also after stratification by period of diagnosis. FH of BC was not associated with BC‐mortality HR: 0.99 (95% CI: 0.93 to 1.05). We did not find evidence to support an association between FH of BC and severity and BC‐specific mortality. Our results indicate that clinical management should not differ between women with and without FH, when the underlying mutation is unknown.
doi:10.1002/cam4.648
PMCID: PMC4864823  PMID: 26799372
breast cancer; Family history; mortality; severity
13.  Serum leptin, C‐reactive protein, and cancer mortality in the NHANES III  
Cancer Medicine  2015;5(1):120-128.
Abstract
Adipokines, such as leptin, may affect cancer through its link with inflammation and obesity. We investigated the association between leptin, C‐reactive protein, and risk of cancer death while accounting general and abdominal obesity. From the Third National Health and Examination Survey (NHANES III), we selected 5957 adult men and women with baseline measurements of serum leptin and CRP. Multivariable Cox regression was used to assess leptin and CRP levels (low, moderate, high) in relation to risk of cancer death. Stratification analyses were performed for obesity as defined by body mass index (BMI) and waist circumference. Fine and Gray regression was performed to account for death from cardiovascular disease and other causes as competing events. A total of 385 participants died of cancer during a mean follow‐up of 18 years. After adjusting for BMI and waist circumference, an inverse association with log‐transformed leptin was found for women, with a hazard ratio (HR) of 0.81 (95% confidence interval [CI]: 0.51–1.30) and 0.40 (95% CI: 0.24–0.68) for moderate and high compared to low levels of leptin, respectively; P trend = 0.0007). No association for leptin was observed in men, but higher CRP corresponded to increased risk of dying from cancer (HR: 2.98; 95% CI: 1.57–5.64 for the highest vs. lowest categories of CRP). Similar associations were observed with competing risk analysis also adjusted for BMI and waist circumference. Contrasting associations of serum leptin and CRP with cancer mortality may indicate sex‐specific biological or environmental pathways linking obesity and cancer in men and women which warrant mechanistic investigations.
doi:10.1002/cam4.570
PMCID: PMC4708908  PMID: 26632325
Cancer; C‐reactive protein; leptin; mortality; prospective study
14.  Big Data: the challenge for small research groups in the era of cancer genomics 
British Journal of Cancer  2015;113(10):1405-1412.
In the past decade, cancer research has seen an increasing trend towards high-throughput techniques and translational approaches. The increasing availability of assays that utilise smaller quantities of source material and produce higher volumes of data output have resulted in the necessity for data storage solutions beyond those previously used. Multifactorial data, both large in sample size and heterogeneous in context, needs to be integrated in a standardised, cost-effective and secure manner. This requires technical solutions and administrative support not normally financially accounted for in small- to moderate-sized research groups. In this review, we highlight the Big Data challenges faced by translational research groups in the precision medicine era; an era in which the genomes of over 75 000 patients will be sequenced by the National Health Service over the next 3 years to advance healthcare. In particular, we have looked at three main themes of data management in relation to cancer research, namely (1) cancer ontology management, (2) IT infrastructures that have been developed to support data management and (3) the unique ethical challenges introduced by utilising Big Data in research.
doi:10.1038/bjc.2015.341
PMCID: PMC4815885  PMID: 26492224
cancer research; database management systems; biobanking; genomics; ontology management; data ethics
15.  Prediagnostic serum glucose and lipids in relation to survival in breast cancer patients: a competing risk analysis 
BMC Cancer  2015;15:913.
Background
Abnormal glucose and lipids levels may impact survival after breast cancer (BC) diagnosis, but their association to other causes of mortality such as cardiovascular (CV) disease may result in a competing risk problem.
Methods
We assessed serum glucose, triglycerides (TG) and total cholesterol (TC) measured prospectively 3 months to 3 years before diagnosis in 1798 Swedish women diagnosed with any type of BC between 1985 and 1999. In addition to using Cox regression, we employed latent class proportional hazards models to capture any heterogeneity of associations between these markers and BC death. The latter method was extended to include the primary outcome (BC death) and competing outcomes (CV death and death from other causes), allowing latent class-specific hazard estimation for cause-specific deaths.
Results
A lack of association between prediagnostic glucose, TG or TC with BC death was observed with Cox regression. With latent class proportional hazards model, two latent classes (Class I and II) were suggested. Class I, comprising the majority (81.5 %) of BC patients, had an increased risk of BC death following higher TG levels (HR: 1.87, 95 % CI: 1.01–3.45 for every log TG increase). Lower overall survival was observed in Class II, but no association for BC death was found. On the other hand, TC positively corresponded to CV death in Class II, and similarly, glucose to death from other causes.
Conclusion
Addressing cohort heterogeneity in relation to BC survival is important in understanding the relationship between metabolic markers and cause-specific death in presence of competing outcomes.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-015-1928-z) contains supplementary material, which is available to authorized users.
doi:10.1186/s12885-015-1928-z
PMCID: PMC4650114  PMID: 26577580
Breast cancer; Glucose; Lipid; Competing risk; Survival; Latent class
16.  Prevention and Early Detection of Prostate Cancer 
The Lancet. Oncology  2014;15(11):e484-e492.
Prostate cancer is one of the most common cancers in men and the global burden of this disease is rising. Lifestyle modifications like smoking cessation, exercise and weight control offer opportunities to decrease the risk of developing prostate cancer. Early detection of prostate cancer by PSA screening remains controversial; yet, changes in PSA threshold, frequency of screening, and addition of other biomarkers have potential to minimise overdiagnosis associated with PSA screening. Several new biomarkers appear promising in individuals with elevated PSA levels or those diagnosed with prostate cancer, these are likely to guide in separating individuals who can be spared of aggressive treatment from those who need it. Several pharmacological agents like 5α-reductase inhibitors, aspirin etc. have a potential to prevent development of prostate cancer. In this review, we discuss the current evidence and research questions regarding prevention, early detection of prostate cancer and management of men either at high risk of prostate cancer or diagnosed with low-grade prostate cancer.
doi:10.1016/S1470-2045(14)70211-6
PMCID: PMC4203149  PMID: 25281467
prostate cancer; prevention; risk factors; PSA; screening
18.  5-α reductase inhibitors, benign prostatic hyperplasia, and risk of male breast cancer 
Cancer Causes & Control  2015;26(9):1289-1297.
Purpose
5-α reductase inhibitors (5-ARI) have been suggested to increase the risk of male breast cancer. The aim of this study was to study the risk of breast cancer in men on 5-ARI, in men with benign prostatic hyperplasia (BPH) not on 5-ARI, and in men without BPH.
Methods
We performed a population-based cohort study in Sweden with data from The Prescribed Drug Register, The Patient Register, and The Cancer Register. Men on 5-ARI, men on α-blockers, or men who had undergone a transurethral resection of the prostate (TUR-P) prior to or during 2006–2008 were included as exposed to BPH and a specific treatment thereof. For each exposed man, five unexposed men were selected. Risk of breast cancer was calculated in Cox proportional hazard models.
Results
There were 124,183 exposed men and 545,293 unexposed men, and during follow-up (median 6 years), 99 men with breast cancer were diagnosed. Compared to unexposed men, men on 5-ARI had a hazard ratio (HR) of breast cancer of 0.74 (95 % confidence interval (CI) 0.27–2.03), men on α-blockers had HR 1.47 (95 % CI 0.73–2.95), and men with a TUR-P had HR 1.99 (95 % CI 1.05–3.75).
Conclusion
No increased risk of breast cancer was observed for men on 5-ARI. However, the increased risk of breast cancer among men who had undergone a TUR-P, a strong indicator of BPH, suggests that the endocrine milieu conducive to BPH is associated with male breast cancer.
doi:10.1007/s10552-015-0622-4
PMCID: PMC4540753  PMID: 26109464
5-α reductase inhibitors; Male breast cancer; Benign prostatic hyperplasia
19.  Serum glucose and risk of cancer: a meta-analysis 
BMC Cancer  2014;14:985.
Background
Raised serum glucose has been linked to increased risk of many solid cancers. We performed a meta-analysis to quantify and summarise the evidence for this link.
Methods
Pubmed and Embase were reviewed, using search terms representing serum glucose and cancer. Inclusion and exclusion criteria focused on epidemiological studies with clear definitions of serum glucose levels, cancer type, as well as well-described statistical methods with sufficient data available. We used 6.1 mmol/L as the cut-off for high glucose, consistent with the WHO definition of metabolic syndrome. Random effects analyses were performed to estimate the pooled relative risk (RR).
Results
Nineteen studies were included in the primary analysis, which showed a pooled RR of 1.32 (95% CI: 1.20 – 1.45). Including only those individuals with fasting glucose measurements did not have a large effect on the pooled RR (1.32 (95% CI: 1.11-1.57). A stratified analysis showed a pooled RR of 1.34 (95% CI: 1.02-1.77) for hormonally driven cancer and 1.21 (95% CI: 1.09-1.36) for cancers thought to be driven by Insulin Growth Factor-1.
Conclusion
A positive association between serum glucose and risk of cancer was found. The underlying biological mechanisms remain to be elucidated but our subgroup analyses suggest that the insulin- IGF-1 axis does not fully explain the association. These findings are of public health importance as measures to reduce serum glucose via lifestyle and dietary changes could be implemented in the context of cancer mortality.
doi:10.1186/1471-2407-14-985
PMCID: PMC4320469  PMID: 25526881
Glucose; Cancer; Metabolic syndrome; Meta-analysis; Diabetes
20.  Obesity and cancer: the role of vitamin D 
BMC Cancer  2014;14:712.
Background
It is estimated that 20% of all cancer cases are caused by obesity. Vitamin D is thought to be one of the mechanisms underlying this association. This review aims to summarise the evidence for the mediating effect of vitamin D on the link between obesity and cancer.
Methods
Three literature searches using PubMed and Embase were conducted to assess whether vitamin D plays an important role in the pathway between obesity and cancer: (1) obesity and cancer; (2) obesity and vitamin D; and (3) vitamin D and cancer. A systematic review was performed for (1) and (3), whereas a meta-analysis including random effects analyses was performed for (2).
Results
(1) 32 meta-analyses on obesity and cancer were identified; the majority reported a positive association between obesity and risk of cancer. (2) Our meta-analysis included 12 original studies showing a pooled relative risk of 1.52 (95% CI: 1.33-1.73) for risk of vitamin D deficiency (<50 nmol/L) in obese people (body mass index >30 kg/m2). (3) 21 meta-analyses on circulating vitamin D levels and cancer risk were identified with different results for different types of cancer.
Conclusion
There is consistent evidence for a link between obesity and cancer as well as obesity and low vitamin D. However, it seems like the significance of the mediating role of vitamin D in the biological pathways linking obesity and cancer is low. There is a need for a study including all three components while dealing with bias related to dietary supplements and vitamin D receptor polymorphisms.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2407-14-712) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2407-14-712
PMCID: PMC4182855  PMID: 25255691
Cancer; Obesity; Vitamin D
21.  Radical Prostatectomy or Watchful Waiting in Early Prostate Cancer 
The New England journal of medicine  2014;370(10):932-942.
BACKGROUND
Radical prostatectomy reduces mortality among men with localized prostate cancer; however, important questions regarding long-term benefit remain.
METHODS
Between 1989 and 1999, we randomly assigned 695 men with early prostate cancer to watchful waiting or radical prostatectomy and followed them through the end of 2012. The primary end points in the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) were death from any cause, death from prostate cancer, and the risk of metastases. Secondary end points included the initiation of androgen-deprivation therapy.
RESULTS
During 23.2 years of follow-up, 200 of 347 men in the surgery group and 247 of the 348 men in the watchful-waiting group died. Of the deaths, 63 in the surgery group and 99 in the watchful-waiting group were due to prostate cancer; the relative risk was 0.56 (95% confidence interval [CI], 0.41 to 0.77; P = 0.001), and the absolute difference was 11.0 percentage points (95% CI, 4.5 to 17.5). The number needed to treat to prevent one death was 8. One man died after surgery in the radical-prostatectomy group. Androgen-deprivation therapy was used in fewer patients who underwent prostatectomy (a difference of 25.0 percentage points; 95% CI, 17.7 to 32.3). The benefit of surgery with respect to death from prostate cancer was largest in men younger than 65 years of age (relative risk, 0.45) and in those with intermediate-risk prostate cancer (relative risk, 0.38). However, radical pros-tatectomy was associated with a reduced risk of metastases among older men (relative risk, 0.68; P = 0.04).
CONCLUSIONS
Extended follow-up confirmed a substantial reduction in mortality after radical prostatectomy; the number needed to treat to prevent one death continued to decrease when the treatment was modified according to age at diagnosis and tumor risk. A large proportion of long-term survivors in the watchful-waiting group have not required any palliative treatment. (Funded by the Swedish Cancer Society and others.)
doi:10.1056/NEJMoa1311593
PMCID: PMC4118145  PMID: 24597866
22.  Early Detection of Prostate Cancer: AUA Guideline 
The Journal of urology  2013;190(2):419-426.
Purpose
The guideline purpose is to provide the urologist with a framework for the early detection of prostate cancer in asymptomatic average risk men.
Materials and Methods
A systematic review was conducted and summarized evidence derived from over 300 studies that addressed the predefined outcomes of interest (prostate cancer incidence/mortality, quality of life, diagnostic accuracy and harms of testing). In addition to the quality of evidence, the panel considered values and preferences expressed in a clinical setting (patient-physician dyad) rather than having a public health perspective. Guideline statements were organized by age group in years (age <40; 40 to 54; 55 to 69; >70).
Results
With the exception of prostate-specific antigen (PSA)-based prostate cancer screening, there was minimal evidence to assess the outcomes of interest for other tests. The quality of evidence for the benefits of screening was moderate, and evidence for harm was high for men age 55 to 69 years. For men outside this age range, evidence was lacking for benefit, but the harms of screening, including over diagnosis and over treatment, remained. Modeled data suggested that a screening interval of two years or more may be preferred to reduce the harms of screening.
Conclusions
The Panel recommended shared decision-making for men age 55 to 69 years considering PSA-based screening, a target age group for whom benefits may outweigh harms. Outside this age range, PSA-based screening as a routine could not be recommended based on the available evidence. The entire guideline is available at www.AUAnet.org/education/guidelines/prostate-cancer-detection.cfm
doi:10.1016/j.juro.2013.04.119
PMCID: PMC4020420  PMID: 23659877
prostate cancer; prostate specific antigen; screening; early detection
23.  Reducing the noise in signal detection of adverse drug reactions by standardizing the background: a pilot study on analyses of proportional reporting ratios-by-therapeutic area 
Purpose
Disproportionality screening analysis is acknowledged as a tool for performing signal detection in databases of adverse drug reactions (ADRs), e.g., in the European Union (EU) Drug Authority setting. The purpose of this study was to explore the possibility of decreasing false-positive signals of disproportionate reporting (SDR) by calculating the proportional reporting ratio (PRR)-by-therapeutic area (TA), while still maintaining the ability to detect relevant SDRs.
Methods
In the EudraVigilance (EV) Database, output from PRR calculated with a restricted TA comparator background was compared in detail to output from conventional authority-setting PRR calculations for four drugs: bicalutamide, abiraterone, metformin, and vildagliptin, within the TAs of prostate gland disease and type 2 diabetes mellitus.
Results
ADR reports per investigated drug ranged from 2,400 to 50,000. The PRR-TA’s ability to detect true-positive SDRs (as acknowledged in approved labeling) was increased compared to the conventional PRR, and performed 8–31 % better than a recently proposed stricter EU-SDR definition. The PRR-TA removed false SDRs confounded by disease or disease spill-over by up to 63 %, while retaining/increasing the number of unclassified SDRs relevant for manual validation, and thereby improving the ratio between confounded SDRs (i.e., noise) and unclassified SDRs for all investigated drugs (possible signals).
Conclusions
The performance of the PRR was improved by background restriction with the PRR-TA method; the number of false-positive SDRs decreased, and the ability to detect true-positive SDRs increased, improving the signal-to-noise ratio. Further development and validation of the method is needed within other TAs and databases, and for disproportionality analysis methods.
Electronic supplementary material
The online version of this article (doi:10.1007/s00228-014-1658-1) contains supplementary material, which is available to authorized users.
doi:10.1007/s00228-014-1658-1
PMCID: PMC3978377  PMID: 24599513
PRR; Adverse drug reactions; ADR; Signal detection; Pharmacovigilance; Disproportionality analysis
24.  Mortality following Hip Fracture in Men with Prostate Cancer 
PLoS ONE  2013;8(9):e74492.
Background
Hip fractures are associated with increased mortality and are a known adverse effect of androgen deprivation therapy (ADT) for prostate cancer (PCa). It was our aim to evaluate how mortality after hip fracture is modified by PCa and ADT.
Methods
PCa dataBase Sweden (PCBaSe 2.0) is based on the National PCa Register and also contains age and county-matched PCa-free men. We selected all men (n = 14,205) who had been hospitalized with a hip fracture between 2006 and 2010; 2,300 men had a prior PCa diagnosis of whom 1,518 (66%) were on ADT prior to date of fracture. Risk of death was estimated with cumulative incidence and standardized mortality ratios (SMRs) to make comparisons with the entire PCa population and the general population.
Results
Cumulative incidences indicated that there was a higher risk of death following a hip fracture for PCa men on ADT than for PCa men not on ADT or PCa-free men, particularly in the first year. The SMRs showed that PCa men on ADT with a hip fracture were 2.44 times more likely to die than the comparison cohort of all PCa men (95%CI: 2.29-2.60). This risk was especially increased during the first month (5.64 (95%CI: 4.16–7.48)). In absolute terms, hip fractures were associated with 20 additional deaths per 1,000 person-years in PCa men not on ADT, but 30 additional deaths per 1,000 person-years for PCa men on ADT, compared to all PCa men.
Conclusion
Hip fractures are associated with higher all-cause mortality in PCa men on ADT than in PCa men not on ADT or PCa-free men, especially within the first three months.
doi:10.1371/journal.pone.0074492
PMCID: PMC3785484  PMID: 24086350
25.  Integrated genomic analysis of triple-negative breast cancers reveals novel microRNAs associated with clinical and molecular phenotypes and sheds light on the pathways they control 
BMC Genomics  2013;14:643.
Background
This study focuses on the analysis of miRNAs expression data in a cohort of 181 well characterised breast cancer samples composed primarily of triple-negative (ER/PR/HER2-negative) tumours with associated genome-wide DNA and mRNA data, extensive patient follow-up and pathological information.
Results
We identified 7 miRNAs associated with prognosis in the triple-negative tumours and an additional 7 when the analysis was extended to the set of all ER-negative cases. miRNAs linked to an unfavourable prognosis were associated with a broad spectrum of motility mechanisms involved in the invasion of stromal tissues, such as cell-adhesion, growth factor-mediated signalling pathways, interaction with the extracellular matrix and cytoskeleton remodelling. When we compared different intrinsic molecular subtypes we found 46 miRNAs that were specifically expressed in one or more intrinsic subtypes. Integrated genomic analyses indicated these miRNAs to be influenced by DNA genomic aberrations and to have an overall influence on the expression levels of their predicted targets. Among others, our analyses highlighted the role of miR-17-92 and miR-106b-25, two polycistronic miRNA clusters with known oncogenic functions. We showed that their basal-like subtype specific up-regulation is influenced by increased DNA copy number and contributes to the transcriptional phenotype as well as the activation of oncogenic pathways in basal-like tumours.
Conclusions
This study analyses previously unreported miRNA, mRNA and DNA data and integrates these with pathological and clinical information, from a well-annotated cohort of breast cancers enriched for triple-negative subtypes. It provides a conceptual framework, as well as integrative methods and system-level results and contributes to elucidate the role of miRNAs as biomarkers and modulators of oncogenic processes in these types of tumours.
doi:10.1186/1471-2164-14-643
PMCID: PMC4008358  PMID: 24059244
miRNAs; Breast cancer; Data integration; Pathway analysis

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