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1.  Metabolic serum biomarkers for the prediction of cancer: a follow-up of the studies conducted in the Swedish AMORIS study 
ecancermedicalscience  2015;9:555.
The Swedish Apolipoprotein MOrtality RISk study (AMORIS) contains information on more than 500 biomarkers collected from 397,443 men and 414,630 women from the greater Stockholm area during the period 1985–1996. Using a ten-digit personal identification code, this database has been linked to Swedish national registries, which provide data on socioeconomic status, vital status, cancer diagnosis, comorbidity, and emigration. Within AMORIS, 18 studies assessing risk of overall and site-specific cancers have been published, utilising a range of serum markers representing glucose and lipid metabolism, immune system, iron metabolism, liver metabolism, and bone metabolism. This review briefly summarises these findings in relation to more recently published studies and provides an overview of where we are today and the challenges of observational studies when studying cancer risk prediction.
Overall, more recent observational studies supported previous findings obtained in AMORIS, although no new results have been reported for serum fructosamine and inorganic phosphate with respect to cancer risk. A drawback of using serum markers in predicting cancer risk is the potential fluctuations following other pathological conditions, resulting in non-specificity and imprecision of associations observed. Utilisation of multiple combination markers may provide more specificity, as well as give us repeated instead of single measurements. Associations with other diseases may also necessitate further analytical strategies addressing effects of serum markers on competing events in addition to cancer. Finally, delineating the role of serum metabolic markers may generate valuable information to complement emerging clinical studies on preventive effects of drugs and supplements targeting metabolic disorders against cancer.
PMCID: PMC4531132  PMID: 26284119
cancer; serum lipids; serum glucose; C-reactive protein; leukocytes; IgE; calcium; iron; gamma-glutamyl transferase
2.  Serum Lipids and the Risk of Gastrointestinal Malignancies in the Swedish AMORIS Study 
Journal of Cancer Epidemiology  2012;2012:792034.
Background. Metabolic syndrome has been linked to an increased cancer risk, but the role of dyslipidaemia in gastrointestinal malignancies is unclear. We aimed to assess the risk of oesophageal, stomach, colon, and rectal cancers using serum levels of lipid components. Methods. From the Swedish Apolipoprotein Mortality Risk (AMORIS) study, we selected 540,309 participants (> 20 years old) with baseline measurements of total cholesterol (TC), triglycerides (TG), and glucose of whom 84,774 had baseline LDL cholesterol (LDL), HDL cholesterol (HDL), apolipoprotein B (apoB), and apolipoprotein A-I (apoA-I). Multivariate Cox proportional hazards regression was used to assess glucose and lipid components in relation to oesophageal, stomach, colon, and rectal cancer risk. Results. An increased risk of oesophageal cancer was observed in persons with high TG (e.g. HR: 2.29 (95% CI: 1.42–3.68) for the 4th quartile compared to the 1st) and low LDL, LDL/HDL ratio, TC/HDL ratio, log (TG/HDL), and apoB/apoA-I ratio. High glucose and TG were linked with an increased colon cancer risk, while high TC levels were associated with an increased rectal cancer risk. Conclusion. The persistent link between TC and rectal cancer risk as well as between TG and oesophageal and colon cancer risk in normoglycaemic individuals may imply their substantiality in gastrointestinal carcinogenesis.
PMCID: PMC3437288  PMID: 22969802
4.  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.
PMCID: PMC5095878  PMID: 27557616
prostate cancer; type two diabetes; androgen deprivation therapy
5.  Serum lactate dehydrogenase and survival following cancer diagnosis 
British Journal of Cancer  2015;113(9):1389-1396.
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.
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.
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.
Our findings demonstrated an inverse association of baseline serum LDH with cancer-specific survival, corroborating its role in cancer progression.
PMCID: PMC4815785  PMID: 26469834
LDH; the Warburg effect; survival; prospective study
6.  Is there a role for IGF‐1 in the development of second primary cancers? 
Cancer Medicine  2016;5(11):3353-3367.
Cancer survival rates are increasing, and as a result, more cancer survivors are exposed to the risk of developing a second primary cancer (SPC). It has been hypothesized that one of the underlying mechanisms for this risk could be mediated by variations in insulin‐like growth factor‐1 (IGF‐1). This review summarizes the current epidemiological evidence to identify whether IGF‐1 plays a role in the development of SPCs. IGF‐1 is known to promote cancer development by inhibiting apoptosis and stimulating cell proliferation. Epidemiological studies have reported a positive association between circulating IGF‐1 levels and various primary cancers, such as breast, colorectal, and prostate cancer. The role of IGF‐1 in increasing SPC risk has been explored less. Nonetheless, several experimental studies have observed a deregulation of the IGF‐1 pathway, which may explain the association between IGF‐1 and SPCs. Thus, measuring serum IGF‐1 may serve as a useful marker in assessing the risk of SPCs, and therefore, more translational experimental and epidemiological studies are needed to further disentangle the role of IGF‐1 in the development of specific SPCs.
PMCID: PMC5119990  PMID: 27734632
Breast cancer; colorectal cancer; IGF‐1; lung cancer; prostate cancer; second primary cancer
7.  Lamellipodin promotes invasive 3D cancer cell migration via regulated interactions with Ena/VASP and SCAR/WAVE 
Oncogene  2016;35(39):5155-5169.
Cancer invasion is a hallmark of metastasis. The mesenchymal mode of cancer cell invasion is mediated by elongated membrane protrusions driven by the assembly of branched F-actin networks. How deregulation of actin regulators promotes cancer cell invasion is still enigmatic. We report that increased expression and membrane localization of the actin regulator Lamellipodin correlates with reduced metastasis-free survival and poor prognosis in breast cancer patients. In agreement we find that Lamellipodin depletion reduced lung metastasis in an orthotopic mouse breast cancer model. Invasive 3D cancer cell migration as well as invadopodia formation, and matrix degradation were impaired upon Lamellipodin depletion. Mechanistically, we show that Lamellipodin promotes invasive 3D cancer cell migration via both actin-elongating Ena/VASP proteins and the Scar/WAVE complex, which stimulates actin branching. In contrast, Lamellipodin interaction with Scar/WAVE but not Ena/VASP is required for random 2D cell migration. We identify a phosphorylation-dependent mechanism that regulates selective recruitment of these effectors to Lamellipodin: Abl-mediated Lamellipodin phosphorylation promotes its association with both Scar/WAVE and Ena/VASP, while Src-dependent phosphorylation enhances binding to Scar/WAVE but not Ena/VASP. Through these selective, regulated interactions Lamellipodin mediates directional sensing of EGF gradients and invasive 3D migration of breast cancer cells. Our findings imply that increased Lamellipodin levels enhance Ena/VASP and Scar/WAVE activities at the plasma membrane to promote 3D invasion and metastasis.
PMCID: PMC5031503  PMID: 26996666
Lamellipodin; breast cancer metastasis; 3D migration; Ena/VASP proteins; Scar/WAVE complex
8.  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.
PMCID: PMC5037765  PMID: 27608013
calcium; breast cancer; albumin; prospective study
10.  Prostate-specific antigen testing in inner London general practices: are those at higher risk most likely to get tested? 
BMJ Open  2016;6(7):e011356.
To investigate the association between factors influencing prostate-specific antigen (PSA) testing prevalence including prostate cancer risk factors (age, ethnicity, obesity) and non-risk factors (social deprivation and comorbidity).
A cross-sectional database of 136 inner London general practices from 1 August 2009 to 31 July 2014.
Men aged ≥40 years without prostate cancer were included (n=150 481).
Primary outcome
Logistic regression analyses were used to estimate the association between PSA testing and age, ethnicity, social deprivation, body mass index (BMI) and comorbidity while adjusting for age, benign prostatic hypertrophy, prostatitis and tamsulosin or finasteride use.
PSA testing prevalence was 8.2% (2013–2014), and the mean age was 54 years (SD 11). PSA testing was positively associated with age (OR 70–74 years compared to 40–44 years: 7.34 (95% CI 6.82 to 7.90)), ethnicity (black) (OR compared to white: 1.78 (95% CI 1.71 to 1.85)), increasing BMI and cardiovascular comorbidity. Testing was negatively associated with Chinese ethnicity and with increasing social deprivation.
PSA testing among black patients was higher compared to that among white patients, which differs from lower testing rates seen in previous studies. PSA testing was positively associated with prostate cancer risk factors and non-risk factors. Association with non-risk factors may increase the risk of unnecessary invasive diagnostic procedures.
PMCID: PMC4947776  PMID: 27406644
Prostate-specific antigen; testing prevalence; general practice; prostate cancer; ethnicity; comorbidity
11.  Laparoscopic radical prostatectomy outcome data: how should surgeon’s performance be reported? A retrospective learning curve analysis of two surgeons 
ecancermedicalscience  2016;10:651.
To document the learning curve for the laparoscopic radical prostatectomy (LRP) procedure and discuss the optimal usage of prospectively documented outcome data for reporting a surgeon’s performance.
Materials and methods
Using prospectively collected data from the first series of patients to undergo LRP by two surgeons in the same institution, linear and logistic regression multivariate analyses per 25 patients were carried out to graphically represent the surgical learning curve for operative time, blood loss, complications, length of stay (LOS), and positive margins. Surgeon A carried out 275 operations between 2003–2009; Surgeon B carried out 225 between 2008–2012.
Learning curves showing continuous improvement of each of the above outcomes were demonstrated for both cohorts. For surgeon A, a plateau was observed for LOS and T2 positive margins after 100 and 150 surgeries respectively. No such plateau was observed for surgeon B.
On documenting these learning curves and discussion of the reporting methods used, we concluded that the most informative outcome measure, with the least potential observer bias was T2 positive margins. Whether as a single measure or in combination with others, this has potential for use as an objective outcome representative of improvement in a surgeon’s skill over time.
PMCID: PMC4970620  PMID: 27563346
prostatic neoplasms; prostatectomy; learning curve; patient outcome assessment; surgeons
12.  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.
PMCID: PMC4905698  PMID: 27294662
13.  Elevated IgG4 in patient circulation is associated with the risk of disease progression in melanoma 
Oncoimmunology  2015;4(11):e1032492.
Emerging evidence suggests pathological and immunoregulatory functions for IgG4 antibodies and IgG4+ B cells in inflammatory diseases and malignancies. We previously reported that IgG4 antibodies restrict activation of immune effector cell functions and impair humoral responses in melanoma. Here, we investigate IgG4 as a predictor of risk for disease progression in a study of human sera (n = 271: 167 melanoma patients; 104 healthy volunteers) and peripheral blood B cells (n = 71: 47 melanoma patients; 24 healthy volunteers). IgG4 (IgG4/IgGtotal) serum levels were elevated in melanoma. High relative IgG4 levels negatively correlated with progression-free survival (PFS) and overall survival. In early stage (I–II) disease, serum IgG4 was independently negatively prognostic for progression-free survival, as was elevation of IgG4+ circulating B cells (CD45+CD22+CD19+CD3−CD14−). In human tissues (n = 256; 108 cutaneous melanomas; 56 involved lymph nodes; 60 distant metastases; 32 normal skin samples) IgG4+ cell infiltrates were found in 42.6% of melanomas, 21.4% of involved lymph nodes and 30% of metastases, suggesting inflammatory conditions that favor IgG4 at the peripheral and local levels. Consistent with emerging evidence for an immunosuppressive role for IgG4, these findings indicate association of elevated IgG4 with disease progression and less favorable clinical outcomes. Characterizing immunoglobulin and other humoral immune profiles in melanoma might identify valuable prognostic tools for patient stratification and in the future lead to more effective treatments less prone to tumor-induced blockade mechanisms.
PMCID: PMC4590000  PMID: 26451312
B cells; biomarker; cancer inflammation; humoral response; immunomodulation; immunomonitoring; immunosuppression; IgG4; melanoma; prognosis
14.  Serial transperineal sector prostate biopsies: impact on long-term erectile dysfunction 
ecancermedicalscience  2016;10:643.
We wanted to determine whether serial transperineal sector prostate biopsies have a long-term effect on erectile dysfunction (ED). A total of 64 men with prostate cancer entered our active surveillance (AS) programme after a transrectal prostate biopsy as well as a confirmatory initial transperineal sector prostate biopsy (TPSBx). A repeat TPSBx was performed 24 months later as part of our active surveillance protocol. The International Index of Erectile Function-5 (IIEF-5) questionnaire assessed ED at baseline prior to each TPSBx, and at one, three, and six months after first and second TPSBx.
There was a significant short-term deterioration in erectile function on mean IIEF-5 score between baseline (19.5), when compared to one month (10.5) (P <0.001) and three months (18.7) (P = 0.001) following first TPSBx. This resolved at six month follow-up (19.6) (P = 0.681). Following second TPSBx, there was a deterioration in erectile function between baseline (16.6), compared to one month (7.3), three months (13.8), and six months (15.9) (P <0.05) following second TPSBx. Initial TPSBx caused significant short-term ED, which resolved by six months. Serial TPSBx appears to have an adverse impact on erectile function in men monitored on AS, increasing the risk of long-term ED. This risk should be highlighted and discussed during the consent process.
PMCID: PMC4898939  PMID: 27350788
prostatic neoplasms; biopsy; erectile dysfunction; urologic surgical procedures
15.  Causes of death in men with localized prostate cancer: a nationwide, population‐based study 
Bju International  2015;117(3):507-514.
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).
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.
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.
PMCID: PMC4832314  PMID: 25604807
comorbidities; prostate cancer death; curative treatment; localized disease
16.  Confirmatory biopsy for the assessment of prostate cancer in men considering active surveillance: reference centre experience 
ecancermedicalscience  2016;10:633.
To evaluate how accurate a 12-core transrectal biopsy derived low-risk prostate cancer diagnosis is for an active surveillance programme by comparing the histological outcome with that from confirmatory transperineal sector biopsy.
Subjects and methods
The cohort included 166 men diagnosed with low volume Gleason score 3+3 prostate cancer on initial transrectal biopsy who also underwent a confirmatory biopsy. Both biopsy techniques were performed according to standard protocols and samples were taken for histopathology analysis. Subgroup analysis was performed according to disease severity at baseline to determine possible disease parameters of upgrading at confirmatory biopsy.
After confirmatory biopsy, 34% demonstrated Gleason score upgrade, out of which 25% were Gleason score 3+4 and 8.5% primary Gleason pattern 4. Results remained consistent for the subgroup analysis and a weak positive association, but not statistically significant, between prostate specific antigen (PSA), age, and percentage of positive cores, and PCa upgrading at confirmatory biopsy was found.
In our single centre study, we found that one-third of patients had higher Gleason score at confirmatory biopsy. Furthermore 8.5% of these upgraders had a primary Gleason pattern 4. Our results together with previously published evidence highlight the need for the revision of current guidelines in prostate cancer diagnosis for the selection of men for active surveillance.
PMCID: PMC4854226  PMID: 27170833
prostate cancer; active surveillance; confirmatory biopsy; transperineal sector biopsy; transrectal biopsy; prostate biopsy
17.  Investigating the association between allergen-specific immunoglobulin E, cancer risk and survival 
Oncoimmunology  2016;5(6):e1154250.
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.
PMCID: PMC4938379  PMID: 27471625
Allergy; atopy; cancer; immunoglobulin E; cohort
18.  Family history of breast cancer and its association with disease severity and mortality 
Cancer Medicine  2016;5(5):942-949.
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.
PMCID: PMC4864823  PMID: 26799372
breast cancer; Family history; mortality; severity
20.  Serum leptin, C‐reactive protein, and cancer mortality in the NHANES III  
Cancer Medicine  2015;5(1):120-128.
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.
PMCID: PMC4708908  PMID: 26632325
Cancer; C‐reactive protein; leptin; mortality; prospective study
21.  How to model temporal changes in comorbidity for cancer patients using prospective cohort data 
The presence of comorbid conditions is strongly related to survival and also affects treatment choices in cancer patients. This comorbidity is often quantified by the Charlson Comorbidity Index (CCI) using specific weights (1, 2, 3, or 6) for different comorbidities. It has been shown that the CCI increases at different times and with different sizes, so that traditional time to event analysis is not adequate to assess these temporal changes. Here, we present a method to model temporal changes in CCI in cancer patients using data from PCBaSe Sweden, a nation-wide population-based prospective cohort of men diagnosed with prostate cancer. Our proposed model is based on the assumption that a change in comorbidity, as quantified by the CCI, is an irreversible one-way process, i.e., CCI accumulates over time and cannot decrease.
CCI was calculated based on 17 disease categories, which were defined using ICD-codes for discharge diagnoses in the National Patient Register. A state transition model in discrete time steps (i.e., four weeks) was applied to capture all changes in CCI. The transition probabilities were estimated from three modelling steps: 1) Logistic regression model for vital status, 2) Logistic regression model to define any changes in CCI, and 3) Poisson regression model to determine the size of CCI change, with an additional logistic regression model for CCI changes ≥ 6. The four models combined yielded parameter estimates to calculate changes in CCI with their confidence intervals.
These methods were applied to men with low-risk prostate cancer who received active surveillance (AS), radical prostatectomy (RP), or curative radiotherapy (RT) as primary treatment. There were large differences in CCI changes according to treatment.
Our method to model temporal changes in CCI efficiently captures changes in comorbidity over time with a small number of regression analyses to perform – which would be impossible with tradition time to event analyses. However, our approach involves a simulation step that is not yet included in standard statistical software packages. In our prostate cancer example we showed that there are large differences in development of comorbidities among men receiving different treatments for prostate cancer.
Electronic supplementary material
The online version of this article (doi:10.1186/s12911-015-0217-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4652373  PMID: 26582418
Temporal changes; Comorbidity; Cancer; Cox proportional hazards; State transition model
22.  Prediagnostic serum glucose and lipids in relation to survival in breast cancer patients: a competing risk analysis 
BMC Cancer  2015;15:913.
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.
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.
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.
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.
PMCID: PMC4650114  PMID: 26577580
Breast cancer; Glucose; Lipid; Competing risk; Survival; Latent class
23.  The association between circulating IGF1, IGFBP3, and calcium: results from NHANES III 
Endocrine Connections  2015;4(3):187-195.
Despite mounting evidence linking both calcium and IGF1, there is a lack of studies investigating any association between circulating levels of IGF1 and serum calcium.
Serum calcium, IGF1, and IGF-binding protein 3 (IGFBP3) were measured for 5368 participants in NHANES III. We calculated multivariable-adjusted geometric means of serum concentrations of IGF1, IGFBP3, and IGF1/IGFBP3 by categories of calcium (lowest 5% (<1.16 mmol/l), mid 90%, and top 5% (≥1.31 mmol/l)). We also performed stratified analyses by sex, age, ethnicity, BMI, serum levels of vitamin D, and bone mineral density (BMD).
Overall, we found that circulating calcium was positively associated with circulating levels of IGF1 and IGFBP3, but not their molar ratio (i.e., geometric mean of IGF1 by increasing calcium categories: 237.63, 246.51, and 264.22 ng/nl; P trend: 0.43; P first vs third category: 0.01). In particular, these associations were observed in women, people aged <60, non-Hispanic whites, those with vitamin D levels above the mean, and those with low BMD. In contrast, there was an inverse association with the molar ratio for those with BMI ≥30 kg/m2.
We found an overall positive association between circulating levels of IGF1 and IGFBP3 and serum calcium. However, stratification by potential effect-modifiers did not support all suggested hypotheses. Our findings provide more insight into the interplay between calcium and IGF1, which in the future can be investigated in larger observational studies allowing for additional stratifications based on a combination of the different effect-modifiers investigated here.
PMCID: PMC4547399  PMID: 26304028
IGF-1; IGFBP3; calcium; cross-sectional
24.  Quantifying the Evidence for the Risk of Metabolic Syndrome and Its Components following Androgen Deprivation Therapy for Prostate Cancer: A Meta-Analysis 
PLoS ONE  2015;10(3):e0117344.
No meta-analysis is yet available for the risk of metabolic syndrome (MetS) following androgen deprivation therapy (ADT) for men with prostate cancer. To summarize the evidence for the link between ADT and MetS or its components quantitatively with a meta-analysis including all studies published to date.
PubMed and Embase were searched using predefined inclusion criteria to perform meta-analyses on the association between metabolic syndrome, hyperglycemia, diabetes, hypertension, dyslipidemia or obesity and androgen deprivation therapy in patients with prostate cancer. Random effects methods were used to estimate pooled relative risks (RRs) and 95% confidence intervals (CI).
A total of nine studies was included. There was a positive association between ADT and risk of MetS (RR: 1.75 (95% CI: 1.27–2.41)). Diabetes was the only MetS component present in more than 3 studies, and also showed an increased risk following ADT (RR: 1.36 (95% CI: 1.17–1.58)).
This is the first quantitative summary addressing the potential risk of MetS following ADT in men with PCa. The positive RRs indicate that there is a need to further elucidate how type and duration of ADT affect these increased risks of MetS and diabetes as the number of men with PCa treated with ADT is increasing.
PMCID: PMC4368630  PMID: 25794005
25.  CanWalk: study protocol for a randomized feasibility trial of a walking intervention for people with recurrent or metastatic cancer 
Increasing numbers of people in the UK are living with recurrent or metastatic cancer, many of whom experience reduced quality of life resulting from the physical and psychosocial consequences of cancer and its treatment. While drug treatments are important at alleviating some symptoms, there is increasing evidence of the benefits of exercise in enhancing quality of life and health outcomes. Walking is an inexpensive and accessible form of exercise. To our knowledge, no studies have investigated whether a walking intervention is sufficient to enhance quality of life and alleviate symptoms in people with recurrent or metastatic cancer across a range of tumor types. This paper describes the CanWalk study protocol, which aims to assess the feasibility and acceptability of undertaking a randomized controlled trial of a community-based walking program to enhance quality of life and well-being in people with recurrent or metastatic cancer.
A mixed methods feasibility study includes an exploratory two-center randomized controlled trial and qualitative interviews. A minimum of 60 participants will be recruited from two London NHS Trusts and randomized 1:1 between the walking intervention and standard care using minimization. The walking intervention consists of the initial provision of written/online information followed by a short motivational interview. Participants are instructed to walk for 30 min on alternate days and attend an organized volunteer-led walk once a week. Half of all participants will be asked to use a pedometer. Postal questionnaires will be completed at baseline (pre-randomization) and at 6, 12 and 24 weeks. A subsample of participants and stakeholders will be interviewed at the end of the study.
Primary outcomes will be the acceptability and feasibility of the intervention and trial. A range of secondary outcome assessments needed to design a main study, including estimates of recruitment, adherence and variability in quality of life, will be evaluated.
Data from this study will be used to refine the walking intervention, investigate the acceptability of the intervention and study design, and determine the most appropriate outcome measures thereby providing estimates of the factors needed to design the main study.
Trial registration
PMCID: PMC5153811  PMID: 27965787
Randomized controlled trial; Feasibility studies; Qualitative evaluation; Metastatic cancer; Recurrent cancer; Secondary cancer; Walking

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