M. Van Hemelrijck

Systematic review of high-intensity focused ultrasound ablation in the treatment of breast cancer

A systematic review was undertaken to assess the clinical efficacy of non‐invasive high‐intensity focused ultrasound (HIFU) ablation in the treatment of breast cancer.

Adjuvant taxanes and the development of breast cancer-related arm lymphoedema

Despite affecting approximately one‐quarter of all patients undergoing axillary lymph node dissection, the pathophysiology of breast cancer‐related lymphoedema (BCRL) remains poorly understood. More extensive locoregional treatment and higher body mass index have long been identified as major risk factors. This study aimed to identify risk factors for BCRL with a specific focus on the potential impact of chemotherapy on the risk of BCRL.

Association of serum inorganic phosphate with sex steroid hormones and vitamin D in a nationally representative sample of men.

Defects in bone regulatory pathways have been linked to chronic diseases including cardiovascular disease and cancer. In men, a link between bone metabolism and gonadal hormones has been suggested. However, to date, there is lack of evidence on the association between serum inorganic phosphate (Pi) and sex steroid hormones. The objective of this study was to investigate the association between Pi, sex steroid hormones and a known Pi metabolic regulator, vitamin D, in men in the National Health and Nutrition Examination Survey III (NHANES III). From NHANES III, we selected 1412 men aged 20+ who participated in the morning session of Phase I (1988–1991) with serum measurements of Pi, sex hormones, and vitamin D. Multivariable linear regression was used to calculate crude and geometric mean Pi by total and estimated free testosterone and estradiol, sex hormone‐binding globulin, androstanediol glucuronide (AAG), and vitamin D. Similar analyses were performed while stratifying by race/ethnicity and vitamin D levels. We found a lack of statistically significant difference in geometric means of Pi across quintiles of concentrations of sex hormones, indicating a tight regulation of Pi. However, Pi levels were inversely associated with calculated free testosterone in non‐Hispanic black men, with geometric mean levels of Pi of 1.16 and 1.02 ng/mL for those in the lowest and highest quintiles of free testosterone, respectively (p‐trend < 0.05). A similar but weaker pattern was seen between total testosterone and Pi. An inverse association was also seen between AAG and Pi in men with vitamin D concentration below the median (<24.2 ng/mL). No associations were observed among men with vitamin D levels at or above the median. Our findings suggest a weak link among sex hormones, vitamin D, and Pi in men. The observed effects of race/ethnicity and vitamin D indicate a complex association involving various regulators of Pi homeostasis.

Pre-diabetes and serum sex steroid hormones among US men

Several studies demonstrate a link between diabetes and sex steroid hormones, but the link with pre‐diabetes remains elusive. In this study, we hypothesize that pre‐diabetes, which is characterised by having impaired fasting glucose and/or impaired glucose tolerance and/or impaired HbA1C, may influence circulating sex steroid hormone concentrations in men. Thus, we investigated whether serum sex steroid hormone concentrations differ between men with and without pre‐diabetes. We analyzed data for 1139 men who were aged 20+ years when they participated in the Third National Health and Nutrition Examination Survey. We calculated adjusted geometric mean serum concentrations of total and estimated free testosterone, androstanediol glucuronide, total and estimated free estradiol, and sex hormone‐binding globulin (SHBG) in men with and without pre‐diabetes. Logistic regression was used to calculate adjusted odds ratios (OR) of lower concentrations of androgens and SHBG, and higher concentrations of estradiol by prediabetes status. Adjusting for age and race/ethnicity, total testosterone concentration was lower among men with (geometric mean: 4.68 ng/mL) than without (5.36 ng/mL, p = 0.01) pre‐diabetes. SHBG concentration was also lower in men with (31.67 nmol/L) than without (36.16 nmol/L; p = 0.01) pre‐diabetes. Concentrations of the other hormones did not differ between men with and without pre‐diabetes. After adjusting for demographic and lifestyle factors, pre‐diabetic men had a higher odds of lower testosterone (OR: 2.58; 95% CI: 1.54–4.29), higher free estradiol level (OR: 1.59; 95% CI: 1.14–2.22), and lower SHBG level (OR: 2.27; 95% CI: 1.32–3.92) compared to men without pre‐diabetes. These associations were attenuated after adjusting for adiposity (testosterone OR: 1.76; 95% CI 0.95–3.27, free estradiol OR: 1.29, 95% CI: 0.88–1.88, SHBG OR: 1.71; 95% CI 0.88–3.30). Our findings suggest that men with pre‐diabetes have lower circulating total testosterone and SHBG and higher free estradiol levels.

A comparison of the left thoracoabdominal and Ivor–Lewis esophagectomy

The purpose of this study was to assess the oncological outcomes of a large multicenter series of left thoracoabdominal esophagectomies, and compare these to the more widely utilized Ivor-Lewis esophagectomy. With ethics approval and an established study protocol, anonymized data from five centers were merged into a structured database. The study exposure was operative approach (ILE or LTE). The primary outcome measure was time to death. Secondary outcome measures included time to tumor recurrence, positive surgical resection margins, lymph node yield, postoperative death, and hospital length of stay. Cox proportional hazards models provided hazard ratios (HR) with 95% confidence intervals (CI) adjusting for age, pathological tumor stage, tumor grade, lymphovascular invasion, and neoadjuvant treatment. Among 1228 patients (598 ILE; 630 LTE), most (86%) had adenocarcinoma (AC) and were male (81%). Comparing ILE and LTE for AC patients, no difference was seen in terms of time to death (HR 0.904 95%CI 0.749-1.1090) or time to recurrence (HR 0.973 95%CI 0.768-1.232). The risk of a positive resection margin was also similar (OR 1.022 95%CI 0.731-1.429). Median lymph node yield did not differ between approaches (LTE 21; ILE 21; Pxa0=xa00.426). In-hospital mortality was 2.4%, significantly lower in the LTE group (LTE 1.3%; ILE 3.6%; Pxa0=xa00.004). Median hospital stay was 11 days in the LTE group and 14 days in the ILE group (Pxa0<xa00.0001). In conclusion, this is the largest series of left thoracoabdominal esophagectomies to be submitted for publication and the only one to compare two different transthoracic esophagectomy strategies. It demonstrates oncological equivalence between operative approaches but possible short- term advantages to the left thoracoabdominal esophagectomy.

A latent class model for competing risks

Survival data analysis becomes complex when the proportional hazards assumption is violated at population level or when crude hazard rates are no longer estimators of marginal ones. We develop a Bayesian survival analysis method to deal with these situations, on the basis of assuming that the complexities are induced by latent cohort or disease heterogeneity that is not captured by covariates and that proportional hazards hold at the level of individuals. This leads to a description from which risk-specific marginal hazard rates and survival functions are fully accessible, decontaminated of the effects of informative censoring, and which includes Cox, random effects and latent class models as special cases. Simulated data confirm that our approach can map a cohorts substructure and remove heterogeneity-induced informative censoring effects. Application to data from the Uppsala Longitudinal Study of Adult Men cohort leads to plausible alternative explanations for previous counter-intuitive inferences on prostate cancer. The importance of managing cardiovascular disease as a comorbidity in women diagnosed with breast cancer is suggested on application to data from the Swedish Apolipoprotein Mortality Risk Study. Copyright

Investigating nutrition and lifestyle factors as determinants of abdominal obesity: an environment-wide study

Background:The increasing global trends in obesity and its associated burden of disease indicate a need to identify modifiable determinants of obesity.Methods:A total of 182 nutrition and lifestyles factors were investigated in relation to abdominal obesity among 7,403 male and 8,328 female participants of the Third U.S. National Health and Examination Survey (NHANES III). We used the first phase (1988–1991) of the NHANES III to identify factors with a false discovery rate (FDR) of <5%. Of these, we tentatively replicated our findings in the second phase (1992–1994) of the survey. Principal component analysis was performed to identify unobserved factors underlying the association between validated factors and abdominal obesity, defined as waist circumference >88u2009cm for women and >102u2009cm for men.Results:We found five tentatively replicated factors showing significant associations with abdominal obesity in men: serum α-carotene, β-carotene, serum β-cryptoxanthin, serum vitamin D and vigorous physical activity. In women, 7 factors were identified: serum α-carotene, β-carotene, serum β-cryptoxanthin, serum vitamin C, serum vitamin D, vigorous physical activity and aspartame intake. In contrast to the other factors which showed inverse associations with abdominal obesity, aspartame intake displayed a positive relationship with this outcome (OR: 1.18, 95% CI: 1.10–1.26 for each log increase in aspartame intake in women). Principal component analysis suggested three principal components underlying such associations, each comprising: (1) serum antioxidants; (2) serum vitamin D and vigorous physical activity; and (3) aspartame intake. All three principal components also displayed significant associations with abdominal obesity.Conclusion:Our observational investigation that systematically investigates multiple modifiable factors simultaneously has enabled the creation of data-driven hypotheses regarding the possible role of determinants of abdominal obesity and has identified potential avenues for mechanistic investigations to clarify suitable targets of intervention.

PO-083 The role of the humoral immune system in pancreatic cancer

Introduction Epidemiological data suggest a positive association between Helicobacter pylori, Porphyromonas gingivalis and the risk of pancreatic cancer. On the other hand, higher levels of antibodies against commensal oral bacteria was associated with reduced risk of pancreatic cancer in one study. To our knowledge, this is the first prospective study that examines different markers of the adaptive immune system in relation to pancreatic cancer risk. We evaluated associations between prediagnostic serum markers of the humoral immune system, immunoglobulin A (IgA), immunoglobulin G (IgG) and immunoglobulin M (IgM), and pancreatic cancer risk in the Swedish Apolipoprotein-related MORtality RISk (AMORIS) study. Material and methods We selected all participants (>20 years old) with baseline measurements of IgA, IgG and IgM measured at the same health examination between 1985 and 1996 (n=29,876). Participants were excluded if they had a history of chronic pancreatitis, as defined in the National Patient Register and all individuals were free from pancreatic cancer at baseline, as registered in the National Cancer Register. Cox proportional hazards regression was carried out for medical cut-offs of IgA, IgG and IgM. Results and discussions Compared to the IgG reference level of 6.10–14.99u2009g/L, we observed a statistically non-significant positive association with risk of pancreatic cancer for those with IgG levels<6.10u2009g/L [HR: 2.17 (95% CI 0.79–5.96)] and an inverse association for those with IgG levels≥15.00u2009g/L [0.52 (95% CI 0.22–1.20); Ptrend=0.030]. There was a stronger trend for women than for men [HR: 0.59 (95% CI 0.37–0.95) and 0.96 (95% CI 0.68–1.35) for women and men with IgG levels≥15.00u2009g/L (Pinteraction=0.003)]. No associations were found for IgA and IgM. Conclusion We observed an inverse association between levels of IgG and the risk of pancreatic cancer. Our findings highlight the need to investigate the role of microbiota and the role of the immune response in carcinogenesis. Future studies using repeated measurements of serum markers of the humoral immune system may provide further insight into these associations.

PO-308 Identification of genomic patterns predictive of upgrading in low-grade prostate cancer

Introduction Active surveillance (AS) for men with low-risk prostate cancer (PCa) currently depends on repeated biopsies for prognostication. We aim to identify molecular patterns that are present in initial PCa biopsies that inform future histopathological upgrading of PCa for men on AS. Material and methods TAPS2.0 and Patchwork were respectively used to establish somatic copy number aberrations (SCNAs) for 44 Gleason score (GS)6 (3+3) TCGA PRAD Affymetrix SNP6.0 and 18 GS6 (3+3) ICGC WGS samples. Elastic net regularisation was used to identify SCNA predictors of biochemical recurrence (BCR). In an internal cohort, SCNAs were established using QDNAseq from initial and repeat biopsies of 5 men on AS, using low-pass WGS. Four of the 5 men upgraded from a GS6 to GS7 (3+4) upon repeat biopsy whilst one remained GS6. Results and discussions SCNAs were robustly established for 62 GS6 TCGA and ICGC PCas. The most frequent copy number losses were at 8u2009p (50%), 13q (29%) and 6q (26%). Applying a Shannon-diversity index on SCNAs provided a measure of genomic heterogeneity and indicated a trend towards increased diversity in PCa of men with BCR (p-value=0.087, t-test). Six cytobands with recurrent SCNAs were identified as predictive of BCR, including a loss on 10q11 and a gain on 2u2009p13. These predictive SCNAs were interrogated in genomes from our internal cohort of initial and repeat biopsies. Copy number losses were identified at 8u2009p (46%), 13q (23%), and 6q (46%), and were comparable in frequency to losses in TCGA and ICGC. None of the six predictors were detected in the initial PCa biopsy of the stable patient, while two predictors were found in men who had upgraded to GS7: 14q13 (gain), present in two men, and 6q11 (loss), in another man. Patients that upgraded had the highest similarities (81%) of SCNAs between patient-matched initial and repeat biopsies. Given that these biopsies were taken furthest apart in the prostate gland, missampling and GS is likely not to affect prediction. Conclusion SCNAs indicative of upgrading were identified in GS6 TCGA-ICGC data using BCR as a surrogate for histopathological upgrading whilst on AS. These were observed to some extent in an internal cohort of men on AS. Validation of these predictors in men on AS is currently on-going in a further 8 men and may provide the basis for developing a prognostication tool to guide therapy for men with early prostate cancer.

Serum inflammatory markers in relation to prostate cancer severity and death in the Swedish AMORIS study: Serum inflammatory markers and prostate cancer

Inflammation is a well‐documented driver of cancer development and progression. However, little is known about its role in prostate carcinogenesis. Thus, we examined the association of C‐reactive protein (CRP), haptoglobin, albumin and white blood cells (WBC) with prostate cancer (PCa) severity (defined by PCa risk category and clinicopathological characteristics) and progression (defined by PCa death). We selected 8,471 Swedish men with newly diagnosed PCa who had exposure measurements taken approximately 14 years prior to diagnosis. We calculated odds ratio (OR) and 95% confidence interval (CI) for the associations between the inflammatory markers and PCa severity using logistic regression, while Cox proportional hazard regression was used for the associations with overall and PCa death. Serum CRP levels were associated with increased odds of high risk and metastatic PCa, and high PSA levels (≥20 µg/L) (OR: 1.29; 95% CI: 1.06–1.56, 1.32; 1.05–1.65 and 1.51; 1.26–1.81, respectively). Similarly, higher haptoglobin levels were associated with increased odds of metastatic PCa, high PSA level and possibly high grade PCa (1.38; 1.10–1.74, 1.50; 1.17–1.93 and 1.25; 1.00–1.56, respectively). Albumin was positively associated with Gleason 4u2009+u20093 tumour (1.38; 1.02–1.86) and overall death (HRunit increase in log: 1.60; 95% CI: 1.11–2.30), but inversely associated with high risk PCa and high PSA levels (≥20 µg/L) (0.71; 0.56–0.89 and 0.72; 0.5 9–0.90). WBC was associated with increased odds of T3–T4 PCa. Except for albumin, none of these markers were associated with PCa death or overall death. Systemic inflammation as early as 14 years prior to diagnosis may influence prostate cancer severity.