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The majority of lung cancer (LC) patients are diagnosed at a late stage, and survival is poor. Circulating RNA molecules are known to have a role in cancer; however, their involvement before diagnosis remains an open question. In this study, we investigated circulating RNA dynamics in prediagnostic LC samples, focusing on smokers, to identify if and when disease‐related signals can be detected in serum. We sequenced small RNAs in 542 serum LC samples donated up to 10 years before diagnosis and 519 matched cancer‐free controls coming from 905 individuals in the Janus Serum Bank. This sample size provided sufficient statistical power to independently analyze time to diagnosis, stage, and histology. The results showed dynamic changes in differentially expressed circulating RNAs specific to LC histology and stage. The greatest number of differentially expressed RNAs was identified around 7 years before diagnosis for early‐stage LC and 1–4 years prior to diagnosis for locally advanced and advanced‐stage LC, regardless of LC histology. Furthermore, NSCLC and SCLC histologies have distinct prediagnostic signals. The majority of differentially expressed RNAs were associated with cancer‐related pathways. The dynamic RNA signals pinpointed different phases of tumor development over time. Stage‐specific RNA profiles may be associated with tumor aggressiveness. Our results improve the molecular understanding of carcinogenesis. They indicate substantial opportunity for screening and improved treatment and will guide further research on early detection of LC. However, the dynamic nature of the RNA signals also suggests challenges for prediagnostic biomarker discovery., We investigated circulating RNA dynamics in prediagnostic lung cancer (LC) samples, focusing on smokers, to identify if and when disease‐related signals can be detected in serum. The results showed dynamic changes in differentially expressed circulating RNAs specific to LC histology and stage. The dynamic RNA signals identified different phases of tumor development over time and were associated with cancer‐related pathways.

Elevated pre-diagnostic serum levels of the immune activation markers sCD27 and sCD30 have been associated with non-Hodgkin lymphoma (NHL). However, the use of a single sample per participant in these studies has limited etiologic inferences. We report findings, overall and by NHL subtype, from a case-control analysis (422 cases, 434 controls) within the Janus Serum Bank with two samples per subject collected on average five years apart. Chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL/SLL) was associated with elevated sCD27 in the later, but not earlier, pre-diagnostic sample (odds ratio [OR] 4.2, 95% confidence interval [CI] 1.5-11.6 and 1.7, 0.7-4.7 per log increase respectively) in analyses adjusting for both analytes, while follicular lymphoma (FL) was associated with elevated sCD30 in both the later and earlier samples (OR 2.9, 95% CI 1.4-4.4 and 2.3, 1.2-4.4 respectively). CLL/SLL cases were significantly more likely than controls to have higher sCD27 in the later vs. earlier sample (OR 1.4, 95% CI 1.1-1.9 per standard deviation increase); no such difference in sCD30 was apparent for FL. In a joint analysis, NHL cases were more likely than controls to have below-median sCD27 in the earlier sample and above-median sCD27 in the later sample (OR 1.5, 95% CI 1.0-2.3). For sCD30, the association between sCD30 and FL was confined to subjects with above-median analyte levels in both samples (OR 2.5, 95% CI 1.1-5.9). Our findings are compatible with elevated sCD27 representing a disease-induced effect and sCD30 representing a marker of increased FL susceptibility.

Bettina K Andreassen,1 Helga H Hektoen,1 Karol Axcrona,2 Hilde Langseth,1 Jo S Stenehjem,1 Trude E Robsahm1 1Department of Research, Cancer Registry of Norway, Oslo, Norway; 2Department of Urology, Akershus University Hospital, Lørenskog, NorwayCorrespondence: Helga H Hektoen Email Helga.Helseth.Hektoen@kreftregisteret.no View the original paper by Dr Hektoen and colleagues This is in response to the Letter to the Editor

Helga H Hektoen,1 Randi E Gislefoss,1 Jo S Stenehjem,1 Hilde Langseth,1 Karol Axcrona,2 Alison M Mondul,3 Trude E Robsahm,1 Bettina K Andreassen1 1Department of Research, Cancer Registry of Norway, Oslo, Norway; 2Department of Urology, Akershus University Hospital, Lørenskog, Norway; 3Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USACorrespondence: Helga H Hektoen Ullernchausseen 64, Oslo, 0379, NorwayTel +47 22 92 89 21Email Helga.helseth.hektoen@kreftregisteret.noPurpose: Circulating 25-hydroxyvitamin D (25(OH)D) is inversely associated with overall cancer mortality and selected cancers, while for urothelial bladder cancer (BC) this relationship is unclear. We aimed to examine the association between 25(OH)D and BC mortality.Materials and Methods: We used prediagnostic serum from 378 BC cases within the population-based Janus Cohort. Cox regression models estimated hazard ratios (HRs), with 95% confidence intervals (CIs), for the association between 25(OH)D and BC-specific and all-cause mortality. Restricted cubic splines were assessed to examine non-linear risk associations. Analyses were stratified by tumor invasiveness (non-muscle invasive BC (NMIBC) and muscle invasive BC (MIBC)). Additionally, the association between 25(OH)D and all-cause mortality was assessed for 378 cancer-free matched controls.Results: 25(OH)D deficiency (< 50 nmol/L) was associated with higher BC-specific mortality (HR 1.87, 95% CI 1.10– 3.20), when compared with insufficient levels (50– 74 nmol/L). Stratification by tumor invasiveness revealed that this result was evident for NMIBC only, both with respect to BC-specific mortality (HR 2.84, 95% CI 1.14– 7.12) and all-cause mortality (HR 1.97, 95% CI 1.06– 3.65). No association between 25(OH)D levels and all-cause mortality was found in cancer-free controls.Conclusion: 25(OH)D deficiency (< 50 nmol/L) prior to a BC diagnosis was associated with increased risk of BC-specific mortality, when compared to insufficient levels (50– 74 nmol/L). The results were evident among NMIBC patients only, suggesting a more critical role of vitamin D deficiency in an early stage of the disease.Keywords: cancer, vitamin D, mortality, cancer death, prospective study

There is justified optimism regarding the use of miRNAs as early detection biomarkers of cancer. They are well characterized and are involved in all the hallmarks of cancer. Less is known about the role of most other non-coding RNA (ncRNAs) classes in normal physiology and tumorigenesis. The JanusRNA dataset consist of circulating RNA profiles of pre-clinical samples from 1631 cancer patients and 673 cancer-free controls. We studied eight cancer types including cancer of the: lung, colon, rectum, prostate, breast, testis, ovaries and gallbladder. JanusRNA has its origin from the large population-based Janus Serum Bank Cohort which consists of 318 628 Norwegians. The dataset combines information from the complete nationwide cancer registry, RNA sequencing profiles from 1631 cancer patients and 673 cancer-free controls, as well as data on lifestyle, anthropometry and biochemical measurements from national health surveys. The Janus Serum Bank is specifically suited for studies of early detection and risk biomarkers of cancer, since samples are collected nationwide over a large time span, pre-clinically and cancer occurs at different points in time after blood draw. We used a nested case-control design, selecting both cases and controls among the Janus cohort members. We restricted our selection to cases with at least one sample collected within 10 years prior to cancer diagnosis. We selected 673 cancer-free Janus participants for comparison of RNA levels with the cancer cases. The controls were frequency matched to the case group on sex, age at blood donation and date of blood donation. The JanusRNA dataset has been used to investigate the natural variation of circulating RNAs in cancer-free individuals. This data resource was also used in a study of variation in RNA expression associated with common traits like age, sex, smoking, BMI and physical activity in cancer-free individuals. RNA dynamics in lung and testicular carcinogenesis throughout a 10-year follow-up has also been studied.

Background In the era of widespread prostate-specific antigen testing, it is important to focus etiologic research on the outcome of aggressive prostate cancer, but studies have defined this outcome differently. We aimed to develop an evidence-based consensus definition of aggressive prostate cancer using clinical features at diagnosis for etiologic epidemiologic research. Methods Among prostate cancer cases diagnosed in 2007 in the National Cancer Institute’s Surveillance, Epidemiology, and End Results-18 database with follow-up through 2017, we compared the performance of categorizations of aggressive prostate cancer in discriminating fatal prostate cancer within 10 years of diagnosis, placing the most emphasis on sensitivity and positive predictive value (PPV). Results In our case population (n = 55 900), 3073 men died of prostate cancer within 10 years. Among 12 definitions that included TNM staging and Gleason score, sensitivities ranged from 0.64 to 0.89 and PPVs ranged from 0.09 to 0.23. We propose defining aggressive prostate cancer as diagnosis of category T4 or N1 or M1 or Gleason score of 8 or greater prostate cancer, because this definition had one of the higher PPVs (0.23, 95% confidence interval = 0.22 to 0.24) and reasonable sensitivity (0.66, 95% confidence interval = 0.64 to 0.67) for prostate cancer death within 10 years. Results were similar across sensitivity analyses. Conclusions We recommend that etiologic epidemiologic studies of prostate cancer report results for this definition of aggressive prostate cancer. We also recommend that studies separately report results for advanced category (T4 or N1 or M1), high-grade (Gleason score ≥8), and fatal prostate cancer. Use of this comprehensive set of endpoints will facilitate comparison of results from different studies and help elucidate prostate cancer etiology.

Small non-coding RNAs such as microRNAs are master regulators of gene expression. One of the most promising applications of miRNAs is the use as liquid biopsy. Especially early diagnosis is an effective means to increase patients’ overall survival. E.g. in oncology a tumor is detected at best prior to its clinical manifestation. We generated genome-wide miRNA profiles from serum of patients and controls from the population-based Janus Serum Bank (JSB) and analyzed them by bioinformatics and artificial intelligence approaches. JSB contains sera from 318,628 originally healthy persons, more than 96,000 of whom later developed cancer. We selected 210 serum samples of patients with lung, colon or breast cancer at three time points prior to diagnosis, after cancer diagnosis and controls. The controls were matched with regard to age of the blood donor and to the time points of blood drawing, which were 27, 32, or 38 years prior to diagnosis. Using ANOVA we report 70 significantly deregulated markers (adjusted p-value−10). Further, 91miRNAs were differently expressed in pre-diagnostic samples as compared to controls (nominal p

Phytoestrogens may influence prostate cancer development. This study aimed to examine the association between prediagnostic circulating concentrations of isoflavones (genistein, daidzein, equol) and lignans (enterolactone and enterodiol) and the risk of prostate cancer. Individual participant data were available from seven prospective studies (two studies from Japan with 241 cases and 503 controls and five studies from Europe with 2,828 cases and 5,593 controls). Because of the large difference in circulating isoflavone concentrations between Japan and Europe, analyses of the associations of isoflavone concentrations and prostate cancer risk were evaluated separately. Prostate cancer risk by study-specific fourths of circulating concentrations of each phytoestrogen was estimated using multivariable-adjusted conditional logistic regression. In men from Japan, those with high compared to low circulating equol concentrations had a lower risk of prostate cancer (multivariable-adjusted OR for upper quartile [Q4] vs. Q1 = 0.61, 95% confidence interval [CI] = 0.39–0.97), although there was no significant trend (OR per 75 percentile increase = 0.69, 95 CI = 0.46–1.05, ptrend = 0.085); Genistein and daidzein concentrations were not significantly associated with risk (ORs for Q4 vs. Q1 = 0.70, 0.45–1.10 and 0.71, 0.45–1.12, respectively). In men from Europe, circulating concentrations of genistein, daidzein and equol were not associated with risk. Circulating lignan concentrations were not associated with the risk of prostate cancer, overall or by disease aggressiveness or time to diagnosis. There was no strong evidence that prediagnostic circulating concentrations of isoflavones or lignans are associated with prostate cancer risk, although further research is warranted in populations where isoflavone intakes are high.

Background Much of the marked increase in incidence of non-Hodgkin lymphoma (NHL) over the past few decades remains unexplained. Organochlorines, including organochlorine pesticides (OCPs), have been implicated as possible contributors to the increase, but the evidence is inconsistent. Objectives To investigate the relation between pre-diagnostic levels of OCPs and risk of NHL in a case-control study nested within the population-based Janus Serum Bank Cohort in Norway. Methods Prediagnostic concentrations of 11 OCPs or OCP metabolites were measured in baseline blood samples collected between 1972 and 1978 from 190 cases and 190 controls matched on sex, county, age at blood draw, and date of blood draw. We conducted conditional logistic regression to estimate adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) for each quartile of lipid-corrected OCP/metabolite relative to the lowest quartile. Results We observed non-significantly elevated ORs across quartiles of β-hexachlorocyclohexane compared to the lowest quartile (OR range: 1.40–1.82) although with no apparent monotonic exposure-response relationship. We also found an inverse association between risk of NHL and o,p'-DDT (OR for Q4 vs. Q1 = 0.44, 95% CI: 0.19, 1.01; p-trend = 0.05). In analyses stratified by age at blood collection and duration of follow-up, several other analytes, primarily chlordane-related compounds, showed inverse associations among younger participants or those with longer follow-up time between blood draw and NHL diagnosis. Conclusions We found only limited evidence of positive association between selected OCPs and development of NHL.

Introduction The aim of this study was to investigate whether secondary cytoreductive surgery and platinum-based chemotherapy improved survival among patients with recurrent, platinum-sensitive epithelial ovarian cancer compared with those who received platinum-based chemotherapy alone, and to identify possible predictors for selection to secondary cytoreductive surgery. Material and methods We included 397 patients who had a primary diagnosis of FIGO stage I-IV epithelial ovarian cancer recorded in the Cancer Registry of Norway between 1 January 2002 and 31 December 2012, received primary surgery with no residuals followed by platinum-based chemotherapy, had first recurrence six or more months after completion of primary platinum-based chemotherapy, and received secondary treatment with either secondary cytoreductive surgery and platinum-based chemotherapy (secondary cytoreductive surgery+platinum-based chemotherapy group) or platinum-based chemotherapy alone (platinum-based chemotherapy group). Outcomes were progression-free survival to second recurrence or death and overall survival. Hazard ratios were estimated using multivariable Cox regression. Results There were 75 patients in the secondary cytoreductive surgery+platinum-based chemotherapy group in whom complete resection was achieved for 60 (80%), and 322 patients in the platinum-based chemotherapy group. Both progression-free survival (hazard ratio 0.45, 95% confidence interval 0.32-0.62) and overall survival (hazard ratio 0.50, 95% confidence interval 0.32-0.70) were improved in the secondary cytoreductive surgery+platinum-based chemotherapy compared with the platinum-based chemotherapy group. A survival benefit was only seen in patients with no residuals at secondary cytoreductive surgery. Conclusions In selected epithelial ovarian cancer patients with no residuals after primary surgery and a recurrent, platinum-sensitive tumor, the complete resection of recurrent tumor at secondary cytoreductive surgery improves progression-free survival and overall survival. Our results suggest that a long treatment-free interval and non-disseminated lesions (three or fewer lesions) on radiological images could be useful predictors for complete resection at secondary cytoreductive surgery.

Background: Reproductive factors, including parity, breastfeeding, and contraceptive use, affect lifetime ovulatory cycles and cumulative exposure to gonadotropins and are associated with ovarian cancer. To understand the role of ovulation-regulating hormones in the etiology of ovarian cancer, we prospectively analyzed the association of anti-Mullerian hormone (AMH), follicle-stimulating hormone (FSH), and inhibin B with ovarian cancer risk. Methods: Our study included 370 women from the Janus Serum Bank, including 54 type I and 82 type II invasive epithelial ovarian cancers, 49 borderline tumors, and 185 age-matched controls. We used conditional logistic regression to assess the relationship between hormones and risk of ovarian cancer overall and by subtype (types I and II). Results: Inhibin B was associated with increased risk of ovarian cancer overall [OR, 1.97; 95% confidence interval (CI), 1.14–3.39; Ptrend = 0.05] and with type I ovarian (OR, 3.10; 95% CI, 1.04–9.23; Ptrend = 0.06). FSH was not associated with ovarian cancer risk overall, but higher FSH was associated with type II ovarian cancers (OR, 2.78; 95% CI, 1.05–7.38). AMH was not associated with ovarian cancer risk. Conclusions: FSH and inhibin B may be associated with increased risk in different ovarian cancer subtypes, suggesting that gonadotropin exposure may influence risk of ovarian cancer differently across subtypes. Impact: Associations between prospectively collected AMH, FSH, and inhibin B levels with risk of ovarian cancer provide novel insight on the influence of premenopausal markers of ovarian reserve and gonadotropin signaling. Heterogeneity of inhibin B and FSH effects in different tumor types may be informative of tumor etiology.

Background Human papillomavirus type 16 (HPV16)-E6 antibodies are detectable in peripheral blood before diagnosis in the majority of HPV16-driven oropharyngeal squamous cell carcinoma (OPSCC), but the timing of seroconversion is unknown. Patients and methods We formed the HPV Cancer Cohort Consortium which comprises nine population cohorts from Europe, North America and Australia. In total, 743 incident OPSCC cases and 5814 controls provided at least one pre-diagnostic blood sample, including 111 cases with multiple samples. Median time between first blood collection and OPSCC diagnosis was 11.4 years (IQR = 6–11 years, range = 0–40 years). Antibodies against HPV16-E6 were measured by multiplex serology (GST fusion protein based Luminex assay). Results HPV16-E6 seropositivity was present in 0.4% of controls (22/5814; 95% CI 0.2% to 0.6%) and 26.2% (195/743; 95% CI 23.1% to 29.6%) of OPSCC cases. HPV16-E6 seropositivity increased the odds of OPSCC 98.2-fold (95% CI 62.1–155.4) in whites and 17.2-fold (95% CI 1.7–170.5) in blacks. Seropositivity in cases was more frequent in recent calendar periods, ranging from 21.9% pre-1996 to 68.4% in 2005 onwards, in those with blood collection near diagnosis (lead time 30 years (N = 24), 20–30 years (N = 148), 10–20 years (N = 228), and

Glioblastoma is associated with poor prognosis with a median survival of one year. High doses of ionizing radiation is the only established exogenous risk factor. To explore new potential biological risk factors for glioblastoma, we investigated alterations in metabolite concentrations in pre-diagnosed serum samples from glioblastoma patients diagnosed up to 22 years after sample collection, and undiseased controls. The study points out a latent biomarker for future glioblastoma consisting of nine metabolites (gamma-tocopherol, alpha-tocopherol, erythritol, erythronic acid, myo-inositol, cystine, 2-keto-L-gluconic acid, hypoxanthine and xanthine) involved in antioxidant metabolism. We detected significantly higher serum concentrations of alpha-tocopherol (p=0.0018) and gamma-tocopherol (p=0.0009) in future glioblastoma cases. Compared to their matched controls, the cases showed a significant average fold increase of alpha- and gamma-tocopherol levels: 1.2 for alpha-T (p=0.018) and 1.6 for gamma-T (p=0.003). These tocopherol levels were associated with a glioblastoma odds ratio of 1.7 (alpha-T, 95% CI: 1.0-3.0) and 2.1 (gamma-T, 95% CI: 1.2-3.8). Our exploratory metabolomics study detected elevated serum levels of a panel of molecules with antioxidant properties as well as oxidative stress generated compounds. Additional studies are necessary to confirm the association between the observed serum metabolite pattern and future glioblastoma development.

Background To evaluate the individual and combined effects of enterolactone, vitamin D, free testosterone, Chlamydia trachomatis and HPV-18 on the risk of prostate cancer in a large population-based biochemical material that combined three Nordic serum sample banks. Material and methods A joint cohort of 209 000 healthy men was followed using cancer registry linkages. From this cohort altogether 699 incident cases of prostate cancer were identified. Four controls were selected by incidence density sampling and matching for country, age and date of the blood sampling. Complete data for all investigated exposures was available for 483 eligible cases and 1055 eligible controls. Multivariate regression analyses were performed to investigate the solitary and combined effects. Results The solitary effects were small. Significantly increased risk [rate ratio 1.6 (95% CI 1.0-2.5)] was found in those seronegative for C. trachomatis infection. The joint effect in risk levels of enterolactone and vitamin D was antagonistic [observed rate ratio (RR) 1.4 (1.0-2.1), expected RR 2.0 (1.0-4.1)] as well as that of HPV-18 and C. trachomatis [observed RR 1.9 (0.8-4.5), expected RR 9.9 (1.1-87.0)]. Conclusion A large follow-up study combining data from several previously investigated exposures to investigate joint effects found no evidence that exposure to two risk factors would increase the risk of prostate cancer from that expected on basis of exposure to one risk factor. If anything, the results were consistent with antagonistic interactions.

ObjectivesEpithelial ovarian cancer is characterized by nonspecific signs and clinical symptoms arising at late stages. Early detection is therefore important and may significantly improve the survival rate. Cancer antigen 125 (CA125) has been the most extensively studied serum biomarker in epithelial ovarian cancer, but low specificity limits its usefulness. A relatively novel biomarker, human epididymis protein 4 (HE4), has shown promise in early detection of the disease. The aim of this study was to investigate how early the tumor marker increases before diagnosis.Methods/MaterialsA nested case-control design was used to evaluate the performance of HE4 and CA125 in prediagnostic serum samples from the Janus Serumbank. Serial specimens from 120 women with invasive epithelial ovarian cancer were compared with healthy controls. Serum level of CA125, HE4, and cotinine was measured. Spearman correlation and multiple linear regression analyses were used to investigate impact of smoking, age, storage time, and lag time (time from sampling until date of diagnosis).ResultsSpearman correlation showed a strong positive correlation between HE4 and smoking in both cases and controls. Multiple linear regression analyses for pairwise differences between case and control showed that serum level of HE4 and CA125 was significantly increased (P= 0.002 andP< 0.001, respectively) 2 years before diagnosis and that CA125 also was significantly increased up to 4 years before diagnosis (P= 0.002).ConclusionsThe present study showed that a difference between cases and controls in serum concentration of HE4 seemed to be increased 2 years before diagnosis and that CA125 was increased until 4 years before diagnosis.

The aim of this study was to determine the association of HPV16 antibodies (Abs) and oropharyngeal cancer (OPC) risk in sera obtained prior to clinical diagnosis.We identified 92 participants with incident OPC and 460 matched controls from the Janus Serum Bank Cohort in Norway. Archived tumor specimens were requested for a subset of the cases. Serum samples were collected from cases, on average, 9.3years before diagnosis (range, 0.1-14.9years). Ten cases had serum samples from multiple time points. IgG seropositivity to 8 HPV16 antigens was determined, and a logistic regression classifier of a panel of all early-antigen (EA) Abs for the predictive diagnosis of OPC was applied.HPV16 EA seropositivity was present in 25.0% of patients with OPC and 7.6% of controls (odds ratio (OR), 4.1; 95% CI, 2.3-7.2, p0.0001). Abs to E2 were strongly associated with cases 0-2years pre- diagnosis (OR, 150.1; 95% CI, 27.4-1040.0, p0.0001), and the probability of seropositivity was inversely associated with time to diagnosis (OR, 0.7 per additional year; 95% CI, 0.6-0.9, p=0.0002). Abs to E2 were also strongly associated with tumor HPV status (OR, 35.6; 95% CI, 8.7-200.0, p0.0001). A positive score on the binary classifier was associated with an overall OR of 15.8 (95% CI, 5.6-53.4) compared with controls (p0.05), and was strongly associated with tumor HPV status (OR, 27.4; 95% CI, 8.6-99.6, p0.001).HPV16 Abs are detectable years prior to diagnosis of OPC, and the probability of seropositivity increases closer to diagnosis.

Introduction The aim of this study was to investigate whether secondary cytoreductive surgery and platinum-based chemotherapy improved survival among patients with recurrent, platinum-sensitive epithelial ovarian cancer compared with those who received platinum-based chemotherapy alone, and to identify possible predictors for selection to secondary cytoreductive surgery. Material and methods We included 397 patients who had a primary diagnosis of FIGO stage I-IV epithelial ovarian cancer recorded in the Cancer Registry of Norway between 1 January 2002 and 31 December 2012, received primary surgery with no residuals followed by platinum-based chemotherapy, had first recurrence six or more months after completion of primary platinum-based chemotherapy, and received secondary treatment with either secondary cytoreductive surgery and platinum-based chemotherapy (secondary cytoreductive surgery+platinum-based chemotherapy group) or platinum-based chemotherapy alone (platinum-based chemotherapy group). Outcomes were progression-free survival to second recurrence or death and overall survival. Hazard ratios were estimated using multivariable Cox regression. Results There were 75 patients in the secondary cytoreductive surgery+platinum-based chemotherapy group in whom complete resection was achieved for 60 (80%), and 322 patients in the platinum-based chemotherapy group. Both progression-free survival (hazard ratio 0.45, 95% confidence interval 0.32-0.62) and overall survival (hazard ratio 0.50, 95% confidence interval 0.32-0.70) were improved in the secondary cytoreductive surgery+platinum-based chemotherapy compared with the platinum-based chemotherapy group. A survival benefit was only seen in patients with no residuals at secondary cytoreductive surgery. Conclusions In selected epithelial ovarian cancer patients with no residuals after primary surgery and a recurrent, platinum-sensitive tumor, the complete resection of recurrent tumor at secondary cytoreductive surgery improves progression-free survival and overall survival. Our results suggest that a long treatment-free interval and non-disseminated lesions (three or fewer lesions) on radiological images could be useful predictors for complete resection at secondary cytoreductive surgery.

Background:To maintain the best performance a frozen serum sample should be thawed once to prevent repeated freeze-thaw cycles. Archival biobanks often have one tube of a sample available, causing repeated freeze-thaw cycles when the sample is used in multiple research projects. In this study, we investigated potential effects of freeze-thaw cycles on several biochemical components in serum.Methods:Serum from 40 fasting donors of both genders, aged 30–60 years, were frozen at –25 °C. Aliquots of the 40 different samples went through 1, 2, 3, 4, 5 and 10 thaws, respectively. They were analyzed after 3 month of storage for 15 serum components including electrolytes and metabolites, proteins and enzymes, lipids, hormones and vitamins. One-way analyses of variance (ANOVA) with repeated measurements and equivalence tests were used to examine differences in component levels.Results:Albumin, aspartate-aminotransferase (ASAT), cholesterol, creatinine, C-reactive protein, glucose, immunoglobulin G, potassium, testosterone, triglycerides, urea and vitamin B12 levels did not show significant difference for pairwise comparisons after 10 repeated thaws. Although albumin, ASAT, bilirubin, potassium, sodium, testosterone and thyroid stimulating hormone (TSH) showed overall statistically significant changes in serum levels, only bilirubin, sodium and TSH were significant for the pairwise comparisons investigated. Clinical significance were shown for albumin, ASAT, bilirubin, sodium and testosterone.Conclusions:Twelve components (albumin, ASAT, cholesterol, creatinine, C-reactive protein, glucose, immunoglobulin G, potassium, testosterone, triglycerides, urea and vitamin B12) were robust to 10 repeated thaws compared to baseline level. Three components (bilirubin, sodium and TSH) showed statistical significant difference for pairwise comparisons, however, TSH was not clinically affected.

Several studies report varying incidence rates of cancer in subsites of the colorectum, as an increasing proportion appears to develop in the proximal colon. Varying incidence trends together with biological differences between the colorectal segments raise questions of whether lifestyle factors impact on the risk of cancer differently at colorectal subsites. We provide an updated overview of the risk of cancer at different colorectal subsites (proximal colon, distal colon, and rectum) according to BMI and physical activity to shed light on this issue. Cohort studies of colorectal cancer, published in English throughout 2010, were identified using PubMed. The risk estimates from 30 eligible studies were summarized for BMI and physical activity. A positive relationship was found between BMI and cancer for all colorectal subsites, but most pronounced for the distal colon [relative risk (RR) 1.59, 95% confidence interval (CI) 1.34-1.89]. For the proximal colon and rectum, the risk estimates were 1.24 (95% CI 1.08-1.42) and 1.23 (95% CI 1.02-1.48), respectively. Physical activity was related inversely to the risk of cancer at the proximal (RR 0.76, 95% CI 0.70-0.83) and distal colon (RR 0.77, 95% CI 0.71-0.83). Such a relationship could not be established for the rectum (RR 0.98, 95% CI 0.88-1.08). In conclusion, the results suggest minor differences in the associations of BMI and the risk of cancer between the colorectal subsites. For physical activity, the association does not seem to differ between the colonic subsites, but a difference was observed between the colon and the rectum, perhaps indicating that different mechanisms are operating in the development of colon and rectal cancer.

Background: Lung cancer in never smokers is a significant contributor of cancer mortality worldwide. In this analysis, we explored the role of nine human polyomaviruses, including JC virus (JCV), BK virus (BKV) and Merkel cell virus (MCV), in lung cancer development in never smokers as there are data to support that polyomaviruses are potentially carcinogenic in the human lung. Methods: We used multiplex serology to detect serum antibodies to polyomaviruses in a nested case-control design combining lung cancer cases and controls from four cohort studies - NYU Women's Health Study (NYU-WHS), Janus Serum Bank, Shanghai Women's Health Study and Singapore Chinese Health Study (SCHS). Results: The final analyses included 511 cases and 508 controls. Seroprevalence for each polyomavirus showed significant heterogeneity by study, but overall there were no statistically significant differences between cases and controls. In total, 69.1% of the cases and 68.7% of the controls were seropositive for JCV VP1 antibody. Seropositivity for BKV was higher at 89.0% in cases and 89.8% in controls and lower for MCV at 59.3% in cases and 61.6% in controls. Similar results were obtained after adding an additional retrospective case-control study (Xuanwei study) to the analysis. Conclusions: Our results do not support the hypothesis that seropositivity for polyomaviruses is associated with increased lung cancer risk in never smokers. Future research to evaluate relationship between polyomavirus infection and lung carcinogenesis should focus more on evaluating the presence of virus or viral nucleic acids (DNA or RNA) in lung tumour samples. © 2016 Cancer Research UK. All rights reserved.

IntroductionBladder cancer (BC) (including renal pelvis, ureter and urethra) is one of the most common urogenital cancers and the fourth most frequent cancer in men in the USA. In Norway, the incidence of BC has increased over the last decades. The age-standardised incidence rates per 100 000 for 2011-2015 were 53.7 in men and 16.5 in women. Compared to the 5-year period 2006–2010, the percentage increase in incidence was 6.1% in men and 12.3% in women. The recurrence rate of BC is over 50%, the highest recurrence rate of any malignancy. Smoking and occupational exposure to aromatic amines are recognised as the major risk factors. Recently, low-serum level of 25-hydroxy vitamin D (25(OH)D) and obesity have been suggested to increase the BC risk, and leptin, which is important in weight regulation, may be involved in bladder carcinogenesis. More knowledge on potential risk factors for BC is necessary for planning and implementing primary prevention measures.Methods and analysesCohort and nested case–control studies will be carried out using the population-based Janus Serum Bank Cohort consisting of prediagnostic sera, clinical measurement data (body height and weight, body surface area and weight change over time, blood pressure, cholesterol and triglycerides) and self-reported information on lifestyle factors (smoking, physical activity). Participants were followed from cohort inclusion (1972–2003) through 2014. The cohort will be linked to the Cancer Registry of Norway (cancer data), the National Cause of Death Registry (date and cause of death), National Population Registry (vital status) and Statistic Norway (education and occupation). Serum samples will be analysed for 25(OH)D, vitamin D binding protein, leptin, albumin, calcium and parathyroid hormone. Cox regression and conditional logistic regression models and mediation analysis will be used to estimate association between the exposures and BC.Ethics and disseminationThe study has been approved by the Regional Committee for Medical Research Ethics and is funded by the Norwegian Cancer Society. Results will be published in peer-reviewed journals, at scientific conferences and through press releases.

Objective. A shift in the total incidence from left- to right-sided colon cancer has been reported and raises the question as to whether lifestyle risk factors are responsible for the changing subsite distribution of colon cancer. The present study provides a review of the subsite-specific risk estimates for the dietary components presently regarded as convincing or probable risk factors for colorectal cancer: red meat, processed meat, fiber, garlic, milk, calcium, and alcohol.Methods. Studies were identified by searching PubMed through October 8, 2012 and by reviewing reference lists. Thirty-two prospective cohort studies are included, and the estimates are compared by sex for each risk factor.Results. For alcohol, there seems to be a stronger association with rectal cancer than with colon cancer, and for meat a somewhat stronger association with distal colon and rectal cancer, relative to proximal colon cancer. For fiber, milk, and calcium, there were only minor differences in relative risk across subsites. No statement could be given regarding garlic. Overall, many of the subsite-specific risk estimates were nonsignificant, irrespective of exposure.Conclusion. For some dietary components the associations with risk of cancer of the rectum and distal colon appear stronger than for proximal colon, but not for all.

The purpose of the study was to identify and describe cervical cancer specific changes in humoral immune response by using a novel technology platform Mimotope Variation Analysis (MVA) developed by Protobios. The Janus Serum Bank is one of the world's oldest and largest population-based research biobanks established in 1973. The cohort is annually linked to the Cancer Registry of Norway using personal identification numbers. More than 1000 women have developed cervical cancer after donating sera. We identified sets of successive sera samples from ten patients with invasive cervical cancer, ten patients with pre-invasive cervical neoplasia and twenty cancer-free individuals (matched for age, gender, length of sample storage +3 months). For each subject we identified 4-10 samples donated to Janus over a period of up to 18 years, in total 213 samples. We applied MVA which combines phage display technology and high-throughput sequencing analysis to generate quantitative serologic profiles of millions of 12-mer peptide antigens called mimotopes from 2 μl of blood serum per analysis. Hierarchical clustering analysis of the top 5000 mimotopes from each sample resulted in individual-specific immunoprofiles. Multiple samples from the same person clustered together. Moreover, clustering reflected the time the sera was drawn suggesting that part of the individual immunoprofile is stabile over time. In conclusion, preliminary results suggests that Mimotope Variance Analysis generates individual-specific immunological profiles. This profile most likely reflect prior exposure environmental pathogens. Further, we aim to decode the differences in the immunological profiles between cancer patients and cancer-free subjects. Citation Format: Espen Enerly, Mari Nygård, Madleen Orumaa, Arno Pihlak, Susan Pihelgas, Hilde Langseth, Toomas Neuman, Kaia Palm. Mimotope variance analysis: A novel immunoprofiling method to monitor progression of cervical cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4039.

Ovarian cancer is one of the most common gynaecological neoplasms, especially in industrialised countries. The aetiology of the disease is not well understood, except that inherited mutations in the breast cancer genes BRCA-1 and BRCA-2 account for up to 10% of all cases, and child-bearing, oral contraceptive use and breast-feeding reduce the risk. Some environmental exposures, notably talc and asbestos, have been suspected as ovarian carcinogens.

Introduction: Human papillomavirus type 16 (HPV16) infection is associated with an increasing fraction of oropharyngeal cancer. The aim of our study was to determine the association of HPV16 antibodies (Abs) and oropharyngeal cancer (OPC) risk in sera obtained prior to clinical diagnosis. Methods: We identified 92 participants with incident oropharyngeal cancers and 460 age-, gender-, region- and year- matched controls from the Janus Serumbank in Norway. Serum samples were collected from cases, on average, 9.2 years before diagnosis (range, -0.6-14.9 years). 11 cases had serum samples from multiple time points. IgG Abs to the HPV16 antigens E1, E4, E5, E6, E7, L1, L2, and the N-terminal and C-terminal fragments of E2 (NE2, CE2) were quantified in blinded fashion using a custom RAPID ELISA assay. Full-length genes were expressed as GST fusion proteins with a mammalian protein expression system, incubated with sera, and bound IgG was measured. The ratio of relative luminescence units (RLU) values for each antigen to control GST protein was determined. Cutoff values were pre-established as 3 SD>median of 247 healthy controls. A logistic regression classifier of a 7-Ab biomarker panel (E1, NE2, CE2, E4, E5, E6, E7) for the predictive diagnosis of OPC was trained on an independent sample set, and applied to these samples. P-values were calculated by Fisher's exact test. Odds ratios (ORs) of cancer and 95% CIs were calculated. Results: HPV16 early antigen seropositivity was present in 13% of patients with OPC and 1% of controls (OR, 17.0; 95% CI, 5.0-74.0, p10 years, 5.4). Abs to CE2 were strongly associated with cases 0-2 years pre-diagnosis (OR, 112.0; 95% CI, 15.0-971.2, p Conclusion: HPV16 Abs to multiple early viral antigens are detectable years prior to diagnosis of oropharyngeal cancer, and the probability of seropositivity increases closer to diagnosis. A model for screening would help identify individuals at risk for whom interventions and surveillance may be evaluated. Citation Format: Karen S. Anderson, Hilde Langseth, Garrick Wallstrom, Marshall Posner, Julia N. Cheng, Rizwan Alam, Diego Chowell, Jon Mork. Association of a serum HPV16 IgG signature and risk of oropharyngeal cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1566. doi:10.1158/1538-7445.AM2015-1566

The aims of the present study were to find the frequency of the most common BRCA1 mutations in women with ovarian tumours identified from a population-based cancer registry and in the general population, to estimate the relative risk of ovarian tumours among the mutation carriers, and to explore the value of using CA125 as a prediagnostic test. The study was designed as a nested case-control study within a cohort mainly consisting of participants in population-based health examinations. The data files of The Cancer Registry of Norway and the Janus serum bank were linked to identify cases with ovarian cancer and borderline tumours. Hereditary BRCA1 mutations were determined using archived serum samples and capillary electrophoresis. Altogether 478 ovarian cancer patients and 190 patients with borderline tumours were identified, and 1421 and 568 matching controls were selected. Odds ratios (OR) of developing ovarian cancer and borderline tumours in the presence of BRCA1 mutations and CA125 level were derived from conditional logistic regression models. Among the 478 ovarian cancer patients, 19 BRCA1 mutations were identified (1675delA, 1135insA, 816delGT and 3347delAG), none among the patients with borderline tumours. Only two of the 1989 controls were BRCA1 mutation carriers (0.10%). The risk of ovarian cancer among the mutation carriers was strongly elevated (OR=29, 95% CI=6.6-120). CA125 was a marker for ovarian cancer, but the sensitivity was low. This study showed that BRCA1 mutation carriers have a very high risk of ovarian cancer. However, since the prevalence of BRCA1 mutations in the Norwegian population was low, the proportion of ovarian cancers due to BRCA1 mutations seemed to be low, about 4%. The sensitivity of using CA125 only as a screening test for ovarian cancer was low.

Background: In recent years there has been an increased interest in utilizing biorepositories in cancer research. More specifically to detect novel cancer biomarkers for early detection, treatment and prognosis, and to investigate etiological factors. This demands large series of cases including high quality biospecimens and their associated data. The present study communicate the potentials in combining information from a high quality cancer registry with analytical information from the population-based Janus biobank of Norway. It was established in 1973 with the intention to collect premorbid serum for future use in cancer research. The philosophy is to make valuable biological samples and data available to researchers worldwide. Studies of cancer etiology and early cancer detection typically measure biochemical and immunological changes several years before cancer diagnosis. Most human cancer studies involve data from patients after the tumor has been diagnosed. The opportunity to detect important factors in the pathogenesis or etiology of cancer may then be lost. Use of the Janus biobank facilitates evaluation of the preclinical stage, the latent period before the cancer has been diagnosed. For a small sub-group of the Janus donors both pre-diagnostic and diagnostic samples from the same individuals are available. Cancer incidence and scientific results: Today the Janus biobank is one of the world's largest and oldest population-based biobanks. The repository consist of prediagnostic serum samples from 317 000 individuals of whom 52 464 have developed cancer at a later point in life. In male donors prostate cancer is the most common cancer (n=7468), followed by cancer of the lung (n=3222), colon (n=2205), bladder (n=2040) and malignant melanoma (n=1663). Breast cancer is the most common cancer in female donors (n=6774) followed by genital organs (cervix uteri, corpus uteri and ovaries combined n=4176), colon (n=1707), lung (n=1650) and malignant melanoma (n=1423). A considerable number of rare cancer cases have developed among Janus donors, for instance 179 cases of liver cancer and 660 multiple myeloma cases, giving opportunity to set up valid studies of cancers with poor prognosis, and where the knowledge of etiology is limited. Predictions of the future cancer burden indicates that the aging Janus cohort will generate a considerable number of new cancer cases in the years to come. The biobank has been used in a large number of studies investigating biomarkers of susceptibility, exposure and effect. Important contributing results for cancer prevention were early observations of the association between PSA, CA125, HPV, Helicobacter pylori and risk of prostate, ovarian, cervical and stomach cancer respectively. Furthermore, important quality and stability studies have shown that the sample quality in the Janus repository is good for a number of components after long-term storage at −25°. Future potentials: The Janus biobank comprises samples stored over a long period of time and present the opportunity to investigate accumulated, prospectively occurred cancer cases. The samples accessibility to a large number of healthy controls make it very timely to set up large studies with adequate statistical power to demonstrate contrasts in exposure between cancer cases and healthy controls, and to address the long-term effect of past exposure profiles, individual susceptibility and time-lag effects. An important future perspective is to utilize modern technology to enable the use of the Janus biobank in gene-environment-interaction studies, microRNA profiling, and omics-based studies. Statement of conclusion: The unique arrangement of the integration between the Janus biobank and the Cancer Registry of Norway, and the comprehension of this type of resources in the scientific milieus, makes the use of the biobank in cancer prevention and care very timely. Citation Information: Cancer Prev Res 2011;4(10 Suppl):A7.

Background Recent findings suggest that exposure to organochlorine (OC) compounds, chlordanes and p,p′-dichlorodiphenyldichloroethylene (p,p′-DDE) in particular, may increase the risk of developing testicular germ cell tumors (TGCTs). Objective To further investigate this question, we conducted a nested case–control study of TGCTs within the Norwegian Janus Serum Bank cohort. Methods The study was conducted among individuals with serum collected between 1972 and 1978. TGCT cases diagnosed through 1999 (n = 49; 27–62 years of age at diagnosis) were identified through linkage to the Norwegian Cancer Registry. Controls (n =51) were matched to cases on region, blood draw year, and age at blood draw. Measurements of 11 OC insecticide compounds and 34 polychlorinated biphenyl (PCB) congeners were performed using gas chromatography/high-resolution mass spectrometry. Case–control comparisons of lipid-adjusted analyte concentrations were performed using the Wilcoxon signed-rank test. Odds ratios (ORs) and 95% confidence intervals (CIs) for tertiles of analyte concentration were calculated using conditional logistic regression. Results TGCT cases had elevated concentrations of p,p′-DDE (tertile 3 vs. tertile 1 OR (ORT3) 2.2; 95% CI, 0.7–6.5; pWilcoxon = 0.07), oxychlordane (ORT3 3.2; 95% CI, 0.6–16.8; pWilcoxon = 0.05), trans-nonachlor (ORT3 2.6; 95% CI, 0.7–8.9; pWilcoxon = 0.07), and total chlordanes (ORT3 2.0; 95% CI, 0.6–7.2; pWilcoxon = 0.048) compared with controls, although no ORs were statistically significant. Seminoma cases had significantly lower concentrations of PCB congeners 44, 49, and 52 and significantly higher concentrations of PCBs 99, 138, 153, 167, 183, and 195. Conclusions Our study provides additional but qualified evidence supporting an association between exposures to p,p′-DDE and chlordane compounds, and possibly some PCB congeners, and TGCT risk.

Genetic variants have been associated with the risk of developing glioma, but functional mechanisms on disease phenotypic traits remain to be investigated. One phenotypic trait of glioblastoma is the mutation and amplification of the epidermal growth factor receptor (EGFR) gene. We investigated associations between pre-diagnostic serum protein concentrations of EGFR and ErbB2, both members of the EGFR family, and future risk of glioma. Further, we studied if EGFR glioma risk variants were associated with EGFR and ErbB2 serum levels. We assessed the associations between genetic glioma risk variants and serum concentrations of EGFR and ErbB2, as measured in pre-diagnostic cohort serum samples of 593 glioma patients and 590 matched cancer-free controls. High serum EGFR and ErbB2 levels were associated with risk of developing glioblastoma (P = 0.008; OR = 1.58, 95 % CI = 1.13–2.22 and P = 0.017, OR = 1.63, 95 % CI = 1.09–2.44, respectively). High serum ErbB2 concentration was also associated with glioma risk overall (P = 0.049; OR = 1.39, 95 % CI = 1.00–1.93). Glioma risk variants were not associated with high serum protein abundance. In contrast, the EGFR risk variant rs4947986 (T) was correlated with decreased EGFR serum levels (study cohort P = 0.024 and controls P = 0.009). To our knowledge, this is the first study showing an association of EGFR and ErbB2 serum levels with glioma more than a decade before diagnosis, indicating that EGFR and ErbB2 serum proteins are important in early gliomagenesis. However, we did not find evidence that glioma risk variants were associated with high pre-diagnostic serum concentrations of EGFR and ErbB2. Electronic supplementary material The online version of this article (doi:10.1007/s13277-015-4742-y) contains supplementary material, which is available to authorized users.