Circulating vitamin D and breast cancer risk: an international pooling project of 17 cohorts.

Laboratory and animal research support a protective role for vitamin D in breast carcinogenesis, but epidemiologic studies have been inconclusive. To examine comprehensively the relationship of circulating 25-hydroxyvitamin D [25(OH)D] to subsequent breast cancer incidence, we harmonized and pooled participant-level data from 10 U.S. and 7 European prospective cohorts. Included were 10,484 invasive breast cancer cases and 12,953 matched controls. Median age (interdecile range) was 57 (42-68) years at blood collection and 63 (49-75) years at breast cancer diagnosis. Prediagnostic circulating 25(OH)D was either newly measured using a widely accepted immunoassay and laboratory or, if previously measured by the cohort, calibrated to this assay to permit using a common metric. Study-specific relative risks (RRs) for season-standardized 25(OH)D concentrations were estimated by conditional logistic regression and combined by random-effects models. Circulating 25(OH)D increased from a median of 22.6 nmol/L in consortium-wide decile 1 to 93.2 nmol/L in decile 10. Breast cancer risk in each decile was not statistically significantly different from risk in decile 5 in models adjusted for breast cancer risk factors, and no trend was apparent (P-trend = 0.64). Compared to women with sufficient 25(OH)D based on Institute of Medicine guidelines (50- < 62.5 nmol/L), RRs were not statistically significantly different at either low concentrations (< 20 nmol/L, 3% of controls) or high concentrations (100- < 125 nmol/L, 3% of controls; ≥ 125 nmol/L, 0.7% of controls). RR per 25 nmol/L increase in 25(OH)D was 0.99 [95% confidence intervaI (CI) 0.95-1.03]. Associations remained null across subgroups, including those defined by body mass index, physical activity, latitude, and season of blood collection. Although none of the associations by tumor characteristics reached statistical significance, suggestive inverse associations were seen for distant and triple negative tumors. Circulating 25(OH)D, comparably measured in 17 international cohorts and season-standardized, was not related to subsequent incidence of invasive breast cancer over a broad range in vitamin D status.

Long-term outcomes of stage IIB-IV melanoma patients: nationwide data from Norway.

Aim: This study was performed to investigate the characteristics and overall survival (OS) of patients with completely resected stage IIB-IV cutaneous melanoma identified in the Cancer Registry of Norway. Methods: A retrospective cohort study of all adult patients with stage ≥IIB cutaneous melanoma was performed in Norway (January 2008 to December 2018), excluding patients with stage IV melanoma without evidence of surgery. Results: 5-year OS varied by stage (IIB 65%, IIC 38%, IIIA 79%, IIIB 66%, IIIC 52%, IIID 37% and IV 39%). Adjusted Cox models showed that stage IIIA and IIIB patients showed similar survival to stage IIB patients (hazard ratio [95% CI]: IIIA 0.67 [0.44-1.04]; IIIB 1.18 [0.96-1.45]), while all other stages had lower survival than IIB. Conclusion: Survival for stage II patients, particularly IIC, can be poor and in some cases worse than patients with more advanced stage melanoma. Our data highlight an unmet need for effective adjuvant treatment options among stage IIB/C patients.

The number of people diagnosed with skin cancer cutaneous melanoma is increasing globally, with Norway having the second highest rate of death due to melanoma in the world. The stage of disease (how much the tumor has spread) determines which treatment is most effective. While early-stage disease is typically considered of low risk, people diagnosed at this stage have a high risk of disease recurrence and a similar chance of survival to those diagnosed at a later disease stage. By researching how long people with melanoma survive based on their disease stage, we gain greater insight into which groups of patients may have an unmet need for therapy. This study aimed to understand how long patients with melanoma in Norway survive after diagnosis, based on their disease stage at diagnosis. The study used patient data from the Cancer Registry of Norway and included only the patients diagnosed with at least stage IIB melanoma from January 2008 to December 2018, unless they had stage IV disease that had not been treated with surgery. This study found that the proportion of patients who survived to 5 years was dependent on the disease stage at diagnosis; however, patients in earlier stages had similar survival to those in later (although not very late) stages of disease. This research shows that patients diagnosed with early-stage melanoma in Norway have an unmet need for treatment options following surgery that address the severity of their risk. This research may help inform decision-making around which treatments patients with early-stage melanoma have access to.

Risk and survival in colorectal cancer with increasing body mass index: A nationwide population-based cohort study.

AIM: The aim was to explore potential associations between the body mass index (BMI) and the risk of colorectal cancer (CRC), including subsites of the colon, and cancer-specific death. METHODS: A registry-based cohort study was conducted with baseline data gathered from the Norwegian Tuberculosis Screening Programme, collected between 1963 and 1975, and linked to follow-up data from the Cancer Registry of Norway and the Norwegian Cause of Death Registry. Cox regression models were used to explore associations between BMI and CRC risk and cancer-specific death. RESULTS: Of 1 723 692 included individuals, 76 616 developed CRC during 55 370 707 person-years of follow-up. In men, a 5 kg/m2 increase in BMI was associated with an increased risk of colon cancer, including both right and left subsites, and rectal cancer. Allowing for nonlinearities, we found a U-shaped association for the right colon and an inverse U-shape for the left colon and rectum cancer. In women, a 5 kg/m2 increase in BMI in early adulthood was associated with increased risk of colon cancer, including both subsites. In women, an increased risk of CRC death with increasing BMI was found for colon cancer. CONCLUSIONS: Men of all ages have an increased risk of CRC with increasing BMI, with the highest risk for right-sided colon cancer. An increased risk for colon cancer was also found in women with high BMI in early adulthood. Furthermore, women of all age groups appeared to have an increased risk of CRC death with higher BMI.

Nevus Count, Pigmentary Characteristics, and Melanoma-specific Mortality among Norwegian Women with Melanoma >1.0 mm Thick.

Little is known about if and how nevi and pigmentation are associated with melanoma-specific mortality. However, increased melanoma awareness in people with lighter pigmentation and many nevi may result in earlier diagnosis of thinner less-lethal tumors. The aim of this study was to investigate associations between nevus count (asymmetrical > 5 mm and small symmetrical), pigmentary characteristics (hair colour, eye colour, skin colour, freckling, pigmentary score), and melanoma-specific mortality in subjects with melanomas > 1 mm. Data from the Norwegian Women and Cancer cohort, established in 1991, with complete follow-up of melanoma patients until 2018 through the Cancer Registry of Norway, were used to estimate hazard ratios with 95% confidence intervals for the associations between nevus count, pigmentary characteristics, and melanoma-specific mortality, stratified by tumor thickness using Cox regression. Estimated hazard ratios consistently indicated a higher risk of melanoma death for those with darker vs lighter pigmentary characteristics in patients with tumors > 1.0-2.0 mm and > 2.0 mm thick (e.g. pigmentary score hazard ratio 1.25, 95% confidence interval (0.74-2.13)). Among women with melanomas > 1.0 mm thick, lighter pigmentation and asymmetrical nevi may be associated with lower melanoma-specific mortality, suggesting that factors that increase the risk of melanoma may also be associated with decreased risk of death from melanoma.

National health registries - a 'goldmine' for studying non-communicable disease occurrence in Norway - the NCDNOR project.

To estimate occurrence of non-communicable diseases (NCDs) over the life-course in the Norwegian population, national health registries are a vital source of information since they fully represent the entire non-institutionalised population. However, as they are mainly established for administrative purposes, more knowledge about how NCDs are recorded in the registries is needed. To establish this, we begin by counting the number of individuals registered annually with one or more NCDs in any of the registries. The study population includes all inhabitants who lived in Norway from 2004 to 2020 (N~6.4m). The NCD outcomes are diabetes, cardiovascular diseases, chronic obstructive lung diseases, cancer and mental disorders/substance use disorders. Further, we included hip fractures in our NCD concept. The data sources used to identify individuals with NCDs, including detailed information on diagnoses in primary and secondary health care and dispensings of prescription drugs, are the Cancer Registry of Norway, The Norwegian Patient Registry, The Norwegian Control and Payment of Health Reimbursement database, and The Norwegian Prescription Database. The number of individuals registered annually with an NCD diagnosis and/or a dispensed NCD drug increased over the study period. Changes over time may reflect changes in disease incidence and prevalence, but also changes in disease-specific guidelines, reimbursement schemes and access to and use of health services. Data from more than one health registry to identify individuals with NCDs are needed since the registries reflect different levels of health care services and therefore may reflect disease severity.

Use of ionizing radiation in a Norwegian cohort of children with congenital heart disease: imaging frequency and radiation dose for the Health Effects of Cardiac Fluoroscopy and Modern Radiotherapy in Pediatrics (HARMONIC) study.

BACKGROUND: The European-funded Health Effects of Cardiac Fluoroscopy and Modern Radiotherapy in Pediatrics (HARMONIC) project is a multicenter cohort study assessing the long-term effects of ionizing radiation in patients with congenital heart disease. Knowledge is lacking regarding the use of ionizing radiation from sources other than cardiac catheterization in this cohort. OBJECTIVE: This study aims to assess imaging frequency and radiation dose (excluding cardiac catheterization) to patients from a single center participating in the Norwegian HARMONIC project. MATERIALS AND METHODS: Between 2000 and 2020, we recruited 3,609 patients treated for congenital heart disease (age < 18 years), with 33,768 examinations categorized by modality and body region. Data were retrieved from the radiology information system. Effective doses were estimated using International Commission on Radiological Protection Publication 60 conversion factors, and the analysis was stratified into six age categories: newborn; 1 year, 5 years, 10 years, 15 years, and late adolescence. RESULTS: The examination distribution was as follows: 91.0% conventional radiography, 4.0% computed tomography (CT), 3.6% diagnostic fluoroscopy, 1.2% nuclear medicine, and 0.3% noncardiac intervention. In the newborn to 15 years age categories, 4-12% had ≥ ten conventional radiography studies, 1-8% underwent CT, and 0.3-2.5% received nuclear medicine examinations. The median effective dose ranged from 0.008-0.02 mSv and from 0.76-3.47 mSv for thoracic conventional radiography and thoracic CT, respectively. The total effective dose burden from thoracic conventional radiography ranged between 28-65% of the dose burden from thoracic CT in various age categories (40% for all ages combined). The median effective dose for nuclear medicine lung perfusion was 0.6-0.86 mSv and for gastrointestinal fluoroscopy 0.17-0.27 mSv. Because of their low frequency, these procedures contributed less to the total effective dose than thoracic radiography. CONCLUSION: This study shows that CT made the largest contribution to the radiation dose from imaging (excluding cardiac intervention). However, although the dose per conventional radiograph was low, the large number of examinations resulted in a substantial total effective dose. Therefore, it is important to consider the frequency of conventional radiography while calculating cumulative dose for individuals. The findings of this study will help the HARMONIC project to improve risk assessment by minimizing the uncertainty associated with cumulative dose calculations.

Cancer risk and survival according to body mass index in hepatobiliary malignancies: a nationwide registry-based cohort study.

BACKGROUND: The aim of this study was to explore the associations between BMI and cancer of the liver, bile ducts, and gallbladder. METHODS: A registry-based cohort study was performed by linking data from several national registries in Norway. RESULTS: The cohort comprised 1 723 692 individuals including 4768 hepatobiliary cancer cases during 55 743 509 person-years of follow-up. In men, we found increased risk of cancer per 5 kg/m2 BMI increase for hepatocellular carcinoma and extrahepatic cholangiocarcinoma. In women there was increased risk of extrahepatic cholangiocarcinoma and gallbladder cancer. Women with high BMI in early adulthood had increased risk of intrahepatic cholangiocarcinoma. Reduced cancer-specific survival was found for all hepatobiliary malignancies in women with overweight and obesity. In men, reduced survival was observed in individuals with obesity for all hepatobiliary cancers, except gallbladder cancer. Increased risk of cancer-death per 5 kg/m2 BMI increase was found for hepatocellular carcinoma, intra-, and extrahepatic cholangiocarcinoma in women. For men, 5 kg/m2 BMI increase was positively associated with cancer-death from intrahepatic cholangiocarcinoma. DISCUSSION: This study supports the notion of an increased risk of hepatobiliary cancers with increasing BMI, with sex and age variations. The findings also suggest a higher risk of cancer-death with increasing BMI.

Sunscreens With High Versus Low Sun Protection Factor and Cutaneous Squamous Cell Carcinoma Risk: A Population-Based Cohort Study.

Evidence on sunscreen use and cutaneous squamous cell carcinoma (cSCC) risk is limited. Most studies have not taken sun protection factor (SPF) into consideration and used nonusers of sunscreen as the reference group. Nonusers are likely a priori at lower cSCC risk than users. No study has investigated the effect of high- versus low-SPF sunscreens on cSCC, appropriately adjusting for time-varying confounding. Using data from the Norwegian Women and Cancer Study (1991-2016), we investigated whether use of SPF ≥15 versus SPF <15 sunscreens reduces cSCC risk. We used a marginal structural Cox proportional hazards model with inverse probability of treatment and censoring weights to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). During follow-up of 148,781 women (mean follow-up, 14.3 years), 653 women were diagnosed with cSCC. The effect on cSCC risk of sunscreens with SPF ≥15 versus SPF <15 was close to the null when used at any latitudes (HR = 1.02, 95% CI: 0.82, 1.27) and when used in lower-latitude settings (HR = 1.05, 95% CI: 0.84, 1.32). In conclusion, we found no indication that sunscreens with SPF ≥15 reduced Norwegian women's cSCC risk more than sunscreens with SPF <15, suggesting that either there is no difference in their effects long-term or the difference is diluted by incorrect application.

Skin melanoma deaths within 1 or 3 years from diagnosis in Europe.

The steep increase in incidence of cutaneous malignant melanoma in white populations mainly applies to thin lesions with good survival suggesting overdiagnosis. Based on population-based cancer registries (CRs), we have investigated changes in aggressive melanoma, selecting only cases who died within 1 or 3 years after diagnosis in 11 European countries between 1995 and 2012. Trends in fatal cases were analysed by period of diagnosis, sex, tumour thickness, histologic subtype of the lesion, tumour site and CR with a multivariate generalised linear mixed effects model, where geographical area was considered as a random effect. We collected data on 123 360 invasive melanomas, with 5133 fatal cases at 1 year (4%) and 12 330 (10%) at 3 years. The number of fatal cases showed a 16% decrease at 1 year and 8% at 3 years between the first (1995-2000) and the last (2007-2012) period. The highest proportion of fatal cases was seen for men, older age (≥65 years), thick lesions (>1 mm), nodular melanoma, melanoma on the trunk and for poorly documented cases, lacking information about thickness and histologic subtype. The mixed-effects model showed a remarkable variability among European countries. The majority of registries showed a decreasing trend in fatal cases, but a few registries showed an opposite pattern. Trends in fatal melanoma cases, highlighting real changes in risk not related to overdiagnosis, showed a decrease in most European countries, with a few exceptions. Stronger efforts for early detection could lead to a more efficient treatment of melanoma in general.

Physical activity and cutaneous melanoma risk: A Norwegian population-based cohort study.

Physical activity (PA) is an important factor in cancer prevention, but positive association between PA and risk of cutaneous melanoma found in recent studies may complicate this strategy. Ultraviolet radiation (UVR) exposure during outdoor PA is a plausible explanation for a positive association. We investigated the associations between PA, UVR and melanoma risk in the Norwegian Women and Cancer cohort. Overall PA was reported by 151,710 women, aged 30-75 at inclusion, using a validated 10-point-scale at enrolment and during follow-up, together with recent numbers of sunburns, indoor tanning sessions and weeks on sunbathing vacations. Seasonal outdoor walking and seasonal PAs were recorded in subsamples (n = 102,671 and n = 29,077, respectively). Logistic and Cox regression were used. Mean follow-up was 18.5 years, and 1565 invasive incident melanoma cases were diagnosed. Overall PA was inversely associated with sunburns, while positively associated with sunbathing vacations and indoor tanning. Overall PA was not associated with melanoma risk in all body sites combined (ptrend = 0.61), but reduced risk was found in upper limb melanomas (hazard ratio (HR) = 0.70, 95% confidence interval (CI) 0.51-0.96; high versus low PA). Non-significant reduced risks were found for seasonal outdoor walking >2 h/day versus 30-60 min/day (summer HR = 0.81, 95% CI 0.66-1.00; autumn HR = 0.74, 95%CI 0.55-1.01). Seasonal PAs were not associated with melanoma risk. In conclusion, we found positive associations between overall PA and sunbathing vacations and indoor tanning, and, unlike literature, inverse association between overall PA and sunburns. Our results do not support a positive association between PA and melanoma risk in Norwegian women.

Clinical Suspicion Sensitivity of Nodular and Superficial Spreading Melanoma.

In Norway, nodular melanoma is the most fatal melanoma subtype and superficial spreading melanoma the most common, indicating diagnostic challenges. The aim of this study was to assess the clinical suspicion sensitivity of nodular melanoma and superficial spreading melanoma, by diagnosing physician, using randomly selected 100 nodular melanomas and 100 superficial spreading melanomas from the Norwegian Melanoma Registry, diagnosed in 2014 to 2015. Information about suggested diagnoses and diagnosing physician was collected from pathology request forms. Suspicion sensitivity was defined as the proportion (%) of cases with "melanoma" as a suggested diagnosis, estimated with 95% confidence interval (95% CI). Most melanomas (74.5%) were diagnosed by non-dermatologists, with a suspicion sensitivity of 23% (95% CI 15-34) for nodular melanoma and 24% (95% CI 16-35) for superficial spreading melanoma. Corresponding estimates for dermatologists were 50% (95% CI 32-68) and 96% (95% CI 80-99), respectively (pinteraction=0.007). The low suspicion sensitivity for both subtypes among non-dermatologists calls for educational efforts.

Phenotypic Characteristics and Melanoma Thickness in Women.

Patients' phenotypic characteristics might be associated with melanoma aggressiveness, but the evidence is scarce. This study examined the associations be-tween pigmentary characteristics, naevi and melanoma thickness. Data from the Norwegian Women and Cancer (NOWAC) study were analysed. By 2014, 1,243 women were diagnosed with a primary melanoma, and 1,140 had information on thickness. Using ordinal logistic regression models, the probability of being diagnosed with a specific thickness category was calculated by pigmentary score and naevi. Fair pigmentary score was associated with thinner trunk melanomas (probabilities of being diagnosed with a tumour ≤1.0 mm thickness were 74%, 66%, and 51% for fair, medium and dark pigmentary scores, respectively), but not the other sites. High number of naevi was associated with thicker nodular melanoma (NM) but not with super-ficial spreading melanoma. These findings suggest the need for greater overall vigilance and skin checks among women with fair pigmentary score. The association between naevi and NM suggest possible biological mechanisms.

Ultraviolet radiation and risk of cutaneous melanoma and squamous cell carcinoma in males and females in the Norwegian Offshore Petroleum Workers cohort.

BACKGROUND: Increased risk of cutaneous melanoma and squamous cell carcinoma (SCC) has been reported among petroleum workers, but few studies include females, exposure data on ultraviolet radiation (UVR), and potential confounding factors. We aimed to examine UVR exposure in relation to risk of melanoma and SCC among male and female offshore petroleum workers. We also examined the association between UVR exposure and melanoma (Breslow) thickness. METHODS: The Norwegian Offshore Petroleum Workers (NOPW) cohort (n = 27,917) holds information on sunbathing, indoor tanning, sunburns, sunscreen use, and other lifestyle factors recorded in 1998. Linkage to the Cancer Registry of Norway gave information on cancer diagnosis through 2017. We used Cox and logistic regression to estimate hazard ratios (HRs) of skin cancer and odds ratios (OR) of thick (≥1 mm) melanomas, respectively, with 95% confidence intervals (CIs). RESULTS: Melanoma risk increased with increasing frequency of sunbathing after age 20 (ptrend = 0.031), sunburn average intensity (ptrend = 0.028), and sunscreen use (HR = 2.16; 95% CI: 1.42 -3.27 for almost always vs. never/rarely). The risk of thick melanoma was inversely associated with sunbathing frequency after age 20 (OR = 0.38; 95% CI: 0.16 - 0.90 for ≥4 weeks/year vs. 1 week/year). SCC risk increased with increasing frequency of indoor tanning after age 20 (HR = 2.72; 95% CI: 1.22 - 6.05 for ≥3 times/months vs. never), sunburn average intensity (ptrend < 0.001), and sunscreen use (ptrend < 0.001). CONCLUSIONS: Our results support associations between UVR exposure and skin cancer risk in male and female offshore petroleum workers. This occupational group may be especially relevant for targeted sun protection advice.

Women who develop ovarian cancer show an increase in serum calcium and a decrease in serum albumin. A longitudinal study in the Janus Serum Bank Cohort.

BACKGROUND: Ovarian cancer is associated with high serum calcium and low serum albumin in clinical and epidemiologic studies. Whether high calcium and low albumin predispose to ovarian cancer or reflect existing cancer is unclear. OBJECTIVE: Test the hypothesis that serum calcium increases and serum albumin decreases in women who develop ovarian cancer. METHODS: Two hundred and four women donated sera to the Janus Serum Bank in Norway pre- and post-diagnosis of ovarian cancer, donations separated by approximately 14 years. We measured calcium and albumin in these sera and calculated the albumin-corrected calcium. Sera were adjusted for patient age and storage time. RESULTS: Post-diagnosis, mean age- and storage-adjusted calcium increased, from 2.53 to 2.68 mmol/L (p < .001). Mean age- and storage-adjusted, albumin-corrected calcium increased from 2.3 to 2.7 mmol/L (p < .001). Conversely, mean age- and storage-adjusted albumin decreased, from a mean of 51.3 to 40.9 g/L (p < .001). Significant changes were observed in women with early stage and metastatic cancer. CONCLUSIONS: These data support the hypothesis that calcium and albumin are serum biomarkers of extant ovarian cancer. Longitudinal changes in calcium and albumin may be useful in ovarian cancer early detection.

Anthropometric factors and cutaneous melanoma: Prospective data from the population-based Janus Cohort.

The aim of the present study was to prospectively examine risk of cutaneous melanoma (CM) according to measured anthropometric factors, adjusted for exposure to ultraviolet radiation (UVR), in a large population-based cohort in Norway. The Janus Cohort, including 292,851 Norwegians recruited 1972-2003, was linked to the Cancer Registry of Norway and followed for CM through 2014. Cox regression was used to estimate hazard ratios (HRs) of CM with 95% confidence intervals (CIs). Restricted cubic splines were incorporated into the Cox models to assess possible non-linear relationships. All analyses were adjusted for attained age, indicators of UVR exposure, education, and smoking status. During a mean follow-up of 27 years, 3,000 incident CM cases were identified. In men, CM risk was positively associated with body mass index, body surface area (BSA), height and weight (all ptrends < 0.001), and the exposure-response curves indicated an exponential increase in risk for all anthropometric factors. Weight loss of more than 2 kg in men was associated with a 53% lower risk (HR 0.47, 95% CI: 0.39, 0.57). In women, CM risk increased with increasing BSA (ptrend = 0.002) and height (ptrend < 0.001). The shape of the height-CM risk curve indicated an exponential increase. Our study suggests that large body size, in general, is a CM risk factor in men, and is the first to report that weight loss may reduce the risk of CM among men.

Melanoma staging: Varying precision and terminal digit clustering in Breslow thickness data is evident in a population-based study.

BACKGROUND: Errors in Breslow thickness reporting can give misclassification of T category, an important classifier in melanoma staging. OBJECTIVE: We sought to investigate precision (number of digits) and terminal digit clustering in Breslow thickness and potential consequences for T category. METHODS: All first primary and morphologically verified invasive melanomas in Norway between 2008 and 2015 were included. A smoothing model was fitted to estimate the underlying Breslow thickness distribution without digit clustering. RESULTS: Thickness was reported for 13,057 (97.5%) patients; the median was 1.0 mm (range, 0.09-85). It was reported as whole numbers (15.6%), to 1 decimal (78.2%) and 2 decimal places (6.2%)-thin tumors with more precision than thick tumors. Terminal digit clustering was found with marked peaks in the observed frequency distribution for terminal digits 0 and 5, and with drops around these peaks. Terminal digit clustering increased proportions of patients classified with T1 and T4 tumors and decreased proportions classified with T2 and T3. LIMITATIONS: Breslow thickness was not reported in 2.5% of cases. CONCLUSIONS: The Norwegian recommendation of measurement to the nearest 0.1 mm was not followed. Terminal digit clustering was marked, with consequences for T category. Pathologists, clinicians, and epidemiologists should know that clustering of thickness data around T category cut points can impact melanoma staging with consequent effect on patient management and prognosis.