Association between night work and prostate cancer: a systematic review and meta-analysis.

OBJECTIVE: The aim was to conduct a systematic review and meta-analysis to study the association between night work and the development of prostate cancer. METHODS: A systematic literature search was conducted in CINAHL, Embase, MEDLINE, and Web of Science. Studies were included based on a PECOS; the population included men in/above the working age, exposure defined as night work, outcome defined as prostate cancer, and study design restricted to cohort studies. The exclusion of articles, risk-of-bias assessment, and data extraction were performed by two reviewers. A meta-analysis was conducted using a random-effects model, including a sensitivity analysis stratified based on the risk-of-bias assessment. We evaluated publication bias using a funnel plot and Egger´s test, and the level of evidence was assessed using GRADE. RESULTS: A total of 528 articles were identified, and eight cohort studies were included. Three studies had a moderate risk of bias, while five studies had a high risk of bias. The meta-analysis showed a pooled hazard ratio (HR) of 1.0 (95% CI 0.6-1.7). In the sensitivity analysis, moderate vs. high risk-of-bias studies showed a pooled HR of 1.2 (95% CI 0.3-4.1) and 0.9 (95% CI 0.6-1.3), respectively. Based on GRADE, the level of evidence was rated low. CONCLUSION: We found no association between night work and the development of prostate cancer. The evidence was assessed as limited and inconsistent. Future studies encompassing consistent definitions of night work, including objective exposure data, are highly warranted.

Long-term follow-up study of work status among patients with work-related mental disorders referred to departments of occupational medicine in Denmark.

OBJECTIVES: To describe the 5 year work status in patients referred for suspected work-related common mental disorders. To develop a prognostic model. DESIGN: Register-based nationwide longitudinal follow-up study. SETTING: All departments of occupational medicine in Denmark. PARTICIPANTS: 17 822 patients aged 18-67 years, seen for the first time at a Department of Occupational Medicine in Denmark from 2000 to 2013 and diagnosed with stress, depression, post-traumatic stress disorder, anxiety or other mental disorders. INTERVENTIONS: All patients were seen for diagnostic assessment and causal evaluation of the work-relatedness of their disorders. Some departments offered patients with stress disorders psychological treatment, which, however, was not organised according to patient selection or type of treatment. PRIMARY AND SECONDARY OUTCOME MEASURES: Register data were collected for 5 year periods before and after the patients' first assessment at a department. Weekly percentages of patients are presented according to work status. The outcome in the prognostic model was a high Work Participation Score (ie, working>75% of potential work weeks/year) at 5 year follow-up. RESULTS: For all subgroups of patients, a high proportion were working (>75%) 1-5 years before assessment, and all experienced a large reduction in work status at time of assessment. At 1 year follow-up, almost 60% of patients with stress were working, whereas in the other patient subgroups, less than 40% were working. In the following years, practically no increase was observed in the percentage of patients working in any of the subgroups. Based on these 5 year follow-up data, we developed a work participation model with only moderate discrimination and calibration. CONCLUSIONS: In Denmark, not all return to previous work status 5 years after a referral due to a suspected work-related common mental disorder. We developed a prognostic model with only moderate discrimination and calibration for long-term work participation after suggested work-related common mental disorders.

Developing prognostic models for health care utilization in patients with work-related mental health problems.

BACKGROUND: The long-term prognosis for employees with work-related mental health problems is unclear. We aim to describe long-term trends in health care utilization (HCU) and develop multivariable prognostic models for long-term mental health care utilization. METHODS: From the Danish Occupational Medicine Cohort we included mental health patients (N = 17,822) assessed from 2000 to 2013 at Departments of Occupational Medicine. Outcomes were general health (general practitioner, somatic hospital) and mental health (psychiatrist/psychologist, psychiatric hospital) HCU obtained from registries five years before/after assessment. The 10-year period was divided into phases relative to assessment: 5 - 3 years before, 2 years before/after, and 3-5 years after. We developed gender-stratified Lasso-penalized multivariable prognostic models for HCU 3-5 years after assessment assessing both calibration and discrimination. RESULTS: Prevalent HCU for general practitioner, psychiatrist/psychologist and psychiatric hospital services was relatively stable 5 - 3 years prior to assessment, then rising during the 2 years before/after. At 3-5 years after assessment prevalent general practitioner HCU declined to previous levels, while prevalent HCU for psychologist/psychiatrist and psychiatric hospital services remained elevated compared to previous levels during years 5 - 3. Prognostic models for long-term psychologist/psychiatrist and psychiatric hospital HCU indicated acceptable calibration and modest discrimination. CONCLUSIONS: Prevalent HCU rose two years before/after assessment and remained elevated for psychiatrist/psychologist and psychiatric hospital HCU 3-5 years after. Gender-stratified prognostic models were developed for long-term mental health HCU, but discrimination and calibration should be further improved before out-of-sample application for personal prognosis. TRIAL REGISTRATION: The study was registered at clinicaltrials.gov (Identifier: NCT04459793) prior to analyses.

Influence of intra-tumoral heterogeneity on the evaluation of BCL2, E-cadherin, EGFR, EMMPRIN, and Ki-67 expression in tissue microarrays from breast cancer.

INTRODUCTION: The influence of intra-tumoral heterogeneity on the evaluation of immunohistochemical (IHC) biomarker expression may affect the analytical validity of new biomarkers substantially and hence compromise the clinical utility. The aim of this study was to examine the influence of intra-tumoral heterogeneity as well as inter-observer variability on the evaluation of various IHC markers with potential prognostic impact in breast cancer (BCL2, E-cadherin, EGFR, EMMPRIN and Ki-67). MATERIAL AND METHODS: From each of 27 breast cancer patients, two tumor-containing paraffin blocks were chosen. Intra-tumoral heterogeneity was evaluated (1) within a single tumor-containing paraffin block ('intra-block agreement') by comparing information from a central, a peripheral tissue microarray (TMA) core and a whole slide section (WS), (2) between two different tumor-containing blocks from the same primary tumor ('inter-block agreement') by comparing information from TMA cores (central/peripheral) and WS. IHC markers on WS and TMA cores were evaluated by two observers independently, and agreements were estimated by Kappa statistics. RESULTS: For BCL2, E-cadherin and EGFR, an almost perfect intra- and inter-block agreement was found. EMMPRIN and Ki-67 showed a more heterogeneous expression with moderate to substantial intra-block agreements. For both stainings, there was a moderate inter-block agreement that improved slightly for EMMPRIN, when using WS instead of TMA cores. Inter-observer agreements were found to be almost perfect for BCL2, E-cadherin and EGFR (WS: κ > 0.82, TMAs: κ > 0.90), substantial for EMMPRIN (κ > 0.63), but only fair to moderate for Ki-67 (WS: κ = 0.54, TMAs: κ = 0.33). CONCLUSIONS: BCL2, E-cadherin and EGFR were found to be homogeneously expressed, whereas EMMPRIN and Ki-67 showed a more pronounced degree of intra-tumoral heterogeneity. The results emphasize the importance of securing the analytical validity of new biomarkers by examining the intra-tumoral heterogeneity of immunohistochemical stainings applied to TMA cores individually in each type of cancer.

Development and validation of a gene profile predicting benefit of postmastectomy radiotherapy in patients with high-risk breast cancer: a study of gene expression in the DBCG82bc cohort.

PURPOSE: To identify genes predicting benefit of radiotherapy in patients with high-risk breast cancer treated with systemic therapy and randomized to receive or not receive postmastectomy radiotherapy (PMRT). EXPERIMENTAL DESIGN: The study was based on the Danish Breast Cancer Cooperative Group (DBCG82bc) cohort. Gene-expression analysis was performed in a training set of frozen tumor tissue from 191 patients. Genes were identified through the Lasso method with the endpoint being locoregional recurrence (LRR). A weighted gene-expression index (DBCG-RT profile) was calculated and transferred to quantitative real-time PCR (qRT-PCR) in corresponding formalin-fixed, paraffin-embedded (FFPE) samples, before validation in FFPE from 112 additional patients. RESULTS: Seven genes were identified, and the derived DBCG-RT profile divided the 191 patients into "high LRR risk" and "low LRR risk" groups. PMRT significantly reduced risk of LRR in "high LRR risk" patients, whereas "low LRR risk" patients showed no additional reduction in LRR rate. Technical transfer of the DBCG-RT profile to FFPE/qRT-PCR was successful, and the predictive impact was successfully validated in another 112 patients. CONCLUSIONS: A DBCG-RT gene profile was identified and validated, identifying patients with very low risk of LRR and no benefit from PMRT. The profile may provide a method to individualize treatment with PMRT.

Relationship between the prognostic and predictive value of the intrinsic subtypes and a validated gene profile predictive of loco-regional control and benefit from post-mastectomy radiotherapy in patients with high-risk breast cancer.

BACKGROUND: Breast cancer is characterized by great molecular heterogeneity demonstrated, e.g. by the intrinsic subtypes. Administration of post-mastectomy radiotherapy (PMRT) does, however, not reflect this heterogeneity. A gene profile (DBCG-RT profile) has recently been developed and validated, and has shown prognostic impact in terms of loco-regional failure and predictive impact for PMRT. Reports have also shown predictive value in terms of benefit of PMRT from intrinsic subtypes and derived approximations. The aim of this study was to examine: 1) the agreement between various methods for determining the intrinsic subtypes; and 2) the relationship between the prognostic and predictive impact of the DBCG-RT profile and the intrinsic subtypes. MATERIAL AND METHODS: Intrinsic subtypes and the DBCG-RT profile was determined from microarray analysis based on fresh frozen tissue from 191 patients included in the Danish Breast Cancer Cooperative Group (DBCG) 82bc trial. Corresponding formalin-fixed, paraffin-embedded tissue was available from 146 of these patients and from another 890 DBCG82bc patients. Estrogen receptor, progesterone receptor, HER2, CK5/6, Ki-67 and EGFR were combined into immunohistochemical approximations of the intrinsic subtypes. Endpoint considered was loco-regional recurrence (LRR). RESULTS: The DBCG-RT profile identified a group of patients with low risk of LRR and no additional benefit from PMRT among all subtypes. Combining six immunohistochemical markers identified a subgroup of triple negative patients with high risk of LRR and significant benefit from PMRT. Agreement in the different assignments of tumors to the subtypes was suboptimal, and the clinical outcome and predicted benefit from PMRT varied according to the method used for assignment. CONCLUSION: The prognostic and predictive information obtained from the DBCG-RT profile cannot be substituted by any approximation of the tumors intrinsic subtype. The predictive value of the intrinsic subtypes in terms of PMRT was influenced by the method used for assignment to the intrinsic subtypes.

Reliable PCR quantitation of estrogen, progesterone and ERBB2 receptor mRNA from formalin-fixed, paraffin-embedded tissue is independent of prior macro-dissection.

Gene expression analysis on messenger RNA (mRNA) purified from formalin-fixed, paraffin-embedded tissue is increasingly used for research purposes. Tissue heterogeneity may question specificity and interpretation of results from mRNA isolated from a whole slide section, and thresholds for minimal tumor content in the paraffin block or macrodissection are used to avoid contamination from non-neoplastic tissue. The aim was to test if mRNA from tissue surrounding breast cancer affected quantification of estrogen receptor α (ESR1), progesterone receptor (PGR) and human epidermal growth factor receptor 2 (ERBB2), by comparing gene expression from whole slide and tumor-enriched sections, and correlating gene expression from whole slide sections with corresponding immunohistochemistry. Gene expression, based on mRNA extracted from a training set (36 paraffin blocks) and two validation sets (133 + 1,083 blocks), were determined by quantitative reverse transcription polymerase chain reaction for all samples, as well as by microarray for 133 validation samples. In the training set, agreement between high vs. low mRNA expression from whole slide and tumor-enriched sections was absolute for ESR1 and ERBB2, and 83 % for PGR. Overall agreements, when comparing mRNA expression to immunohistochemistry, were 100 % (ERBB2), 89 % (ESR1) and 83 % (PGR), which was confirmed in the validation sets. Percentage of tumor in the sections did not influence the results. In conclusion, reliable quantification of ESR1, PGR and ERBB2 mRNA expression can be obtained from a whole slide section, and correlates well with immunohistochemistry. Prior removal of surrounding tissue was found to be unnecessary even with minimal tumor content in the section.

High local recurrence risk is not associated with large survival reduction after postmastectomy radiotherapy in high-risk breast cancer: a subgroup analysis of DBCG 82 b&c.

BACKGROUND AND PURPOSE: International consensus reports recommend postmastectomy radiotherapy only to patients at high risk of a local recurrence (LR). MATERIALS AND METHODS: The present analysis included 1000 out of 3083 high-risk breast cancer patients randomly assigned to postmastectomy radiotherapy in the DBCG82 b&c trials. Tissue microarrays had been constructed and sections stained for estrogen, progesterone and HER2 receptors. Median potential follow-up time was 17 years. Endpoints were LR as isolated first event, breast cancer mortality and overall mortality. RESULTS: Among patients randomly assigned to not receive radiotherapy, three prognostic subgroups of LR risk were found. "The good" defined by at least four out of five favorable criteria (3 positive nodes, tumor size <2cm, Grade 1 malignancy, estrogen or progesterone receptor positive, HER2 negative), "the Poor" defined by at least two out of three un-favorable criteria (>3 positive nodes, tumor size >5cm, Grade 3 malignancy) and finally "the Intermediate" the group in between. The smallest absolute reduction in 5-year LR probability (11%) after radiotherapy was seen for the good prognosis group. A similar absolute reduction in 15-year breast cancer mortality after radiotherapy (11%) was seen. The largest absolute reduction in 5-year LR probability after radiotherapy was seen for the poor prognosis group (36%). However, this large LR reduction did not translate into any reduction in 15-year breast cancer mortality (0%). CONCLUSION: Translation of LR reduction into breast cancer mortality reduction after postmastectomy radiotherapy to high-risk breast cancer patients seems to be heterogeneous, with the largest translation occurring within the good prognosis group.

A comparison between p53 accumulation determined by immunohistochemistry and TP53 mutations as prognostic variables in tumours from breast cancer patients.

BACKGROUND: p53 accumulation and TP53 mutations are known prognostic markers for breast cancer. To clarify their interrelationship and the importance of different TP53 mutation types, these markers were investigated in tumours from 630 patients with breast cancer. MATERIALS AND METHODS: Tumour sections were stained for p53 and scored based on staining intensity and percentages of invasive tumour cells with nuclear staining. TP53 mutations were identified by sequencing. Patient cohorts were from the DBCG (Danish Breast Cancer Cooperative Group) protocols DBCG82 and DBCG89. RESULTS: TP53 was mutated in 29% of the patients. The disease-specific survival (DSS) at 15 years of follow-up for patients with missense mutations directly involved in DNA or zinc binding was 21+/-8%. Patients with the remaining missense mutations within the structural/conserved domains and patients with null mutations had a DSS of 36+/-6% and 31+/-17%, respectively. For patients without TP53 mutations and patients with mutations affecting amino acids outside these domains, the 15 year DSS was 51+/-3% and 71+/-10%, respectively. p53 accumulation was successfully scored in 567 patients and categorized into three groups. Tumours with no p53 expression had a high frequency of null mutations (37% compared to 10% in the whole cohort), and tumours with high p53 expression contained 82% of the missense mutations inside structural/conserved domains including those directly involved in DNA or zinc binding. CONCLUSION: The clinical outcome for breast cancer patients is significantly different for different TP53 mutation types, but further functional studies are required to clarify the exact role of these mutation types. Most of the mutations that lead to mutant p53 protein accumulation can be detected by immunohistochemistry but the specificity is low. Samples showing lack of detectable p53 protein should be considered as an indication of a possible null mutation.

Carbonic anhydrase IX and response to postmastectomy radiotherapy in high-risk breast cancer: a subgroup analysis of the DBCG82 b and c trials.

INTRODUCTION: A significant survival improvement after postmastectomy radiotherapy was identified in the Danish Breast Cancer Cooperative Group (DBCG82) b and c studies and in the British Columbia Randomized Radiation Trial. Recently, potential predictive value regarding response to postmastectomy radiotherapy was reported for carbonic anhydrase (CA) IX in a study (reported in abstract form) that included 160 patients. The purpose of the present study was to examine the importance of CA IX to response to postmastectomy radiotherapy in the larger scaled DBCG82 b and c studies. METHODS: The DBCG82 b and c studies included 3,083 high-risk Danish breast cancer patients. The women were randomly assigned to postmastectomy radiotherapy plus systemic therapy (cyclophosfamide, methotrexate and fluorouracil in premenopausal women; and tamoxifen in postmenopausal women) or to systemic therapy alone. Cores from invasive tumour-containing paraffin blocks from 1,000 patients (more than seven nodes surgically removed) were transferred to tissue microarrays. Tissue microarray sections were stained immunohistochemically for CA IX (M75). The median follow up for patients remaining alive was 17 years. Clinical end-points were loco-regional recurrence, distant metastases, disease-specific survival and overall survival. Statistical analyses included kappa statistics, chi2 or exact tests, Kaplan-Meier probability plots, Log-rank test and Cox regression analyses. RESULTS: CA IX was assessable in 945 cores. The percentage of tumours positive for CA IX was 16% (> or = 10% invasive tumour staining). CA IX was not an independent prognostic marker for survival, distant metastases, or locoregional recurrence in the subgroup of 945 patients or within either of the two randomization arms. In subgroup analyses, however, CA IX was an independent prognostic marker for overall survival among postmenopausal women (P = 0.001), women with one to three positive nodes (P = 0.02) and hormone receptor positive women (P = 0.001). Fifteen-year probabilities of overall survival were improved by 9% and 7% after postmastectomy radiotherapy for the subgroups of CA IX negative and CA IX positive patients, respectively. CONCLUSION: Within this series of 945 high-risk premenopausal and postmenopausal women, positivity for CA IX was not overall an independent prognostic marker for survival; only in subgroup analyses was it found to have prognostic value. The improvement in 15-year survival after postmastectomy radiotherapy was of similar magnitude in the two subgroups of CA IX positive and CA IX negative patients.

Estrogen receptor, progesterone receptor, HER-2, and response to postmastectomy radiotherapy in high-risk breast cancer: the Danish Breast Cancer Cooperative Group.

PURPOSE: To examine the importance of estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER-2), and constructed subtypes in a large study randomly assigning patients to receive or not receive postmastectomy radiotherapy (PMRT). PATIENTS AND METHODS: The present analysis included 1,000 of the 3,083 high-risk breast cancer patients randomly assigned to PMRT in the Danish Breast Cancer Cooperative Group (DBCG) protocol 82 trials b and c. Tissue microarray sections were stained for ER, PgR, and HER-2. Median follow-up time for patients alive was 17 years. End points were locoregional recurrence as isolated first event, distant metastases, and overall survival. For statistical analyses four subgroups were constructed from hormonal receptors (Rec). Rec+ was defined as ER+ and/or PgR+. Rec-as both ER-and PgR-. The four subgroups were Rec+/HER-2-, Rec+/HER-2+, Rec-/HER-2-(triple negative), and Rec-/HER-2+. RESULTS: A significantly improved overall survival after PMRT was seen only among patients characterized by good prognostic markers such as hormonal receptor-positive and HER-2- patients (including the two Rec+ subtypes). No significant overall survival improvement after PMRT was found among patients with an a priori poor prognosis, the hormonal receptor-negative and HER-2+ patients, and in particular the Rec-/HER-2+ subtype. Furthermore, comparing hazard ratios and 95% CIs, significantly smaller improvements in locoregional recurrence control after PMRT were found for ER-and PgR-tumors compared with the ER+ and PgR+ tumors (P = .003 and .04, respectively), and for the triple-negative (P = .02), and the Rec-/HER-2+ subtypes (P = .003) compared with the Rec+/HER-2-subtype. CONCLUSION: Hormonal receptor status, HER-2, and the constructed subtypes may be predictive of locoregional recurrence and survival after postmastectomy radiotherapy.

LOH rather than genotypes of TP53 codon 72 is associated with disease-free survival in primary breast cancer.

Mutations in the TP53 gene are a well-documented strong prognostic factor in breast cancer. A prognostic value of the Arg72Pro polymorphism of the TP53 gene is more contradictory. We assessed TP53 mutations and genotypes of the Arg72Pro polymorphism in a study including 204 Danish women. Patients with mutations in the TP53 gene had a significant reduction in disease-free survival of breast cancer (p < 0.0001). Genotypes of the Arg72Pro polymorphism were neither significantly associated with TP53 mutations nor with disease-free survival (p = 0.4). Among heterozygous patients a reduction in disease-free survival was found for patients with LOH and retention of the Pro allele as compared to patients with LOH and retention of the Arg allele and patients with no LOH (p = 0.05). In conclusion, we find a highly significant prognostic value of TP53 mutations but find a possible prognostic value of the Arg72Pro polymorphism only related to LOH.

Cervical cancer incidence in Denmark over six decades (1943-2002).

INTRODUCTION: The purpose of the study was to describe developments in the incidence of invasive cervical cancer in Denmark, focusing on histological types, over a period of 60 years. We also describe developments in the incidence of carcinoma in situ and mortality. MATERIAL AND METHODS: The study is based on the Danish Cancer Registry database of 39,623 reported cases of invasive cervical cancer diagnosed among Danish women in the period 1943-2002. The most important variables and measures are age-specific and age-standardized incidence and estimated annual percent changes in incidence. RESULTS: A significant reduction in incidence of invasive squamous cell carcinoma among women over 30 during the last 35 years and in incidence of invasive adenocarcinoma among women over 40 during the last 15 years has been seen. In both histological subgroups the relative estimated annual percent change in incidence was largest in the period 1988-2002 as compared to 1968-1987, coinciding with an increase in the number of Danish women covered by the organized screening program. Women 20-29 years old showed a relatively stable squamous cell carcinoma incidence but an increasing adenocarcinoma incidence throughout the study period. CONCLUSIONS: These results suggest that the increasing coverage of the Danish organized screening program is associated with a significant reduction in incidence of invasive squamous cell carcinoma among women over 30, and of invasive adenocarcinoma among women over 40. So far, squamous cell carcinoma incidence and adenocarcinoma incidence among women 20-29 years old seem quite unaffected by the organized screening program.