Unsolicited information letters to increase awareness of Lynch syndrome and familial colorectal cancer: reactions and attitudes.

Dissemination of information on a genetically increased risk should according to guidelines primarily be family-mediated. Incomplete and incorrect information spread has, however, been documented and implies missed possibilities for prevention. In Denmark, the national HNPCC register has been granted an exception to send unsolicited letters with information on hereditary colorectal cancer and an invitation to genetic counseling to members of families with familial and hereditary colorectal cancer. To evaluate this approach, we investigated reactions and attitudes to unsolicited letters in 708 members of families with genetic predisposition and in 1600 individuals from the general population. Support for information letters was expressed by 78% of the family members and by 82% of the general population. Regarding route of information, 90% of family members preferred a letter to no information, 66% preferred information from the hospital rather than from family members and 40% preferred to obtain information from a close family member. Our results suggest that use of unsolicited information letters from the health care system may be a feasible and highly acceptable strategy to disseminate information to families at high risk of colorectal cancer.

Outcome of 24†years national surveillance in different hereditary colorectal cancer subgroups leading to more individualised surveillance.

BACKGROUND: Individuals with hereditary non-polyposis colorectal cancer (HNPCC) have a high risk of colorectal cancer (CRC). The benefits of colonic surveillance in Lynch syndrome and Amsterdam-positive (familial CRC type X familial colorectal cancer type X (FCCTX)) families are clear; only the interval between colonoscopies is debated. The potential benefits for families not fulfilling the Amsterdam criteria are uncertain. The aim of this study was to compare the outcome of colonic surveillance in different hereditary subgroups and to evaluate the surveillance programmes. METHODS: A prospective, observational study on the outcome of colonic surveillance in different hereditary subgroups based on 24 years of surveillance data from the national Danish HNPCC register. RESULTS: We analysed 13 444 surveillance sessions, including 8768 incidence sessions and 20 450 years of follow-up. CRC was more incident in the Lynch subgroup (2.0%) than in any other subgroup (0.0-0.4%, p<0.0001), but the incidence of advanced adenoma did not differ between the Lynch (3.6%) and non-Lynch (2.3-3.9%, p=0.28) subgroups. Non-Lynch Amsterdam-positive and Amsterdam-negative families were similar in their CRC (0.1-0.4%, p=0.072), advanced adenoma (2.3-3.3%, p=0.32) and simple adenoma (8.4-9.9%, p=0.43) incidence. In moderate-risk families, no CRC and only one advanced adenoma was found. CONCLUSIONS: The risk of CRC in Lynch families is considerable, despite biannual surveillance. We suggest less frequent and more individualised surveillance in non-Lynch families. Individuals from families with a strong history of CRC could be offered 5-year surveillance colonoscopies (unless findings at the preceding surveillance session indicate shorter interval) and individuals from moderate-risk families could be handled with the population-based screening programme for CRC after an initial surveillance colonoscopy.

Combined effects of socioeconomic position, smoking, and hypertension on risk of ischemic and hemorrhagic stroke.

BACKGROUND AND PURPOSE: Combined effects of socioeconomic position and well-established risk factors on stroke incidence have not been formally investigated. METHODS: In a pooled cohort study of 68 643 men and women aged 30 to 70 years in Denmark, we examined the combined effect and interaction between socioeconomic position (ie, education), smoking, and hypertension on ischemic and hemorrhagic stroke incidence by the use of the additive hazards model. RESULTS: During 14 years of follow-up, 3613 ischemic strokes and 776 hemorrhagic strokes were observed. Current smoking and hypertension were more prevalent among those with low education. Low versus high education was associated with greater ischemic, but not hemorrhagic, stroke incidence. The combined effect of low education and current smoking was more than expected by the sum of their separate effects on ischemic stroke incidence, particularly among men: 134 (95% confidence interval, 49-219) extra cases per 100 000 person-years because of interaction, adjusted for age, cohort study, and birth cohort. There was no clear evidence of interaction between low education and hypertension. The combined effect of current smoking and hypertension was more than expected by the sum of their separate effects on ischemic and hemorrhagic stroke incidence. This effect was most pronounced for ischemic stroke among women: 178 (95% confidence interval, 103-253) extra cases per 100 000 person-years because of interaction, adjusted for age, cohort study, and birth cohort. CONCLUSIONS: Reducing smoking in those with low socioeconomic position and in those with hypertension could potentially reduce social inequality stroke incidence.

Education and cause-specific mortality: the mediating role of differential exposure and vulnerability to behavioral risk factors.

BACKGROUND: Differential exposures to behavioral risk factors have been shown to play an important mediating role on the education-mortality relation. However, little is known about the extent to which educational attainment interacts with health behavior, possibly through differential vulnerability. METHODS: In a cohort study of 76,294 participants 30 to 70 years of age, we estimated educational differences in cause-specific mortality from 1980 through 2009 and the mediating role of behavioral risk factors (smoking, alcohol intake, physical activity, and body mass index). With the use of marginal structural models and three-way effect decomposition, we simultaneously regarded the behavioral risk factors as intermediates and clarified the role of their interaction with educational exposure. RESULTS: Rate differences in mortality comparing participants with low to high education were 1,277 (95% confidence interval = 1,062 to 1,492) per 100,000 person-years for men and 746 (598 to 894) per 100,000 person-years for women. Smoking was the strongest mediator for cardiovascular disease, cancer, and respiratory disease mortality when conditioning on sex, age, and cohort. The proportion mediated through smoking was most pronounced in cancer mortality as a combination of the pure indirect effect, owing to differential exposure (men, 42% [25% to 75%]; women, 36% [17% to 74%]) and the mediated interactive effect, owing to differential vulnerability (men, 18% [2% to 35%], women, 26% [8% to 50%]). The mediating effects through body mass index, alcohol intake, or physical activity were partial and varied for the causes of deaths. CONCLUSION: Differential exposure and vulnerability should be addressed simultaneously, as these mechanisms are not mutually exclusive and may operate at the same time.

Cohort profile: the Social Inequality in Cancer (SIC) cohort study.

The Social Inequality in Cancer (SIC) cohort study was established to determine pathways through which socioeconomic position affects morbidity and mortality, in particular common subtypes of cancer. Data from seven well-established cohort studies from Denmark were pooled. Combining these cohorts provided a unique opportunity to generate a large study population with long follow-up and sufficient statistical power to develop and apply new methods for quantification of the two basic mechanisms underlying social inequalities in cancer-mediation and interaction. The SIC cohort included 83 006 participants aged 20-98 years at baseline. A wide range of behavioural and biological risk factors such as smoking, physical inactivity, alcohol intake, hormone replacement therapy, body mass index, blood pressure and serum cholesterol were assessed by self-administered questionnaires, physical examinations and blood samples. All participants were followed up in nationwide demographic and healthcare registries. For those interested in collaboration, further details can be obtained by contacting the Steering Committee at the Department of Public Health, University of Copenhagen, at inan@sund.ku.dk.

Trends in quality of care among patients with incident heart failure in Denmark 2003-2010: a nationwide cohort study.

BACKGROUND: The treatment of heart failure (HF) is complex and the prognosis remains serious. A range of strategies is used across health care systems to improve the quality of care for HF patients. We present results from a nationwide multidisciplinary initiative to monitor and improve the quality of care and clinical outcome of HF patients using indicator monitoring combined with systematic auditing. METHODS: We conducted a nationwide, population-based prospective study using data from the Danish Heart Failure Registry. The registry systematically monitors and audits the use of guideline recommended processes of care at Danish hospital departments treating incident HF patients. We identified patients registered between 2003 and 2010 (n = 24,504) and examined changes in use of recommended processes of care and 1-year mortality. RESULTS: The use of the majority of the recommended processes of care increased substantially from 2003 to 2010: echocardiography (from 62.7% to 90.5%; Relative Risk (RR) 1.45 (95% CI, 1.39-1.50)), New York Heart Association classification (from 29.4% to 85.5%; RR 2.91 (95% CI, 2.69-3.14)), betablockers (from 72.6% to 88.3%; RR 1.23 (95% CI, 1.15-1.29)), physical training (from 5.6% to 22.8%; RR 4.04 (95% CI, 2.96-4.52)), and patient education (from 49.3% to 81.4%; RR 1.65 (95% CI, 1.52-1.80)). Use of ACE/ATII inhibitors remained stable (from 92.0% to 93.2%; RR 1.01 (95% CI, 0.99-1.04)). During the same period, 1-year mortality dropped from 20.5% to 12.8% (adjusted Hazard Ratio 0.79 (95% CI, 0.65-0.96). CONCLUSIONS: Use of guideline recommended processes of care has improved among patients with incident HF included in the Danish Heart Failure Registry between 2003 and 2010. During the same period, a decrease in mortality was observed.

Education and risk of coronary heart disease: assessment of mediation by behavioral risk factors using the additive hazards model.

Educational-related gradients in coronary heart disease (CHD) and mediation by behavioral risk factors are plausible given previous research; however this has not been comprehensively addressed in absolute measures. Questionnaire data on health behavior of 69,513 participants, 52 % women, from seven Danish cohort studies were linked to registry data on education and incidence of CHD. Mediation by smoking, low physical activity, and body mass index (BMI) on the association between education and CHD were estimated by applying newly proposed methods for mediation based on the additive hazards model, and compared with results from the Cox proportional hazards model. Short (vs. long) education was associated with 277 (95 % CI: 219, 336) additional cases of CHD per 100,000 person-years at risk among women, and 461 (95 % CI: 368, 555) additional cases among men. Of these additional cases 17 (95 % CI: 12, 22) for women and 37 (95 % CI: 28, 46) for men could be ascribed to the pathway through smoking. Further, 39 (95 % CI: 30, 49) cases for women and 94 (95 % CI: 79, 110) cases for men could be ascribed to the pathway through BMI. The effects of low physical activity were negligible. Using contemporary methods, the additive hazards model, for mediation we indicated the absolute numbers of CHD cases prevented when modifying smoking and BMI. This study confirms previous claims based on the Cox proportional hazards model that behavioral risk factors partially mediates the effect of education on CHD, and the results seems not to be particularly model dependent.

[Use of clinical databases and central health registries for description of disease courses]. / Anvendelse af kliniske kvalitetsdatabaser og centrale registre til beskrivelse af sygdomsforløb.

In Denmark, the linkage between national clinical databases and central health administrative and socio-demographic registries provides unique opportunities for describing and analysing disease courses in ways that can be applied for quality improvement purposes, in the evaluation of new organisational initiatives, and for research. This status article presents an overview of the possibilities and discusses the potentials and challenges.

Socioeconomic position and stage of cervical cancer in Danish women diagnosed 2005 to 2009.

BACKGROUND: To reduce social disparities in cervical cancer survival, it is important to understand the mechanisms by which social position influence cancer prognosis. We investigated the relations between socioeconomic factors, comorbidity, time since last Papanicolau smear, and stage at diagnosis in Danish women with cervical cancer. METHODS: We identified 1,651 cervical cancer cases diagnosed 2005 to 2009 from the Danish Gynaecological Cancer Database. Date of diagnosis, clinical cancer stage, tumor histology, and treating hospital were retrieved; Pap smear registrations were obtained from the Danish Pathology Register; data on comorbid conditions from the Danish National Patients Register; and data on education, income, and cohabitation from Statistics Denmark. Logistic regression models were used to analyze the relations between socioeconomic factors and cancer stage in a four-step model, with stepwise inclusion of mediators. RESULTS: The risk for advanced (stage II-IV) compared with early-stage cancer (stage I) was increased for women with short and medium education (OR = 2.40; 1.67-3.45 and 1.76; 1.44-2.16), women living without a partner (OR = 1.31; 1.10-1.55), and older women (OR = 1.07; 1.06-1.08 increase per year). The relations between socioeconomic factors and cancer stage were partly mediated by time since last Pap smear test and to a lesser extent by comorbidity. CONCLUSIONS: Shorter education, living alone, and older age were related to advanced stage cervical cancer, due partly to Pap smear testing and less to comorbidity. IMPACT: It is relevant to further investigate how to decrease delay in cervical cancer diagnosis among disadvantaged groups.

Body mass and risk of complications after hysterectomy on benign indications.

BACKGROUND: This study examines BMI in relation to risk of complications after hysterectomy on benign indications, and explores whether any associations vary by route of surgery. METHODS: In this cohort study, we included data on health and lifestyle collected prospectively for all hysterectomy referrals for benign indications in Denmark from 2004 to 2009. Logistic regression was used to investigate relationship between BMI and complications reported at surgery or during the first 30 days after surgery. RESULTS; Of the 20 353 women with complete data, 6.0% had a BMI < 20 kg/m(2), 31.9% with BMI between 25 and 30 kg/m(2) (classified as overweight) and 17.5% with a BMI ≥ 30 kg/m(2) (categorized as obese). The overall rate of complications was 17.6%, with bleeding being the most common specific complication (6.8%). After adjustment for age, ethnicity, education, indication for surgery, uterus weight, use of prophylaxis, American Society of Anaesthesiologists classification, co-morbidity status and route of hysterectomy, obesity was associated with an increased risk of heavy bleeding during surgery [odds ratio (OR) = 3.64 (2.90-4.56)], all bleeding complications [OR = 1.27 (1.08-1.48)] and infection [OR = 1.47 (1.23-1.77)]. The risk of all bleeding complications [OR = 1.48 (1.28-1.82)] and re-operation [OR = 1.66 (1.26-2.17)] were also increased among women with a BMI < 20. This U-shaped relation between BMI and bleeding, and the association between high BMI and infections were only seen for the abdominal route [abdominal hysterectomy (AH)]. The risk of infections was elevated among women with BMI<20 who underwent laparoscopic surgery [laparoscopic hysterectomy (LH)]. CONCLUSIONS; Obesity increases the risks of bleeding and infections after AH. A BMI below 20 seems to increase the risks of bleeding and infection after AH and LH, respectively.

Socioeconomic inequalities in prognostic markers of non-Hodgkin lymphoma: analysis of a national clinical database.

The survival of non-Hodgkin lymphoma patients strongly depends on a range of prognostic factors. This registry-based clinical cohort study investigates the relation between socioeconomic position and prognostic markers in 6234 persons included in a national clinical database in 2000-2008, Denmark. Several measures of individual socioeconomic position were achieved from Statistics Denmark. The risk of being diagnosed with advanced disease, as expressed by the six prognostic markers (Ann Arbor stage III or IV, more than one extranodal lesion, elevated serum lactate dehydrogenase (LDH), performance status of two or more, presence of B symptoms and International Prognostic Index (IPI) of two or more), increased with decreasing level of education, in patients living alone, and in men. For instance, a significant decrease in the odds of being diagnosed with elevated LDH (p=0.02), high performance status (p=0.004), high IPI score (p=0.004) and B symptoms (p=0.02) was seen with higher level of education, whereas high stage of disease was significantly less likely in the higher educated (odds ratio [OR]=0.85 (0.74-0.99)). The difference in risk seemed not to be mediated by differences in histological subgroups reflecting aggressiveness of disease among the social groups. One of the most likely mechanisms of the social difference is longer delay in those with low socioeconomic position. The findings of social inequality in prognostic markers in non-Hodgkin lymphoma (NHL) patients could already be implemented in the clinical practice if general practitioners (GP's) and physicians on hospitals paid special attention to patients with low educational level and unspecific symptoms.

Psychological distress following fecal occult blood test in colorectal cancer screening--a population-based study.

OBJECTIVE: To evaluate the possible psychological side-effect of participating in a colorectal cancer (CRC)-screening program. MATERIALS AND METHODS: Six hundred participants in a Danish CRC screening feasibility study were invited to complete a short version of the SCL92 (symptom check list) questionnaire relating to the domains: anxiety, depression and somatization following information on the result of their fecal occult blood test. The questionnaire was repeated after 3 and 12 months. Results were analyzed according to age, gender and test result. RESULTS: Participation rate was high, 84.5% at entry, and declined only slightly. The decline was not related to test results nor initial results from the questionnaire. At entry, scores in each dimension in the study population were similar to expected scores in the background population. Participants tested positive at entry had significantly higher scores in all three domains, this difference disappeared at 12 months follow-up. Men had declining scores in all three domains at 3 and 12 months follow-up, whereas women had declining scores only in the domain anxiety. Identical patterns in changes in scoring were found regardless of age and gender. Participants tested positive had, regardless of later results of diagnostic work-up, declining scores during follow-up. CONCLUSIONS: Given the limitations of the study, the results demonstrate no adverse effect on psychological well-being within 12 months following CRC screening regardless of age, gender or test result.

Do patient characteristics, disease, or treatment explain social inequality in survival from colorectal cancer?

This paper investigates the association between individually measured socioeconomic status (SES) and all-cause survival in colorectal cancer patients, and explores whether factors related to the patient, the disease, or the surgical treatment mediate the observed social gradient. The data were derived from a nationwide clinical database of all adenocarcinomas of the colon or rectum diagnosed in Denmark between 2001 and 2004 (inclusive). These data were linked to those from several central registries providing information on income, education, and housing status, as well as to data on comorbidity from previous hospitalizations and use of medication. Only patients with colorectal cancer as their first primary tumour and those born after 1920 were included. A total of 8763 patients were included in the study. Cox proportional hazard regression models revealed a positive social gradient in survival for increasing levels of education and income, and in owners versus renters of housing. A series of regression analyses were used to test potential mediators of the association between the socioeconomic indicators and survival by stepwise inclusion of lifestyle factors (smoking, alcohol intake, body mass index), comorbidity, stage of disease, mode of admission, type of operation, specialization of the surgeon, and curative versus palliative resection. A causal diagram guided the analyses. Inclusion of comorbidity, and to a lesser extent lifestyle, reduced the variation associated with SES, while no evidence of a mediating effect was found for disease or surgical treatment factors. This indicates that the difference in survival among colorectal cancer patients from different social groups was probably not caused by unintentional differences in treatment factors related to surgery, and suggests that primary prevention of chronic diseases among the socially deprived might be one way to reduce social differences in prognosis.

Does erythropoietin augment noise induced hearing loss?

Noise-induced hearing loss may result from excessive release of glutamate, nitrogen oxide and reactive oxygen species. The effects of these factors on the inner ear may potentially be prevented or reduced by erythropoietin (EPO), as indicated by previously demonstrated neuro-protective effects of EPO upon damage to the central nervous system and the retina. This paper reports three separate trials, conducted to investigate the hypothesis that noise-induced hearing loss is prevented or reduced by erythropoietin. The trials employed three different modes of drug application, different administration time windows and different rodent species. In trial 1, guinea pigs were exposed to 110dB SPL, 4-20kHz wide band noise (WBN) for 8h. EPO was administered to the round window membrane 24h after noise exposure, either sustained by pump for a week or by single dose middle ear instillation. In trial 2, rats were exposed to 105dB SPL, 4-20kHz WBN for 8h. EPO was administered by single dose middle ear instillation 1 or 14h after noise exposure. In trial 3, rats were exposed to 105dB SPL, 4-20kHz WBN for 8 or 3x8h. EPO was injected intraperitoneally 1h before noise exposure. Oto-acoustic emissions and auditory brainstem responses (at 16kHz) were recorded before and after noise exposure in all trials. The noise exposure induced a hearing loss in all animals. In trial 1, no recovery and no improvement of hearing occurred in any treatment group. In trial 2 and 3, a partial hearing recovery was seen. However, the hearing loss of the EPO treated animals was significantly worse than controls in trial 2. In trial 3, the hearing of the EPO treated animals exposed for 3x8h was significantly worse than controls. Thus, surprisingly, the results from 2 of the 3 present trials indicate that erythropoietin may in fact augment noise-induced hearing loss. This is contradictory to the beneficial effect of EPO reported by the vast majority of studies on stressed neural tissues. EPO administration may alter the blood flow dynamics of the cochlear vascular bed during or after noise exposure, by a potential induction of vasoconstriction. This may be the cause of the surprising findings.