Morten Frisch

Sexually Transmitted Infection as a Cause of Anal Cancer

Interviews were carried out with 423 women and 93 men with invasive or in situ anal cancer in Denmark and Sweden in a search for clues to the aetiology of this neoplasm. Patients with rectal adenocarcinoma (n = 534) and persons drawn from the background population (n = 554) served as controls. Multivariate logistic regression analyses confirmed previous observations of a strong association between either male homosexual experience or a history of anogenital warts and the risk for anal cancer. Moreover, hitherto unknown, but strong and consistent associations were observed between measures of high heterosexual activity and the risk for anal cancer among both sexes. Polymerase chain reaction analysis revealed human papilloma-virus DNA in the majority (88%) of anal cancer specimens but in none of 20 examined rectal adenocarcinomas. It is concluded that most anal cancers appear to be caused by sexually transmitted types of human papillomaviruses and, consequently, that anal cancer is a potentially preventable neoplasm.

Merkel cell carcinoma and HIV infection.

Merkel cell carcinoma (MCC) is a rare skin cancer that occurs more frequently after organ transplantation or B-cell malignancy, conditions of suppressed or disordered immunity. To assess further whether immune suppression increases MCC risk, we studied its occurrence in a cohort of 309365 individuals with acquired immunodeficiency syndrome (AIDS) by using linked AIDS and cancer registries. We identified six cases of MCC, corresponding to a relative risk of 13.4 (95% CI 4.9-29.1) compared with the general population. These results suggest that immune suppression induced by the human immunodeficiency virus increases MCC risk.

Antibiotic use and inflammatory bowel diseases in childhood

Background The composition of the intestinal microflora has been proposed as an important factor in the development of inflammatory bowel diseases (IBD). Antibiotics have the potential to alter the composition of the intestinal microflora. A study was undertaken to evaluate the potential association between use of antibiotics and IBD in childhood. Methods A nationwide cohort study was conducted of all Danish singleton children born from 1995 to 2003 (N=577 627) with individual-level information on filled antibiotic prescriptions, IBD and potential confounding variables. Using Poisson regression, rate ratios (RRs) of IBD were calculated according to antibiotic use. Antibiotic use was classified according to time since use, type, number of courses used and age at use. Results IBD was diagnosed in 117 children during 3 173 117 person-years of follow-up. The RR of IBD was 1.84 (95% CI 1.08 to 3.15) for antibiotic users compared with non-users. This association appeared to be an effect on Crohns disease (CD) alone (RR 3.41) and was strongest in the first 3 months following use (RR 4.43) and among children with ≥7 courses of antibiotics (RR 7.32). Conclusions Antibiotic use is common in childhood and its potential as an environmental risk factor for IBD warrants scrutiny. This is the first prospective study to show a strong association between antibiotic use and CD in childhood. However, as with any observational study, causality cannot be inferred from our results and confounding by indication—in particular, prescribing of antibiotics to children with intestinal symptoms of as yet undiagnosed CD—should also be considered as a possible explanation.

Evidence of an association between non-Hodgkin's lymphoma and skin cancer

Abstract Objective: To investigate a possible link between exposure to ultraviolet light and the almost epidemic increase in non-Hodgkins lymphoma worldwide. Because ultraviolet light is known to cause skin cancers, the association between non-Hodgkins lymphoma and skin cancer was studied. Design: Secondary occurrence of either malignant melanoma or squamous cell skin cancer in cohorts of patients with a first diagnosis of either non-Hodgkins lymphoma or chronic lymphocytic leukaemia, and vice versa, were studied. Expected numbers of subsequent cancers were calculated by sex, age, and period specific national incidence rates multiplied by the person years under observation in the cohorts. Setting: Denmark (1943-89) and Sweden (1958-89). Subjects: Four population based cohorts identified in the nationwide cancer registries (34641 people with non-Hodgkins lymphoma, 17400 with chronic lymphocytic leukaemia, 34989 with malignant melanoma, 25980 with squamous cell skin cancer). A total of 562085 person years were accrued for the analysis. Main outcome measures: The ratios of observed to expected cancers (the standardised incidence ratio) served as a measure of the relative risk. Results: The relative risk for developing squamous cell skin cancer was 5.5 (95% confidence interval 4.6 to 6.6) among patients with non-Hodgkins lymphoma and 8.6 (7.2 to 10.3) among patients with chronic lymphocytic leukaemia. The relative risks remained high over more than 15 years of follow up. Relative risks for malignant melanoma were 2.4 (1.8 to 3.2) for patients with non-Hodgkins lymphoma and 3.1 (2.1 to 4.4) for patients with chronic lymphocytic leukaemia. After squamous cell skin cancer had been diagnosed there was a twofold excess risk for non-Hodgkins lymphoma and chronic lymphocytic leukaemia. By contrast, in each of the cohorts the general cancer risks excluding skin and lymphoproliferative malignancies were close to the expected. Conclusions: The occurrence of non-Hodgkins lymphoma and skin cancer are strongly associated; this supports the hypothesis that the secular increase in exposure to ultraviolet light may have contributed to the increasing incidence of non-Hodgkins lymphoma in recent decades Key messages Key messages Ultraviolet light is known to be immunosuppressive and to have causal links to skin cancer Non-Hodgkins lymphoma is strongly associated with skin cancer Exposure to ultraviolet light may have contributed to the increasing incidence of non-Hodgkins lymphoma in recent decades

INDUCED ABORTION AND THE RISK OF BREAST CANCER

BACKGROUND It has been hypothesized that an interrupted pregnancy might increase a womans risk of breast cancer because breast cells could proliferate without the later protective effect of differentiation. METHODS We established a population-based cohort with information on parity and vital status consisting of all Danish women born from April 1, 1935, through March 31, 1978. Through linkage with the National Registry of Induced Abortions, information on the number and dates of induced abortions among those women was combined with information on the gestational age of each aborted fetus. All new cases of breast cancer were identified through linkage with the Danish Cancer Registry. RESULTS In the cohort of 1.5 million women (28.5 million person-years), we identified 370,715 induced abortions among 280,965 women (2.7 million person-years) and 10,246 women with breast cancer. After adjustment for known risk factors, induced abortion was not associated with an increased risk of breast cancer (relative risk, 1.00; 95 percent confidence interval, 0.94 to 1.06). No increases in risk were found in subgroups defined according to age at abortion, parity, time since abortion, or age at diagnosis of breast cancer. The relative risk of breast cancer increased with increasing gestational age of the fetus at the time of the most recent induced abortion: <7 weeks, 0.81 (95 percent confidence interval, 0.58 to 1.13); 7 to 8 weeks, 1.01 (0.89 to 1.14); 9 to 10 weeks, 1.00 >12 weeks, 1.38 (1.00 to 1.90) (reference category, 9 to 10 weeks). CONCLUSIONS Induced abortions have no overall effect on the risk of breast cancer.

Alcohol consumption is associated with decreased risk of rheumatoid arthritis: results from two Scandinavian case–control studies

OBJECTIVES To determine the association between risk of rheumatoid arthritis (RA) and alcohol consumption in combination with smoking and HLA-DRB1 shared epitope (SE). METHODS Data from two independent case-control studies of RA, the Swedish EIRA (1204 cases and 871 controls) and the Danish CACORA (444 cases and 533 controls), were used to estimate ORs of developing RA for different amounts of alcohol consumed. RESULTS Alcohol consumption was significantly more common in controls (p<0.05) and dose-dependently associated with reduced risk of RA (p for trend <0.001) in both studies. Among alcohol consumers, the quarter with the highest consumption had a decreased risk of RA of the order of 40-50% compared with the half with the lowest consumption (EIRA, OR = 0.5 (95% CI 0.4 to 0.6); CACORA, OR = 0.6 (95% CI 0.4 to 0.9)). For the subset of RA that is seropositive for antibodies to citrullinated peptide antigens, alcohol consumption reduced the risk most in smokers carrying HLA-DRB1 SE alleles. CONCLUSIONS The observed inverse association between alcohol intake and risk of RA and the recent demonstration of a preventive effect of alcohol in experimental arthritis indicate that alcohol may protect against RA. This highlights the potential role of lifestyle in determining the risk of developing RA, and emphasises the advice to stop smoking, but not necessarily to abstain from alcohol in order to diminish risk of RA. The evidence of potential RA prevention should prompt additional studies on how this can be achieved.

Changing patterns of tonsillar squamous cell carcinoma in the United States

AbstractObjective: Tonsillar squamous cell carcinoma (SCC) may differ etiologically from other oral cancers. The aim of this study was to provide a detailed description of the incidence patterns of tonsillar SCC in the United States. Methods: Population-based incidence data from the Connecticut Tumor Registry (period 1945–1994) and from the SEER program (period 1973–1995) were used to calculate age-standardized (US 1970) and age-specific incidence rates and confidence intervals (CIs). Linear regression was used to evaluate trends. Results: The incidence of tonsillar SCC increased fourfold among white women in Connecticut during 1945–1994 but remained rather constant in white men. During 1973–1995, incidence rates per million person-years were considerably higher in blacks (31.6; 95% CI: 29.0–34.4 in men, and 9.6; 95% CI: 8.3–10.9 in women) than whites (14.8; 95% CI: 14.3–15.3 in men, and 6.1; 95% CI: 5.8–6.4 in women). Men, but not women, who were younger than 60 years experienced significant annual increases in tonsillar SCC incidence during 1973–1995 (2.7% in blacks and 1.9% in whites). No similar increases occurred for oral SCC at non-tonsillar sites. Conclusion: Incidence rates of tonsillar SCC vary considerably by sex, race and time in a way that cannot be explained by changes in tonsillectomy practices alone. Changes in environmental risk factors, including changes in smoking patterns and an increase in oral human papillomavirus infections, may have contributed.

Trends in incidence of anal cancer in Denmark.

OBJECTIVE--To study long term trends in incidence of anal cancer in a well monitored, unselected population. DESIGN--Descriptive epidemiological study based on data from the Danish Cancer Registry. SETTING--Denmark, 1943-87. MAIN OUTCOME MEASURES--Time related changes in anal cancer incidence according to sex, age, birth cohort, urban or rural residence, and marital status. RESULTS--The incidence of anal cancer remained fairly constant in the period 1943-57 and was similar for men and women, but it increased 1.5-fold among men and nearly tripled among women thereafter. Among men the incidence increased from 0.25 per 100,000 population (world standardised) in 1958-62 to 0.38 in 1983-7 (p = 0.01) and among women from 0.28 to 0.74 (p < 0.01). The greatest increase was among residents of the capital (Copenhagen). During 1943-87 age specific trends increased in young and middle aged men and in all age groups among women. Men with anal cancer were significantly more likely throughout the study period to be unmarried than were patients with cancer of the colon (adjusted odds ratio 2.7; 95% confidence interval 2.0 to 3.6) and stomach (2.1; 1.5 to 2.8), but no association with marital status was found among women. CONCLUSIONS--The distribution and incidence of anal cancer have changed appreciably since around 1960, especially among women, which indicates important aetiological changes. Changes in sexual behaviour may have facilitated the spread of a transmittable agent of aetiological importance. It has recently been suggested that cigarette smoking promotes anal cancer, and this finds indirect support in the synchronism between changes in anal cancer incidence and heavy smoking behaviour. Factors associated with homosexuality are likely to explain some of the cases among men.

Cancer risk in fathers and brothers of testicular cancer patients in Denmark. A population-based study

There are several reports of familial testicular cancer in the literature but few systematic attempts have been made to estimate the risk of testicular cancer in first‐degree relatives of patients with this neoplasm, and the risk remains to be fully assessed in population‐based studies. By means of data from the Danish Cancer Registry, we identified all testicular cancer patients (index cases) born and diagnosed during 1950–1993 in Denmark. Their fathers were identified from national registries, as were the brothers of a subcohort of these patients. Familial cancer occurrence was determined through linkage with the cancer registry and compared with the cancer incidence in the general male population in Denmark. The ratio of observed to expected cancers generated the measure used for the relative risk. Fathers of 2,113 index cases with testicular cancer experienced an almost 2‐fold risk of developing testicular cancer themselves (RR = 1.96; 95% CI: 1.01–3.43). Overall, the fathers had a decreased relative cancer risk (RR = 0.84; 95% CI: 0.74–0.95) with a significantly decreased risk of cancers of the lung and digestive organs. Brothers of a subcohort of 702 index cases showed a markedly increased risk of testicular cancer (RR = 12.3; 95% CI: 3.37ndash;31.5). In conclusion, we documented a significantly increased familial risk of testicular cancer which was relatively more pronounced between brothers than between fathers and sons. These findings support the possible involvement of a genetic component in the aetiology of testicular cancer, but also leave room for a hypothesized influence of in‐utero exposures, such as specific maternal hormone levels, that might be shared by brothers.

Cytokines, autoantibodies and viral antibodies in premorbid and postdiagnostic sera from patients with rheumatoid arthritis: case–control study nested in a cohort of Norwegian blood donors

Objective: To assess the timing of changes in cytokines, cytokine-related markers, autoantibodies and viral antibodies in the pathogenesis of rheumatoid arthritis (RA). Methods: Case–control study nested in a prospective cohort of 31 330 blood donors in Oslo, Norway. Forty-nine donors developed RA up to 23 years after their most recent blood donation. Stored sera from these donors (case sera) and a sex- and age-matched sample of 245 healthy donors (control sera), and postdiagnostic sera from 33 of the 49 RA cases, were analysed for a panel of cytokines and cytokine-related markers, autoantibodies and antibodies against Epstein–Barr virus and parvovirus B19. Results: Cytokines and cytokine-related markers were generally negative in case sera from >5 years before the diagnosis of RA. In the 5-year interval immediately before the diagnosis of RA, more case than control sera were positive (odds ratios >2) for interleukin (IL)-1α, IL-1β, IL-1 receptor antagonist, IL-4, IL-10, tumour necrosis factor-α and soluble tumour necrosis factor receptor I. In postdiagnostic sera, however, 11 of 16 examined cytokines and cytokine-related markers were statistically significantly elevated compared with control sera. Seropositivity for IgG antibodies against cyclic citrullinated peptides and for IgM and IgA rheumatoid factors were seen in case sera from up to 18 years before the diagnosis of RA. IgG antibodies against Epstein–Barr virus and parvovirus B19 did not differ significantly between case and control sera. Conclusions: Cytokines and cytokine-related markers appear to be upregulated rather late in RA pathogenesis. In contrast, IgM rheumatoid factor and IgG anti-cyclic citrullinated peptide autoantibodies may precede the diagnosis of RA by up to two decades.