125. Application of biomarkers for the identification of health hazards and risk in human populations

The emerging area of molecular epidemiology uses biomarkers of exposure, susceptibility and effect to evaluate the risk of cancer and other diseases in human popultations. This approach has considerable potential for improving exposure assessment, identifying genotoxic agents as well as susceptible individuals within the population, detecting early pre-clinical stages of disease, and allowing intervention steps to be taken to reduce the incidence of disease. Our knowledge of carcinogenesis and other genetic diseases has expanded rapidly over the past two decades as has our ability to detect and measure genetic changes in human cells and     

Cigarette smoking and the risk of Barrett’s esophagus

Introduction  We examined the association between smoking and the risk of Barrett’s esophagus (BE), a metaplastic precursor to esophageal adenocarcinoma. Methods  We conducted a case–control study within the Kaiser Permanente Northern California population. Patients with a new diagnosis of BE (n = 320) were matched to persons with gastroesophageal reflux disease (GERD) (n = 316) and to population controls (n = 317). Information was collected using validated questionnaires from direct in-person interviews and electronic databases. Analyses used multivariate unconditional logistic regression that controlled for age, gender, race, and education. Results  Ever smoking status, smoking intensity (pack-years), and smoking cessation were not associated with the risk of BE. Stratified analyses suggested that ever smoking may be associated with an increased risk of BE among some groups (compared to population controls): persons with long-segment Barrett’s esophagus (odds ratio [OR] = 1.72, 95% confidence interval [CI] 1.12–2.63); subjects without GERD symptoms (OR = 3.98, 95% CI 1.58–10.0); obese subjects (OR = 3.38, 95% CI 1.46–7.82); and persons with a large abdominal circumference (OR = 3.02, 95% CI (1.18–2.75)). Conclusion  Smoking was not a strong or consistent risk factor for BE in a large community-based study, although associations may be present in some population subgroups.     

Dupuytren’s disease and the risk of malignant neoplasms

The object of this study was the investigation of the risk of occurrence of malignant neoplasms in 508 patients with Dupuytren’s disease (DD) and in 2157 of their 1st degree relatives. In the first stage of the study, we evaluated the tumour spectrum as well as the age of the patient at diagnosis of cancers in DD families along with the observed and expected frequencies of malignancies. In the second stage of the study, we examined the distribution of 20 common mutations/polymorphisms in 12 known cancer susceptibility genes among DD patients and 508 matched healthy controls. No such study has been published to date. Results. No significant differences were noted between malignancies diagnosed among members of DD families and the general population. Molecular examination of 20 mutations/polymorphisms in 12 cancer susceptibility genes in Dupuytren’s patients and controls showed a statistically significant association of one mutation with Dupuytren disease: D312M in XPD (OR = 1.75, p = 0.004). We observed a tendency toward changed frequencies of occurrence of central nervous system tumors, laryngeal cancer and non-melanoma skin cancers in DD families. The results of our study indicate a lack of a strong association between Dupuytren disease and familial cancer risk.     

Maté: a risk factor for oral and oropharyngeal cancer

Maté is a tea-like beverage consumed mainly in Argentina, Uruguay, Paraguay, southern Brazil and to a lesser degree in other areas of the world such as Germany, Syria, Lebanon and Northern Israel. It is brewed from the dried leaves and stemlets of the perennial tree Ilex paraguarensis ("yerba mate") a species that belongs to the Aquifoliaceae family. Maté consumption has been associated with an increased rate of oral and oropharyngeal cancers. The purpose of this study is to review the literature and discuss the role of Maté consumption in the development of oral and oropharyngeal cancer and the potential carcinogenic mechanisms. A review of the relevant literature linking Maté consumption with oral and oropharyngeal cancer and the carcinogenicity of Maté was performed. The search was performed using Medline, library catalogues, OCLC first search and ISI web of science databases. Case control studies on Maté drinking populations and, in vivo and in vitro studies on the carcinogenicity of Maté were reviewed. The populations reviewed in many of these studies also used alcohol and tobacco products confounding the influence of Maté as an independent risk factor. There is evidence in the literature that Maté consumption is in itself carcinogenic and plays a role in the development of cancers of the oral cavity and oropharynx. Although the exact mechanism of carcinogenesis is still unknown, available information suggests that Maté drinking should be considered one of the risk factors for oral and oropharyngeal cancer.     

Male gynecomastia and risk for malignant tumours – a cohort study

Background

Men with gynecomastia may suffer from absolute or relative estrogen excess and their risk of different malignancies may be increased. We tested whether men with gynecomastia were at greater risk of developing cancer.

Methods

A cohort was formed of all the men having a histopathological diagnosis of gynecomastia at the Department of Pathology, University of Lund, following an operation for either uni- or bilateral breast enlargement between 1970–1979. All possible causes of gynecomastia were accepted, such as endogenous or exogenous hormonal exposure as well as cases of unknown etiology. Prior to diagnosis of gynecomastia eight men had a diagnosis of prostate carcinoma, two men a diagnosis of unilateral breast cancer and one had Hodgkin's disease. These patients were included in the analyses. The final cohort of 446 men was matched to the Swedish Cancer Registry, Death Registry and General Population Registry.

Results

At the end of the follow up in December 1999, the cohort constituted 8375.2 person years of follow-up time. A total of 68 malignancies versus 66.07 expected were observed; SIR = 1.03 (95% CI 0.80–1.30). A significantly increased risk for testicular cancer; SIR = 5.82 (95% CI 1.20–17.00) and squamous cell carcinoma of the skin; SIR = 3.21 (95% CI 1.71–5.48) were noted. The increased risk appeared after 2 years of follow-up. A non-significantly increased risk for esophageal cancer was also seen while no new cases of male breast cancer were observed. However, in the prospective cohort, diagnostic operations for gynecomastia may substantially have reduced this risk

Conclusions

There is a significant increased risk of testicular cancer and squamous cell carcinoma of the skin in men who have been operated on for gynecomastia.     

Familial adenomatous polyposis, hereditary nonpolyposis colon cancer, and familial risk: what are the implications for the surgeon?

Recent advances in the understanding of the molecular biology of colorectal cancer have resulted in many new implications for surgeons. To continue providing sound patient care, surgeons must familiarize themselves with associated issues that include genetic counseling and its role in patient and family management. Issues related to genetic counseling are reviewed in this article. Recommendations for surgical therapy and surveillance methods are summarized for each of the hereditary syndromes. Failure to use these patient management tools in an effective way may be a source of future litigation.     

Are smoking and chlamydial infection risk factors for CIN? Different results after adjustment for HPV DNA and antibodies

To identify the risk factors for cervical intraepithelial neoplasia (CIN), we reanalysed the data from our previous case-control study by adjusting for human papillomavirus (HPV) antibodies. Unlike our previous study based only on HPV DNA, smoking and Chlamydia trachomatis infection were revealed as significant risk factors for CIN after adjustment for HPV antibodies.     

Does the time interval between first and last birth influence the risk of endometrial and ovarian cancer?

Background

Age at first and last birth and the number of children are known to influence the risk of endometrial and ovarian cancers. However, it remains unknown whether the difference in years between first and last childbirth plays a role. The Swedish Family-Cancer Database allowed us to carry out the largest study ever on reproductive factors in these cancers.

Material and methods

We selected over 5.7 million women from the database. We estimated the effect of number of children, age at birth and difference between age at first and last birth by Poisson regression adjusted for age, period, region and socioeconomic status.

Results

The risk for endometrial cancer is negatively associated with increasing number of children and increasing age at first as well as age at last birth. Weaker associations are found for ovarian cancer. Age at last birth is the factor that shows highest influence. A large difference in first and last childbirth shows a protective effect on the risk of endometrial cancer.

Conclusion

Our findings suggest that the risk of endometrial cancer is significantly decreased for women having at least a difference of 10 years between their first and last birth. Ovarian cancer does not seem to be influenced by the time interval between first and last birth.     

Coffee and caffeine intake and the risk of ovarian cancer: the Iowa Women’s Health Study

Laboratory data suggest that caffeine or some components of coffee may cause DNA mutations and inhibit tumor suppressor mechanisms, leading to neoplastic growth. However, coffee consumption has not been clearly implicated in the etiology of human postmenopausal ovarian cancer. This study evaluated the relationship of coffee and caffeine intake with risk of epithelial ovarian cancer in a prospective cohort study of 29,060 postmenopausal women. The participants completed a mailed questionnaire that assessed diet and health history and were followed for ovarian cancer incidence from 1986 to 2004. Age-adjusted and multivariate-adjusted hazard ratios were calculated for four exposure variables: caffeinated coffee, decaffeinated coffee, total coffee, and total caffeine to assess whether or not coffee or caffeine influences the risk of ovarian cancer. An increased risk was observed in the multivariate model for women who reported drinking five or more cups/day of caffeinated coffee compared to women who reported drinking none (HR = 1.81, 95% CI: 1.10–2.95). Decaffeinated coffee, total coffee, and caffeine were not statistically significantly associated with ovarian cancer incidence. Our results suggest that a component of coffee other than caffeine, or in combination with caffeine, may be associated with increased risk of ovarian cancer in postmenopausal women who drink five or more cups of coffee a day.     

Active surveillance for favorable risk prostate cancer: what are the results, and how safe is it?

Active surveillance for favorable risk prostate cancer has become increasingly popular in populations in which prostate cancer screening is widespread because of evidence that prostate cancer screening results in the detection of disease that is not clinically significant in many patients (ie, untreated, would not pose a threat to health). The approach is supported by data showing that patients who fall into the category of clinically insignificant disease can be identified with reasonable accuracy and that patients who are initially classified as low risk who reclassify over time as higher risk and are treated radically are still cured in most cases. This means (1) identifying patients who have a low likelihood of disease progression during their lifetime based on clinical and pathologic features of the disease and patient age and comorbidity, (2) close monitoring over time, (3) reasonable criteria for intervention that will both identify more aggressive disease in a timely fashion and not result in excessive treatment, and (4) meeting the communication challenge to reduce the psychological burden of living with untreated cancer. The results of active surveillance, the criteria for patient selection, and the appropriate triggers for intervention are reviewed.     

Do diagnostic and treatment delays for colorectal cancer increase risk of death?

Background

Using 1998–2005 SEER-Medicare data, we examined the effect of diagnostic and treatment delays on all-cause and colorectal cancer (CRC)-specific death among US adults aged ≥ 66 years with invasive colon or rectal cancer. We hypothesized that longer delays would be associated with a greater risk of death.

Methods

We defined diagnostic and treatment delays, respectively, as days between (1) initial medical consult for CRC symptoms and pathologically confirmed diagnosis (maximum: 365 days) and (2) pathologically confirmed diagnosis and treatment (maximum: 120 days). Cases (CRC deaths) and controls (deaths due to other causes or censored) were matched on survival time. Logistic regression analyses adjusted for sociodemographic, tumor, and treatment factors.

Results

Median diagnostic delays were 60 (colon) and 40 (rectal) days and treatment delays were 13 (colon) and 16 (rectal) days in 10,663 patients. Colon cancer patients with the longest diagnostic delays (8–12 months vs. 14–59 days) had higher odds of all-cause (aOR: 1.31 CI: 1.08–1.58), but not CRC-specific death. Colon cancer patients with the shortest treatment delays (<1 vs. 1–2 weeks) had higher odds of all-cause (aOR: 1.23 CI: 1.01–1.49), but not CRC-specific death. Among rectal cancer patients, delays were not associated with risk of all-cause or CRC-specific death.

Conclusions

Longer delays of up to 1 year after symptom onset and 120 days for treatment did not increase odds of CRC-specific death. There may be little clinical benefit in detecting and treating existing symptomatic disease earlier. Screening prior to symptom onset must remain the primary goal to reduce CRC incidence, morbidity, and mortality.     

Assessing environmental and occupational risk factors for lung cancer in Mexican–Americans

Background

We investigated environmental and occupational exposures and smoking history (while controlling for demographics) in a population of Mexican–American lung cancer cases and controls from the Houston metropolitan area.

Methods

Data were collected between 1991 and 2005 as part of an on-going multi-racial/ethnic, lung cancer case–control study. Cases included 212 Mexican–American lung cancer cases from UT MD Anderson Cancer Center. Controls (n = 328) were recruited from Houston’s largest multispecialty group practice and frequency matched to the cases by age (±5 years), sex, and ethnicity. Environmental and occupational factors were analyzed and odds ratios and 95% confidence intervals were calculated using logistic regression.

Results

We detected elevated risks of lung cancer associated with pesticide exposure and found conventional and antimicrobial (e.g., sterilizers, disinfectants, antiseptics) pesticides were associated with an increased risk of lung cancer in Mexican–Americans (conventional pesticides and antimicrobial pesticides combined: OR = 1.80, 95% CI 1.13–2.86; conventional pesticides: OR = 2.05, 95% CI 1.23–2.39; antimicrobial pesticides: OR = 2.48, 95% CI 1.46–4.21).

Conclusions

Although we found over a two-fold increased risk of lung cancer among Mexican–Americans for pesticides, we could not identify individual pesticides. Our findings are an important preliminary step in identifying factors that are specifically associated with lung cancer risk among Mexican Americans.     

Smarter screening for prostate cancer: for the few, not the many? A stratified approach based on baseline risk

Evaluation of: van Leeuwen PJ, Connolly D, Tammela TLJ et al. Balancing the harms and benefits of early detection of prostate cancer. Cancer 116(20), 4857-4865 (2010). Prostate cancer screening remains controversial, with different countries taking different views on its value. We review the study by van Leeuwen and colleagues, evaluating the risk-benefit ratio for screening from the European Randomized study of Screening for Prostate Cancer (ERSPC) stratified by age and serum prostate-specific antigen level at study entry. Though the overall results from the ERSPC demonstrated a 20% relative reduction in prostate cancer mortality in the screened arm, the current study demonstrated that the benefit was minimal for men aged 55-74 years with a serum prostate-specific antigen <4 ng/ml and came at the expense of significant overdiagnosis and overtreatment. This study adds to the growing body of evidence that prostate cancer screening works, but not for everyone, and suggests a smarter strategy of targeted screening to those most at risk from prostate cancer mortality.     

Fruit and vegetable intake and risk of cancer in the Swedish women’s lifestyle and health cohort

Objective  

To investigate whether intake of fruits and vegetables is associated with overall cancer incidence in a large prospective cohort of women in Sweden characterised by young age at enrolment (30–49 years) and relatively low intake of fruits and vegetables.     

Does radiotherapy around the time of pregnancy for Hodgkin's disease modify the risk of breast cancer?

PURPOSE: To determine whether the risk of secondary breast cancer after radiotherapy (RT) for Hodgkin's disease is greater among women who underwent RT around time of pregnancy. METHODS AND MATERIALS: The records of 382 women treated with RT for Hodgkin's disease were reviewed and divided into those who received RT around the time of pregnancy and those who were not pregnant. Comparisons of the overall incidence, actuarial rates, and latency to breast cancer between the two groups were made. Multivariate Cox regression modeling was performed to determine possible contributing factors. RESULTS: Of the 382 women, 14 developed breast cancer (3.7%). The increase in the overall incidence (16.0% vs. 2.3%, p = 0.0001) and the actuarial rate of breast cancer among the women in the pregnant group (p = 0.011) was statistically significant. The women treated around the time of pregnancy had a 10- and 15-year actuarial rate of breast cancer of 6.7% and 32.6%, respectively. The 10-year and 15-year actuarial rate for the nonpregnant women was 0.4% and 1.7%, respectively. The median latency from RT to the diagnosis of breast cancer was 13.1 and 18.9 years for women in the pregnant and nonpregnant groups, respectively. In the multivariate analysis, pregnancy around the time of RT was the only variable associated with an increased risk of breast cancer. The risk was dependent on the length of time from pregnancy to RT, with women receiving RT during pregnancy and within 1 month of pregnancy having an increased risk of breast cancer compared with nonpregnant women and women irradiated later than 1 month after pregnancy (hazard ratio, 22.49; 95% confidence interval, 5.56-90.88; p <0.001). CONCLUSION: The results of this study indicate that the risk of breast cancer after RT is greater with irradiation around the time of pregnancy. This suggests that pregnancy is a time of increased sensitivity of breast tissue to the carcinogenic effects of radiation. Because of the small sample size and limited follow-up, additional studies are recommended to confirm these findings.     

Tumour shrinkage and contour change during radiotherapy increase the dose to organs at risk but not the target volumes for head and neck cancer patients treated on the TomoTherapy HiArt™ system

Aims

To quantify the changes in contours of the target and organs at risk and the differences between planned and delivered doses to the target and organs at risk during the course of radiotherapy in head and neck cancer patients treated with intensity-modulated radiotherapy on the TomoTherapy HiArt™ system.

Materials and methods

Five patients with squamous cell carcinoma of the head and neck treated with radical chemoradiotherapy using the TomoTherapy HiArt system were included in the study. The target volumes were treated to three different dose levels depending on the level of clinical risk for harbouring disease. Patient positions were assessed daily with megavoltage computed tomography (MVCT) and positional correction made before each treatment when necessary. MVCTs were superimposed on to the planning kilovoltage computed tomography images for each patient and target volumes and organ at risk volumes were re-outlined on MVCT images. Doses to clinical target volumes and organs at risk were recalculated to show the actual delivered doses.

Results

There was shrinkage in the volume of the parotid glands during treatment in all cases. The mean volume reduction in the ipsilateral parotid gland was more marked at 30.2%, compared with the contralateral parotid glands. However, the mean percentage dose per fraction increase was higher in the contralateral parotid glands at 24%, compared with the ipsilateral parotids. The calculated doses were higher than the planned doses in all CTV-54, CTV-60 and CTV-68, but the mean dose differences were modest, in the range 1.3-2.4%.

Conclusions

We have shown that there were considerable changes in the volume and dose to the parotids during treatment. The changes in volume and dose to the clinical target volume were more modest in comparison. Adaptive radiotherapy planning can be helpful in improving the dose to the parotid glands. However, its role in the optimisation of the dosage to the clinical target volume is less likely to result in a significant clinical benefit.