Heribert Ramroth

Exposure to cement dust, related occupational groups and laryngeal cancer risk: Results of a population based case-control study

A population‐based case‐control study was performed in the Rhein‐Neckar region, Germany, to evaluate occupational risk factors for the development of laryngeal cancer (“Rhein‐Neckar‐Larynx Study”). Between May 1998 and December 2000, 257 patients (236 males, 21 females), aged 37–80, with histologically confirmed laryngeal cancer, as well as 769 population control persons (702 males, 67 females), were included (1:3 frequency matched by age and sex). History of occupational exposures, as well as other risk factors (tobacco, alcohol), was obtained with face‐to‐face interviews using a detailed standardized questionnaire. The complete individual work history was assessed. A detailed assessment of work conditions was obtained by job‐specific questionnaires (JSQs) for selected jobs known to be associated with exposure to potential laryngeal carcinogens. Estimates for total exposure hours by substance were calculated based on JSQs. Published occupational hygiene data were used to infer semiquantitative scores of exposure intensity for specific job tasks. After adjustment for tobacco and alcohol intake, a significant elevated odds ratios (OR) could be demonstrated for persons that were exposed to cement during their work as building and construction workers. An OR of 2.42 was calculated for workers of the high exposed subgroup (95% confidence interval: 1.14‐5.15; p < 0.001). Smoking was the main confounding factor because the unadjusted cement OR of 3.20 dropped down to 2.42 after adjustment for tobacco intake. We conclude that there is good evidence for cement dust exposure acting as a tobacco, alcohol and asbestos independent risk factor for laryngeal carcinoma. Our study gives a base for further toxicologic investigations on this topic.

Laryngeal cancer risk associated with smoking and alcohol consumption is modified by genetic polymorphisms in ERCC5, ERCC6 and RAD23B but not by polymorphisms in five other nucleotide excision repair genes.

Laryngeal cancer is known to be associated with smoking and high alcohol consumption. Nucleotide excision repair (NER) plays a key role in repairing DNA damage induced by these exposures and might affect laryngeal cancer susceptibility. In a population‐based case‐control study including 248 cases and 647 controls, the association of laryngeal cancer with 14 single nucleotide polymorphisms (SNPs) in 8 NER genes (XPC, XPA, ERCC1, ERCC2, ERCC4, ERCC5, ERCC6 and RAD23B) was analyzed with respect to smoking and alcohol exposure. For genotyping, sequence specific hybridization probes were used. Data were evaluated by conditional logistic regression analysis, stratified for age and gender, and adjusted for smoking, alcohol consumption and education. Pro‐carriers of ERCC6 Arg1230Pro showed a decreased risk for laryngeal cancer (OR = 0.53, 95% CI 0.34–0.85), strongest in heavy smokers and high alcohol consumers. ERCC5 Asp1104His was associated with risk in heavy smokers (OR = 1.70, 95% CI 1.1–2.5). Val‐carriers of RAD23B Ala249Val had an increased cancer risk in heavy smokers (OR = 1.6, 95% CI 1.1–2.5) and high alcohol consumers (OR = 2.0, 95% CI 1.1–3.4). The combined effect of smoking and alcohol intake affected risk, at high exposure level, for ERCC6 1230Pro carriers (OR = 0.47, 95% CI 0.22–0.98) and RAD23B 249Val carriers (OR = 2.6, 95% CI 1.3–4.9). When tested for gene–gene interaction, presence of 3 risk alleles in the XPC‐RAD23B complex increased the risk 2.1‐fold. SNPs in the other genes did not show a significant association with laryngeal cancer risk. We conclude that common genetic variations in NER genes can significantly modify laryngeal cancer risk.

Effects of tumour stage, comorbidity and therapy on survival of laryngeal cancer patients: a systematic review and a meta-analysis.

Laryngeal cancer is the second most common cancer of the respiratory tract with a relative 5-year survival over all tumour sites in the USA (61.6%; SEER 2009), which is much better than other head and neck cancers. The aim of this paper is to review and summarise data on the survival of laryngeal cancer patients. Literature search was conducted to identify articles in PubMed up to June 2009. Thirty studies with different study aims including sufficient information on survival of laryngeal cancer patients were identified. The 5-year overall survival ranged from 0 to 100%, depending on the T- and N-category, therapeutic approach and tumour location. The involvement of other factors such as genetics, nutrition and lifestyle habits remains uncertain. Our meta-analysis on a subgroup of published studies yielded an overall 5-year relative survival rate of 64.2% (95% confidence interval 63.7–64.7%). Different study aims and patient selection criteria prohibit general conclusions. However, this review may provide an actual picture of the complexity of factors influencing the survival of laryngeal cancer patients.

Estimating and explaining the effect of education and income on head and neck cancer risk: INHANCE consortium pooled analysis of 31 case-control studies from 27 countries

Low socioeconomic status has been reported to be associated with head and neck cancer risk. However, previous studies have been too small to examine the associations by cancer subsite, age, sex, global region and calendar time and to explain the association in terms of behavioral risk factors. Individual participant data of 23,964 cases with head and neck cancer and 31,954 controls from 31 studies in 27 countries pooled with random effects models. Overall, low education was associated with an increased risk of head and neck cancer (OR = 2.50; 95% CI = 2.02 – 3.09). Overall one‐third of the increased risk was not explained by differences in the distribution of cigarette smoking and alcohol behaviors; and it remained elevated among never users of tobacco and nondrinkers (OR = 1.61; 95% CI = 1.13 – 2.31). More of the estimated education effect was not explained by cigarette smoking and alcohol behaviors: in women than in men, in older than younger groups, in the oropharynx than in other sites, in South/Central America than in Europe/North America and was strongest in countries with greater income inequality. Similar findings were observed for the estimated effect of low versus high household income. The lowest levels of income and educational attainment were associated with more than 2‐fold increased risk of head and neck cancer, which is not entirely explained by differences in the distributions of behavioral risk factors for these cancers and which varies across cancer sites, sexes, countries and country income inequality levels.

Estimating and explaining the effect of education and income on head and neck cancer risk

Low socioeconomic status has been reported to be associated with head and neck cancer risk. However, previous studies have been too small to examine the associations by cancer subsite, age, sex, global region and calendar time and to explain the association in terms of behavioral risk factors. Individual participant data of 23,964 cases with head and neck cancer and 31,954 controls from 31 studies in 27 countries pooled with random effects models. Overall, low education was associated with an increased risk of head and neck cancer (OR = 2.50; 95% CI = 2.02 – 3.09). Overall one‐third of the increased risk was not explained by differences in the distribution of cigarette smoking and alcohol behaviors; and it remained elevated among never users of tobacco and nondrinkers (OR = 1.61; 95% CI = 1.13 – 2.31). More of the estimated education effect was not explained by cigarette smoking and alcohol behaviors: in women than in men, in older than younger groups, in the oropharynx than in other sites, in South/Central America than in Europe/North America and was strongest in countries with greater income inequality. Similar findings were observed for the estimated effect of low versus high household income. The lowest levels of income and educational attainment were associated with more than 2‐fold increased risk of head and neck cancer, which is not entirely explained by differences in the distributions of behavioral risk factors for these cancers and which varies across cancer sites, sexes, countries and country income inequality levels.

Reduced poly(ADP‐ribosyl)ation in lymphocytes of laryngeal cancer patients: Results of a case‐control study

Poly(ADP‐ribose) polymerase (PARP), a nuclear enzyme that is catalytically activated by DNA strand breaks, plays a complex role in DNA repair. Using NAD+ as a precursor, it catalyzes the formation of ADP‐ribose polymers, which are attached to various proteins. Defects in DNA repair pathways have been associated with increased risks for cancer in humans. We investigated whether differences in the activity of PARP are associated with the risk for laryngeal cancer. In a case‐control study on genetic, lifestyle and occupational risk factors for laryngeal cancer, PARP activity was assessed as DNA damage–induced poly(ADP‐ribose) formation in human peripheral blood lymphocytes by quantitative immunofluorescence analysis. Polymer formation was determined as the cellular response to bleomycin, a well‐known inducer of DNA strand breaks, in lymphocytes from 69 laryngeal cancer patients and 125 healthy controls. The frequency of bleomycin‐induced polymer formation, measured as mean pixel intensity, was significantly lower in cases (74.6, SE = 3.7) than in controls (94.5, SE = 3.5) and not influenced by smoking, age or sex. There was no significant difference between cases (59.1, SE = 5.2) and controls (50.5, SE = 3.7) in basal polymer formation (in cells not treated with bleomycin). When the highest tertile of polymer formation was used as the reference, the odds ratio for the lowest tertile of bleomycin‐induced polymer formation was 3.79 (95% confidence interval 1.37–10.47, p = 0.01). Peripheral blood lymphocytes from laryngeal cancer patients thus showed significantly less bleomycin‐induced poly(ADP‐ribose) formation. Our results suggest that a reduced capacity of somatic cells to synthesize poly(ADP‐ribose) might be associated with an increased risk for laryngeal cancer. The underlying mechanism remains to be investigated.

Virological Failure and Drug Resistance in Patients on Antiretroviral Therapy after Treatment Interruption in Lilongwe, Malawi

BACKGROUND Since 2004, Malawi has rapidly scaled up access to antiretroviral therapy (ART) in the national program following a public health approach with limited laboratory monitoring. We examined virological outcomes in patients with treatment interruption at 2 clinics of the Lighthouse Trust, Lilongwe, Malawi. METHODS We evaluated patients who resumed first-line ART after having at least 1 treatment interruption documented in the electronic data system in 2008-2009. Viral load (VL) was analyzed at least 2 months after resumption of ART. For VL ≥1000 copies/mL, drug-resistance genotype was characterized using the Stanford database. RESULTS Between June and November 2009, we enrolled 133 patients (58.7% female) with a mean age of 38.4 years. Mean duration of ART prior to treatment interruption was 14.3 months. After a minimum of 2 months following ART resumption, VL was undetectable in 81 (60.9%) patients, was 400-1000 copies/mL in 12 (9.0%) patients, and was ≥1000 copies/mL in 40 (30.1%) patients. Genotyping and drug-resistance testing were successfully performed for 36 of 40 patients, all carrying human immunodeficiency virus type 1 subtype C. Relevant mutations affecting nonnucleoside reverse transcriptase inhibitors were found in 32 of 133 (24.1%) patients and combined with relevant nucleoside reverse transcriptase mutations in 27 of 133 (20.3%) patients. CONCLUSIONS Virological failure combined with drug resistance after resumption of first-line ART occurred in 24.1% of the patients with treatment interruption, requiring a switch to protease inhibitor-based second-line therapy. Patients with treatment interruption should receive VL assessment after resumption of ART to detect treatment failure and to reduce development and spread of drug resistance.

Hospitalizations during the last months of life of nursing home residents: a retrospective cohort study from Germany

BackgroundTo describe hospitalisations of nursing home (NH) residents in Germany during their last months of life.MethodsRetrospective cohort study on 792 NH residents in the Rhine-Neckar region in South-West Germany, newly institutionalized in the year 2000, who died until the study end (December 2001). Baseline variables were derived from a standardized medical examination routinely conducted by the medical service of the health care insurance plans in Germany. Information on hospitalisations and deaths was extracted form records of the pertinent health insurance plans.ResultsNH residents who died after NH stay of more than 1 year spent 5.8% of their last year of life in hospitals. Relative time spent in hospitals increased from 5.2% twelve months before death (N = 139 persons) to 24.1% in their last week of life (N = 769 persons). No major differences could be observed concerning age, gender or duration of stay in NH. Overall, 229 persons (28.9%) died in hospital. Among these, the last hospital stay lasted less than 3 days for 76 persons (31.9%). Another 25 persons (3.2%) died within three days after hospital discharge.ConclusionOur study indicates that proximity of death is the most important driver of health care utilization among NH residents. The relation of age or gender to health care expenditures seem to be weak once time to death is controlled for. Duration of NH stay does not markedly change rates of hospitalisation during the last months of life.

Factors predicting survival after diagnosis of laryngeal cancer

Survival in patients with laryngeal cancer has not increased remarkably within the last years. It is presumed that a variety of factors act jointly in predicting survival after diagnosis: tumour stage, tumour site, treatment approaches, age and comorbidities. The aim of this German clinical multi-centre study is to present results from multivariate analysis. A retrospective cohort study was conducted in four hospitals in South-West Germany. Incident cases with laryngeal squamous cell carcinoma were included for the years 1998 to 2004, resulting in a population sample of 594 patients. Multivariate regression analysis was performed using the Cox proportional hazards model. Patients were followed up for 64.1months on average. Overall 5-year survival was 66% (95% confidence interval (CI): 62-70%). The strongest risk factors in multivariate analysis were age at first diagnosis (hazard ratio (HR): 1.5; 95% CI: 1.5-1.7 per each additional 10years), tumour stage, and the development of recurrences (HR 3.1; 95% CI: 2.3-4.2) or second primary carcinomas (HR 2.1; 95% CI: 1.4-3.1). A somewhat weaker effect was shown for patients with comorbidities (using Charlsons comorbidity index). The choice of treatment did not strongly affect survival when adjusting for other factors, possibly because the optimal treatment approach was applied for the specific constitution and requirements of each patient. For future research it would be desirable to study the effect of treatment on quality of life in multivariate analysis as well as other modifiable risk factors as smoking and drinking reduction or cessation after diagnosis.

The INHANCE consortium: toward a better understanding of the causes and mechanisms of head and neck cancer

The International Head and Neck Cancer Epidemiology (INHANCE) consortium is a collaboration of research groups leading large epidemiology studies to improve the understanding of the causes and mechanisms of head and neck cancer. The consortium includes investigators of 35 studies who have pooled their data on 25 500 patients with head and neck cancer (i.e., cancers of the oral cavity, oropharynx, hypopharynx, and larynx) and 37 100 controls. The INHANCE analyses have confirmed that tobacco use and alcohol intake are key risk factors of these diseases and have provided precise estimates of risk and dose response, the benefit of quitting, and the hazard of smoking even a few cigarettes per day. Other risk factors include short height, lean body mass, low education and income, and a family history of head and neck cancer. Risk factors are generally similar for oral cavity, pharynx, and larynx, although the magnitude of risk may vary. Some major strengths of pooling data across studies include more precise estimates of risk and the ability to control for potentially confounding factors and to examine factors that may interact with each other. The INHANCE consortium provides evidence of the scientific productivity and discoveries that can be obtained from data pooling projects.