Rare cancers of unknown etiology: lessons learned from a European multi-center case-control study.

Rare cancers together constitute one fourth of cancers. As some rare cancers are caused by occupational exposures, a systematic search for further associations might contribute to future prevention. We undertook a European, multi-center case-control study of occupational risks for cancers of small intestine, bone sarcoma, uveal melanoma, mycosis fungoides, thymus, male biliary tract and breast. Incident cases aged 35-69 years and sex-and age-matched population/colon cancer controls were interviewed, including a complete list of jobs. Associations between occupational exposure and cancer were assessed with unconditional logistic regression controlled for sex, age, country, and known confounders, and reported as odds ratios (OR) with 95% confidence intervals (CI). Interviewed were 1053 cases, 2062 population, and 1084 colon cancer controls. Male biliary tract cancer was associated with exposure to oils with polychlorinated biphenyls; OR 2.8 (95% CI 1.3-5.9); male breast cancer with exposure to trichloroethylene; OR 1.9 (95% CI 1.1-3.3); bone sarcoma with job as a carpenter/joiner; OR 4.3 (95% CI 1.7-10.5); and uveal melanoma with job as a welder/sheet metal worker; OR 1.95 (95% CI 1.08-3.52); and cook; OR 2.4 (95% CI 1.4-4.3). A confirmatory study of printers enhanced suspicion of 1,2-dichloropropane as a risk for biliary tract cancer. Results contributed to evidence for classification of welding and 1,2-dichloropronane as human carcinogens. However, despite efforts across nine countries, for some cancer sites only about 100 cases were interviewed. The Rare Cancer Study illustrated both the strengths and limitations of explorative studies for identification of etiological leads.

BRCA1 gene-related hereditary susceptibility to breast and ovarian cancer in Latvia.

PURPOSE: In this report, we summarise data on BRCA1 gene analysis in Latvia to characterise criteria of genetic testing for breast and ovarian cancer susceptibility. MATERIAL/METHODS: Analysis by SSCP/HD, MALDI-TOF mass spectrometry or DNA sequencing was used for mutation detection. Mutations identified were confirmed by direct DNA sequencing. RESULTS: Out of 1068 breast and 231 ovarian cancer patients from different families: 58 carried the c.5266dupC and 43 carried the c.4035delA mutations. Every 4th patient in our study did not report cancer in the family. The breast cancer was diagnosed earlier in carriers of the c.5266dupC than in carriers of the c.4035delA (p=0.003). The incidence of breast or ovarian cancer does not differ among the 2 mutation carriers in our patient group. The nature of the c.5266dupC mutation might be more deleterious. CONCLUSIONS: We recommend the screening of 4 founder BRCA1 mutations in all breast and ovarian cancer patients in Latvia at diagnosis of disease regardless of family history or age. The BRCA1 screening can be carried out efficiently using the MALDI-TOF mass spectrometry mutation detection method developed in the Biomedical Research and Study Centre (Riga, Latvia).

Site-specific cancer risk in the Baltic cohort of Chernobyl cleanup workers, 1986-2007.

OBJECTIVE: To assess site-specific cancer risk in the Baltic cohort of Chernobyl cleanup workers, 1986-2007. METHODS: The Baltic cohort includes 17,040 men from Estonia, Latvia and Lithuania who participated in the environmental cleanup after the accident at the Chernobyl Nuclear Power Station in 1986-1991 and who were followed up for cancer incidence until the end of 2007. Cancer cases diagnosed in the cohort and in the male population of each country were identified from the respective national cancer registers. The proportional incidence ratio (PIR) with 95% confidence interval (CI) was used to estimate the site-specific cancer risk in the cohort. For comparison and as it was possible, the site-specific standardised incidence ratio (SIR) was calculated for the Estonian sub-cohort, which was not feasible for the other countries. RESULTS: Overall, 756 cancer cases were reported during 1986-2007. A higher proportion of thyroid cancers in relation to the male population was found (PIR=2.76; 95%CI 1.63-4.36), especially among those who started their mission shortly after the accident, in April-May 1986 (PIR=6.38; 95%CI 2.34-13.89). Also, an excess of oesophageal cancers was noted (PIR=1.52; 95% CI 1.06-2.11). No increased PIRs for leukaemia or radiation-related cancer sites combined were observed. PIRs and SIRs for the Estonian sub-cohort demonstrated the same site-specific cancer risk pattern. CONCLUSION: Consistent evidence of an increase in radiation-related cancers in the Baltic cohort was not observed with the possible exception of thyroid cancer, where conclusions are hampered by known medical examination including thyroid screening among cleanup workers.

Risk of thyroid cancer among chernobyl liquidators.

After the Chernobyl accident in 1986, the "liquidators" or clean-up workers were among those who received the highest radiation doses to the thyroid from external radiation. Some were also exposed to radioiodines through inhalation or ingestion. A collaborative case-control study nested within cohorts of Belarusian, Russian and Baltic liquidators was conducted to evaluate the radiation-induced risk of thyroid cancer. The study included 107 cases and 423 controls. Individual doses to the thyroid from external radiation and from iodine-131 ((131)I) were estimated for each subject. Most subjects received low doses (median 69 mGy). A statistically significant dose-response relationship was found with total thyroid dose. The Excess Relative Risk (ERR) per 100 mGy was 0.38 [95% confidence interval (CI): 0.10, 1.09]. The risk estimates were similar when doses from (131)I and external radiation were considered separately, although for external radiation the ERR was not statistically significantly elevated. The ERR was similar for micro carcinomas and larger size tumors, and for tumors with and without lymph node involvement. Although recall bias and uncertainties in doses could have affected the magnitude of the risk estimates, the findings of this study contribute to a better characterization the risk of thyroid cancer after radiation exposure in adulthood.

Pesticide exposure in farming and forestry and the risk of uveal melanoma.

PURPOSE: Since pesticides are disputed risk factors for uveal melanoma, we studied the association between occupational pesticide exposure and uveal melanoma risk in a case-control study from nine European countries. METHODS: Incident cases of uveal melanoma and population as well as hospital controls were included and frequency-matched by country, 5-year age groups and sex. Self-reported exposure was quantified with respect to duration of exposure and pesticide application method. We calculated the exposure intensity level based on application method and use of personal protective equipment. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated by unconditional logistic regression analyses and adjusted for several potential confounders. RESULTS: 293 case and 3,198 control subjects were interviewed. We did not identify positive associations with activities in farming or forestry, pesticide application or pesticide mixing. No consistent positive associations were seen with exposure intensity level scores either. The only statistically significantly raised association in this study was for exposure to chemical fertilizers in forestry (OR = 8.93; 95% CI 1.73-42.13), but this observation was based on only six exposed subjects. Results did not change when we restricted analyses to morphologically verified cases and excluded proxy interviews as well as cancer controls. We did not observe effect modification by sex or eye color. CONCLUSIONS: Risk estimates for pesticide exposures and occupational activities in agriculture and forestry were not increased and did not indicate a hormonal mechanism due to these exposures.

Occupational exposure to endocrine-disrupting chemicals and the risk of uveal melanoma.

OBJECTIVES: We investigated the association between occupational exposure to endocrine-disrupting chemicals (EDC) and the risk of uveal melanoma using international data of a case-control study from nine European countries. METHODS: After exclusion of proxy interviews, 280 cases and 3084 control subjects were included in the final analysis. Information on possible exposure to EDC was derived from 27 job-specific questionnaires (JSQ), which solicited detailed questions on occupational tasks. Relative risk estimates were based on the JSQ and potential exposure to a group of endocrine-disrupting agents. We constructed several exposure scores, taking into account intensity of exposure, use of personal protective equipment, and exposure duration. We calculated unconditional logistic regression analyses, adjusting for country, age, sex, eye color and a history of ocular damage due to intense ultraviolet (UV) exposure. RESULTS: The overall exposure prevalence to EDC was low reaching a maximum of 11% for heavy metals with endocrine-disrupting properties. Although working in some industries was associated with increased melanoma risk [such as dry cleaning: odds ratio (OR) 6.15, 95% confidence interval (95% CI) 2.0-18.96 and working in the glass manufacturing industry: OR 3.49, 95% CI 1.10-11.10], agent-specific risks were not elevated. The strongest possible risk increase was observed for organic solvents with endocrine-disrupting properties (OR 1.31, 95% CI 0.78-2.21). Calculation of exposure scores did not indicate consistently elevated results with higher score values. Sensitivity analyses did not alter these results. CONCLUSION: Occupational exposure to EDC was not associated with an increased risk for uveal melanoma.

Sperm-associated antigens as targets for cancer immunotherapy: expression pattern and humoral immune response in cancer patients.

The identification of novel cancer-related and immunogenic proteins is still a challenge to be faced to improve antigen-specific tumor immunotherapy. The category of so-called cancer-testis (CT) antigens is one of the most perspective groups of proteins for anticancer immune response activation as normally they are expressed in immunoprivileged tissues and are immunogenic if aberrantly generated in tumors. The heterogeneous group of proteins called sperm-associated antigens (SPAG) might encompass novel CT antigens owing to their common expression in male germ cells, their ability to elicit immune response underlying infertility, and lately proposed oncogenic properties. We carried out a comprehensive analysis of the expression pattern in various normal and cancerous tissues and assessed the frequency of spontaneous humoral immune response against members of the SPAG group in cancer patients using phage-displayed antigen microarrays. Our results show that out of 15 analyzed SPAG genes only SPAG1, SPAG6, SPAG8, SPAG15, and SPAG17 are predominantly expressed in testis, whereas the others are ubiquitously expressed with only a testis-associated alternative splice variant of SPAG16. mRNA expression of SPAG1, SPAG6, and alternative splice variants of SPAG8, SPAG16, and SPAG17 was elevated in various tumors with frequencies ranging from approximately 10% to 70%. The upregulation of SPAG6 in lung and breast cancer was confirmed by immunohistochemical analysis of tumor and normal tissue microarrays. Cancer-associated spontaneous humoral immune response was detected against SPAG1, SPAG6, SPAG8, and a novel testis-specific splice variant of SPAG17 and ascribe these as novel CT antigens that potentially are applicable as immunotherapeutic targets and serologic biomarkers.

Trends in cervical cancer incidence and mortality in the Baltic countries, Bulgaria and Romania.

The burden of cervical cancer varies considerably in the European Union (EU). In this article, we describe trends in incidence of and mortality from this cancer in the two most affected areas: the Baltic countries (Estonia, Latvia and Lithuania) and Southeast Europe (Bulgaria and Romania). Incidence data were obtained from the national cancer registries. Data on population and number of deaths from uterine cancers were extracted from the World Health Organization mortality database. Mortality rates were corrected for inaccuracies in the death certification of not otherwise specified uterine cancer. Joinpoint regression was used to study the annual variation of corrected and standardized incidence and mortality rates. Changes were assessed by calendar period and age group, whereas the evolution by birth cohort was synthesized by computing standardized cohort incidence/mortality ratios. Joinpoint regression revealed rising trends of incidence (in Lithuania, Bulgaria and Romania) and of mortality (in Latvia, Lithuania, Bulgaria and Romania). In Estonia, rates were rather stable. Women born between 1940 and 1960 were at continuously increasing risk of both incidence of and mortality from cervical cancer. Although some quality issues in the registration of cancer and causes of death cannot be ignored, the trends indicate increased exposure to human papillomavirus infection and absence of effective screening programs. Rising trends of cervical cancer in the most affected EU member states reveal a worrying pattern that warrants urgent preventive actions.

Trends in cervical cancer incidence and mortality in Bulgaria, Estonia, Latvia, Lithuania and Romania.

OBJECTIVE: The burden of cervical cancer varies considerably in the European Union. In this paper, we describe trends in incidence of and mortality from this cancer in the five most affected member states. METHODS: Data on number of deaths from uterine cancers and the size of the female population of Estonia, Latvia, Lithuania, Bulgaria and Romania were extracted from the WHO mortality database. Mortality rates were corrected for inaccuracies in the death certification of not otherwise specified uterine cancer. Incidence data were obtained from the national cancer registries. Joinpoint regression was used to study the annual variation of corrected and standardized incidence and mortality rates. Changes by birth cohort were assessed for specific age groups and subsequently synthesized by computing standardized cohort incidence/mortality ratios. RESULTS: Joinpoint regression revealed rising trends of incidence (in Lithuania, Bulgaria and Romania) and of mortality (in Latvia, Lithuania, Bulgaria and Romania). In Estonia, rates were rather stable. Women born between 1940 and 1960 were at continuously increasing risk of both incidence of and mortality from cervical cancer. CONCLUSIONS: Rising trends of cervical cancer in the most affected EU member states reveal a worrying pattern that warrants urgent introduction of effective preventive actions as described in the European guidelines.

Occupational exposure to electromagnetic fields and sex-differential risk of uveal melanoma.

OBJECTIVES: The association between occupational exposure to electromagnetic fields (EMF) and the risk of uveal melanoma was investigated in a case-control study in nine European countries. METHODS: Incident cases of uveal melanoma and population as well as hospital controls were included and frequency matched by country, 5-year birth cohort and sex. Subjects were asked whether they had worked close to high-voltage electrical transmission installations, computer screens and various electrical machines, or in complex electrical environments. Measurements of two Scandinavian job-exposure matrices were applied to estimate lifelong cumulative EMF exposure. Unconditional logistic regression analyses, stratified by sex and eye colour were calculated, adjusting for several potential confounders. RESULTS: 293 patients with uveal melanoma and 3198 control subjects were interviewed. Women exposed to electrical transmission installations showed elevated risks (OR 5.81, 95% CI 1.72 to 19.66). Positive associations with exposure to control rooms were seen among men and women, but most risk increases were restricted to subjects with dark iris colour. Application of published EMF measurements revealed stronger risk increases among women compared to men. Again, elevated risks were restricted to subjects with dark eye colour. CONCLUSION: Although based on a low prevalence of exposure to potential occupational sources of EMF, our data indicate that exposed dark-eyed women may be at particular risk for uveal melanoma.

Hormonal exposures and the risk of uveal melanoma.

OBJECTIVES: Several studies suggest that hormonal mechanisms may be associated with the development of uveal melanoma. Therefore, the association between the risk of uveal melanoma and exposure to hormonal exposures was investigated in a case-control study from nine European countries. METHODS: Incident cases of uveal melanoma were frequency-matched to population and hospital controls by country, age, and sex. Female subjects were asked about their reproductive history, use of menopausal hormone replacement therapy and oral contraceptives. Among men, occupational handling of oils while working with transformers or capacitors which contain polychlorinated biphenyls (PCB) was solicited. Unconditional logistic regression analyses were calculated, adjusting for several potential confounders. Analyses were stratified by sex. RESULTS: Two hundred and ninety-three cases (165 men, 128 women) and 3,198 control subjects (2,121 men, 1,077 women) were interviewed. Among women, no associations were observed with hormonal status variables, intake of hormonal therapy or intake of oral contraceptives. Men showed an increased risk with occupational exposure to transformer/capacitor oils (OR = 2.74; Bonferroni-corrected 99.3% CI 1.07-7.02). However, these results were based on few exposed subjects only. CONCLUSION: The results of this study do not support the hypothesis of a hormonal influence in the carcinogenesis of uveal melanoma. Our finding of a potentially increased risk with PCB-containing oils requires further research.

Risk of hematological malignancies among Chernobyl liquidators.

A case-control study of hematological malignancies was conducted among Chernobyl liquidators (accident recovery workers) from Belarus, Russia and Baltic countries to assess the effect of low- to medium-dose protracted radiation exposures on the relative risk of these diseases. The study was nested within cohorts of liquidators who had worked around the Chernobyl plant in 1986-1987. A total of 117 cases [69 leukemia, 34 non-Hodgkin lymphoma (NHL) and 14 other malignancies of lymphoid and hematopoietic tissue] and 481 matched controls were included in the study. Individual dose to the bone marrow and uncertainties were estimated for each subject. The main analyses were restricted to 70 cases (40 leukemia, 20 NHL and 10 other) and their 287 matched controls with reliable information on work in the Chernobyl area. Most subjects received very low doses (median 13 mGy). For all diagnoses combined, a significantly elevated OR was seen at doses of 200 mGy and above. The excess relative risk (ERR) per 100 mGy was 0.60 [90% confidence interval (CI) -0.02, 2.35]. The corresponding estimate for leukemia excluding chronic lymphoid leukemia (CLL) was 0.50 (90% CI -0.38, 5.7). It is slightly higher than but statistically compatible with those estimated from A-bomb survivors and recent low-dose-rate studies. Although sensitivity analyses showed generally similar results, we cannot rule out the possibility that biases and uncertainties could have led to over- or underestimation of the risk in this study.

Cancer risk among Chernobyl cleanup workers in Estonia and Latvia, 1986-1998.

Two cohorts of Chernobyl cleanup workers from Estonia (4,786 men) and Latvia (5,546 men) were followed from 1986 to 1998 to investigate cancer incidence among persons exposed to ionizing radiation from the Chernobyl accident. Each cohort was identified from various independent sources and followed using nationwide population and mortality registries. Cancers were ascertained by linkage with nationwide cancer registries. Overall, 75 incident cancers were identified in the Estonian cohort and 80 in the Latvian cohort. The combined-cohort standardized incidence ratio (SIR) for all cancers was 1.15 (95% confidence interval (CI) = 0.98-1.34) and for leukemia, 1.53 (95% CI = 0.62-3.17; n = 7). Statistically significant excess cases of thyroid (SIR = 7.06, 95% CI = 2.84-14.55; n = 7) and brain cancer (SIR = 2.14, 95% CI = 1.07-3.83; n = 11) were found, mainly based on Latvian data. However, there was no evidence of a dose response for any of these sites, and the relationship to radiation exposure remains to be established. Excess of thyroid cancer cases observed may have been due to screening, the leukemia cases included 2 unconfirmed diagnoses, and the excess cases of brain tumors may have been a chance finding. There was an indication of increased risk associated with early entry to the Chernobyl area and late follow-up, though not statistically significant. Further follow-up of Chernobyl cleanup workers is warranted to clarify the possible health effects of radiation exposure.

Occupational risks for uveal melanoma results from a case-control study in nine European countries.

OBJECTIVE: Uveal melanoma is a rare disease with poor prognosis and largely unknown etiology. We studied potential occupational risk factors. METHODS: A population based case-control study was undertaken during 1995-1997 in nine European countries using population and colon cancer controls with personal interviews. Occupational exposure to sunlight and artificial UV radiation was assessed with a job exposure matrix. In total, 320 uveal melanoma cases were eligible at pathology review, and 292 cases were interviewed, participation 91%. Out of 3357 population controls, 2062 were interviewed, 61%, and out of 1272 cancer controls 1094 were interviewed, 86%. RESULTS: Using population controls, occupational exposure to sunlight was not associated with an increased risk (RR=1.24, 95% CI=0.88-1.74), while an excess risk found with use of colon cancer controls was attributed to confounding factors. An excess risk in welders was restricted to the French part of the data. Cooks, RR=2.40; cleaners, RR 2.15; and laundry workers, RR=3.14, were at increased risk of uveal melanoma. CONCLUSION: Our study does overall not support an association between occupational sunlight exposure and risk of uveal melanoma. The finding of an excess risk of eye melanoma in cooks in several European countries is intriguing.

High prevalence of two BRCA1 mutations, 4154delA and 5382insC, in Latvia.

Our aim was to characterise the germline BRCA1 mutation profile in Latvian breast cancer and ovarian cancer patients, to develop an effective BRCA1 gene mutation detection strategy, and to document genotype-phenotype correlations in mutation carriers. The entire BRCA1 gene was analysed in 75 breast cancer and 30 ovarian cancer patients. Screening for three mutations (5382insC, 4154delA and 300T>G) was carried out in 55 breast cancer and 66 ovarian cancer patients, and for two mutations, 5382insC and 4154delA, in 376 unselected patients with any cancer (including 51 breast cancer and 29 ovarian cancers) and 215 women with any gynaecological tumour. Mutation detection techniques used were SSCP/HD analysis or F-SSCP (ABI PRISM 310). Five different deleterious mutations were detected by analysis of the entire BRCA1 gene. The proportion of cases with mutations amongst 50 breast cancer patients diagnosed before 48 years was 26.0% (95% CI: 14.6-40.3%). Two mutations (5382insC and 4154delA) made up more than 80% of all mutations identified by the analysis of the entire BRCA1 gene in Latvia, at present. Further screening for only the prevalent mutations in different cancer patient groups resulted in the identification of 53 more mutation carriers. We conclude that breast cancer diagnosed before the age of 48 years and ovarian cancer before 65 years are criteria for DNA testing to be offered to women in Latvia, regardless of cancer history in the family. The observed associations of specific prevalent mutations with cancer site and age at onset of disease are discussed.

European multi-centre case-control study on risk factors for rare cancers of unknown aetiology.

To search for occupational risk factors, we conducted a case-control study in nine European countries of cancers of the small intestine, male gall bladder, thymus, bone, male breast, melanoma of the eye, and mycosis fungoides. Recruitment was population based in Denmark, Latvia, France, Germany, Italy, and Sweden, from hospital areas in Spain and Portugal, and from one United Kingdom (UK) hospital. We recruited 1457 cases (84% interviewed). Numbers identified corresponded to those in the EUROCIM database for Denmark, but were below those observed for France, Italy and Sweden in the database. We recruited 3374 population (61% interviewed) and 1284 colon cancer controls (86% interviewed). It was possible to undertake this complicated study across Europe, but we encountered three main problems. It was difficult to ensure complete case ascertainment, for population controls, we found a clear divide in the response rate from 75% in the South to only 55% in the North, and a somewhat selective recruitment was noted for the colon cancer controls. The study showed there is a clear dose-response relationship between alcohol intake and the risk of male breast cancer, and an excess risk of mycosis fungoides among glass formers, pottery and ceramic workers. Further data are expected.

Testicular cancer incidence in eight northern European countries: secular and recent trends.

OBJECTIVE: Striking geographic variation and marked increasing secular trends characterize the incidence of testicular cancer. However, it is not known whether these patterns have attenuated in recent years and whether they are similar for seminomas and nonseminomas, the two main histologic groups of testicular cancer. METHOD: Cancer registry data, including 27,030 testicular cancer cases, were obtained from Denmark, Estonia, Finland, Latvia, Lithuania, Norway, Poland, and Sweden. Between 57 (Denmark) and 9 (Poland) years of registration were covered. Country-specific temporal trends were estimated, with focus on the last decade and seminomas and nonseminomas. Data from the Nordic countries were further analyzed using an age-period-cohort approach. RESULTS: Age-standardized incidence rates increased annually by 2.6% to 4.9% during the study period, with marginal differences between seminomas and nonseminomas. In the last decade, the increasing trend attenuated only in Denmark (annual change, -0.3%; 95% confidence interval, -1.5 to 0.9). In 1995, the highest and the lowest age-standardized incidence rates (per 10(5)) were 15.2 in Denmark and 2.1 in Lithuania. Incidence rates (i.e., for all cancers and for seminomas and nonseminomas, separately) depended chiefly on birth cohort rather than on calendar period of diagnosis (although both birth cohort and period determined the Danish incidence rates). CONCLUSIONS: Testicular cancer incidence is still increasing, with the exception of Denmark, and a large geographic difference exists. The increasing trend is mainly a birth cohort phenomenon also in recent cohorts. Temporal trends for seminomas and nonseminomas are similar, which suggests that they share important causal factors.

Breast cancer mortality patterns and time trends in 10 new EU member states: mortality declining in young women, but still increasing in the elderly.

Breast cancer is the cancer diagnosed most frequently in women worldwide. In Europe it is the most common cancer in the female population, with approximately 350,000 new cases diagnosed each year including 130,000 deaths. Incidence rates are increasing in the majority of European countries, whereas a decline in mortality rates has been observed in many West European countries since the late 1980s and early 1990s. Our study examines breast cancer mortality patterns and time trends in the new European Union (EU) member states and compares them with the situation in current EU member states. A Joinpoint regression analysis was used to assess temporal changes in mortality rates and the trends examined in the light of known risk factors, screening programs and advances in treatment. In the majority of the countries analyzed, a deceleration in the increase of mortality rates appeared, followed by a decrease of mortality in many of them in the second half of the 1990s. The declining tendency was visible primarily in young women, and to a lesser extent in middle-aged women, whereas in elderly women a continuing increase of mortality was observed. Analysis of mortality data, information from previous publications, as well as analysis of known factors influencing breast cancer risk suggest that changes observed are due mainly to recent advances in treatment rather than changes in lifestyle risk factors or the result of screening programs. Early detection and a shift toward more favorable stage distribution could have played the leading role for mortality decline in younger patients.

Lung cancer mortality patterns in selected Central, Eastern and Southern European countries.

Significant changes in the prevalence of tobacco smoking have been observed in many European countries. EU candidate countries have also experienced major changes with respect to tobacco smoking, which have resulted in changes in the frequency of lung cancer. In men in the majority of these countries, a reduction of mortality rates has been observed recently, while in Hungary and Poland a deceleration of mortality increase was observed in the 1990s. The situation is much less favorable in females, where in the majority of countries a continuous increase of mortality rates has been observed, the only exceptions being Latvia, Lithuania and, to a lesser extent, Estonia. In Hungarian women, an acceleration of the increase rate was observed in the 1980s and 1990s (compared with the 1970s). Patterns of lung cancer mortality in analyzed countries are somewhat similar to those observed in EU member states. Recent analyses of time trends of lung cancer in EU countries showed, in general, a decreasing risk in the majority of male populations and an increase in several countries in women. If the decrease of mortality is to be achieved and maintained in the longer term, efforts have to be focused on young generations (entering adulthood now or in the near future). Despite all the difficulties present in reducing tobacco smoking in youth, it seems that one of the most important ways to reduce the future lung cancer burden in current and new EU member states is to strengthen efforts toward changing smoking attitudes in young generations.

Randomized trial with fruits and vegetables in prevention of cancer.

Along with tobacco use, diet has the greatest impact on the development of human cancer. Within the broad category 'diet', the consumption of fruits and vegetables apparently plays a dominant role. Considerable efforts have been made to prove the preventive effect of different kinds of fruits and vegetables but randomized chemoprevention trials have failed to prove this presumed effectiveness of their single ingredients. The conclusive demonstration of a cancer-protective effect of a high consumption of fruits and vegetables is considered to be impractical. However, current historical changes in Europe offer a unique opportunity to conduct such a randomized trial in specific European countries. This study describes the nutritional situation and the conditions of the health system in the Baltic countries as appropriate geographic areas and demonstrates some basic design issues of the trial for three variants of outcome assumptions. A realistic assumption would be that a trial needs about 30000 participants, an intervention period of 10 years and a subsequent follow-up time of 20 years. Annual costs could range between dollars 5 and dollars 10 million. A high intake of fruits and vegetables should be proven scientifically as a valid tool for cancer prevention. For a comparably short period the Baltic countries offer a time-window for a randomized trial. It is unlikely that the costs of such a trial would considerably exceed the costs of the available chemoprevention trials.