ESMO Expert Consensus Statements on Cancer Survivorship: promoting high-quality survivorship care and research in Europe.

BACKGROUND: The increased number of cancer survivors and the recognition of physical and psychosocial challenges, present from cancer diagnosis through active treatment and beyond, led to the discipline of cancer survivorship. DESIGN AND METHODS: Herein, we reflected on the different components of survivorship care, existing models and priorities, in order to facilitate the promotion of high-quality European survivorship care and research. RESULTS: We identified five main components of survivorship care: (i) physical effects of cancer and chronic medical conditions; (ii) psychological effects of cancer; (iii) social, work and financial effects of cancer; (iv) surveillance for recurrences and second cancers; and (v) cancer prevention and overall health and well-being promotion. Survivorship care can be delivered by structured care models including but not limited to shared models integrating primary care and oncology services. The choice of the care model to be implemented has to be adapted to local realities. High-quality care should be expedited by the generation of: (i) focused and shared European recommendations, (ii) creation of tools to facilitate implementation of coordinated care and (iii) survivorship educational programs for health care teams and patients. The research agenda should be defined with the participation of health care providers, researchers, policy makers, patients and caregivers. The following patient-centered survivorship research areas were highlighted: (i) generation of a big data platform to collect long-term real-world data in survivors and healthy controls to (a) understand the resources, needs and preferences of patients with cancer, and (b) understand biological determinants of survivorship issues, and (ii) develop innovative effective interventions focused on the main components of survivorship care. CONCLUSIONS: The European Society for Medical Oncology (ESMO) can actively contribute in the efforts of the oncology community toward (a) promoting the development of high-quality survivorship care programs, (b) providing educational material and (c) aiding groundbreaking research by reflecting on priorities and by supporting research networking.

Rationale and design of the CRAFT (Continuous ReAssessment with Flexible ExTension in Rare Malignancies) multicenter phase II trial.

BACKGROUND: Approvals of cancer therapeutics are primarily disease entity specific. Current molecular diagnostic approaches frequently identify actionable alterations in rare cancers or rare subtypes of common cancers for which the corresponding treatments are not approved and unavailable within clinical trials due to entity-related eligibility criteria. Access may be negotiated with health insurances. However, approval rates vary, and critical information required for a scientific evaluation of treatment-associated risks and benefits is not systematically collected. Thus clinical trials with optimized patient selection and comprehensive molecular characterization are essential for translating experimental treatments into standard care. PATIENTS AND METHODS: Continuous ReAssessment with Flexible ExTension in Rare Malignancies (CRAFT) is an open-label phase II trial for adults with pretreated, locally advanced, or metastatic solid tumors. Based on the evaluation by a molecular tumor board, patients are assigned to combinations of six molecularly targeted agents and a programmed death-ligand 1 (PD-L1) antagonist within seven study arms focusing on (i) BRAF V600 mutations; (ii) ERBB2 amplification and/or overexpression, activating ERBB2 mutations; (iii) ALK rearrangements, activating ALK mutations; (iv and v) activating PIK3CA and AKT mutations, other aberrations predicting increased PI3K-AKT pathway activity; (vi) aberrations predicting increased RAF-MEK-ERK pathway activity; (vii) high tumor mutational burden and other alterations predicting sensitivity to PD-L1 inhibition. The primary endpoint is the disease control rate (DCR) at week 16; secondary and exploratory endpoints include the progression-free survival ratio, overall survival, and patient-reported outcomes. Using Simon's optimal two-stage design, 14 patients are accrued for each study arm. If three or fewer patients achieve disease control, the study arm is stopped. Otherwise, 11 additional patients are accrued. If the DCR exceeds 7 of 25 patients, the null hypothesis is rejected for the respective study arm. CONCLUSIONS: CRAFT was activated in October 2021 and will recruit at 10 centers in Germany. TRIAL REGISTRATION NUMBERS: EudraCT: 2019-003192-18; ClinicalTrials.gov: NCT04551521.

Different endurance exercises modulate NK cell cytotoxic and inhibiting receptors.

PURPOSE: Induction of IDO depends on the activation of AhR forming the AhR/IDO axis. Activated AhR can transcribe various target genes including cytotoxic and inhibiting receptors of NK cells. We investigated whether AhR and IDO levels as well as activating (NKG2D) and inhibiting (KIR2DL1) NK cell receptors are influenced by acute exercise and different chronic endurance exercise programs. METHODS: 21 adult breast and prostate cancer patients of the TOP study (NCT02883699) were randomized to intervention programs of 12 weeks of (1) endurance standard training or (2) endurance polarized training after a cardiopulmonary exercise test (CPET). Serum was collected pre-CPET, immediately post-CPET, 1 h post-CPET and after 12 weeks post-intervention. Flow cytometry analysis was performed on autologous serum incubated NK-92 cells for: AhR, IDO, KIR2DL1 and NKG2D. Differences were investigated using analysis-of-variance for acute and analysis-of-covariance for chronic effects. RESULTS: Acute exercise: IDO levels changed over time with a significant increase from post-CPET to 1 h post-CPET (p = 0.03). KIR2DL1 levels significantly decreased over time (p < 0.01). NKG2D levels remained constant (p = 0.31). Chronic exercise: for both IDO and NKG2D a significant group × time interaction, a significant time effect and a significant difference after 12 weeks of intervention were observed (IDO: all p < 0.01, NKG2D: all p > 0.05). CONCLUSION: Both acute and chronic endurance training may regulate NK cell function via the AhR/IDO axis. This is clinically relevant, as exercise emerges to be a key player in immune regulation.

Effects and moderators of exercise on sleep in adults with cancer: Individual patient data and aggregated meta-analyses.

OBJECTIVES: To evaluate the effects of exercise interventions on sleep disturbances and sleep quality in patients with mixed cancer diagnoses, and identify demographic, clinical, and intervention-related moderators of these effects. METHODS: Individual patient data (IPD) and aggregated meta-analyses of randomized controlled trials (RCTs). Using data from the Predicting OptimaL cAncer RehabIlitation and Supportive care project, IPD of 2173 adults (mean age = 54.8) with cancer from 17 RCTs were analyzed. A complementary systematic search was conducted (until November 2018) to study the overall effects and test the representativeness of analyzed IPD. Effect sizes of exercise effects on self-reported sleep outcomes were calculated for all included RCTs. Linear mixed-effect models were used to evaluate the effects of exercise on post-intervention outcome values, adjusting for baseline values. Moderator effects were studied by testing interactions for demographic, clinical and intervention-related characteristics. RESULTS: For all 27 eligible RCTs from the updated search, exercise interventions significantly decreased sleep disturbances in adults with cancer (g = -0.09, 95% CI [-0.16; -0.02]). No significant effect was obtained for sleep quality. RCTs included in IPD analyses constituted a representative sample of the published literature. The intervention effects on sleep disturbances were not significantly moderated by any demographic, clinical, or intervention-related factor, nor by sleep disturbances. CONCLUSIONS: This meta-analysis provides some evidence that, compared to control conditions, exercise interventions may improve sleep disturbances, but not sleep quality, in cancer patients, although this effect is of a small magnitude. Among the investigated variables, none was found to significantly moderate the effect of exercise interventions on sleep disturbances.

Effects of 12-week resistance training during radiotherapy in breast cancer patients.

Exercise is considered to be an effective supportive treatment approach in breast cancer (BC) patients. We conducted a randomized controlled trial to assess the efficacy of a 12-week PRT during radiotherapy. Strength performance was assessed by maximal isokinetic peak torque (MIPT) in two different angular velocities (60°/s and 180°/s) and maximal voluntary isometric contraction for shoulder external and internal rotation, as well as for knee extension and flexion were assessed pre- and post-intervention in 146 patients randomized to PRT or a control group. Statistical analyses were based on analysis of covariance models for the individual changes from baseline to week 13. Intention-to-treat analyses showed significant between-group differences favoring the exercise group (EX) for MIPT in knee flexion and shoulder internal and external rotation (P < 0.05). Subgroup analyses showed borderline significant differences with regard to pretreatment history, revealing that pretreated chemotherapy patients tend to benefit more from PRT than patients without chemotherapy (P = 0.06). Strength gain at the operated arm was significantly higher than at the non-operated arm in EX. PRT was efficacious in increasing upper and lower limb strength in BC patients undergoing adjuvant radiotherapy. Patients with restrictions due to breast cancer-related surgery and pretreated with chemotherapy might benefit the most.

Randomized, controlled trial of resistance training in breast cancer patients receiving adjuvant radiotherapy: results on cancer-related fatigue and quality of life.

BACKGROUND: Exercise has been reported to decrease cancer-related fatigue and to increase quality of life (QoL) in various breast cancer (BC) populations. However, studies investigating exercise during radiotherapy or resistance training are scarce. We conducted a randomized, controlled trial (BEST study) to assess the efficacy of 12-week resistance training on fatigue beyond possible psychosocial effects of a group-based intervention. PATIENTS AND METHODS: One hundred sixty patients with BC stage 0-III were randomly assigned to a 12-week progressive resistance training (2 times/week) or a 12-week relaxation control (RC, 2 times/week). Both interventions were group-based. The primary end point fatigue was assessed with a 20-item multidimensional questionnaire, QoL with EORTC questionnaires. Statistical analyses were based on analysis of covariance models for the individual changes from baseline to week 13. RESULTS: Adherence to the intervention program as well as the completion rate (97%) for the primary outcome variable fatigue was high. In intention-to-treat analyses for the N = 155 patients, significant between-group mean differences (MD) favoring the exercise group (EX) were observed for general fatigue (P = 0.044), especially for the subscale physical fatigue [MD = -0.8; 95% confidence interval -1.5 to -0.2, P = 0.013], but not for affective (P = 0.91) or cognitive fatigue (P = 0.65). For QoL, significantly larger improvements regarding the role function (P = 0.035) and pain (P = 0.040) were noted among exercisers compared with RCs. Future perspective improved significantly stronger in the RC group compared with the EX group (P = 0.047). CONCLUSIONS: The 12-week resistance training program was a safe, feasible and efficacious strategy to improve cancer-related fatigue and components of QoL in BC patients during adjuvant radiotherapy. As exercise was compared with another group-based intervention, results indicate that resistance training effects on fatigue and QoL go beyond psychosocial benefits, and that the clinically relevant overall benefit of resistance exercise compared with usual care can be assumed to be higher. TRIAL REGISTRATION: ClinicalTrials.gov NCT01468766.

[Physiologic and molecular mechanisms linking physical activity to cancer risk and progression]. / Physiologische und molekulare Mechanismen der Wirkung von körperlicher Aktivität auf das Krebsrisiko und den Verlauf einer Krebserkrankung.

Physical activity is associated with a reduced risk of colon, breast, endometrial, lung, and pancreatic cancer. Evidence for mediating molecular mechanisms from experimental studies substantially strengthens the causal inference for this relationship. Randomized controlled trials indicate that exercise affects metabolic profiles, including hormone levels (estrogen, insulin signaling), inflammation (e.g., C-reactive protein), and adipokine concentrations (e.g., leptin). The size of the effect depends frequently on concurrent changes in body composition. There is also initial evidence for effects on immune function, oxidative stress, and possibly DNA repair capacity. Finally, outdoor physical activity can directly increase 25(OH)-vitamin D levels, providing another potential mechanism for linking physical activity to cancer risk. Randomized controlled studies with biomarker measurements are essential to increase evidence for causality and to identify the most effective intervention strategies and pharmacologic targets.

[Effects of physical activity on cancer risk and disease progression after cancer diagnosis]. / Welche Effekte hat körperliche Bewegung auf das Krebsrisiko und auf den Krankheitsverlauf nach einer Krebsdiagnose?

Numerous epidemiologic studies have demonstrated that regular physical activity convincingly reduces risk for colon cancer, probably for endometrium and postmenopausal breast cancer, and possibly for premenopausal breast, prostate, lung, and pancreas cancer. Relative risk reductions range from 10-30%. On the absolute scale about 9-19% of the most frequent cancers can be attributed to a lack of sufficient physical activity. Thus, exercise, as a modifiable health behavior, has a strong potential for primary cancer prevention. Current recommendations call for at least 30-60 min of moderate to vigorous activity daily. Physical activity is also increasingly gaining importance in cancer treatment and is now considered to be feasible, safe, and even recommended in almost all stages of disease. Randomized-controlled trials show that disease- and treatment-related symptoms, such as fatigue, sleep disorders, and depression which sometimes limit quality of life in cancer patients over years, can be reduced by physical activity. For disease-specific and total mortality, clinical studies are not yet available. However, preliminary observational studies with breast, colon, and prostate cancer patients show risk reductions.

Statistical methods for the validation of questionnaires--discrepancy between theory and practice.

OBJECTIVES: Questionnaires used in epidemiological studies should be validated. However, unclarity exists about the appropriate statistical methods and interpretation of validation studies. Thus, we investigated the theory and practice of statistical evaluation approaches. METHODS: Using three platforms, a literature review, own simulations, and a validation study performed by ourselves, we worked out relevant limitations, advantages, and new important aspects of evaluation methods. RESULTS: Our systematic literature review, based on physical activity questionnaires, revealed that correlation coefficients are still the common approach in validation studies, found in 41 of 46 reviewed publications (89.1%). This practice has been criticized in the theoretically oriented literature for more than 20 years. Appropriate evaluation methods as recommended by Bland and Altman were found in only ten publications (21.7%). We showed that serious bias in questionnaires can be revealed by Bland-Altman plots but may remain undetected by correlation coefficients. With our simulations we refuted the argument that correlation coefficients properly investigate whether a questionnaire ranks the subjects sufficiently well. Further, with Bland-Altman analyses we could evaluate differential errors with respect to case-control status in our validation study. Yet, this was not possible with correlation coefficients, because they generally do not identify systematic bias. In addition, we show a potential pitfall in the interpretation of Bland-Altman plots that might occur in specific rare instances. CONCLUSIONS: The commonly used correlation approach can yield misleading conclusions in validation studies. A more frequent and proper use of the Bland-Altman methods would be desirable to improve epidemiological data quality.

Lack of association of herpesviruses with brain tumors.

Gliomas are the most frequent primary brain tumors in humans. Many studies have been carried out on their etiology; however, the only confirmed risk factors are hereditary predisposing conditions and high dose of ionizing radiation. Recently, human cytomegalovirus (HCMV) gene products and nucleic acids were reported to be present in all of 27 glioma samples investigated in contrast to other brain tissues, and it was hypothesized that HCMV might play a role in glioma pathogenesis. To evaluate these findings, samples of 40 gliomas, 31 meningiomas, and 6 acoustic neurinomas (ACNs) were analyzed for the presence of HCMV macromolecules using polymerase chain reaction (PCR) and immunohistochemistry. Additionally, corresponding blood samples from 72 patients were analyzed for the presence of HCMV DNA to check for a possible contamination of tumor tissues with HCMV-infected blood cells. No HCMV DNA sequences were found, neither in brain tumor tissues nor in corresponding blood samples. Immunohistochemistry did not detect HCMV-specific proteins. Addressing a possible role of other herpesviruses as has been suggested in seroepidemiological studies, seroprevalence of antibodies to HCMV, herpes simplex virus (HSV), Epstein-Barr virus (EBV), and varicella-zoster virus (VZV) were determined by enzyme-linked immunosorbent assay (ELISA). Serological analyses of brain tumor patients showed no significant differences in the prevalences of antibodies to HCMV, HSV, EBV, or VZV compared to the general population. Thus, the data of the present study do not support the hypothesis of an association of herpesviruses with the development of primary brain tumors.

Case-control study of lifetime occupational and recreational physical activity and risks of colon and rectal cancer.

Important aspects of the inverse relation between physical activity and colon cancer risk are still under discussion. In 2000-2003, 239 incident cases of colorectal cancer confirmed by histopathology and 239 hospital-based controls, matched by age and gender, were enrolled. In standardized interviews, data on occupational and recreational physical activity for ages 20, 30, 40, 50 and 60 years were collected from 98 colon cancer cases, 141 rectal cancer cases, and from 193 controls. Besides lifestyle and sociodemographic characteristics, a detailed food frequency questionnaire was assessed. In multivariate logistic regression for colon cancer, significant risk reductions for the highest quartile of total physical activity were found for almost all ages. For lifetime mean physical activity, the multivariate odds ratio for the highest quartile was 0.37 [95% confidence interval (CI) 0.17, 0.83]. For lifelong constantly high-exercisers compared with lifelong non-exercisers an odds ratio of 0.26 (95% CI 0.08, 0.84) was estimated. For rectal cancer, no consistent association with physical activity was found. No confounding effects were observed but the authors found effect modification with total energy intake. These data support an inverse association of colon cancer risk and physical activity which is most expressed if activity is kept up throughout life.

Risk of colorectal cancer from alcohol consumption at lower vitamin intakes. A hospital-based case-control study in Poland.

The purpose of the study was to assess the relation between the simultaneous exposure to alcohol and consumption of micronutrients that have protective properties against colorectal cancer. A hospital-based case-control study of colorectal cancer was carried out between January 1998 and November 1999 at the University Hospital in Krakow, Poland. In total, 180 incident cases of colorectal cancer, confirmed by histopathology, were recruited and an equal number of controls, individually matched by gender and age (+/-5 y), were chosen amongst patients with no history of cancer. A food-frequency questionnaire for 148 food items, combined with the quantity of foods eaten, was used to assess the normal dietary pattern. The data confirmed the reported inverse association between the intake of retinol, thiamine, or antioxidant micronutrients (vitamins C, E) and the occurrence of colorectal cancer. Alcohol intake was found to be an important risk factor for this cancer site, and the risk escalated in parallel with increased intake of retinol, carotene, vitamins C and E, but with high consumption of alcohol ran a noticeably high risk of colorectal cancer (OR= 6.79; 95% CI: 2.08-22.18). The risk was markedly lower, however, among alcohol drinkers who reported a high intake of micronutrients (OR = 1.35; 95% CI: 0.39-4.67). The data suggest that a combination of high consumption of alcohol and low intake of retinol and antioxidant vitamins may considerably increase the risk of colorectal cancer.

Nutrient intake patterns in gastric and colorectal cancers.

The purpose of the study was to present the dietary risk pattern in gastric and colorectal cancers, using the same methodological approach in a parallel hospital-based case-control study. In all, 180 cases of colorectal cancer and 80 cases of stomach cancer, confirmed histopathologically, were enrolled from the University Hospital in Cracow. A high intake of carbohydrates was associated with an increased risk of colorectal cancer (OR = 2.45). For stomach cancer, a moderate consumption of carbohydrates markedly increased relative risk (OR = 4.29), while a high intake of carbohydrates increased the risk by 8.73. The patterns of dietary risk factors related to intake of fats were definitively different in both cancer sites. The higher fat consumption was not associated with the higher risk of stomach cancer. A medium intake of fats increased the risk of colorectal cancer by 1.96 and that above 83 g/day by 2.20. In colorectal cancer, the significant protective effect of retinol, carotene and vitamin C has been evidenced, however, only carotene and vitamin E were inversely correlated with stomach cancer.

Combined risk assessment of physical activity and dietary habits on the development of colorectal cancer. A hospital-based case-control study in Poland.

The purpose of the study was to assess the importance of physical activity performed both in occupational settings and in leisure time on the risk of colorectal cancer, considering the possible confounding effects of dietary habits. The hospital-based case-control study was carried out in Poland. In total, 180 incident cases of colorectal cancer were recruited. An equal number of controls, individually matched by gender and age, were chosen from patients with no history of cancer. A food frequency questionnaire combined with quantity of foods eaten was used to assess the usual dietary pattern for 148 food items. The average physical load of the interviewed patients before the occurrence of disease was ascertained by self-assessment. The degree to which patients' recreational time was sedentary was measured by the number of hours spent watching TV. The adjusted risk of colorectal cancer was reduced by half in those active in leisure time (OR 0.45, 95% CI 0.24-0.84). The effect of occupational physical activity was of about the same order of magnitude in terms of risk reduction (OR 0.61, 95% CI 0.29-1.29) and both activities combined acted as independent protective factors. The protective effect of healthy nutrition appeared to be independent from that attributed to physical effort.

Previous infection and other risk factors for acute cerebrovascular ischaemia: attributable risks and the characterisation of high risk groups.

BACKGROUND: Recent reports indicated that previous infection may be a risk factor for ischaemic stroke in younger adults and that the increased mortality of cerebrovascular diseases in winter months may be partly caused by the increased rate of infection during the cold season. METHODS: We performed a 1:1 matched case-control study with 197 cases (83 females, 114 males) aged between 22 and 80 years (median age 65 years) to investigate risk factors for acute cerebrovascular ischaemia, in particular the effect of previous infection. We estimated the impact of risk factors in terms of attributable and absolute risks. RESULTS: All risk factors together, previous infection, hypertension, diabetes mellitus, smoking, coronary heart disease, previous stroke or transient ischaemic attack and family history of stroke yield a summary attributable risk of 0.74 [95% confidence intervals (CI) 0.64-0.83]. Recent infections showed a relative risk of 4.3 (95% CI 1.8-10.5) and an attributable risk of 0.15 (95% CI 0.09-0.21). Seventeen percent of the German population are estimated to be in a high-risk group. This subgroup contributes about 55% of the estimated yearly 120,000 incident cases in the age group 55-84 in Germany. DISCUSSION: Identification of high-risk groups for stroke on the basis of individual risk factor distribution and the estimation of its size is possible and may produce useful results. Reducing the prevalence of infection and early treatment of bacterial infection may lower the incidence of stroke.

Wegener's granulomatosis associated with renal cell carcinoma.

OBJECTIVE: To determine the frequencies and types of malignant neoplasms occurring before or simultaneously with the diagnosis of Wegener's granulomatosis (WG), and to test for the presence of "Wegener's autoantigen," proteinase 3 (PR3), in malignant tissues from WG patients to ascertain whether an association exists between malignancy and WG. METHODS: A retrospective statistical analysis was performed on the medical records of 477 patients with WG as compared with a control group of 479 patients with rheumatoid arthritis (RA). A murine monoclonal antibody was used to test malignant tissues for the presence of PR3. RESULTS: A malignant neoplasm was found in 23 patients in the WG group and in 18 patients in the control group. The odds ratio for malignant neoplasm in the WG group was 1.79 (P = 0.0876, 95% confidence interval [95% CI] 0.92-3.48). Seven patients with renal cell carcinoma were found in the WG group compared with 1 patient in the control group, for an odds ratio of 8.73 (P = 0.0464, 95% CI 1.04-73.69). Simultaneous occurrence of cancer and WG was observed in 14 patients with WG compared with 1 control patient, for an odds ratio of 18.00 (P = 0.0059, 95% CI 230-140.67). Furthermore, the diseases occurred simultaneously in 5 of the 7 patients with both WG and renal cell carcinoma, but not in the single patient in the control group with RA and renal cell carcinoma. PR3 could not be detected in any of the 8 malignant tissue samples (4 renal cell carcinomas) investigated in the patients from the WG group. CONCLUSION: The close temporal association between renal cell carcinoma and WG suggests that malignancy is, in some cases, a trigger for the development of WG. However, since PR3 was not found in malignant tissues from the WG patients, the immunopathologic mechanisms leading to autoimmunity and vasculitis remain unclear.

Quantitative cancer risk assessment for dioxins using an occupational cohort.

We consider a cohort of 1189 male German factory workers (production period 1952-1984) who produced phenoxy herbicides and were exposed to dioxins. Follow-up until the end of 1992 yielded a significantly increased standardized mortality ratio (SMR) for total cancer (SMR 141; 95% confidence interval 117-168). 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) concentrations up to 2252 ng/kg body fat were measured in 275 cohort members. Other higher chlorinated dioxins and furans also occurred in high concentrations. For quantitative analysis, the integrated TCDD concentration over time was used as an exposure variable, which was calculated using results from half-life estimation for TCDD and workplace history data. The other congeners were expressed as toxic equivalency (TEQ) and compared to TCDD using international toxic equivalency factors. Poisson and Cox regressions were used to investigate dose-response relationships. Various covariables (e.g., exposure to beta-hexachlorocyclohexane, employment characteristics) were considered. In all analyses, TCDD and TEQ exposures were related to total cancer mortality. The power model yielded a relative risk (RR) function RR(x) = (1 + 0.17x)0.326 for TCDD (in microgram/kilogram blood fat x years)--only a slightly better fit than a linear RR function--and RR(x) = (1 + 0.023x)0.795 for TEQ. Investigations on latency did not show strong effects. Different methods were applied to investigate the robustness of the results and yielded almost identical results. The results were used for unit risk estimation. Taking into account different sources of variation, an interval of 10(-3) to 10(-2) for the additional lifetime cancer risk under a daily intake of 1 pg TCDD/kg body weight/day was estimated from the dose-response models considered. Uncertainties regarding the dose-response function remain. These data did not indicate the existence of a threshold value; however, such a value cannot be excluded with any certainty.

Estimation of the cumulated exposure to polychlorinated dibenzo-p-dioxins/furans and standardized mortality ratio analysis of cancer mortality by dose in an occupationally exposed cohort.

For a cohort of 1189 male German former herbicide and insecticide workers with exposure to polychlorinated dibenzo-p-dioxins and -furans (PCDD/F), we report an extended standardized mortality ratio (SMR) analysis based on a new quantitative exposure index. This index characterizes the cumulative lifetime exposure by integrating the estimated concentration of PCDD/F at every point in time (area under the curve). Production department-specific dose rates were derived from blood levels and working histories of 275 workers by applying a first-order kinetic model. These dose rates were used to estimate exposure levels for all cohort members. Total mortality was elevated in the cohort; 413 deaths yielded an SMR of 1.15 (95% confidence interval [Cl] 1.05, 1.27) compared to the mortality of the population of Germany. Overall cancer mortality (n = 124) was significantly increased (SMR = 1.41, 95% Cl 1.17, 1.68). Various cancer sites showed significantly increased SMRs. The exposure index was used for an SMR analysis of total cancer mortality by dose. For 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) a significant trend (p = 0.01) for the SMRs with increasing cumulative PCDD/F exposure was observed. The SMR in the first exposure quartile (0-125.2 ng/kg x years) was 1.24 (95% Cl 0.82, 1.79), increasing to 1.73 (95% Cl 1.21, 2.40) in the last quartile (> or = 2503.0 ng/kg x years). For all congeners combined as toxic equivalencies (TEQ) using international toxic equivalency factors, a significant increase in cancer mortality was observed in the second quartile (360.9-1614.4 ng/kg x years, SMR 1.64; 95% Cl 1.13, 2.29) and the fourth quartile (> or = 5217.7 ng/kg x years TEQ, SMR 1.64, 95% Cl 1.13, 2.29). The trend test was not significant. The results justify the use of this cohort for a quantitative risk assessment for TCDD and to a lesser extent for TEQ.

A topographic analysis of atrophic gastritis and stomach cancer risk. A clinicoepidemiological study in Poland.

The purpose of this cross-sectional study was to assess the relation between intestinal and diffuse stomach cancer at its various locations with topography of atrophic gastritis. The study population consisted of 3435 patients who reported over the period of 1991-1994 for the first time to gastroenterological outpatient clinics of 7 university medical centers in Poland. Among these subjects there were 131 histologically proved consecutive cases of gastric carcinoma. The reference group consisted of 1540 patients among whom endoscopic examination did not reveal peptic ulcers, polyps, deformations of antrum or bulbus duodenum and mucosa erosions. Gastroscopy on gastric cancer patients and the reference group was performed and biopsy specimens were obtained from the tumour and from the antrum and stomach corpus distant from the tumour. Among the gastric cancer cases there was a higher prevalence of atrophic gastritis in the intestinal than in the diffuse type. The highest prevalence of atrophic gastritis irrespective of its degree and stomach area was observed in the tumour-area of intestinal cancer located distally (78.9%), and the lowest in the tumour-free area in diffuse proximal cancer (18.5%). Prevalence of atrophic pangastritis (atrophic gastritis present both in the corpus and antrum) was also highest in intestinal distal cancer (69.2%) and lowest in diffuse proximal cancer (21.7%). The age-adjusted correlation coefficients between gastritis score in the tumour-area and tumour-free area were highly significant. It was shown that only atrophic pangastritis was significantly associated with gastric cancer irrespective of its histology and location (OR = 3.8, 95% CI:2.4-6.0), however, it was much stronger related to the intestinal gastric cancer (OR = 5.9, 95% CI: 3.1-11.0), than to the diffuse carcinoma (OR = 2.2, 95% CI: 1.1-4.3).

Cancer mortality in German male workers exposed to phenoxy herbicides and dioxins.

In an occupational cohort study, the relation between exposure to phenoxy herbicides, and contaminants (dioxins and furans) and cancer mortality was investigated. A total of 2,479 workers from four plants in Germany were included, with a mortality follow-up until the end of 1989 (for one cohort, until the end of 1992). A total of 484 deaths were recorded yielding a standardized mortality ratio (SMR) of 101 (95 percent confidence interval [CI] = 92-111) for total mortality, and an SMR of 119 (CI = 100-141) for all malignant diseases. A variety of herbicides was produced, including those which are known to have been contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). High dioxin and furan exposure (in particular, exposure to TCDD, but also to higher chlorinated dioxins) had occurred in two of the four plants as shown by blood-fat measurements in a sample of workers. Mortality from all neoplasms increased with latency and was highest in the largest plant where the highest TCDD blood levels were recorded. An increased mortality in the total cohort from respiratory cancer (SMR = 154, CI = 115-202), cancer of the buccal cavity and pharynx (SMR = 295, CI = 135-560), and non-Hodgkin's lymphoma (SMR = 326, CI = 119-710) was observed. Our findings are consistent with results from other cohorts which showed an increased overall cancer mortality and mortality of respiratory cancer after long-term exposure to these phenoxy herbicides and dioxins.