Decreasing incidence of cancer after liver transplantation-A Nordic population-based study over 3 decades.

Cancer remains one of the most serious long-term complications after liver transplantation (LT). Data for all adult LT patients between 1982 and 2013 were extracted from the Nordic Liver Transplant Registry. Through linkage with respective national cancer-registry data, we calculated standardized incidence ratios (SIRs) based on country, sex, calendar time, and age-specific incidence rates. Altogether 461 cancers were observed in 424 individuals of the 4246 LT patients during a mean 6.6-year follow-up. The overall SIR was 2.22 (95% confidence interval [CI], 2.02-2.43). SIRs were especially increased for colorectal cancer in recipients with primary sclerosing cholangitis (4.04) and for lung cancer in recipients with alcoholic liver disease (4.96). A decrease in the SIR for cancers occurring within 10 years post-LT was observed from the 1980s: 4.53 (95%CI, 2.47-7.60), the 1990s: 3.17 (95%CI, 2.70-3.71), to the 2000s: 1.76 (95%CI, 1.51-2.05). This was observed across age- and indication-groups. The sequential decrease for the SIR of non-Hodgkin lymphoma was 25.0-12.9-7.53, and for nonmelanoma skin cancer 80.0-29.7-10.4. Cancer risk after LT was found to be decreasing over time, especially for those cancers that are strongly associated with immunosuppression. Whether immunosuppression minimization contributed to this decrease merits further study.

The role of initial clinical presentation, comorbidity and treatment in multiple myeloma patients on survival: a detailed population-based cohort study.

PURPOSE: This prospective, observational population-based cohort study was performed to determine overall survival (OS) in multiple myeloma (MM) patients in Friesland, the Netherlands, in the era of novel agents and to analyse the influence of first-line treatment, MM-related end-organ damage and comorbidities at initial presentation on OS. METHODS: Detailed clinical information was obtained from the population-based registry 'HemoBase' during the period January 2005 to January 2013, with a follow-up to January 2014. RESULTS: Overall, the symptomatic MM patients (n = 225) had a median OS of 40 months. In the age categories <65, 65-75 and ≥75 years, 99, 94 and 87% of the patients received treatment, with a median OS of 92, 42 and 31 months, respectively. OS for patients with or without treatment was 43 and 3 months, respectively. In multivariable analysis, risk factors for worse OS were increasing age (<65: reference; 65-75: HRadj. = 2.2 (95% CI 1.3-3.7) and ≥75: HRadj. = 2.8 (95% CI 1.7-4.8); P < 0.001), not receiving initial treatment (HRadj. = 4.0 (95% CI 2.1-7.7); P < 0.001), hypercalcaemia (P < 0.001, HRadj. = 1.7 (95% CI 1.2-2.6), P = 0.006) and impaired renal function (HRadj. = 2.6 (95% CI 1.7-4.0); P < 0.001). CONCLUSIONS: Increasing age, not receiving initial treatment, hypercalcaemia and impaired renal function at initial presentation were independent risk factors for worse OS. Comorbidity according to Charlson comorbidity index score was not an independent variable predicting OS.

Increased stomach cancer risk following radiotherapy for testicular cancer.

BACKGROUND: Abdominal radiotherapy for testicular cancer (TC) increases risk for second stomach cancer, although data on the radiation dose-response relationship are sparse. METHODS: In a cohort of 22,269 5-year TC survivors diagnosed during 1959-1987, doses to stomach subsites were estimated for 92 patients who developed stomach cancer and 180 matched controls. Chemotherapy details were recorded. Odds ratios (ORs) were estimated using logistic regression. RESULTS: Cumulative incidence of second primary stomach cancer was 1.45% at 30 years after TC diagnosis. The TC survivors who received radiotherapy (87 (95%) cases, 151 (84%) controls) had a 5.9-fold (95% confidence interval (CI) 1.7-20.7) increased risk of stomach cancer. Risk increased with increasing stomach dose (P-trend<0.001), with an OR of 20.5 (3.7-114.3) for ⩾50.0 Gy compared with <10 Gy. Radiation-related risks remained elevated ⩾20 years after exposure (P<0.001). Risk after any chemotherapy was not elevated (OR=1.1; 95% CI 0.5-2.5; 14 cases and 23 controls). CONCLUSIONS: Radiotherapy for TC involving parts of the stomach increased gastric cancer risk for several decades, with the highest risks after stomach doses of ⩾30 Gy. Clinicians should be aware of these excesses when previously irradiated TC survivors present with gastrointestinal symptoms and when any radiotherapy is considered in newly diagnosed TC patients.

Pancreatic cancer risk after treatment of Hodgkin lymphoma.

BACKGROUND: Although elevated risks of pancreatic cancer have been observed in long-term survivors of Hodgkin lymphoma (HL), no prior study has assessed the risk of second pancreatic cancer in relation to radiation dose and specific chemotherapeutic agents. PATIENTS AND METHODS: We conducted an international case-control study within a cohort of 19 882 HL survivors diagnosed from 1953 to 2003 including 36 cases and 70 matched controls. RESULTS: Median ages at HL and pancreatic cancer diagnoses were 47 and 60.5 years, respectively; median time to pancreatic cancer was 19 years. Pancreatic cancer risk increased with increasing radiation dose to the pancreatic tumor location (Ptrend = 0.005) and increasing number of alkylating agent (AA)-containing cycles of chemotherapy (Ptrend = 0.008). The odds ratio (OR) for patients treated with both subdiaphragmatic radiation (≥10 Gy) and ≥6 AA-containing chemotherapy cycles (13 cases, 6 controls) compared with patients with neither treatment was 17.9 (95% confidence interval 3.5-158). The joint effect of these two treatments was significantly greater than additive (P = 0.041) and nonsignificantly greater than multiplicative (P = 0.29). Especially high risks were observed among patients receiving ≥8400 mg/m(2) of procarbazine with nitrogen mustard or ≥3900 mg/m(2) of cyclophosphamide. CONCLUSION: Our study demonstrates for the first time that both radiotherapy and chemotherapy substantially increase pancreatic cancer risks among HL survivors treated in the past. These findings extend the range of nonhematologic cancers associated with chemotherapy and add to the evidence that the combination of radiotherapy and chemotherapy can lead to especially large risks.

Cancer prevalence in United States, Nordic Countries, Italy, Australia, and France: an analysis of geographic variability.

BACKGROUND: The objectives of this study were to quantitatively assess the geographic heterogeneity of cancer prevalence in selected Western Countries and to explore the associations between its determinants. METHODS: For 20 cancer sites, 5-year cancer prevalence, incidence, and survival were observed and age standardised for the mid 2000s in the United States, Nordic European Countries, Italy, Australia, and France. RESULTS: In Italy, 5-year crude prevalence for all cancers was 1.9% in men and 1.7% in women, while it was ∼1.5% in all other countries and sexes. After adjustment for the different age distribution of the populations, cancer prevalence in the United States was higher (20% in men and 10% in women) than elsewhere. For all cancers combined, the geographic heterogeneities were limited, though relevant for specific cancers (e.g., prostate, showing >30% higher prevalence in the United States, or lung, showing >50% higher prevalence in USA women than in other countries). For all countries, the correlations between differences of prevalence and differences of incidence were >0.9, while prevalence and survival were less consistently correlated. CONCLUSION: Geographic differences and magnitude of crude cancer prevalence were more strongly associated with incidence rates, influenced by population ageing, than with survival rates. These estimates will be helpful in allocating appropriate resources.

Nociceptive stimuli responses at different levels of general anaesthesia and genetic variability.

BACKGROUND: Changes in skin conductance (SC), clinical stress score (CSS), the bispectral index spectroscopy (BIS) index and the variation in the BIS index may be used to monitor responses to nociceptive stimuli. We wanted to examine these methods during noxious stimulation during general anaesthesia and if the responses were associated with variability in genes related to pain. METHODS: Sixty patients, given propofol to a BIS level of 40-50, were stimulated with standardised tetanic electrical stimuli during propofol infusion, plasma level of 3 µg/ml alone, or together with remifentanil target plasma level of 3 ng/ml or 10 ng/ml. The CSS, SC, BIS index and the variability of the BIS index were registered. The inter-individual variation in nociceptive responses was analysed for co-variation with genotypes of 89 single nucleotide polymorphisms from 23 candidate genes. RESULTS: During tetanic stimuli, CSS and SC increased significantly and were attenuated with increasing level of remifentanil, different from the BIS index and the variation in the BIS index. Polymorphisms in the P-glycoprotein (ABCB1), tachykinin 1 receptor (TACR1), dopamine receptor D3 (DRD3) and beta arrestin 2 (ARRB2) genes were associated with the co-variation in SC variables or CSS response or both during standardised nociceptive stimuli (P < 0.05). Because of no corrections for multiple testing, the genetic analyses are explorative, and associations must be tested in further studies. CONCLUSION: This exploratory study suggests genes that may be tested further with relation to nociceptive response during anaesthesia. SC and CSS may be useful tools for monitoring nociceptive response during general anaesthesia.

Risk of treatment-related esophageal cancer among breast cancer survivors.

BACKGROUND: Radiotherapy for breast cancer may expose the esophagus to ionizing radiation, but no study has evaluated esophageal cancer risk after breast cancer associated with radiation dose or systemic therapy use. DESIGN: Nested case-control study of esophageal cancer among 289 748 ≥5-year survivors of female breast cancer from five population-based cancer registries (252 cases, 488 individually matched controls), with individualized radiation dosimetry and information abstracted from medical records. RESULTS: The largest contributors to esophageal radiation exposure were supraclavicular and internal mammary chain treatments. Esophageal cancer risk increased with increasing radiation dose to the esophageal tumor location (P(trend )< 0.001), with doses of ≥35 Gy associated with an odds ratio (OR) of 8.3 [95% confidence interval (CI) 2.7-28]. Patients with hormonal therapy ≤5 years preceding esophageal cancer diagnosis had lower risk (OR = 0.4, 95% CI 0.2-0.8). Based on few cases, alkylating agent chemotherapy did not appear to affect risk. Our data were consistent with a multiplicative effect of radiation and other esophageal cancer risk factors (e.g. smoking). CONCLUSIONS: Esophageal cancer is a radiation dose-related complication of radiotherapy for breast cancer, but absolute risk is low. At higher esophageal doses, the risk warrants consideration in radiotherapy risk assessment and long-term follow-up.

Diagnostic work-up and systemic treatment for advanced non-squamous non-small-cell lung cancer in four Southeast Asian countries.

BACKGROUND: Lung cancer is the second most common cancer and leading cause of cancer mortality worldwide. Recent advances in molecular testing and targeted therapy have improved survival among patients with metastatic non-small-cell lung cancer (NSCLC). We sought to quantify and describe molecular testing among metastatic non-squamous NSCLC cases in selected Southeast Asian countries and describe first-line therapy chosen. PATIENTS AND METHODS: A retrospective study was conducted based on incident lung cancer cases diagnosed between 2017 and 2019 in Lampang (Thailand), Penang (Malaysia), Singapore and Yogyakarta (Indonesia). Cases (n = 3413) were defined using the International Classification of Diseases for Oncology third edition. In Singapore, a clinical series obtained from the National Cancer Centre was used to identify patients, while corresponding population-based cancer registries were used elsewhere. Tumor and clinical information were abstracted by chart review according to a predefined study protocol. Molecular testing of epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK) gene rearrangement, ROS1 gene rearrangement and BRAF V600 mutation was recorded. RESULTS: Among 2962 cases with a specified pathological diagnosis (86.8%), most patients had non-squamous NSCLC (75.8%). For cases with staging information (92.1%), the majority presented with metastatic disease (71.3%). Overall, molecular testing rates in the 1528 patients with stage IV non-squamous NSCLC were 67.0% for EGFR, 42.3% for ALK, 39.1% for ROS1, 7.8% for BRAF and 36.1% for PD-L1. Among these patients, first-line systemic treatment included chemotherapy (25.9%), targeted therapy (35.6%) and immunotherapy (5.9%), with 31% of patients having no record of antitumor treatment. Molecular testing and the proportion of patients receiving treatment were highly heterogenous between the regions. CONCLUSIONS: This first analysis of data from a clinically annotated registry for lung cancer from four settings in Southeast Asia has demonstrated the feasibility of integrating clinical data within population-based cancer registries. Our study results identify areas where further development could improve patient access to optimal treatment.

Risk of second cancers after the diagnosis of Merkel cell carcinoma in Scandinavia.

BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive neuroendocrine tumour of the skin that has been associated with a new tumour virus, the MCC polyomavirus. METHODS: To investigate whether MCC may have a shared aetiology with other cancers, we investigated the risk of second cancers after the diagnosis of MCC using the national cancer registries in Denmark, Norway and Sweden. RESULTS: The overall cancer incidence was increased among patients diagnosed with MCC compared with the general population in these countries (79 secondary cancers total, Standardized Incidence Ratio (SIR) 1.38 (95% confidence interval (CI): 1.10-1.72); 49 secondary cancer in females, SIR 1.7 (95% CI: 1.29-2.25); 30 secondary cancers in males and SIR 1.05 (95% CI: 0.73-1.5)). There were significantly increased incidence ratios for non-melanoma skin cancers (34 secondary cancers, SIR 8.35 (95% CI: 5.97-11.68)), melanoma of skin (6 secondary cancers, SIR 4.29 (95% CI: 1.93-9.56)) and laryngeal cancer (2 secondary cancers, SIR 9.51 (95% CI: 2.38-38)). The SIRs for these three cancer sites were also elevated on restricting the follow-up to cancers occurring at least one year after MCC diagnosis. CONCLUSIONS: Patients diagnosed with MCC are at increased risk of a second cancer, particularly, other skin cancers. Conceivable explanations include the impact of increased surveillance of the skin and shared causative factors, for example, ultraviolet light exposure or MCC polyomavirus infection.

Polymorphic MLH1 and risk of cancer after methylating chemotherapy for Hodgkin lymphoma.

BACKGROUND AND OBJECTIVE: Methylating agents are effective chemotherapy agents for Hodgkin lymphoma, but are associated with the development of second primary cancers. Cytotoxicity of methylating agents is mediated primarily by the DNA mismatch repair (MMR) system. Loss of MLH1, a major component of DNA MMR, results in tolerance to the cytotoxic effects of methylating agents and persistence of mutagenised cells at high risk of malignant transformation. We hypothesised that a common substitution in the basal promoter of MLH1 (position -93, rs1800734) modifies the risk of cancer after methylating chemotherapy. METHODS: 133 patients who developed cancer following chemotherapy and/or radiotherapy (n = 133), 420 patients diagnosed with de novo myeloid leukaemia, 242 patients diagnosed with primary Hodgkin lymphoma, and 1177 healthy controls were genotyped for the MLH1 -93 polymorphism by allelic discrimination polymerase chain reaction (PCR) and restriction fragment length polymorphism assay. Odds ratios and 95% confidence intervals for cancer risk by MLH1 -93 polymorphism status, and stratified by previous exposure to methylating chemotherapy, were calculated using unconditional logistic regression. RESULTS: Carrier frequency of the MLH1 -93 variant was higher in patients who developed therapy related acute myeloid leukaemia (t-AML) (75.0%, n = 12) or breast cancer (53.3%. n = 15) after methylating chemotherapy for Hodgkin lymphoma compared to patients without previous methylating exposure (t-AML, 30.4%, n = 69; breast cancer patients, 27.2%, n = 22). The MLH1 -93 variant allele was also over-represented in t-AML cases when compared to de novo AML cases (36.9%, n = 420) and healthy controls (36.3%, n = 952), and was associated with a significantly increased risk of developing t-AML (odds ratio 5.31, 95% confidence interval 1.40 to 20.15), but only in patients previously treated with a methylating agent. CONCLUSIONS: These data support the hypothesis that the common polymorphism at position -93 in the core promoter of MLH1 defines a risk allele for the development of cancer after methylating chemotherapy for Hodgkin lymphoma. However, replication of this finding in larger studies is suggested.

Iron deficiency among children of asylum seekers in the Netherlands.

OBJECTIVES: To investigate, in asylum seekers' children in the Netherlands, biochemical iron status and the prevalence of iron deficiency (ID) and anemia in relation to age, region of origin, length of stay in the Netherlands, body mass index (BMI), and dietary iron intake. PATIENTS AND METHODS: Hemoglobin (Hb) and plasma ferritin concentrations were determined in 122 asylum seekers' children (median age, 7.1 years; range, 2-12 y). ID was defined by plasma ferritin levels <15 microg/L. Anemia was defined by Hb levels <6.8 mmol/L (11 g/dL) for children <6 years of age and Hb levels <7.1 mmol/L (11.5 g/dL) for children between 6 and 12 years of age. Nutritional status of the children was assessed by BMI and dietary intake of iron was estimated by 24-hour recall. RESULTS: Twenty percent of the children had compromised iron status (16% with ID, 4% with ID anemia [IDA]). Another 6% of the children had anemia caused by thalassemia. ID was significantly more prevalent in children <6 years of age and in children of African origin. The iron status was not significantly correlated with the length of stay in the Netherlands (r = 0.6; P = 0.48). Higher BMI z scores were positively correlated with iron status. Adequate or marginal dietary iron intake was not significantly related to the presence of ID (r = 0.02; P = 0.9) or anemia (IDA and thalassemia; r = 0.15; P = 0.9). CONCLUSIONS: Iron deficiency is highly prevalent among the children of asylum seekers in the Netherlands. Our data indicate that systematic biochemical screening for ID is warranted in asylum seekers' children.

Skin conductance as a pain assessment tool during chest tube removal: An observational study.

BACKGROUND: Skin conductance variability to assess pain has shown varying results. Skin conductance responses per second (SCR) during a standardized painful stimulus in awake adults may give further understanding of the method's validity. The purpose of this study was to validate the SCR with the visual analogue scale (VAS) for pain (P-VAS) and anxiety (A-VAS) during chest tube removal (CTR). METHODS: Ninety-five patients receiving epidural or non-epidural treatment, scheduled for CTR, were studied. Pain or anxiety was considered when VAS > 30 mm; the SCR cut-off value reflecting pain was ≥0.2 SCR. RESULTS: SCR values could not be recorded in eight cases before CTR, six cases during CTR and seven cases after CTR. CTR induced increases in SCR, P-VAS and A-VAS (p < 0.001). Seventy-seven percent of all pairs of P-VAS and SCR values were well-classified; P-VAS ≤ 30 mm and SCR < 0.2 or P-VAS > 30 mm and SCR ≥ 0.2. SCR obtained before CTR differentiates between patients with and without pain during CTR in all patients (p = 0.04) and in the subgroup of non-anxious patients (p = 0.02), but not in the subgroup of anxious patients. SCR obtained during CTR had similar values in patients with and without pain in all patients and in the subgroup of anxious patients, but in the subgroup of non-anxious patients SCR during CTR differentiates patients with and without pain (p = 0.009). CONCLUSIONS: SCR increases during painful procedures. Preprocedural SCR may help predict reported pain in patients exposed to painful procedures. SCR during CTR differentiates between patients with and without pain only in non-anxious patients. SIGNIFICANCE: Preprocedural SCR may help predict reported pain in patients exposed to painful procedures. Procedural SCR accuracy improves in a subgroup of non-anxious patients. P-VAS is influenced by anxiety different from SCR.

Bridging the gap between the randomised clinical trial world and the real world by combination of population-based registry and electronic health record data: A case study in haemato-oncology.

Randomised clinical trials (RCTs) are considered the basis of evidence-based medicine. It is recognised more and more that application of RCT results in daily practice of clinical decision-making is limited because the RCT world does not correspond with the clinical real world. Recent strategies aiming at substitution of RCT databases by improved population-based registries (PBRs) or by improved electronic health record (EHR) systems to provide significant data for clinical science are discussed. A novel approach exemplified by the HemoBase haemato-oncology project is presented. In this approach, a PBR is combined with an advanced EHR, providing high-quality data for observational studies and support of best practice development. This PBR + EHR approach opens a perspective on randomised registry trials.

Uveal and conjunctival malignant melanoma in denmark 1943-97: observed and relative survival of patients followed through 2002.

PURPOSE: To evaluate the observed and relative survival of patients diagnosed with a malignant melanoma in the ocular region in Denmark during the period 1943-97. METHODS: The study included 2,504 patients (1,292 men and 1,212 women) diagnosed with a melanoma in the ocular region, of which 2,434 cases could be topographically subclassified into 2,178 in the choroid/ciliary body, 141 in the iris, and 115 in the conjunctiva. The patients were followed through 2002 and the observed survival proportions and relative survival ratios were estimated. RESULTS: For the total ocular region and the choroid/ciliary body, the observed survival did not vary statistically significantly with the year of diagnosis. A statistically insignificant higher observed survival for women than men was found for tumors in the ocular region and the subgroups choroid/ciliary body, iris, and conjunctiva. During the 55-year study period, the 5- and 10-year relative survival remained stable for the ocular region for men at 67% and 57% and for women at 71% and 60%, respectively, and stable for the choroid/ciliary body for men at 66% and 55% and for women at 69% and 57%, respectively. The 5- and 10-year relative survival for the iris was for men 90% and 85% and for women 99% and 101%, respectively, and for the conjunctiva for men 83% and 70% and for women 93% and 82%, respectively. CONCLUSION: The observed and relative survival of patients diagnosed with a melanoma in the ocular region and choroid/ciliary body in Denmark during the period 1943-97 and followed through 2002 has remained stable. The highest observed and relative survival was found for iris melanomas, the lowest for choroid/ciliary body melanomas, and intermediate for conjunctival melanomas.

Cancer incidence among Danish Thorotrast-exposed patients.

BACKGROUND: Studies of groups of patients given injections of the alpha-emitting x-ray contrast medium Thorotrast may provide information on human alpha-ray carcinogenesis. PURPOSE: We re-established a formerly identified cohort of neurological patients receiving injections of Thorotrast for cerebral arteriography and assessed their incidence of cancer. METHODS: Using the national population register, the Danish Cancer Registry, and other registers, we determined the incidence of cancer among Thorotrast-injected patients. Incidence ratios were standardized to the general population and computed for different cancer sites. RESULTS: The cumulative risk for cancer at all sites (excluding brain tumors where the standardized incidence ratio [SIR] was 28) reached 86% 50 years after Thorotrast injection. SIR was greatly elevated at all sites except the brain and CNS (3.3, 95% confidence interval = 3.0-3.7), mainly because of liver cancers (SIR = 126) as well as leukemia (SIR = 10) for which a relationship was found between the time since injection and the estimated dose (but not the age at injection). Other sites with significantly increased risks of cancer included the gallbladder and extrahepatic bile ducts (SIR = 14), peritoneum (SIR = 8.6), sites of multiple myeloma (SIR = 4.6), metastatic sites (SIR = 12), and unspecified sites (SIR = 11). Cancers of the lung and breast also occurred in significant excess, but no relationship between SIR and volume of injected Thorotrast or time since injection was observed. Cancer risk was increased at most other sites, although this increase was not statistically significant. CONCLUSION: Alpha radiation may account for the increased risk of tumors of the liver, gallbladder, and peritoneum as well as leukemia and multiple myeloma, whereas confounding factors most probably contribute to the increased risks at other sites.

Effects of preconceptional irradiation on mortality and cancer incidence in the offspring of patients given injections of Thorotrast.

BACKGROUND: Findings from a British case-control study suggest that a preconceptional paternal external radiation dose of more than 100 mSv (10 rem) is significantly related to risk for leukemia and non-Hodgkin's lymphoma in offspring. The suggestion, however, has not been supported by experimental or other epidemiologic studies. PURPOSE: The purpose of this study was to investigate if preconceptional irradiation of males and females from internally deposited radionuclides affects mortality and risk of developing cancer in their offspring. METHODS: The offspring of 260 females (n = 143) and 320 males (n = 226) who lived longer than 1 year after receiving Thorotrast (a compound no longer in use) for cerebral arteriography were studied for mortality rate and the risk for developing cancer. Thorotrast was used as a contrast medium containing a 20% colloidal solution of thorium dioxide-Th 232, an alpha particle-emitting radionuclide, which is retained lifelong in nearly all organs. The offspring of the exposed patients were identified by manual linkage with the municipal population registers and followed-up for vital status by computerized linkage with the Danish National Central Population Registry and for incidence of cancer by computerized linkage with the Danish National Cancer Registry. The standardized mortality/morbidity ratios (SMRs) for death and for site-specific incidence of cancer in the offspring were calculated as ratios of the observed rates in the study population to the expected rates in the general population. RESULTS: After a median follow-up of 40 years, four cases of cancer (breast [one], uterine cervix [one], melanoma of skin [one], and retinoblastoma [one]) versus 2.9 cases expected, developed among 143 children born to mothers who received injections of Thorotrast (SMR = 1.4; 95% confidence interval [CI] = 0.4-3.5), while six cases of cancer (one case each of cancer of lung, testis, thyroid, and Hodgkin's lymphoma and two cases of melanoma of skin), versus 4.5 expected, occurred among 226 children of exposed fathers (SMR = 1.3; 95% CI = 0.5-2.9). No case of leukemia or non-Hodgkin's lymphoma occurred in any of the offspring studied. Mortality was lower than expected both for children of exposed mothers (SMR = 0.7; 95% CI = 0.3-1.5) and of exposed fathers (SMR = 0.5; 95% CI = 0.2-1.0). CONCLUSIONS: This study does not support the previously proposed association between parental exposure to radiation and the risk of childhood leukemia and lymphoma. Furthermore, since mortality from all causes was not increased in any offspring, our results do not support the belief that preconceptional parental low-dose exposure to alpha radiation increases the incidence of cancer or mortality in the offspring.

Incidence of new primary cancers after adjuvant tamoxifen therapy and radiotherapy for early breast cancer.

The incidence of new primary cancers was evaluated in 3538 postmenopausal patients who had received surgical treatment for primary breast cancer. Of these patients, 1828 with a low risk of recurrence received no further treatment. High-risk patients were randomly assigned to one of two groups. The first group (n = 846) received postoperative radiotherapy, while the second group (n = 864) received radiotherapy plus tamoxifen at a dose of 30 mg given daily for 48 weeks. The median observation time was 7.9 years. In comparison with the number of new cancers in the general population, the number of new cancers in the three groups was elevated mostly due to a high number of cancers of the contralateral breast and of colorectal cancers in the high-risk groups. The cumulative risk of nonlymphatic leukemia was increased among patients who received postoperative radiotherapy (P = .04). Cancer incidence in the high-risk tamoxifen-treated group relative to that in the high-risk group not treated with tamoxifen was not significant (1.3). No protective effect of tamoxifen on the opposite breast was seen (rate ratio for breast cancer = 1.1), but a tendency to an elevated risk of endometrial cancer was observed (rate ratio = 3.3; 95% confidence interval = 0.6-32.4). Continued and careful follow-up of women treated with tamoxifen is necessary to clarify the potential cancer-suppressive or cancer-promoting effects of this drug.

Risk of Hodgkin's disease and other cancers after infectious mononucleosis.

BACKGROUND: Infectious mononucleosis, which is caused by the Epstein-Barr virus, has been associated with an increased risk for Hodgkin's disease. Little is known, however, about how infectious mononucleosis affects long-term risk of Hodgkin's disease, how this risk varies with age at infectious mononucleosis diagnosis, or how the risk for Hodgkin's disease varies in different age groups. In addition, the general cancer profile among patients who have had infectious mononucleosis has been sparsely studied. METHODS: Population-based cohorts of infectious mononucleosis patients in Denmark and Sweden were followed for cancer occurrence. The ratio of observed-to-expected numbers of cancers (standardized incidence ratio [SIR]) served as a measure of the relative risk for cancer. SIRs of Hodgkin's disease in different subsets of patients were compared with the use of Poisson regression analysis. All statistical tests including the trend tests were two-sided. RESULTS: A total of 1381 cancers were observed during 689 619 person-years of follow-up among 38 562 infectious mononucleosis patients (SIR = 1. 03; 95% confidence interval [CI] = 0.98-1.09). Apart from Hodgkin's disease (SIR = 2.55; 95% CI = 1.87-3.40; n = 46), only skin cancers (SIR = 1.27; 95% CI = 1.13-1.43; n = 291) occurred in statistically significant excess. In contrast, the SIR for lung cancer was reduced (SIR = 0.71; 95% CI = 0.58-0.86; n = 102). The SIR for Hodgkin's disease remained elevated for up to two decades after the occurrence of infectious mononucleosis but decreased with time since diagnosis of infectious mononucleosis (P: for trend <.001). The SIR for Hodgkin's disease tended to increase with age at diagnosis of infectious mononucleosis (P: for trend =.05). Following infectious mononucleosis, the SIR for Hodgkin's disease at ages 15-34 years was 3.49 (95% CI = 2.46-4.81; n = 37), which was statistically significantly higher than the SIR for any other age group (P: for difference =.001). CONCLUSION: The increased risk of Hodgkin's disease after the occurrence of infectious mononucleosis appears to be a specific phenomenon.

Adjuvant radiotherapy and risk of contralateral breast cancer.

BACKGROUND: The risk of contralateral breast cancer is increased twofold to fivefold for breast cancer patients. A registry-based cohort study in Denmark suggested that radiation treatment of the first breast cancer might increase the risk for contralateral breast cancer among 10-year survivors. PURPOSE: Our goal was to assess the role of radiation in the development of contralateral breast cancer. METHODS: A nested case-control study was conducted in a cohort of 56,540 women in Denmark diagnosed with invasive breast cancer from 1943 through 1978. Case patients were 529 women who developed contralateral breast cancer 8 or more years after first diagnosis. Controls were women with breast cancer who did not develop contralateral breast cancer. One control was matched to each case patient on the basis of age, calendar year of initial breast cancer diagnosis, and survival time. Radiation dose to the contralateral breast was estimated for each patient on the basis of radiation measurements and abstracted treatment information. The anatomical position of each breast cancer was also abstracted from medical records. RESULTS: Radiotherapy had been administered to 82.4% of case patients and controls, and the mean radiation dose to the contralateral breast was estimated to be 2.51 Gy. Radiotherapy did not increase the overall risk of contralateral breast cancer (relative risk = 1.04; 95% confidence interval = 0.74-1.46), and there was no evidence that risk varied with radiation dose, time since exposure, or age at exposure. The second tumors in case patients were evenly distributed in the medial, lateral, and central portions of the breast, a finding that argues against a causal role of radiotherapy in tumorigenesis. CONCLUSIONS: The majority of women in our series were perimenopausal or postmenopausal (53% total versus 38% premenopausal and 9% of unknown status) and received radiotherapy at an age when the breast tissue appears least susceptible to the carcinogenic effects of radiation. Based on a dose of 2.51 Gy and estimates of radiation risk from other studies, a relative risk of only 1.18 would have been expected for a population of women exposed at an average age of 51 years. Thus, our data provide additional evidence that there is little if any risk of radiation-induced breast cancer associated with exposure of breast tissue to low-dose radiation (e.g., from mammographic x rays or adjuvant radiotherapy) in later life.

Increase in testicular cancer incidence in six European countries: a birth cohort phenomenon.

BACKGROUND: For unknown reasons, the age-standardized incidence of testicular cancer has shown a rapid increase in virtually all countries (mostly Western) studied. For populations with a sufficiently long period of cancer registration, this development can be traced back to the first half of this century. PURPOSE: By evaluating data from six countries with long periods of cancer registration (Denmark, Norway, Sweden, the former German Democratic Republic [East Germany], Finland, and Poland), we sought to determine whether the increase in testicular cancer risk follows a birth cohort pattern and, if so, to quantify and compare any birth cohort effects. METHODS: A total of 30,908 incident cases of testicular cancer, diagnosed from 1945 through 1989 in men who were 20-84 years of age, were identified in population-based cancer registries in the six countries. In addition to performing simple trend analyses, we fitted several Poisson regression models (with the explanatory variables age, time period [calendar time], and birth cohort) to the data. Individual models were estimated by the maximum likelihood method. RESULTS: The age-standardized incidence of testicular cancer was found to vary among the six populations and, on the basis of total registration data, increased annually at rates ranging from 2.3% (in Sweden) to 5.2% (in East Germany). A comparison of several regression models indicated that birth cohort was a stronger determinant of testicular cancer risk than was calendar time for all six populations. Within each population, little variation in testicular cancer risk was observed for men born between 1880 and 1920; thereafter, the risk began to increase. Among men born in Denmark, Norway, and Sweden between 1930 and 1945 (the period encompassing the Second World War), the increasing trend in risk was interrupted (i.e., a leveling in risk occurred). After 1945, an uninterrupted increase in risk was observed for all six populations. With men born around 1905 as the reference group, the relative risk of testicular cancer for those born around 1965 varied from 3.9 (95% confidence interval [CI] = 2.7-5.6) in Sweden to 11.4 (95% CI = 8.3-15.5) in East Germany. CONCLUSIONS AND IMPLICATIONS: The increasing trend in testicular cancer risk observed for these six populations follows a birth cohort pattern. This distinct risk pattern provides a framework for the identification of specific etiologic factors.