Lifetime excess absolute risk for lung cancer due to exposure to radon: results of the pooled uranium miners cohort study PUMA.

The Pooled Uranium Miners Analysis (PUMA) study is the largest uranium miners cohort with 119,709 miners, 4.3 million person-years at risk and 7754 lung cancer deaths. Excess relative rate (ERR) estimates for lung cancer mortality per unit of cumulative exposure to radon progeny in working level months (WLM) based on the PUMA study have been reported. The ERR/WLM was modified by attained age, time since exposure or age at exposure, and exposure rate. This pattern was found for the full PUMA cohort and the 1960 + sub-cohort, i.e., miners hired in 1960 or later with chronic low radon exposures and exposure rates. The aim of the present paper is to calculate the lifetime excess absolute risk (LEAR) of lung cancer mortality per WLM using the PUMA risk models, as well as risk models derived in previously published smaller uranium miner studies, some of which are included in PUMA. The same methods were applied for all risk models, i.e., relative risk projection up to <95 years of age, an exposure scenario of 2 WLM per year from age 18-64 years, and baseline mortality rates representing a mixed Euro-American-Asian population. Depending upon the choice of model, the estimated LEAR per WLM are 5.38 × 10-4 or 5.57 × 10-4 in the full PUMA cohort and 7.50 × 10-4 or 7.66 × 10-4 in the PUMA 1960 + sub-cohort, respectively. The LEAR per WLM estimates derived from risk models reported for previously published uranium miners studies range from 2.5 × 10-4 to 9.2 × 10-4. PUMA strengthens knowledge on the radon-related lung cancer LEAR, a useful way to translate models for policy purposes.

Updated risk models for lung cancer due to radon exposure in the German Wismut cohort of uranium miners, 1946-2018.

UNSCEAR recently recommended that future research on the lung cancer risk at low radon exposures or exposure rates should focus on more contemporary uranium miners. For this purpose, risk models in the German Wismut cohort of uranium miners were updated extending the follow-up period by 5 years to 1946-2018. The full cohort (n = 58,972) and specifically the 1960 + sub-cohort of miners first hired in 1960 or later (n = 26,764) were analyzed. The 1960 + sub-cohort is characterized by low protracted radon exposure of high quality of measurements. Internal Poisson regression was used to estimate the excess relative risk (ERR) for lung cancer per cumulative radon exposure in Working Level Months (WLM). Applying the BEIR VI exposure-age-concentration model, the ERR/100 WLM was 2.50 (95% confidence interval (CI) 0.81; 4.18) and 6.92 (95% CI < 0; 16.59) among miners with attained age < 55 years, time since exposure 5-14 years, and annual exposure rates < 0.5 WL in the full (n = 4329 lung cancer deaths) and in the 1960 + sub-cohort (n = 663 lung cancer deaths), respectively. Both ERR/WLM decreased with older attained ages, increasing time since exposure, and higher exposure rates. Findings of the 1960 + sub-cohort are in line with those from large pooled studies, and ERR/WLM are about two times higher than in the full Wismut cohort. Notably, 20-30 years after closure of the Wismut mines in 1990, the estimated fraction of lung cancer deaths attributable to occupational radon exposure is still 26% in the full Wismut cohort and 19% in the 1960 + sub-cohort, respectively. This demonstrates the need for radiation protection against radon.

Mortality among uranium miners in North America and Europe: the Pooled Uranium Miners Analysis (PUMA).

BACKGROUND: The Pooled Uranium Miners Analysis (PUMA) study draws together information from cohorts of uranium miners from Canada, the Czech Republic, France, Germany and the USA. METHODS: Vital status and cause of death were ascertained and compared with expectations based upon national mortality rates by computing standardized mortality ratios (SMRs) overall and by categories of time since first hire, calendar period of first employment and duration of employment as a miner. RESULTS: There were 51 787 deaths observed among 118 329 male miners [SMR = 1.05; 95% confidence interval (CI): 1.04, 1.06]. The SMR was elevated for all cancers (n = 16 633, SMR = 1.23; 95% CI: 1.21, 1.25), due primarily to excess mortality from cancers of the lung (n = 7756, SMR = 1.90; 95% CI: 1.86, 1.94), liver and gallbladder (n = 549, SMR = 1.15; 95% CI: 1.06, 1.25), larynx (n = 229, SMR = 1.10; 95% CI: 0.97, 1.26), stomach (n = 1058, SMR = 1.08; 95% CI: 1.02, 1.15) and pleura (n = 39, SMR = 1.06; 95% CI: 0.75, 1.44). Lung-cancer SMRs increased with duration of employment, decreased with calendar period and persisted with time since first hire. Among non-malignant causes, the SMR was elevated for external causes (n = 3362, SMR = 1.41; 95% CI: 1.36, 1.46) and respiratory diseases (n = 4508, SMR = 1.32; 95% CI: 1.28, 1.36), most notably silicosis (n = 814, SMR = 13.56; 95% CI: 12.64, 14.52), but not chronic obstructive pulmonary disease (n = 1729, SMR = 0.98; 95% CI: 0.93, 1.02). CONCLUSIONS: Whereas there are important obstacles to the ability to detect adverse effects of occupational exposures via SMR analyses, PUMA provides evidence of excess mortality among uranium miners due to a range of categories of cause of death. The persistent elevation of SMRs with time since first hire as a uranium miner underscores the importance of long-term follow-up of these workers.

Factors Modifying the Radon-Related Lung Cancer Risk at Low Exposures and Exposure Rates among German Uranium Miners.

It is still not fully understood whether and how factors such as time, age and smoking modify the relationship between lung cancer and radon at low exposures and exposure rates. Improved knowledge is necessary for the dose conversion of radon in working level month (WLM) into effective dose, as currently discussed by the International Commission on Radiological Protection (ICRP). An update of the German uranium miner cohort study (n = 58,974 men) with a 10-year extension of mortality follow-up (1946-2013) was used to further examine this issue. Internal Poisson regression was applied to estimate the excess relative risk (ERR) for lung cancer mortality per unit of cumulative radon exposure in WLM with exponential time-related effect modifiers. In the full cohort restricted to <100 WLM the estimated overall ERR/WLM was 0.006 [95% confidence interval (CI): 0.003; 0.010] based on 1,254 lung cancer deaths and 1,620,190 person-years at risk. Both age at and time since exposure turned out to be important modifiers of the ERR/WLM and were included in the final model. Here, the ERR/WLM centered on age at exposure of 30 years, and 20 years since exposure was 0.016 (95% CI: 0.008; 0.028). This value decreased statistically significantly by approximately 40% and 60% for each 10-year increase in age at exposure and time since exposure, respectively. The joint effect of smoking and radon exposure was investigated in the sub-cohort of miners hired in 1960 or later, which includes data on smoking status. The centered ERR/WLM was slightly higher for non/light smokers compared to moderate/heavy smokers (0.022 versus 0.013). The current findings provide evidence for an increased lung cancer risk at low radon exposures or exposure rates that is modified by age and time. The observed risk is lower, but statistically compatible to those of other miner studies at low exposures or exposure rates. These findings reject an additive- and support a sub- to (supra-) multiplicative interaction between smoking and radon.

Lung cancer risk at low radon exposure rates in German uranium miners.

BACKGROUND: A determination of the risk of lung cancer at low levels of radon exposure is important for occupational radiation protection. METHODS: The risk of death from lung cancer at low radon exposure rates was investigated in the subcohort of 26,766 German uranium miners hired in 1960 or later. RESULTS: A clear association between lung cancer mortality (n=334 deaths) and cumulative exposure to radon in working level months (WLM) was found. The excess relative risk per WLM was 0.013 (95% confidence intervals: 0.007; 0.021). CONCLUSIONS: The present findings provide strong evidence for an increased lung cancer risk after long-term exposure to low radon exposure rates among Wismut miners. The results are compatible to those from residential radon studies and miner studies restricted to low levels.

Phase I/II trial for the treatment of cutaneous and subcutaneous tumors using electrochemotherapy.

BACKGROUND: Electroporation is a process that causes a transient increase in the permeability of cell membranes. It can be used to increase the intracellular concentration of chemotherapeutic agents in tumor cells (electrochemotherapy; ECT). A clinical study was initiated to determine if this mode of treatment would be effective against certain primary and metastatic cutaneous malignancies. A group of six patients, three with malignant melanoma, two with basal cell carcinoma, and one with metastatic adenocarcinoma, were enrolled in the study. the treatment was administered in a two-step process. METHODS: Each patient received a 10 unit/m2 dose of bleomycin administered intravenously at 1 to 1.5 units/minute. This was followed by eight 99 microsecond pulses at an amplitude of 1.3 kV/cm administered directly to the tumors 5 to 15 minutes after the bleomycin was completely infused. Pulses were administered after the injection of 1% lidocaine solution around the treatment site. RESULTS: Two of three melanoma patients had objective responses. In these two patients, five of six treated tumors decreased in size, and three completely responded. Untreated tumors displayed continued growth. Objective responses were observed in both basal cell carcinoma (BCC) patients. One patient had partial responses in both treated tumors. The other patient had one of four primary BCCs respond completely, and the remaining three respond partially. Patients with metastatic breast adenocarcinoma showed complete responses in both treated nodules after ECT. All patients tolerated the treatment well with no residual effects from the electric pulses. CONCLUSIONS: ECT was an effective local treatment in the majority of nodules treated. The results thus far are very encouraging and the study is being continued.

Bleomycin-mediated electrochemotherapy of basal cell carcinoma.

BACKGROUND: A new technique, electroporation, enhances the antitumor effects of a variety of chemotherapeutic agents. When used in combination with conventional chemotherapy, the procedure is termed electrochemotherapy. Exposure of cancerous tissues to pulses of electricity during electrochemotherapy appears to increase cell membrane permeability and thus intracellular access to cytotoxic drugs. Electrochemotherapy has been shown to have potent antitumor activity in a variety of in vitro studies, animal tumor models, as well as in clinical trials with squamous cell carcinomas of the head and neck. OBJECTIVE: The purpose of the study was to determine the effects of bleomycin-mediated electrochemotherapy on several basal cell carcinomas (BCCs) in two patients with nevoid BCC syndrome. METHODS: Electrical pulses were delivered to tumor nodules by means of caliper electrodes after systemic doses of bleomycin were administered. Vital signs were closely monitored during application of the electrical pulses. RESULTS: Partial responses were observed in tumors from both of the patients treated with electrochemotherapy; three partial responses were observed in one patient, and one partial response was observed in the other patient. Complete responses were seen in two lesions. Only minimal local or systemic side effects were noted in response to the therapy. CONCLUSION: To our knowledge, this is the first study that documents the effects of bleomycin-mediated electrochemotherapy on BCC. Studies are ongoing with intralesional bleomycin during electrochemotherapy to see whether additional antitumour effects can be produced in patients with BCC by this route of administration.

Human adjuvant disease following augmentation mammoplasty.

Two patients are described in whom a progressive systemic sclerosis-like illness developed several years after silicone augmentation mammoplasty. Both had removal of breast implants, followed by marked-to-complete recovery from clinical abnormalities. This entity is increasingly recognized and has become known as human adjuvant disease.

Compromised wound repair caused by perioperative use of ibuprofen.

Nonsteroidal anti-inflammatory drugs have been shown to inhibit inflammation, an integral part of the wound-healing process. Compromised wound repair has been demonstrated in laboratory animals administered high-dose nonsteroidal anti-inflammatory drugs, a phenomenon we speculate could occur in humans undergoing surgery. We report a dramatic case of impaired wound healing in a patient ingesting high-dose perioperative ibuprofen, a nonsteroidal anti-inflammatory drug.

Diflorasone diacetate ointment 0.05 percent in conjunction with UVB and tar in a modified outpatient Goeckerman regimen.

Nineteen patients with psoriasis were treated with a modified Goeckerman regimen tailored to enhance patient compliance. Treatment consisted of daily coal tar emulsion baths at bedtime, followed by the application of 0.05 percent diflorasone diacetate ointment. Patients received increasing suberythemal dosages of short ultraviolet radiation (UVB) three times weekly at our outpatient phototherapy center. The duration of therapy ranged from three to twenty-eight weeks. The average number of phototherapy treatments was twenty-nine. Eight patients had total clearing of their lesions. Of the remainder, seven had at least 75 percent clearing and one had less than 25 percent clearing of psoriasis. One patient with psoriatic erythroderma experienced no improvement. Two patients did not complete the study. There were no side effects encountered during treatment other than periodic excessive erythema. If the two patients who did not complete the study are excluded from the results, 88 percent (fifteen of the remaining seventeen) had 75 percent or greater resolution of their psoriatic eruption and 47 percent (eight of seventeen) had total clearing. This outpatient modification of the Goeckerman regimen eliminates the use of cosmetically unacceptable topical agents during working hours, promotes patient compliance, and presumably contributes to enhanced therapeutic efficacy.