A two-phase Poisson process model and its application to analysis of cancer mortality among A-bomb survivors.

We consider a two-phase Poisson process model where only early successive transitions are assumed to be sensitive to exposure. In the case where intensity transitions are low, we derive analytically an approximate formula for the distribution of time to event for the excess hazard ratio (EHR) due to a single point exposure. The formula for EHR is a polynomial in exposure dose. Since the formula for EHR contains no unknown parameters except for the number of total stages, number of exposure-sensitive stages, and a coefficient of exposure effect, it is applicable easily under a variety of situations where there exists a possible latency time from a single point exposure to occurrence of event. Based on the multistage hypothesis of cancer, we formulate a radiation carcinogenesis model in which only some early consecutive stages of the process are sensitive to exposure, whereas later stages are not affected. An illustrative analysis using the proposed model is given for cancer mortality among A-bomb survivors.

Detecting a Local Cohort Effect for Cancer Mortality Data Using a Varying Coefficient Model.

BACKGROUND: Cancer mortality is increasing with the aging of the population in Japan. Cancer information obtained through feasible methods is therefore becoming the basis for planning effective cancer control programs. There are three time-related factors affecting cancer mortality, of which the cohort effect is one. Past descriptive epidemiologic studies suggest that the cohort effect is not negligible in cancer mortality. METHODS: In this paper, we develop a statistical method for automatically detecting a cohort effect and assessing its statistical significance for cancer mortality data using a varying coefficient model. RESULTS: The proposed method was applied to liver and lung cancer mortality data on Japanese men for illustration. Our method detected significant positive or negative cohort effects. The relative risk was 1.54 for liver cancer mortality in the cohort born around 1934 and 0.83 for lung cancer in the cohort born around 1939. CONCLUSIONS: Cohort effects detected using the proposed method agree well with previous descriptive epidemiologic findings. In addition, the proposed method is expected to be sensitive enough to detect smaller, previously undetected birth cohort effects.

Workshop report on atomic bomb dosimetry-residual radiation exposure: recent research and suggestions for future studies.

There is a need for accurate dosimetry for studies of health effects in the Japanese atomic bomb survivors because of the important role that these studies play in worldwide radiation protection standards. International experts have developed dosimetry systems, such as the Dosimetry System 2002 (DS02), which assess the initial radiation exposure to gamma rays and neutrons but only briefly consider the possibility of some minimal contribution to the total body dose by residual radiation exposure. In recognition of the need for an up-to-date review of the topic of residual radiation exposure in Hiroshima and Nagasaki, recently reported studies were reviewed at a technical session at the 57th Annual Meeting of the Health Physics Society in Sacramento, California, 22-26 July 2012. A one-day workshop was also held to provide time for detailed discussion of these newer studies and to evaluate their potential use in clarifying the residual radiation exposures to the atomic-bomb survivors at Hiroshima and Nagasaki. Suggestions for possible future studies are also included in this workshop report.

Investigation on circular asymmetry of geographical distribution in cancer mortality of Hiroshima atomic bomb survivors based on risk maps: analysis of spatial survival data.

While there is a considerable number of studies on the relationship between the risk of disease or death and direct exposure from the atomic bomb in Hiroshima, the risk for indirect exposure caused by residual radioactivity has not yet been fully evaluated. One of the reasons is that risk assessments have utilized estimated radiation doses, but that it is difficult to estimate indirect exposure. To evaluate risks for other causes, including indirect radiation exposure, as well as direct exposure, a statistical method is described here that evaluates risk with respect to individual location at the time of atomic bomb exposure instead of radiation dose. In addition, it is also considered to split the risks into separate risks due to direct exposure and other causes using radiation dose. The proposed method is applied to a cohort study of Hiroshima atomic bomb survivors. The resultant contour map suggests that the region west to the hypocenter has a higher risk compared to other areas. This in turn suggests that there exists an impact on risk that cannot be explained by direct exposure.

Effect of mustard gas exposure on incidence of lung cancer: a longitudinal study.

Sulfur mustard, an agent used in chemical warfare, is an alkylating substance with carcinogenic potential. However, the precise long-term carcinogenic effects of mustard gas are unclear. Since 1952, the authors have conducted health surveys of former workers who were employed from 1929 to 1945 in a poisonous gas factory in Okuno-jima, Hiroshima, Japan. This prospective study was undertaken from 1952 to 2005 to examine the incidence of lung cancer among the workers who were exposed to mustard gas (n=480), lewisite (n=55), and/or diphenylcyanarsine (n=178), as well as the incidence among unexposed workers (n=969). The stochastic relation between exposure and lung cancer was explored on the basis of multistage carcinogenesis by using an accelerated hazard model with a transformed age scale. Mustard gas exposure was found to transform the age scale for developing lung cancer. One year of exposure in subjects ≤18 or >18 years old at first exposure shifted the age scale down by 4.9 years and 3.3 years, respectively. On the basis of the long-term follow-up of former workers in the poisonous gas factory, the authors concluded that sulfur mustard decreased the age at which people were at risk of developing lung cancer and that the effect declined with aging.

Optimal cardiac phase for coronary artery calcium scoring on single-source 64-MDCT scanner: least interscan variability and least motion artifacts.

OBJECTIVE: The purpose of our study was to investigate the cardiac phase with the least interscan variability and motion artifacts on coronary artery calcium studies using a 64-MDCT scanner. SUBJECTS AND METHODS: Ninety-one patients with suspected coronary artery disease were scanned twice on retrospective ECG-gated helical scans. Images with 2.5-mm thickness and 1.25-mm interval at nine cardiac phases (center of cardiac phase: 40-80% in 5% increments) were reconstructed. The interscan variability of coronary artery scores (Agatston, volume, and mass) per patient and motion artifact scores per branch, subjectively assigned by motion artifact grading (1, none; 2, minor; and 3, major), were compared between cardiac phases for all patients, low (< 65 beats per minute [bpm]) and high (>or= 65 bpm) heart rate patient groups. RESULTS: For all patients, two-factor factorial analysis of variance revealed that the interscan variability was different between cardiac cycles (p < 0.01); however, this was not statistically significant between scoring algorithms (p = 0.46). The least variability was obtained at 70% on Agatston (8%) and volume (7%) and at 75% on mass (7%). Adjacent categories logit model analysis revealed that the motion artifact score was the least at 75% (left anterior descending coronary artery, 1.3; left circumflex coronary artery, 1.4; and right coronary artery, 1.9 in all patients) and that a smaller difference in calcium scores between the scans led to a smaller motion artifact score (p < 0.05). CONCLUSION: Middiastole reconstruction (center of cardiac phase: 70-75%), with the least interscan variability and the least motion artifacts, is recommended on 64-MDCT.

Haploinsufficiency of the Mus81-Eme1 endonuclease activates the intra-S-phase and G2/M checkpoints and promotes rereplication in human cells.

The Mus81-Eme1 complex is a structure-specific endonuclease that preferentially cleaves nicked Holliday junctions, 3'-flap structures and aberrant replication fork structures. Mus81-/- mice have been shown to exhibit spontaneous chromosomal aberrations and, in one of two models, a predisposition to cancers. The molecular mechanisms underlying its role in chromosome integrity, however, are largely unknown. To clarify the role of Mus81 in human cells, we deleted the gene in the human colon cancer cell line HCT116 by gene targeting. Here we demonstrate that Mus81 confers resistance to DNA crosslinking agents and slight resistance to other DNA-damaging agents. Mus81 deficiency spontaneously promotes chromosome damage such as breaks and activates the intra-S-phase checkpoint through the ATM-Chk1/Chk2 pathways. Furthermore, Mus81 deficiency activates the G2/M checkpoint through the ATM-Chk2 pathway and promotes DNA rereplication. Increased rereplication is reversed by the ectopic expression of Cdk1. Haploinsufficiency of Mus81 or Eme1 also causes similar phenotypes. These findings suggest that a complex network of the checkpoint pathways that respond to DNA double-strand breaks may participate in some of the phenotypes associated with Mus81 or Eme1 deficiency.