Solid cancer incidence in atomic bomb survivors: 1958-1998.

This is the second general report on radiation effects on the incidence of solid cancers (cancers other than malignancies of the blood or blood-forming organs) among members of the Life Span Study (LSS) cohort of Hiroshima and Nagasaki atomic bomb survivors. The analyses were based on 17,448 first primary cancers (including non-melanoma skin cancer) diagnosed from 1958 through 1998 among 105,427 cohort members with individual dose estimates who were alive and not known to have had cancer prior to 1958. Radiation-associated relative risks and excess rates were considered for all solid cancers as a group, for 19 specific cancer sites or groups of sites, and for five histology groups. Poisson regression methods were used to investigate the magnitude of the radiation-associated risks, the shape of the dose response, how these risks vary with gender, age at exposure, and attained age, and the evidence for inter-site variation in the levels and patterns of the excess risk. For all solid cancers as a group, it was estimated that about 850 (about 11%) of the cases among cohort members with colon doses in excess of 0.005 Gy were associated with atomic bomb radiation exposure. The data were consistent with a linear dose response over the 0- to 2-Gy range, while there was some flattening of the dose response at higher doses. Furthermore, there is a statistically significant dose response when analyses were limited to cohort members with doses of 0.15 Gy or less. The excess risks for all solid cancers as a group and many individual sites exhibit significant variation with gender, attained age, and age at exposure. It was estimated that, at age 70 after exposure at age 30, solid cancer rates increase by about 35% per Gy (90% CI 28%; 43%) for men and 58% per Gy (43%; 69%) for women. For all solid cancers as a group, the excess relative risk (ERR per Gy) decreases by about 17% per decade increase in age at exposure (90% CI 7%; 25%) after allowing for attained-age effects, while the ERR decreased in proportion to attained age to the power 1.65 (90% CI 2.1; 1.2) after allowing for age at exposure. Despite the decline in the ERR with attained age, excess absolute rates appeared to increase throughout the study period, providing further evidence that radiation-associated increases in cancer rates persist throughout life regardless of age at exposure. For all solid cancers as a group, women had somewhat higher excess absolute rates than men (F:M ratio 1.4; 90% CI 1.1; 1.8), but this difference disappears when the analysis was restricted to non-gender-specific cancers. Significant radiation-associated increases in risk were seen for most sites, including oral cavity, esophagus, stomach, colon, liver, lung, non-melanoma skin, breast, ovary, bladder, nervous system and thyroid. Although there was no indication of a statistically significant dose response for cancers of the pancreas, prostate and kidney, the excess relative risks for these sites were also consistent with that for all solid cancers as a group. Dose-response estimates for cancers of the rectum, gallbladder and uterus were not statistically significant, and there were suggestions that the risks for these sites may be lower than those for all solid cancers combined. However, there was emerging evidence from the present data that exposure as a child may increase risks of cancer of the body of the uterus. Elevated risks were seen for all of the five broadly classified histological groups considered, including squamous cell carcinoma, adenocarcinoma, other epithelial cancers, sarcomas and other non-epithelial cancers. Although the data were limited, there was a significant radiation-associated increase in the risk of cancer occurring in adolescence and young adulthood. In view of the persisting increase in solid cancer risks, the LSS should continue to provide important new information on radiation exposure and solid cancer risks for at least another 15 to 20 years.

Time course study on the development of allergen-induced airway remodeling in mice: the effect of allergen avoidance on established airway remodeling.

OBJECTIVE AND DESIGN: We carried out a time course study on the development of allergen-induced airway remodeling in a mouse model of allergic asthma. Moreover, we examined the effect of allergen avoidance on the established airway remodeling. MATERIALS AND METHODS: BALB/c mice were sensitized to ovalbumin (OA) with alum, and exposed daily for 3 weeks to aerosolized OA. At each designated point, bronchial responsiveness was measured, and bronchoalveolar lavage and histological examination were carried out. RESULTS: The numbers of inflammatory leukocytes in the airways and the percentage of goblet cells in the epithelium, Th2 cytokine production, IgE production, collagen deposition beneath the basement membrane and bronchial responsiveness to acetylcholine were all markedly increased after repeated antigen challenge for 1-3 weeks. In contrast, after cessation of antigen exposure, goblet cell hyperplasia, inflammatory infiltrates and bronchial hyperresponsiveness were gradually attenuated and had almost resolved 4 weeks after cessation, but subepithelial fibrosis was still observed at this time point. CONCLUSIONS: The present findings demonstrated that epithelial changes following repeated allergen challenge are rapidly induced and recover after the cessation of exposure, but subepithelial fibrosis has a late onset and relatively irreversible changes, and subepithelial fibrosis in contrast to goblet cells hyperplasia did not appear to contribute to bronchial hyperresponsiveness, at least, in this mouse model.

Disruption of antigen-induced airway inflammation and airway hyper-responsiveness in low affinity neurotrophin receptor p75 gene deficient mice.

1. Recently, much attention has been paid to the relationship between the nervous and immune systems. The present study was conducted to clarify the role of neurotrophin low affinity receptor (p75N) in allergic airway inflammation and hyper-responsiveness (AHR) in mice by employing p75N gene deficient mice. 2. Mice were immunized twice by intraperitoneal injections of ovalbumin (OA) at intervals of 12 days. OA was inhaled 10 days after the secondary immunization and repeated three times at 4 days interval. Twenty-four hours after the last inhalation, airway responsiveness to acetylcholine was measured and bronchoalveolar lavage fluid (BALF) was obtained for examining the number of inflammatory cells and the level of cytokines. Serum immunoglobulin was measured as a marker of systemic immune response before the final inhalation. 3. In wild-type mice, repeated antigen provocation resulted in airway eosinophilia, AHR and elevations in serum IgE and interleukin (IL)-4 and -5 in BALF. In p75N gene deficient mice, none of the above parameters was observed after antigen provocation. The antigen-induced production of interferon (IFN)-gamma and nerve growth factor (NGF) were not altered by depletion of p75N gene. 4. The present findings suggest that p75 gene deficiency disrupt an allergic airway inflammation and AHR in mice by interfering type 2 helper T (Th2) cell responses.

Liver cancer in atomic-bomb survivors: histological characteristics and relationships to radiation and hepatitis B and C viruses.

Histological features of primary liver cancer among atomic-bomb survivors and their relationship to hepatitis B (HBV) and C viral (HCV) infections are of special interest because of the increased risk of liver cancer in persons exposed to ionizing radiation and the high and increasing liver cancer rates in Japan and elsewhere. We conducted a pathology review of liver cancers occurring from 1958 to 1987 among subjects in the 120,321 member cohort of 1945 Hiroshima and Nagasaki residents. A panel of pathologists classified tumor histological types and defined accompanying cirrhotic changes of the liver. Archival tissue samples were assessed for HBV using pathology stains and PCR. Reverse transcriptase (RT) PCR was used to determine HCV status. We used unconditional logistic regression to compare 302 hepatocellular carcinoma (HCC) cases to 53 cholangiocarcinoma (CC) cases, adjusting for age, year of diagnosis, sex and viral status. Cirrhotic changes occurred significantly more often among HCC than CC cases (76% in HCC and 6% in CC). Compared to CC cases, HCC cases were 10.9 times more likely to be HBV-positive (95% confidence interval: 2.1-83.2) and 4.3 times more likely to be HCV-positive (95% confidence interval: 1.1-20.5). No significant differences were found between HCC and CC cases in radiation exposures. The predominance of HCC in the atomic-bomb survivors follows the background liver cancer pattern in Japan. Our findings suggest that HBV and HCV are involved in the pathogenesis of HCC with or without cirrhosis and are significantly less important in that of CC.

Spatial and temporal analysis of left ventricular filling flow propagation in hypertensive patients before and after regression of myocardial hypertrophy with alacepril therapy.

The purpose of this study was to assess the clinical significance of spatial and temporal analysis of left ventricular (LV) filling-flow propagation using color M-mode Doppler echocardiography before and after regression of LV hypertrophy in patients with hypertension. Seven patients with hypertensive LV hypertrophy were studied. Echocardiographic and Doppler examinations were performed both before and after 6 months administration of alacepril. LV mass index (LVMI), LV flow propagation velocity (FPV), and the maximal early transmitral flow velocity (E) were measured. LVMI, FPV, and FPV/E ratio were compared to before and after administration of alacepril. In addition, the correlation between LVMI and FPV/E ratio was evaluated. Results showed that LVMI was significantly decreased (P < 0.05) and the FPV/E ratio was significantly increased (P < 0.05) after treatment with alacepril. There was no significant change in FPV. In addition, there was a significant negative correlation between LVMI and the FPV/E ratio (r = -0.662, P < 0.001). The present study indicates that the FPV/E ratio could be a useful noninvasive parameter to assess the diastolic dysfunction associated with LV hypertrophy in patients with hypertension.

Temporal changes in liver cancer incidence rates in Japan: accounting for death certificate inaccuracies and improving diagnostic techniques.

Primary liver cancer (PLC) rates have risen dramatically during the past few decades in some regions, particularly in Japan, where PLC is now the third major cause of cancer death. PLC is one of the most difficult tumors to diagnose correctly, because (i) the liver is a frequent site of cancer metastasis and (ii) death from PLC is often attributed to cirrhosis or chronic hepatitis. Also, because the disease is often rapidly fatal, a large proportion of liver cancer cases are identified based on death certificates alone without confirmation by clinical records. Thus, worldwide differences in published incidence rates for this disease reflect regional or national differences in both the accuracy of death certificates and the sensitivity of diagnostic methods. By comparing death certificate causes of death with those based on pathology review, we were able to adjust 1958--1994 incidence rates for a large Japanese cohort for these errors. Although the death certificate false-positive error rate declined, the false-negative error rate remained high throughout the study. The introduction of improved liver cancer diagnostic methods in Japan in the early 1980s was associated with a sharp increase in PLC incidence. We conclude that errors in death certificate causes of death and changes in liver cancer diagnostic techniques have had an important impact on the reported incidence of this disease. Taking these factors into account, rates of hepatocellular carcinoma rose between 2.4- and 4.3-fold in our Japanese cohort from 1960 to 1985, peaked about 1993 and declined thereafter. Incidence rates of cholangiocarcinoma remained stable through 1987.

The effect of leukotriene D(4) inhalation on the antigen-induced airway hyperresponsiveness and inflammation in 5-lipoxygenase gene-deficient mice.

BACKGROUND: The role of 5-lipoxygenase (5-LO) products in the asthmatic bronchoconstriction is evident. However, the role of 5-LO products in airway hyperresponsiveness (AHR) and airway inflammation is still under discussion. The aim of the present study is to investigate the role of leukotriene D(4) (LTD(4)) in AHR and allergic airway eosinophilia in mice. METHODS: The effect of LTD(4) inhalation on antigen-induced AHR and airway eosinophilia was investigated in 5-LO gene-deficient mice. RESULTS: After three inhalations of LTD(4), airway responsiveness to acetylcholine was not altered in normal or allergic wild-type and 5-LO knockout (KO) mice. In contrast, the number of eosinophils in 5-LO KO allergic mice increased to the level of wild-type allergic mice after the inhalation of LTD(4). These observations were confirmed by a histopathological study of the lungs. No change in the cytokine levels in bronchoalveolar lavage fluid and serum immunoglobulin levels was shown after LTD(4) inhalation. CONCLUSION: These findings suggest that LTD(4) plays a role in eosinophilic airway inflammation but not in AHR in mice.

The effect of allergen-induced airway inflammation on airway remodeling in a murine model of allergic asthma.

OBJECTIVE AND DESIGN: We examined the effect of airway inflammation on airway remodeling and bronchial responsiveness in a mouse model of allergic asthma. MATERIALS AND METHODS: BALB/c mice were sensitized to ovalbumin (OA), and exposed to aerosolized OA (0.01, 0.1 and 1%). Twenty-four hours after the final antigen challenge, bronchial responsiveness was measured, and bronchoalveolar lavage (BAL) and histological examinations were carried out. RESULTS: Repeated antigen exposure induced airway inflammation, IgE/IgG1 responses, epithelial changes, collagen deposition in the lungs, subepithelial fibrosis associated with increases in the amount of transforming growth factor (TGF)-beta1 in BAL fluid (BALF), and bronchial hyperresponsiveness to acetylcholine. The number of eosinophils in BALF was significantly correlated with TGF-beta1 production in BALF and the amount of hydroxyproline. Furthermore, significant correlations were found between these fibrogenic parameters and the bronchial responsiveness. CONCLUSION: These findings demonstrated that in this murine model airway eosinophilic inflammation is responsible for the development of airway remodeling as well as bronchial hyperresponsiveness in allergic bronchial asthma.

Novel mutations in the myocilin gene in Japanese glaucoma patients.

Myocilin is a gene responsible for juvenile onset primary open angle glaucoma (POAG) mapped as the GLC1A locus and, many mutations have been reported worldwide. Some mutations were found not only in patients with juvenile onset POAG, but also in patients with late onset POAG and in patients with normal tension glaucoma. To investigate the mutation prevalence in Japan, we performed a mutation analysis in 140 unrelated Japanese patients. We have identified the 10 sequence variants, of which four were highly probable for disease-causing mutations (Arg46ter, Arg158Gln, Ile360Asn, and Ala363Thr), and six polymorphisms (Gln19His, Arg76Lys, Asp208Glu, Val439Val, Arg470His, and Ala488Ala). Thus, myocilin mutations were found at the rate of 4/140 (2.9%) probands, similar to previous reports with other ethnic populations.

Effects of radiation on incidence of primary liver cancer among atomic bomb survivors.

We describe the radiation risk for primary liver cancers between 1958 and 1987 in a cohort of atomic bomb survivors in Hiroshima and Nagasaki, Japan. The analysis is based on a comprehensive pathology review of known or suspected liver neoplasms that generated 518 incident, first primary cases, mostly hepatocellular carcinoma. Excess relative risk from atomic bomb radiation was linear: 0.81 per sievert weighted liver dose (95% CI [0.32, 1.43]; P < 0.001). Males and females had similar relative risk so that, given a threefold higher background incidence in males, the radiation-related excess incidence was substantially higher in males. Excess risk peaked for those with age at exposure in the early 20s; there was essentially no excess risk in those exposed before age 10 or after age 45. Whether this was due to a difference in sensitivity or possible confounding by other factors could not be addressed retrospectively in the full cohort. A paucity of cholangiocarcinoma and hemangiosarcoma cases suggested that they are not significantly associated with whole-body radiation exposure, as they are with the internal alpha-particle-emitting radiological contrast medium Thorotrast. Because most of the radiation-related excess cases occurred among males, it is important to ascertain what factors put men at greater risk of radiation-related liver cancer.

Skin tumor risk among atomic-bomb survivors in Japan.

OBJECTIVES: Elevated risks of skin cancer following high doses of ionizing radiation have long been known. Recent reports on atomic-bomb survivors indicate that nonmelanoma skin cancer can be induced at low to medium doses. We studied atomic-bomb survivors to determine the effects of radiation on specific histologic types of skin cancer and to describe the dose-response relationship. METHODS: Cases of melanoma, nonmelanoma skin cancers, and Bowen's disease were ascertained between 1958 and 1987 for the 80,000 cohort members through the population-based Hiroshima and Nagasaki (Japan) tumor registries augmented by searches of other records. RESULTS: An excess of basal cell carcinoma (n = 80), with some suggestion of a non-linear dose-response, was observed. The excess risk decreased markedly as age at exposure increased, and there was no evidence for an interaction between ionizing and ultraviolet radiation. No dose-response was found for squamous cell carcinoma (n = 69). The excess relative risk point-estimates were large, but statistically nonsignificant for both melanoma (n = 10) and Bowen's disease (n = 26). CONCLUSIONS: The basal layer of the epidermis appears to be quite sensitive to radiation carcinogenesis, particularly at a young age. The suprabasal layer seems to be more resistant, as shown by the lack of an association for squamous cell carcinomas.

RNA from decades-old archival tissue blocks for retrospective studies.

The validity of molecular studies using DNA and RNA extracted from decades-old formalin-fixed and paraffin-embedded tissue blocks has been demonstrated. The quality and usability of DNA and RNA from archival tissues are modified by various factors, such as the fixative, the fixation time, and the postmortem time. However, in contrast to DNA, there are no comprehensive studies quantitatively addressing the feasibility of RNA from old (more than 10 years) archival samples. This study examined the integrity of RNA extracted from 738 autopsy liver and 63 autopsy thyroid cancer tissue blocks procured during a span of nearly four decades, beginning in 1952 and ending in 1989, from the atomic bomb survivors. The integrity of RNA was assessed by amplification of c-BCR messenger RNA (mRNA) between two sequential exons with an intervening intron by reverse-transcription polymerase chain reaction (RT-PCR). The integrity of RNA was influenced by the age of the samples and the postmortem time, but not by the formalin-fixation period. It was possible to amplify more than 60% of the samples. Using these RNAs, the HCV genome in liver cancers and the H4-RET gene in thyroid cancers were detectable. This study illustrates the possibility of molecular studies using RNA from routinely prepared paraffin blocks stored for long periods and provides the statistics and critical factors to consider in assessing the feasibility of such contemplated studies.

Salivary gland tumors among atomic bomb survivors, 1950-1987.

BACKGROUND: Malignant and benign tumors of the salivary glands have been associated with exposure to ionizing radiation from various sources, including the atomic bombings in Hiroshima and Nagasaki. However, questions remain unanswered regarding the nature and size of the risk and specific types of tumors involved. METHODS: The incidence and pathology of malignant and benign tumors of the salivary glands was studied in the Life Span Study cohort of atomic bomb survivors followed by the Radiation Effects Research Foundation (RERF) in Hiroshima and Nagasaki, Japan. Incident cases diagnosed during the period 1950-1987 were ascertained from the tumor and tissue registries of Hiroshima and Nagasaki and supplemented by additional case findings from autopsy, biopsy, and surgical specimens maintained at RERF and other institutions. Pathology slides and medical documents were reviewed by a panel of four pathologists who classified tumors using the World Health Organization classification scheme. Analyses were performed of histologic features associated with radiation exposure. RESULTS: Of 145 tumors of the salivary glands identified (119 of the major and 26 of the minor salivary glands), 120 (83%) were histologically confirmed by the current investigators. Among 41 malignant tumors, the frequency of mucoepidermoid tumor was disproportionately high at high radiation doses (P = 0.04); among 94 benign tumors, the frequency of Warthin's tumor increased with increasing radiation dose (P = 0.06). The nature of the tumor was undetermined for the remaining ten cases. Mortality from malignant tumors of the salivary gland was inversely related to radiation dose, reflecting the predominance of mucoepidermoid carcinoma at high dose levels in this series. In one case with high radiation exposure, mucoepidermoid carcinoma of the parotid gland was accompanied by a preexisting or coexisting Warthin's tumor. CONCLUSIONS: These findings, supported by population-based analyses in a companion study reported elsewhere, suggest a causal role for ionizing radiation in salivary gland tumorigenesis, particularly for mucoepidermoid carcinoma, and in the induction of one type of benign tumor (Warthin's tumor).

Incidence of salivary gland tumors among atomic bomb survivors, 1950-1987. Evaluation of radiation-related risk.

A wide-ranging search for benign and malignant tumors of the major and minor salivary glands among members of the Life Span Study sample of the Radiation Effects Research Foundation identified 41 malignant and 94 benign incident tumors, including 14 malignant and 12 benign tumors of the minor salivary gland, plus 10 major gland tumors of unknown behavior. Dose-response analyses found statistically significant increases in risk with increasing A-bomb dose for both cancer and benign tumors. Estimated relative risks at 1 Sv weighted tissue kerma (RR1Sv, with 90% confidence interval in parentheses) were 4.5 (2.5-8.5) for cancer and 1.7 (1.1-2.7) for benign tumors. When analyzed by histological subtype within these two broad groups, it appeared that most of the dose response for malignant tumors was provided by an exceptionally strong dose response for mucoepidermoid carcinoma [11 exposed cases with dose estimates, RR1Sv = 9.3 (3.5-30.6)], and most or all of that for benign tumors corresponded to Warthin's tumor [12 cases, RR1Sv = 4.1 (1.6-11.3)]. There was a marginal dose response for malignant tumors other than mucoepidermoid carcinoma [RR1Sv = 2.4 (0.99-5.7)] but no significant trend for benign tumors other than Warthin's tumor [RR1Sv = 1.3 (0.9-2.2)]. Re-examination of the original data from published studies of other irradiated populations may shed new light on the remarkable type specificity of the salivary tumor dose response observed in the present study.

[Changes in serum lipoprotein (a) levels related to hyperlipidemia during pregnancy--comparing normal pregnancy and toxemia of pregnancy].

In this study, we investigated fluctuations in serum lipoprotein (a) (Lp(a)) levels in normal and toxemic pregnancy. We measured serum total cholesterol (TC), triglyceride (TG), phospholipid (PL), high-density lipoprotein (HDL), apolipoprotein and Lp(a) levels in 33 normal pregnant and 11 toxemic pregnant women at delivery and in 47 normal pregnant women throughout gestation. Lp(a) and apolipoproteins were detected by turbidimetric immunoassay. The levels of serum lipids, HDL and apolipoproteins were all increased in pregnancy. In toxemia of pregnancy, serum TC and PL levels were lower (p < 0.05) and the apolipoprotein C-III level was higher (p < 0.005) than in normal pregnancy. Serum Lp(a) levels increased until the 20th week and reached a value which was 1.5 times higher than at the 10th week. Thereafter Lp(a) levels were constant until the late stage of pregnancy. In contrast, serum TC and TG levels increased steadily throughout gestation. The serum Lp(a) level was 18.1 +/- 27.5mg/dl in normal pregnancy and 17.8 +/- 17.9mg/dl in toxemia of pregnancy. These results revealed changes in serum Lp(a) levels during pregnancy. Further studies will be required to clarify the metabolic control of Lp(a) in pregnancy and the matabolic disorders of lipids and lipoproteins in toxemia of pregnancy.

Effect of culture supernatants of endometriotic lesions, uterine endometrium and peritoneum from rats with experimental endometriosis on the natural killer activity of spleen cells.

Experimental endometriosis in rats was induced by autotransplanting the uterine endometrium to the peritoneum. In all rats, endometrial implants developed into endometriotic tissues similar to those in humans about 2 weeks after transplantation. Natural killer (NK) activity of spleen cells in the endometriosis model rats was significantly (p < 0.05) lower than that in the sham-operated intact rats. The inhibited NK activity in the endometriosis rats recovered to the level in intact rats with danazol (but not buserelin). The supernatant after 24-hour culture of endometrial tissues from both intact and model rats seemed to have significant inhibitory effects on NK activity. The supernatant from endometrial grafts showed significantly (p < 0.05) higher inhibitory effects than that from the endometrial tissues. The inhibitory effects were significantly (p < 0.05) reduced by treatment with danazol or buserelin to the untreated level. In addition, supernatants of unaffected peritoneal tissues from the endometriosis rats had significantly (p < 0.01) higher inhibitory effects on NK activity than those from the intact rats. Even when uterine serosa or silicone was implanted to the peritoneum, the supernatants of the contralateral peritoneal tissues showed significantly (p < 0.05) higher inhibitory effects than those from the intact rats, while having significantly (p < 0.05) lower inhibitory effects than those from the endometriosis rats. These results suggest that this marked inhibitory effect on NK activity by the peritoneum may be associated with the development and progression of endometriosis.