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.

Breast cancer risk after radiotherapy for heritable and non-heritable retinoblastoma: a US-UK study.

BACKGROUND: Retinoblastoma is a rare childhood eye cancer caused by germline or somatic mutations in the RB1 gene. Previous studies observed elevated breast cancer risk among retinoblastoma survivors. However, there has been no research on breast cancer risk in relation to radiation (primarily scatter radiation from the primary treatment) and genetic susceptibility of retinoblastoma survivors. METHODS: Two groups of retinoblastoma survivors from the US and UK were selected, and breast cancer risk analysed using a case-control methodology, nesting within the respective cohorts, matching on heritability (that is to say, having bilateral retinoblastoma or being unilateral cases with at least one relative with retinoblastoma), and using exact statistical methods. There were a total of 31 cases and 77 controls. RESULTS: Overall there was no significant variation of breast cancer risk with dose (P>0.5). However, there was a pronounced and significant (P=0.047) increase in the risk of breast cancer with increasing radiation dose for non-heritable retinoblastoma patients and a slight and borderline significant (P=0.072) decrease in risk of breast cancer with increasing radiation dose for heritable retinoblastoma patients, implying significant (P=0.024) heterogeneity in radiation risk between the heritable and non-heritable retinoblastoma groups; this was unaffected by the blindness status. There was no significant effect of any type of alkylating-agent chemotherapy on breast cancer risk (P>0.5). CONCLUSIONS: There is significant radiation-related risk of breast cancer for non-heritable retinoblastoma survivors but no excess risk for heritable retinoblastoma survivors, and no significant risk overall. However, these results are based on very small numbers of cases; therefore, they must be interpreted with caution.

Male infertility in long-term survivors of pediatric cancer: a report from the childhood cancer survivor study.

PURPOSE: The purpose of this study was to assess the prevalence of male infertility and treatment-related risk factors in childhood cancer survivors. METHODS: Within the Childhood Cancer Survivor Study, 1,622 survivors and 274 siblings completed the Male Health Questionnaire. The analysis was restricted to survivors (938/1,622; 57.8 %) and siblings (174/274; 63.5 %) who tried to become pregnant. Relative risks (RR) and 95 % confidence intervals (CI) for the prevalence of self-reported infertility were calculated using generalized linear models for demographic variables and treatment-related factors to account for correlation among survivors and siblings of the same family. All statistical tests were two-sided. RESULTS: Among those who provided self-report data, the prevalence of infertility was 46.0 % in survivors versus 17.5 % in siblings (RR = 2.64, 95 % CI 1.88-3.70, p < 0.001). Of survivors who met the definition for infertility, 37 % had reported at least one pregnancy with a female partner that resulted in a live birth. In a multivariable analysis, risk factors for infertility included an alkylating agent dose (AAD) score ≥3 (RR = 2.13, 95 % CI 1.69-2.68 for AAD ≥3 versus AAD <3), surgical excision of any organ of the genital tract (RR = 1.63, 95 % CI 1.20-2.21), testicular radiation ≥4 Gy (RR = 1.99, 95 % CI 1.52-2.61), and exposure to bleomycin (RR = 1.55, 95 % CI 1.20-2.01). CONCLUSION: Many survivors who experience infertility father their own children, suggesting episodes of both fertility and infertility. This and the novel association of infertility with bleomycin warrant further investigation. IMPLICATIONS FOR CANCER SURVIVORS: Though infertility is common, male survivors reporting infertility often father their own children. Bleomycin may pose some fertility risk.

Longitudinal patterns of psychological distress in adult survivors of childhood cancer.

BACKGROUND: This study investigated longitudinal patterns of psychological distress in adult survivors of childhood cancer. METHODS: Participants included 4569 adult survivors in the Childhood Cancer Survivor Study Cohort (CCSS) who completed the Brief Symptom Inventory-18 on three occasions between 1994 and 2010. Longitudinal latent class analysis was used to identify discrete classes of psychological distress. Predictors of class membership were examined through logistic regression modelling with odds ratios (ORs) and 95% confidence intervals (CIs) reported. RESULTS: Survivors were a median of 39 years of age and 30 years from diagnosis at the most recent follow-up. Most survivors reported few or no symptoms of distress over time, although subsets of survivors reported persistently elevated (depression: 8.9%; anxiety: 4.8%; somatisation: 7.2%) or significant increases in distress symptoms over the follow-up period (depression: 10.2%; anxiety: 11.8%; somatisation: 13.0%). Increasing distress symptoms were predicted by survivor perception of worsening physical health over time (depression: OR=3.3; 95% CI=2.4-4.5; anxiety: OR=3.0; 95% CI=2.2-4.0; somatisation: OR=5.3; 95% CI=3.9-7.4). Persistent distress symptoms were also predicted by survivor perception of worsening physical health over time, as well as by worsening pain and ending analgesic use. CONCLUSION: Subgroups of adult survivors are at-risk for chronic distress or significant increases in distress decades following their original cancer diagnosis. Routine screening of psychological distress in adult survivors of childhood cancer is warranted, especially for survivors who experience physical health morbidities.

Long-term survival among Hodgkin's lymphoma patients with gastrointestinal cancer: a population-based study.

BACKGROUND: The increased risk of gastrointestinal (GI) cancers after Hodgkin's lymphoma (HL) is well established. However, no large population-based study has described the actuarial survival after subsequent GI cancers in HL survivors (HL-GI). PATIENTS AND METHODS: For 209 patients with HL-GI cancers (105 colon, 35 stomach, 30 pancreas, 21 rectum, and 18 esophagus) and 484 165 patients with first primary GI cancers (GI-1), actuarial survival was compared, accounting for age, gender, race, GI cancer stage, radiation for HL, and other variables. RESULTS: Though survival of HL patients who developed localized stage colon cancer was similar to that of the GI-1 group, overall survival (OS) of HL patients with regional or distant stage colon cancer was reduced [hazard ratio, (HR)=1.46, P=0.01]. The HL survivors with regional or distant stage colon cancer in the transverse segment had an especially high risk of mortality (HR: 2.7, P=0.001 for OS). For localized stomach cancer, OS was inferior among HL survivors (HR=3.46, P=0.006). CONCLUSIONS: The HL patients who develop GI cancer experience significantly reduced survival compared with patients with a first primary GI cancer. Further research is needed to explain the inferior survival of HL patients and to define selection criteria for cancer screening in HL survivors.

Melanoma as a subsequent neoplasm in adult survivors of childhood cancer: a report from the childhood cancer survivor study.

BACKGROUND: Childhood cancer survivors have a sixfold increased risk of developing subsequent neoplasms when compared to the general population. We sought to describe the occurrence of melanoma as a subsequent neoplasm among adult survivors of childhood cancer. PATIENTS AND METHODS: Among 14,358 5-year survivors of childhood cancer diagnosed between 1970 and 1986, we calculated the cumulative incidence, standardized incidence ratio (SIR), and absolute excess risk (AER) of subsequent melanoma. Potential risk factors were assessed using a cause-specific hazards model. RESULTS: Fifty-seven melanomas (46 invasive, 2 ocular, and 9 in situ) occurred in 51 survivors. The median time to the development of melanoma was 21.0 years (range: 5.6-35.4 years) and the median age at melanoma was 32.3 years (range: 10.9-49.0 years). Initial cancer diagnoses included soft tissue and bone sarcoma (n = 15), leukemia (13), lymphoma (14), central nervous system malignancy (5), Wilms tumor (3), and neuroblastoma (1). The cumulative incidence of first subsequent melanoma at 35 years from initial cancer diagnosis was 0.55% [95% confidence interval (CI): 0.37-0.73]. The SIR of subsequent invasive malignant melanoma of the skin was 2.42 (95% CI: 1.77-3.23), and the AER was 0.10 (95% CI: 0.05-0.15) per 1,000 person-years. No statistically significant associations were found between melanoma risk and family history of cancer, demographic, or treatment-related factors. CONCLUSION: Survivors of childhood cancer have an approximate 2.5-fold increased risk of melanoma. Early screening and prevention strategies are warranted.

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.

Second solid cancers after radiotherapy for breast cancer in SEER cancer registries.

BACKGROUND: Radiotherapy for breast cancer reduces disease recurrence and breast cancer mortality. However, it has also been associated with increased second cancer risks in exposed sites. METHODS: We evaluated long-term second cancer risks among 182 057 5-year survivors of locoregional invasive breast cancer diagnosed between 1973 and 2000 and reported to US NCI-SEER Program cancer registries. Multivariate Poisson regression was used to estimate the relative risk (RR) and excess cases of second cancer in women who had surgery and radiotherapy, compared with those who had surgery alone. Second cancer sites were grouped according to doses received from typical tangential breast fields. RESULTS: By the end of 2005 (median follow-up=13.0 years), 15 498 second solid cancers had occurred, including 6491 contralateral breast cancers. The RRs for radiotherapy were 1.45 (95% confidence interval (CI)=1.33-1.58) for high-dose second cancer sites (1+ Gy: lung, oesophagus, pleura, bone and soft tissue) and 1.09 (1.04-1.15) for contralateral breast cancer ( approximately 1 Gy). These risks decreased with increasing age and year of treatment. There was no evidence of elevated risks for sites receiving medium (0.5-0.99 Gy, RR=0.89 (0.74-1.06)) or low doses (<0.5 Gy, RR=1.01 (0.95-1.07)). The estimated excess cases of cancer in women treated with radiotherapy were as follows: 176 (95% CI=69-284) contralateral breast cancers or 5% (2-8%) of the total in all 1+year survivors, and 292 (222-362) other solid cancers or 6% (4-7%) of the total. CONCLUSIONS: Most second solid cancers in breast cancer survivors are not related to radiotherapy.

Radiotherapy for childhood cancer and risk for congenital malformations in offspring: a population-based cohort study.

Offspring of childhood cancer survivors may be at risk of genetic disease due to the mutagenic cancer treatments received by their parents. Congenital malformations were evaluated in a population-based cohort study of 1715 offspring of 3963 childhood cancer survivors and 6009 offspring of 5657 survivors' siblings. The Danish Central Population Register, Cancer Registry and Hospital Register were used to identify study subjects and congenital malformations. Gonadal and uterine radiation doses were characterized based on standard radiation-treatment regimens. The prevalence of congenital malformations at birth in offspring of survivors (44 cases, 2.6%) was slightly higher but not statistically different from that of offspring of siblings (140 cases, 2.3%) [prevalence proportion ratio (PPR), 1.1; 95% confidence interval, 0.8-1.5] or of the general population (observed-to-expected ratio, 1.2; 0.9-1.6). Including malformations diagnosed later in life did not change the ratios appreciably. The risk for malformations was slightly higher in the offspring of irradiated parents than in that of non-irradiated parents (PPR 1.2 vs 1.0) but was unrelated to gonadal dose. This study provides evidence that cancer therapy of children does not increase the risk for malformations in their offspring. Continued monitoring of genetic risks among their offspring, however, is warranted.

Risk for contralateral breast cancer among carriers of the CHEK2*1100delC mutation in the WECARE Study.

The protein encoded by the CHEK2 gene is involved in cellular repair of DNA damage. The truncating mutation, CHEK2*1100delC, seems to increase the risk for breast cancer. We investigated whether the CHEK2*1100delC mutation carrier status increases the risk for asynchronous contralateral breast cancer (CBC) and whether it interacts with radiation therapy (RT) or chemotherapy in regard to CBC risk. The germline mutation frequency was assessed in 708 women with CBC and 1395 women with unilateral breast cancer (UBC) in the Women's Environment, Cancer and Radiation Epidemiology (WECARE) Study whose first primary breast cancer was diagnosed before age 55 years and during 1985--1999. Seven women with CBC (1.0%) and 10 women with UBC (0.7%) were CHEK2*1100delC variant carriers (rate ratio (RR)=1.8, 95% confidence interval (CI)=0.6-5.4 for CBC vs UBC). Carriers who received RT for their first breast cancer, compared with non-carriers not treated with RT, had an RR of developing CBC of 2.6 (95% CI=0.8-8.7). We found no significant associations between the CHEK2*1100delC mutation and CBC overall or among those treated with RT. However, the sampling variability was such that modest increases in risk could not be excluded. Nonetheless, because this is a rare mutation, it is unlikely to explain a major fraction of CBC in the population.

A study of soft tissue sarcomas after childhood cancer in Britain.

Among 16 541 3-year survivors of childhood cancer in Britain, 39 soft tissue sarcomas (STSs) occurred and 1.1 sarcomas were expected, yielding a standardised incidence ratio (SIR) of 16.1. When retinoblastomas were excluded from the cohort, the SIR for STSs was 15.9, and the cumulative risk of developing a soft tissue tumour after childhood cancer within 20 years of 3-year survival was 0.23%. In the case-control study, there was a significant excess of STSs in those patients exposed to both radiotherapy (RT) and chemotherapy, which was five times that observed among those not exposed (P=0.02). On the basis of individual radiation dosimetry, there was evidence of a strong dose-response effect with a significant increase in the risk of STS with increasing dose of RT (P<0.001). This effect remained significant in a multivariate model. The adjusted risk in patients exposed to RT doses of over 3000 cGy was over 50 times the risk in the unexposed. There was evidence of a dose-response effect with exposure to alkylating agents, the risk increasing substantially with increasing cumulative dose (P=0.05). This effect remained after adjusting for the effect of radiation exposure.

Airway generation-specific differences in the spatial distribution of immune cells and cytokines in allergen-challenged rhesus monkeys.

BACKGROUND: Accumulation of immune cell populations and their cytokine products within tracheobronchial airways contributes to the pathogenesis of allergic asthma. It has been postulated that peripheral regions of the lung play a more significant role than proximal airways with regard to inflammatory events and airflow obstruction. OBJECTIVE: To determine whether immune cell populations and associated cytokines are uniformly distributed throughout the conducting airway tree in a non-human primate model of allergic asthma. METHODS: We used a stereologic approach with a stratified sampling scheme to measure the volume density of immune cells within the epithelium and interstitium of trachea and 4-5 intrapulmonary airway generations from house dust mite (HDM) (Dermatophagoides farinae)-challenged adult monkeys. In conjunction with immune cell distribution profiles, mRNA levels for 21 cytokines/chemokines and three chemokine receptors were evaluated at four different airway generations from microdissected lungs. RESULTS: In HDM-challenged monkeys, the volume of CD1a+ dendritic cells, CD4+ T helper lymphocytes, CD25+ cells, IgE+ cells, eosinophils, and proliferating cells were significantly increased within airways. All five immune cell types accumulated within airways in unique patterns of distribution, suggesting compartmentalized responses with regard to trafficking. Although cytokine mRNA levels were elevated throughout the conducting airway tree of HDM-challenged animals, the distal airways (terminal and respiratory bronchioles) exhibited the most pronounced up-regulation. CONCLUSION: These findings demonstrate that key effector immune cell populations and cytokines associated with asthma differentially accumulate within distinct regions and compartments of tracheobronchial airways from allergen-challenged primates.

Epidemiology of microsporidiosis: sources and modes of transmission.

Microsporidia are single-celled, obligate intracellular parasites that were recently reclassified from protozoa to fungi. Microsporidia are considered a cause of emerging and opportunistic infections in humans, and species infecting humans also infect a wide range of animals, raising the concern for zoonotic transmission. Persistent or self-limiting diarrhea are the most common symptoms associated with microsporidiosis in immune-deficient or immune-competent individuals, respectively. Microsporidian spores appear to be relatively resistant under environmental conditions, and species of microsporidia infecting humans and animals have been identified in water sources, raising concern about water-borne transmission. Sensitive and specific immunomagnetic bead separation and PCR-based methods are being developed and applied for detecting microsporidia in infected hosts and water sources for generating more reliable prevalence data. The most effective drugs for treating microsporidiosis in humans currently include albendazole, which is effective against the Encephalitozoon species but not against Enterocytozoon bieneusi, and fumagillin, which has broader anti-microsporidia activity but is toxic in mammals, suggesting a need to identify better drugs. Strategies to capture and disinfect microsporidia in water are being developed and include filtration, coagulation, chlorination, gamma-irradiation, and ozonation.

[No convincing evidence for a causal relationship between childhood nasopharyngeal radium irradiation and head-neck tumors or hormone-related disorders later in life; a retrospective cohort study]. / Geen overtuigend bewijs voor een causaal verband tussen nasofaryngeale radiumbestraling op de kinderleeftijd en latere hoofd-halstumoren en hormonale aandoeningen; een historisch cohortonderzoek.

OBJECTIVE: To study the risk of malignant and benign tumours and hormone-related disorders among patients treated with nasopharyngeal radium irradiation for hypertrophic adenoid or hearing loss caused by otitis media serosa. DESIGN: Retrospective cohort study. METHOD: The medical record registries of 9 hospitals were used to identify a radium-exposed group (n = 5358) and a control group of unexposed patients (n = 5265), who were treated by an otolaryngologist in the period 1945-1981. The vital status of the subjects was determined using municipal resident registries, and the cause of death of decedents was retrieved from Statistics Netherlands (1950-1997). The data was also coupled with the Netherlands Cancer Registry (1989-1996). For the subjects still alive in 1997, the prevalence of relevant disorders was determined using a self-administered questionnaire and disorders reported by the participants were medically verified. The risk of disease in the radium group was then compared with that of the control group. RESULTS: The average radiation doses were 2.75, 0.109 and 0.015 Gy for nasopharynx, pituitary, and thyroid, respectively. There was no statistically significantly elevated risk for malignancies of the head and neck area (radium-exposed group; n = 14; control group: n = 11 (relative risk (RR): 1.2; 95% CI: 0.6-2.8)). Four of the five thyroid carcinomas were found in the radium-exposed group (RR: 3.8; 0.5-76). Elevated risks were observed for breast cancer (RR: 1.6; 0.9-2.7) and non-Hodgkin's lymphoma (RR: 2.7; 1.0-8.7). There was an increased risk for skin basal cell carcinoma (BCC) of the head and neck (odds ratio (OR): 2.6; 1.0-6.7), but the risk of BCC of other body parts was lower (OR: 0.3; 0.1-1.3). There were no major differences between radium and control subjects with respect to benign head and neck tumours (OR: 1.0; 0.5-1.7) or hormonal disorders. Exposed men reported slightly more fertility disorders than men in the control group (OR: 1.4; 1.0-2.1), but there was no clear dose-response relationship. CONCLUSION: After a mean follow-up of 31 years, there was no strong evidence for an elevated risk of head and neck tumours or hormone-related disorders in adulthood among subjects who had been treated with nasopharyngeal radium irradiation during childhood.

Sex ratio among offspring of childhood cancer survivors treated with radiotherapy.

It has been postulated that paternal gonadal exposure would increase the sex ratio by inducing X-chromosomal dominant lethals but that maternal gonadal exposure would decrease the sex ratio by inducing recessive sex-linked lethals. We therefore evaluated the sex ratio (male-to-female ratio) of children born to survivors of childhood cancers in Denmark. Children with cancer were identified from the Danish Cancer Registry from 1943 to 1996 and their offspring from the Central Population Registry. Radiation treatments were determined from records within the Cancer Registry and gonadal radiation exposures were estimated based on the cancer being treated and the likely proximity of the radiation fields to the gonads. Overall, 1100 survivors of childhood cancer became the parents of 2130 children. The sex ratio for male (0.99) and female (1.00) cancer survivors was similar and did not differ significantly from the Danish population (1.06). Radiotherapy did not influence the sex ratio of the children of either male or female survivors, and there was no evidence for dose-related changes over categories of estimated dose to parental gonads. We saw no consistent association between the sex ratio and the interval between cancer diagnosis of the parent and birth of the child. This nationwide study provides no support for the hypothesis that radiation exposure to the gonads results in an inherited genetic effect that would be manifested by a change in the sex ratio of children born after exposure. It may be, however, that sex ratio alterations are not a good or even a valid indicator of possible genetic effects in humans.

Lung cancer after treatment for Hodgkin's disease: focus on radiation effects.

Aspects of radiation-induced lung cancer were evaluated in an international study of Hodgkin's disease. The study population consisted of 227 patients with lung cancer and 455 matched controls. Unique features included dose determinations to the specific location in the lung where each cancer developed and quantitative data on both chemotherapy and tobacco use obtained from medical records. The estimated excess relative risk (ERR) per Gy was 0.15 (95% CI: 0.06-0.39), and there was little evidence of departure from linearity even though lung doses for the majority of Hodgkin's disease patients treated with radiotherapy exceeded 30 Gy. The interaction of radiation and chemotherapy that included alkylating agents was almost exactly additive, and a multiplicative relationship could be rejected (P = 0.017). Conversely, the interaction of radiation and smoking was consistent with a multiplicative relationship, but not with an additive relationship (P < 0.001). The ERR/Gy for males was about four times that for females, although the difference was not statistically significant. There was little evidence of modification of the ERR/Gy by time since exposure (after a 5-year minimum latent period), age at exposure, or attained age. Because of the very high radiation doses received by Hodgkin's disease patients and the immunodeficiency inherent to this lymphoma and that associated with chemotherapy, generalizing these findings to other populations receiving considerably lower doses of radiation should be done cautiously.

Effect of C-fiber-mediated, ozone-induced rapid shallow breathing on airway epithelial injury in rats.

We examined the relationship between C-fiber-mediated, ozone-induced rapid shallow breathing and airway epithelial cell injury at different airway sites within the lower respiratory tract of conscious Wistar rats (n = 24). We combined an acute 8-h ozone inhalation with vagal perineural capsaicin treatment, a selective C-fiber conduction block, and 5-bromo-2'-deoxyuridine (BrdU) labeling as an index of epithelial injury. Vehicle-treated rats that inhaled ozone developed a rapid shallow breathing pattern during ozone inhalation, whereas the capsaicin-treated rats that inhaled ozone showed no changes in respiratory frequency. In vehicle-treated, ozone-exposed rats that developed rapid shallow breathing, a progressive increase in BrdU-labeling density (no. of BrdU-labeled cells/mm(2) airway) was observed starting at the bifurcation of the left main stem bronchi (central airway) and going down either a short or long airway path. In vehicle-treated, ozone-exposed rats, terminal bronchioles supplied by short and long airway paths had a similar degree of BrdU-labeling density that was significantly (P < 0.05) greater than the BrdU-labeling density of the proximal airways that supply them. In contrast, the attenuation of rapid shallow breathing produced by capsaicin treatment resulted in a significantly reduced BrdU-labeling density in the terminal bronchioles supplied by short airway paths compared with the terminal bronchioles supplied by long airway paths. Our data indicate that ozone-induced rapid shallow breathing protects large conducting airways while producing a more even distribution of injury to terminal bronchioles.