Biomedical subjects

Gerald B Sharp

Publications and source records attributed to Gerald B Sharp.

11 recordsLinked to original sources

PubMed2006

Lack of association between acute exposure to ionizing radiation and liver cirrhosis.

PURPOSE: Although previous studies have shown significantly increased risks of liver cirrhosis and chronic liver disease for acute radiation exposure among survivors of the atomic bombings of Hiroshima and Nagasaki, Japan, these studies have not taken into account hepatitis B virus (HBV) infections. Because HBV is associated with both A-bomb radiation and liver cirrhosis, our goal was to investigate the relationship of acute ionizing radiation to liver cirrhosis adjusting for HBV, co-occurring primary liver cancer (PLC), and other potential confounders. MATERIALS AND METHODS: Using a cross-sectional design and pathology review of a cohort of Japanese atomic-bomb survivors, we found that 213 of 335 (63.6%) subjects with PLC and 55 of 776 (7.1%) subjects without PLC had cirrhosis. RESULTS: We found no association between acute exposure to A-bomb radiation and liver cirrhosis. The adjusted odds ratio of cirrhosis per Sv liver irradiation was 0.59 (95% confidence interval: 0.27 - 1.27). Cirrhosis risks for the highest tertile of radiation exposure (mean exposure 0.7 Sv) were also not elevated (0.8, 0.26 - 2.12 and 0.2, 0.03 - 0.98 among subjects with and without PLC. CONCLUSIONS: Acute exposure to liver irradiation does not increase risks of liver cirrhosis, regardless of PLC status.

Body Burden↗

PubMed2005

Eligibility criteria for HIV clinical trials and generalizability of results: the gap between published reports and study protocols.

OBJECTIVE: Applicability of randomized controlled clinical trial (RCT) results to 'real world' situations is dependent on the comparability of trial participants to general patient populations. A full disclosure of criteria employed for trial enrollment is necessary for clinicians to assess generalizability. We sought to assess both the impact on generalizability and the disclosure rate of enrollment criteria for 32 major HIV RCTs in the AIDS Clinical Trial Group (ACTG) and Community Programs for Clinical Research on AIDS (CPCRA) trial networks. DESIGN AND METHODS: Eligibility criteria were compared in complete protocols to criteria listed in publications from these 32 NIH-funded HIV RCTs. We then applied these criteria to the Women's Interagency HIV Study (WIHS), the largest cohort study of HIV-infected women in the US. RESULTS: When applied to WIHS, eligibility criteria from protocols excluded 0-67.6% (median 42%) of WIHS participants (50.6% excluded from ACTG trials). Eligibility criteria in publications excluded 0-62% (median 19.6%) of WIHS (21.2% excluded from ACTG trials). The number of women in WIHS seemingly ineligible for trial participation per enrollment criteria listed in publications averaged only 60% of those actually excluded based on the protocols. CONCLUSIONS: We found that HIV RCT eligibility criteria excluded a large proportion of a representative cohort of HIV-infected women from trial participation. Furthermore, trial publications are not fully reflective of protocols in terms of disclosing eligibility criteria. Standardization and full disclosure of trial methodology will allow clinicians and researchers to more fully assess the generalizability of findings to their patient populations.

Clinical Protocols↗

PubMed2005

Relationship of hepatocellular carcinoma to soya food consumption: a cohort-based, case-control study in Japan.

To determine if the risk of hepatocellular carcinoma (HCC) is reduced by consumption of soya foods, we conducted a case-control study within a cohort of Japanese A-bomb survivors. We compared the prediagnosis consumption of isoflavone-rich miso soup and tofu to HCC risk, adjusting for hepatitis B (HBV) and C (HCV) viral infections, the major HCC risk factors in this population. The study included 176 pathologist-confirmed cases of HCC diagnosed in 1964-1988 and 560 controls who died of diseases other than liver cancer. We examined dietary information collected at least 2 years before diagnosis or death and tissue-based measures of viral hepatitis. Using logistic regression, crude ORs were 0.5 (95% CI 0.29-0.95) and 0.5 (95% CI 0.20-0.99) for high vs. low miso soup and tofu intake, respectively. Adjusting for year of birth, sex, HBV, HCV and other factors, the OR for miso soup was unchanged at 0.5 (95% CI 0.14-1.55), and miso results were similar when ORs were recalculated separately for earlier and later birth cohorts to assess consistency of results. The adjusted OR for tofu was 0.9 (95% CI 0.20-3.51). We also found a statistically significant (p < 0.0001) interaction between sex and HCV, with risk of HCC being substantially higher for women. We conclude that consumption of miso soup and other soya foods may reduce HCC risk.

Carcinoma, Hepatocellular↗

PubMed2004

Improving the efficiency of nested case-control studies of interaction by selecting controls using counter matching on exposure.

BACKGROUND: Studies of the effect of exposure to a risk factor measured in an entire cohort may be augmented by nested case-control subsets to investigate confounding or effect modification by additional factors not practically assessed on all cohort members. We compared three control-selection strategies-matching on exposure, counter matching on exposure, and random sampling-to determine which was most efficient in a situation where exposure is a known, continuous variable and high doses are rare. METHODS: We estimated the power to detect interaction using four control-to-case ratios (1:1, 2:1, 4:1, and 8:1) in a planned case-control study of the joint effect of atomic bomb radiation exposure and serum oestradiol levels on breast cancer. Radiation dose is measured in the entire cohort, but because neither serum oestradiol level nor the true degree of interaction was known, we simulated values of oestradiol and hypothetical levels of oestradiol-radiation interaction. RESULTS: Compared with random sampling, power to detect interaction was similarly higher with either matching or counter matching with two or more controls. CONCLUSIONS: Because counter matching is generally at least as efficient as random sampling, whereas matching on exposure can result in loss of efficiency and precludes estimation of exposure risk, we recommend counter matching for selecting controls in nested case-control studies of the joint effects of multiple risk factors when one is previously measured in the full cohort.

Breast Neoplasms↗

PubMed2004

Allelic loss of a common microsatellite marker MYCL1: a useful prognostic factor of poor outcomes in colorectal cancer.

PURPOSE: Allelic loss involving chromosome arms 5q, 8p, 17p, and 18q is commonly detected in colorectal cancer (CRC). The short arm of chromosome 1 is also frequently affected in a whole range of cancer types, including CRC. Our aim in the present study was to determine whether allelic losses on 1p were likely to be of much value in predicting the prognosis of CRC cases. EXPERIMENTAL DESIGN: Genomic DNA was prepared from tumor and corresponding normal tissue specimens from 90 patients who had undergone curative resection for CRC. Loss of heterozygosity (LOH) on chromosome arms 1p, 2p, 5q, 7q, 8p, 17p, 17q, and 18q was examined using 14 microsatellite markers, and possible correlations between LOH and clinicopathological factors (including tumor recurrence and patient survival) were investigated. LOH at the MYCL1 microsatellite marker at 1p34 was detected in 12 of 74 (16.2%) patients who were informative for this marker. RESULTS: After controlling for tumor stage and gender and excluding findings for patients with remote metastasis, we found that patients who were positive for LOH at MYCL1 were 31 times more likely to experience recurrence than those who were negative for LOH at this locus (95% confidence intervals, 2.27- infinity; P = 0.04). There were indications of a similar tendency for LOH at the 14-3-3-sigma-TG microsatellite marker at 1p35, but we could find no evidence of a significant association between LOH at this site and tumor recurrence or patient survival. We were also unable to detect significant association between LOH at the various sites on 2p, 5q, 7q, 8p, 17p, 17q, and 18q and either tumor recurrence or patient survival. CONCLUSIONS: CRC patients whose tumors exhibited LOH at MYCL1 at chromosome 1p34 were likely to have a poor prognosis, suggesting that this marker may have clinical relevance.

Chromosome Mapping↗

PubMed2004

Uncertainty in estimating probability of causation in a cross-sectional study: joint effects of radiation and hepatitis-C virus on chronic liver disease.

Exposure to other risk factors is an important consideration in assessing the role played by radiation in producing disease. A cross-sectional study of atomic-bomb survivors suggested an interaction between whole-body radiation exposure and chronic hepatitis-C viral (HCV) infection in the etiology of chronic liver disease (chronic hepatitis and cirrhosis), but did not allow determination of the joint-effect mechanism. Different estimates of probability of causation (POC) conditional on HCV status resulted from additive and multiplicative models. We therefore estimated the risk for radiation conditional on HCV status using a more general, mixture model that does not require choosing between additivity or multiplicativity, or deciding whether there is interaction, in the face of the large uncertainty. The results support the conclusion that POC increases with radiation dose in persons without HCV infection, but are inconclusive regarding individuals with HCV infection, the lower confidence bound on estimated POC for radiation with HCV infection being zero over the entire dose range. Although the mixture model may not reflect the true joint-effect mechanism, it avoids restrictive model assumptions that cannot be validated using the available data yet have a profound influence on estimated POC. These considerations apply more generally, given that the additive and multiplicative models are often used in POC related work. We therefore consider that an empirical approach may be preferable to assuming a specific mechanistic model for estimating POC in epidemiological studies where the joint-effect mechanism is in doubt.

Cross-Sectional Studies↗

PubMed2003

Hypermethylation of O6-methylguanine-DNA methyltransferase promoter may predict nonrecurrence after chemotherapy in colorectal cancer cases.

PURPOSE: Because O(6)-methylguanine-DNA methyltransferase (MGMT) plays an essential role in repairing DNA damage caused by environmental alkylating chemicals, we were interested in determining whether we could see any obvious changes in the properties of colorectal cancers (CRCs) in which the MGMT gene had been silenced by hypermethylation and hence in which very few MGMT protein molecules were being produced. EXPERIMENTAL DESIGN: We used a methylation-specific PCR assay to determine the methylation status of the MGMT promoter in the DNA molecules extracted from CRC and nontumor tissue samples from 116 patients who had undergone CRC surgery and for whom clinical outcome information was available on file. RESULTS: We found evidence of MGMT promoter hypermethylation in 26 of 90 CRC cases, and we noted that the later the stage at which a tumor was diagnosed, the less likely its MGMT promoter was to be methylated (P = 0.03, adjusting for chemotherapy), especially for stage D patients (P = 0.01). We also found that CRC patients with unmethylated MGMT promoters were much more likely to experience recurrence within 36 months than patients with hypermethylated MGMT promoters (crude odds ratio, 14.0; 95% confidence interval, 2.42-81.01). After adjustment for stage, CRC patients with unmethylated MGMT promoters who had been exposed to chemotherapy were found to have a 5.3-fold greater risk of recurrence than those who had no exposure to chemotherapy (95% confidence interval, 1.15-30.92). CONCLUSIONS: Hypermethylation of the MGMT promoter may be predictive of a low risk of recurrence in CRC patients receiving adjuvant chemotherapy.

Aged↗

PubMed2003

Hepatocellular carcinoma among atomic bomb survivors: significant interaction of radiation with hepatitis C virus infections.

We conducted a nested case-control study within the cohort of Japanese survivors of the 1945 atomic bombings to study the joint effects of HBV and HCV with radiation on the risk of HCC. Among subjects who received autopsies during 1954-1988, we analyzed archival tissue samples for 238 pathologically confirmed HCC cases and 894 controls who died from diseases other than liver cancer. Using logistic regression and adjusting for potential confounders and other factors, we found a statistically significant, supermultiplicative interaction between A bomb radiation and HCV in the etiology of HCC. Compared to subjects who were negative for HCV and radiation, ORs of HCC for HCV-positive subjects showed a statistically significant, greater than multiplicative increase for liver irradiation exposures in the second (>0.018-0.186 Sv, p = 0.04) and third (>0.186 Sv, p = 0.05) tertiles of non-zero radiation exposure but not for first tertile exposure (>0-0.018 Sv, p = 0.86). Limiting analysis to subjects without cirrhosis, HCV-infected subjects were at 58.0-fold (95% CI 1.99- infinity ) increased risk of HCC per Sv of radiation exposure (p = 0.017), a supermultiplicative interaction between radiation and HCV that was not found among subjects with cirrhosis (p = 0.67). We found no evidence of interaction between HBV infection and radiation exposure in the etiology of HCC, regardless of cirrhosis status (p = 0.58). We conclude that among survivors of the nuclear bombings of Hiroshima and Nagasaki, subjects who were both HCV-positive and radiation-exposed were at a significantly, supermultiplicatively increased risk of HCC without concurrent cirrhosis.

Adult↗

PubMed2003

Joint effects of radiation and smoking on lung cancer risk among atomic bomb survivors.

Results are given on the joint effect of radiation exposure and cigarette smoking on lung cancer risks among A-bomb survivors, based on 592 cases through 1994. Information on smoking was derived from mail surveys and clinical interviews of 45113 persons in the Radiation Effects Research Foundation cohort. Radiation and smoking effects on lung cancer are found to be significantly sub-multiplicative and quite consistent with additivity. The smoking relative risk, previously very low in studies of this cohort, is now similar to that found in Western populations. This increase is likely to be related to the scarcity of cigarettes during and after the war. The smoking relative risk depends little on sex. After adjusting for smoking, the radiation-related risks relative to background rates for nonsmokers are similar to those for other solid cancers: a sex-averaged ERR/Sv of about 0.9 with a female:male sex ratio of about 1.6. Adjusting for smoking removes a spuriously large female:male ratio in radiation relative risk due to confounding between sex and smoking level. The adjustment also removes an artifactual age-at-exposure effect in the radiation relative risk, opposite in direction to other cancers, which is due to birth cohort variation in lung cancer rates.

Adult↗

PubMed2003

Prevalence of hepatitis B virus infection among atomic bomb survivors.

The aim of this study was to determine whether the prevalence of hepatitis B virus (HBV) carriers increased with atomic bomb radiation dose, and whether radiation decreased the ability to clear HBV among the atomic bomb survivors. The study subjects were 6,121 participants in the Adult Health Study of atomic bomb survivors in Hiroshima and Nagasaki. After adjustment for age, sex, city and potential confounders, the rates of seropositivity for hepatitis B surface antigen (HBsAg), indicating current HBV infections, and anti-hepatitis B core antibody, indicating either cured or current infections, increased with radiation dose. However, no relationship was observed between radiation and anti-hepatitis B surface antibody (indicating cured infection). The proportion of persons who were unable to clear the virus, as the proportion of HBsAg-positive persons among those ever infected by HBV (positive for HBsAg or surface or core hepatitis B antibody), increased significantly with radiation dose among those receiving blood transfusions. This proportion was not related to dose among those who reported no such transfusions. The findings may suggest a lower likelihood of clearance after HBV infection among those who were more likely to have been infected with HBV as adults after atomic bomb irradiation rather than as infants or adults prior to irradiation.

Adult↗

PubMed2002

The relationship between internally deposited alpha-particle radiation and subsite-specific liver cancer and liver cirrhosis: an analysis of published data.

Chronic exposure to high LET radiation has been shown to cause liver cancer in humans based on studies of patients who received Thorotrast, a colloidal suspension of thorium dioxide formerly used as a radiological contrast agent, and on studies of Russian nuclear weapons workers exposed to internally ingested plutonium. Risk estimates for these exposures and specific subtypes of liver cancer have not been previously reported. Combining published data with tumor registry data pertinent to the Thorotrast cohorts in Germany, Denmark, Portugal, and Japan and to Russian workers, we generally found significantly elevated risks of three major histologic types of liver tumors: hepatocellular carcinoma (HCC), cholangiocarcinoma (CC), and hemangiosarcoma (HS) for Thorotrast exposures. In contrast, HS was the only liver tumor significantly associated with the lower alpha-particle doses experienced by the Russian workers. Excess cases per 1,000 persons exposed to Thorotrast were similar for the three liver cancer subtypes but lower for plutonium exposure. Odds ratios (OR) of HS and CC for Thorotrast were from 26 to 789 and from 1 to 31 times higher than those for HCC, respectively. ORs of liver cirrhosis for Thorotrast exposure ranged from 2.7 (95% confidence interval (CI): 2.2-3.4) to 6.7 (5.1-8.7).

Alpha Particles↗