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M R Karagas

Publications and source records attributed to M R Karagas.

At least 19 recordsLinked to original sources
PubMed2004

A population-based study of immunohistochemical detection of p53 alteration in bladder cancer.

The molecular pathology of bladder cancer has been the subject of considerable interest and mutation of the p53 gene, which has been associated with more invasive bladder cancer, has been widely studied. Further, there is evidence that p53 inactivation (either mutation or protein dysregulation), independent of stage, may be predictive of bladder cancer progression. In an effort to avoid possible biases associated with selection of more advanced cases, we examined p53 inactivation in a population-based study of bladder cancer in New Hampshire, using both mutation and immunohistochemical methods. We found the overall prevalence of mutation to be approximately 10%, while immunohistochemical analysis suggests that approximately 66% of the tumours have dysregulated p53 at the protein level. There was a significant association of mutation with persistent p53 staining, but there remained a marked number of tumours discordant for mutation and aberrant p53 immunohistochemistry. Based upon immunohistochemical staining alone, intensity rather than extent of p53 staining was more strongly related to tumour invasiveness. Additionally, all tumours with a mutation in exon 8 stained intensely. Taken together, this suggests that intense staining represents a distinct phenotype of dysfunctional protein. Our data indicate that population-based approaches to somatic alteration of p53 in bladder cancer are crucial to understanding the relationship of p53 changes to aetiology and the outcome of this disease, and further suggest that the pattern of immunohistochemical staining may represent distinct, discernible phenotypes. British Journal of Cancer (2004) 90, 1572-1576. doi:10.1038/sj.bjc.6601748 www.bjcancer.com Published online 6 April 2004

Aged↗
PubMed2002

A pooled analysis of 10 case-control studies of melanoma and oral contraceptive use.

Data regarding the effects of oral contraceptive use on women's risk of melanoma have been difficult to resolve. We undertook a pooled analysis of all case-control studies of melanoma in women completed as of July 1994 for which electronic data were available on oral contraceptive use along with other melanoma risk factors such as hair colour, sun sensitivity, family history of melanoma and sun exposure. Using the original data from each investigation (a total of 2391 cases and 3199 controls), we combined the study-specific odds ratios and standard errors to obtain a pooled estimate that incorporates inter-study heterogeneity. Overall, we observed no excess risk associated with oral contraceptive use for 1 year or longer compared to never use or use for less than 1 year (pooled odds ratio (pOR)=0.86; 95% CI=0.74-1.01), and there was no evidence of heterogeneity between studies. We found no relation between melanoma incidence and duration of oral contraceptive use, age began, year of use, years since first use or last use, or specifically current oral contraceptive use. In aggregate, our findings do not suggest a major role of oral contraceptive use on women's risk of melanoma.

Adolescent↗
PubMed2001

Non-melanoma skin cancers and glucocorticoid therapy.

Non-melanoma skin cancer (NMSC) is an important cause of morbidity and long-term mortality in organ transplant recipients receiving immunosuppressive drugs such as azathioprine and cyclosporin, often combined with adrenocortical steroids (glucocorticoids). At lower doses, glucocorticoids alone are prescribed for other conditions including musculoskeletal, connective tissue and respiratory disorders. Presently, it is unknown whether patients taking glucocorticoids are at an increased risk of skin malignancies. In a population-based case-control study in New Hampshire, USA, we compared use of glucocorticoids in 592 basal cell carcinoma (BCC) and 281 squamous cell carcinoma (SCC) cases and in 532 age and gender matched controls; neither cases nor controls had a history of organ transplantation. Participants underwent a structured personal interview regarding history of medication use and skin cancer risk factors. We used unconditional logistic regression analysis to compute odds ratios associated with glucocorticoid use for 1 month or longer while controlling for potential confounding factors. Risk of SCC was increased among users of oral glucocorticoids (adjusted odds ratio = 2.31; 95% CI = 1.27, 4.18), and risk of BCC was elevated modestly (adjusted odds ratio = 1.49; 95% CI = 0.90, 2.47). In contrast, risk of both SCC and BCC were unrelated to use of inhaled steroids. Our data suggest that use of oral glucocorticoids may increase risk of NMSC, and SCC in particular, among patients other than organ transplant recipients. We hypothesize that immunosuppression induced by oral glucocorticoids may allow these cancers to emerge from immunosurveillance.

Administration, Inhalation↗
PubMed2001

Two-stage methods for the analysis of pooled data.

Epidemiologic studies of disease often produce inconclusive or contradictory results due to small sample sizes or regional variations in the disease incidence or the exposures. To clarify these issues, researchers occasionally pool and reanalyse original data from several large studies. In this paper we explore the use of a two-stage random-effects model for analysing pooled case-control studies and undertake a thorough examination of bias in the pooled estimator under various conditions. The two-stage model analyses each study using the model appropriate to the design with study-specific confounders, and combines the individual study-specific adjusted log-odds ratios using a linear mixed-effects model; it is computationally simple and can incorporate study-level covariates and random effects. Simulations indicate that when the individual studies are large, two-stage methods produce nearly unbiased exposure estimates and standard errors of the exposure estimates from a generalized linear mixed model. By contrast, joint fixed-effects logistic regression produces attenuated exposure estimates and underestimates the standard error when heterogeneity is present. While bias in the pooled regression coefficient increases with interstudy heterogeneity for both models, it is much smaller using the two-stage model. In pooled analyses, where covariates may not be uniformly defined and coded across studies, and occasionally not measured in all studies, a joint model is often not feasible. The two-stage method is shown to be a simple, valid and practical method for the analysis of pooled binary data. The results are applied to a study of reproductive history and cutaneous melanoma risk in women using data from ten large case-control studies.

Adolescent↗
PubMed2001

Skin cancer risk in relation to toenail arsenic concentrations in a US population-based case-control study.

Arsenic is a known carcinogen specifically linked to skin cancer occurrence in regions with highly contaminated drinking water or in individuals who took arsenic-containing medicines. Presently, it is unknown whether such effects occur at environmental levels found in the United States. To address this question, the authors used data collected on 587 basal cell and 284 squamous cell skin cancer cases and 524 controls interviewed as part of a case-control study conducted in New Hampshire between 1993 and 1996. Arsenic was determined in toenail clippings using instrumental neutron activation analysis. The odds ratios for squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) were close to unity in all but the highest category. Among individuals with toenail arsenic concentrations above the 97th percentile, the adjusted odds ratios were 2.07 (95% confidence interval (CI): 0.92, 4.66) for SCC and 1.44 (95% CI: 0.74, 2.81) for BCC, compared with those with concentrations at or below the median. While the risks of SCC and BCC did not appear elevated at the toenail arsenic concentrations detected in most study subjects, the authors cannot exclude the possibility of a dose-related increase at the highest levels of exposure experienced in the New Hampshire population.

Adult↗
PubMed2001

Bacteremia due to Mycobacterium tuberculosis or M. bovis, Bacille Calmette-Guérin (BCG) among HIV- positive children and adults in Zambia.

BACKGROUND: Among adults with advanced HIV infection in developing countries, bacteremia due to Mycobacterium tuberculosis (MTB) is common and bacteremia due to M. bovis (bacille Calmette-Guérin; BCG) is rare. Comparable data are not available for children with HIV. OBJECTIVE: To compare the prevalence of bacteremia due to M. tuberculosis or M. bovis BCG in hospitalized children and adults with HIV infection in a developing country with a high prevalence of tuberculosis and HIV and > 95% BCG immunization coverage. DESIGN: Descriptive cross-sectional study. METHODS: Prospectively hospitalized patients in Lusaka, Zambia who were suspected to have HIV infection underwent phlebotomy for HIV ELISA, HIV viral load, and lysis-centrifugation blood culture for mycobacteria. Histories were obtained and patients were examined for BCG scars. Mycobacterial isolates were identified using DNA probes for MTB complex (MTBC), multiplex PCR and IS6110 typing. RESULTS: The median age of 387 HIV-positive children was 15 months; 98% were BCG immunized. The median age of 344 HIV-positive adults was 32 years; 44% were BCG immunized. Blood cultures were positive for mycobacteria in six children (2%) and 38 adults(11%) (P < 0.001). The six pediatric isolates included five MTBC (40% clustered) and one BCG. The 38 adult isolates included 36 MTBC (16% clustered) and two M. avium complex. CONCLUSION: Bacteremia due to MTB is less common among children than adults with advanced HIV infection in Zambia. Bacteremia due to M. bovis BCG is rare even among children with recent BCG immunization and symptomatic HIV infection.

AIDS-Related Opportunistic Infections↗
PubMed2001

Markers of low level arsenic exposure for evaluating human cancer risks in a US population.

Epidemiologic studies conducted in the US have not previously detected an association between regional drinking water arsenic concentrations and corresponding cancer occurrence or mortality rates. To improve our estimation of cancer risk and arsenic exposure in the USA, we have investigated the reliability of several exposure markers. In the current study, we specifically evaluated the long-term reproducibility of tap water and toenail concentrations of arsenic, and the relation between water, toenail, and urinary measurement. Subjects included 99 controls in our case-control study on whom we requested a household tap water sample and toenail clipping three to five years apart. Additionally, participants were asked to provide a first morning void sample at the second interview. Tap water arsenic concentrations ranged from undetectable (<0.01 microg/L) to 66.6 microg/L. We found a significant correlation between both replicate water and toenail samples (intraclass correlation coefficient = 0.85, 95% confidence interval = 0.79-0.89 for water, and intraclass correlation coefficient = 0.60, 95% confidence interval = 0.48-0.70 for toenails). The inter-method correlations for water, urinary and toenail arsenic were all statistically significant (r = 0.35, p = 0.0024 for urine vs water; r = 0.33, p = 0.0016 for toenail vs water and r = 0.36, p = 0.0012 for urine vs toenails). Thus, we found both toenail and water measurements of arsenic reproducible over a three- to five-year period. Our data suggest that biologic markers may provide reliable estimates of internal dose of low level arsenic exposure that can be used to assess cancer risk.

Aged↗
PubMed2000

Measurement of low levels of arsenic exposure: a comparison of water and toenail concentrations.

A study was conducted to evaluate toenail arsenic concentrations as a biologic marker of drinking water arsenic exposure. Study subjects were controls in a US population-based case-control study of nonmelanoma skin cancer, randomly selected from drivers' license records (those < 65 years of age) and Medicare enrollment files (those > or = 65 years of age). Between 1994 and 1997, a total of 540 controls were interviewed and toenail samples of sufficient weight were collected from 506 (93.7%) of these. Beginning in 1995, a sample of tap water was taken from the participants' homes; a total of 217 (98.6%) water samples were obtained from the 220 subjects interviewed. Arsenic determinations were made from toenail samples using neutron activation analysis. Water samples were analyzed using hydride-generation magnet sector inductively coupled mass spectrometry. Among 208 subjects with both toenail and water measurements, the correlation (r) between water and nail arsenic was 0.65 (p < 0.001) among those with water arsenic concentrations of 1 microg/liter or higher and 0.08 (p = 0.31) among those with concentrations below 1 microg/liter (overall r = 0.46, p < 0.001). Our data suggest that toenail samples provide a useful biologic marker for quantifying low-level arsenic exposure.

Adult↗
PubMed2000

Therapeutic ionizing radiation and the incidence of basal cell carcinoma and squamous cell carcinoma. The New Hampshire Skin Cancer Study Group.

OBJECTIVE: To estimate the relative risk of developing basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) after receiving therapeutic ionizing radiation. DESIGN: Population-based case-control study. SETTING: New Hampshire. PATIENTS: A total of 592 cases of BCC and 289 cases of SCC identified through a statewide surveillance system and 536 age- and sex-matched controls selected from population lists. MAIN OUTCOME MEASURES: Histologically confirmed BCC and invasive SCC diagnosed between July 1, 1993, through June 30, 1995, among New Hampshire residents. RESULTS: Information regarding radiotherapy and other factors was obtained through personal interviews. An attempt was made to review the radiation treatment records of subjects who reported a history of radiotherapy. Overall, an increased risk of both BCC and SCC was found in relation to therapeutic ionizing radiation. Elevated risks were confined to the site of radiation exposure (BCC odds ratio, 3. 30; 95% confidence interval, 1.60-6.81; SCC odds ratio, 2.94; 95% confidence interval, 1.30-6.67) and were most pronounced for those irradiated for acne exposure. For SCC, an association with radiotherapy was observed only among those whose skin was likely to sunburn with sun exposure. CONCLUSIONS: These results largely agree with those of previous studies on the risk of BCC in relation to ionizing radiation exposure. In addition, they suggest that the risk of SCC may be increased by radiotherapy, especially in individuals prone to sunburn with sun exposure. Arch Dermatol. 2000;136:1007-1011

Adult↗
PubMed2000

Safety and immunogenicity of a five-dose series of inactivated Mycobacterium vaccae vaccination for the prevention of HIV-associated tuberculosis.

Five doses of inactivated Mycobacterium vaccae vaccine were administered intradermally to 22 human immunodeficiency virus (HIV)-infected patients (11 bacille Calmette-Guérin [BCG]-positive and 11 BCG-negative) in Zambia whose CD4 lymphocyte counts were >/=200 cells/mm(3). HIV viral load and lymphocyte proliferation responses were compared for vaccine recipients and 22 HIV-infected control patients (11 BCG-positive and 11 BCG-negative). Immunization was safe and well tolerated in all patients, and induration at the vaccine site decreased from dose 1 to dose 5. A transient decrease in HIV viral load was observed in BCG-positive vaccine recipients after dose 3 but not after subsequent doses. Median lymphocyte stimulation indices to M. vaccae were 6.0 in vaccine recipients and 2.3 in control patients (P<.001). Stimulation indices were >/=3.0 in 19 vaccine recipients (86%) and 7 control patients (32%; P=.001). A 5-dose series of vaccination with inactivated M. vaccae is safe in HIV-infected patients and induces lymphocyte proliferation responses to the vaccine antigen. M. vaccae vaccine is a candidate for the prevention of tuberculosis in HIV infection.

AIDS-Related Opportunistic Infections↗
PubMed2000

Racial differences in pancreatic cancer: comparison of survival and histologic types of pancreatic carcinoma in Asians, blacks, and whites in the United States.

SEER data for histologically confirmed carcinomas of the pancreas for 1973-1995 from Hawaii, San Francisco, and Seattle (n = 10,621) were analyzed to compare the survival and types of carcinomas in various racial groups. These geographic sites were selected because each included a sizable number of Asian patients. The median survival after diagnosis in unadjusted data was longer in Asian patients than in whites. After adjustment for age at diagnosis and year of diagnosis, only the survival advantage of Asian women over whites and blacks persisted as a statistically significant difference. Racial differences were no longer statistically significant when further adjustments were made for stage, grade, and morphology. The proportion of papillary carcinomas or mucinous cystadenocarcinomas was higher in Asians than in whites and blacks (p = 0.02), and patients with these neoplasms had a longer median survival than did patients with ductal adenocarcinoma (12 vs. 3.3 months). The fraction of Asian patients with lower stages and grades of carcinomas also was higher than among white and black patients. Longer survival of Asian compared with white and black patients with pancreatic carcinoma is at least partly explained by their higher proportion of less aggressive carcinomas at the time of diagnosis.

Adult↗
PubMed1999

Increase in incidence rates of basal cell and squamous cell skin cancer in New Hampshire, USA. New Hampshire Skin Cancer Study Group.

We conducted a study to estimate the current incidence rates of basal-cell carcinoma (BCC) and squamous-cell carcinoma (SCC) of the skin in the population of New Hampshire (NH), USA, and to quantify recent changes in the incidence rates of these malignancies. BCCs and SCCs diagnosed among NH residents were identified through physician practices and central pathology laboratories in NH and bordering regions from June 1979 through May 1980 and from July 1993 through June 1994. For each diagnosis period, we estimated the age-adjusted incidence rates for both BCC and SCC among both men and women and for separate anatomic sites. Between 1979-1980 and 1993-1994, incidence rates of SCC increased by 235% in men and by 350% in women. Incidence rates of BCC increased by more than 80% in both men and women. While the absolute increase was greatest for tumors of the head and neck, the relative change was most pronounced for tumors on the trunk in men and on the lower limb in women. Thus, there has been a marked rise in the incidence rates of BCC and SCC skin cancers in NH in recent years. The anatomic pattern of increase in BCC and SCC incidence is consistent with an effect of greater sunlight exposure. Studies of BCC and SCC occurrence are needed to identify possible behavioral and environmental factors and to assess possible changes in diagnostic practices that might account for the rise in incidence of these common malignancies.

Adult↗
PubMed1999

Fracture risk in the U.S. Medicare population.

Using data from the 5% U.S. Medicare sample, we estimated the actuarial (life table) risk that a person aged 65 will fracture the upper or lower limbs or the pelvis, by age 75, 80, 85, and 90, taking into account the chance of dying in the interval. The actuarial risk of a 65-year old white woman sustaining a fracture by age 90 is 16% for the hip, 9% for distal forearm, 5% for proximal humerus, and 4% for ankle. Black women and white men have substantially lower risks, and the risks for black men are very low. Although hip fractures pose the single greatest risk, the risk of all other fractures combined is greater. White women have particularly high risks for all fractures, because of their longevity as well as their high fracture rates. It is important to adjust for the probability of dying when estimating risks in an elderly population.

Actuarial Analysis↗
PubMed1998

Design of an epidemiologic study of drinking water arsenic exposure and skin and bladder cancer risk in a U.S. population.

Ingestion of arsenic-contaminated drinking water is associated with an increased risk of several cancers, including skin and bladder malignancies; but it is not yet clear whether such adverse effects are present at levels to which the U.S. population is exposed. In New Hampshire, detectable levels of arsenic have been reported in drinking water supplies throughout the state. Therefore, we have begun a population-based epidemiologic case-control study in which residents of New Hampshire diagnosed with primary squamous cell (n = 900) and basal cell (n = 1200) skin cancers are being selected from a special statewide skin cancer incidence survey; patients diagnosed with primary bladder cancers (n = 450) are being identified through the New Hampshire State Cancer Registry. Exposure histories of these patients will be compared to a control group of individuals randomly selected from population lists (n = 1200). Along with a detailed personal interview, arsenic and other trace elements are being measured in toenail clipping samples using instrumental neutron activation analysis. Household water samples are being tested on selected participants using a hydride generation technique with high-resolution inductively coupled plasma mass spectrometry. In the first 793 households tested arsenic concentrations ranged from undetectable (0.01 microgram/l) to 180 microgram/l. Over 10% of the private wells contained levels above 10 microgram/l and 2.5% were above 50 microgram/l. Based on our projected sample size, we expect at least 80% power to detect a 2-fold risk of basal cell or squamous cell skin cancer or bladder cancer among individuals with the highest 5% toenail concentrations of arsenic.

Adult↗
PubMed1998

Occurrence of other cancers among patients with prior basal cell and squamous cell skin cancer.

Epidemiological studies suggest that individuals with basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) of the skin are more likely to develop other malignancies; however, the factors responsible for this are unknown. To clarify the risk of other cancers following the occurrence of BCC and SCC, we followed participants in a multicenter skin cancer prevention trial for subsequent malignancies. The study group consisted of 1805 BCC and SCC patients who had enrolled in a trial testing the efficacy of oral beta-carotene. Medical confirmation was sought for all cancers (other than BCC or SCC), which were reported by participants or their next-of-kin over a follow-up period of 10 years. We computed the rate ratio (RR) and 95% confidence interval (CI) of time to first new, primary cancer in relation to history of BCC and SCC, using a proportional hazards model. A total of 235 participants had a new primary invasive cancer during 13,887 person-years of follow up. The risk of other cancers was modestly elevated in patients with one or more previous SCCs compared with those who only had a history of BCC (adjusted RR, 1.37; 95% CI, 0.91-2.07). Risk of other cancers also appeared to be increased among those who had multiple prior BCCs relative to those who had only one prior BCC (adjusted RR, 1.21; 95% CI, 0.91-1.61). Further adjustment for smoking history, Quetelet index, radiotherapy, extent of actinic skin damage, treatment assignment, or baseline beta-carotene concentrations did not appreciably alter the results. Cancer of the respiratory system was most strongly related to previous SCC or multiple BCC [RRs (95% CI), 2.20 (1.05-4.62) and 2.34 (1.14-4.83), respectively]. Our data suggest that unidentified exposures or inherited risk factors may play a common etiological role in the pathogenesis of nonmelanoma skin cancer and other cancers, especially respiratory cancers, although larger studies would be necessary to exclude the role of chance in these findings.

Aged↗
PubMed1998

Effects of milk and milk products on rectal mucosal cell proliferation in humans.

Intake of dairy products and major dairy constituents (e.g., calcium) has been proposed to reduce the risk of colorectal cancer, although epidemiological studies have yielded inconclusive results. We conducted a randomized cross-over trial to test the effects of high- and low-dairy consumption diets on rectal mucosal proliferation, a possible intermediary marker for large bowel cancer. From a gastroenterology clinic at an academic medical center, we recruited 40 patients, ages 25-79 years, who had either a history of a large bowel adenoma or a first-degree relative with large bowel cancer. Participants completed a baseline questionnaire covering demographic characteristics, health history, and habits and a food frequency questionnaire. They were randomized to a 12-week diet of either high dairy intake (six dairy servings/day) or low dairy intake (<0.5 serving of dairy products/day), with an intervening 12-week washout period in which they were asked to resume their usual diet before crossing over to the alternate study diet for the last 12-week period of the study. Adherence to the study diets was monitored by a daily dairy intake checklist and periodic, unscheduled 24-h dietary recalls. Biopsies of the rectal mucosa were obtained at the beginning and end of each intervention phase. Two assays of rectal mucosal cell proliferation were performed: immunohistochemical determination of proliferating cell nuclear antigen and whole crypt mitotic count. We found no statistically significant changes in either of these proliferation measures as a result of high or low dairy intake. There was no correlation between the labeling index for proliferating cell nuclear antigen and whole crypt mitotic count; however, measures of the location and intensity of cell proliferation within the rectal crypt were highly correlated between the two assays. Thus, our study indicates that greater consumption of dairy products over a 12-week period does not change rectal mucosal cell proliferation.

Adult↗
PubMed1997

Ascorbic acid deficiency in porphyria cutanea tarda.

Porphyria cutanea tarda (PCT), the most common form of porphyria, is manifested as skin photosensitivity caused by excess hepatic production of uroporphyrin and heptacarboxylporphyrin. In experimental animal models, ascorbic acid modulates chemically induced uroporphyrin accumulation. The purpose of this study was to determine whether ascorbic acid is decreased in the plasma of patients with PCT. Plasma was obtained after an overnight fast from 21 PCT patients, 16 of whom were infected with hepatitis C virus (HCV), and from a separate group of 9 patients with HCV infection but not PCT. Thirteen PCT patients were studied when they had active disease and 8 after treatment-induced remission. Plasma ascorbic acid was low (<23 micromol/L) in 11 (85%) of the 13 untreated PCT patients and deficient (<11 micromol/L) in 8 (62%). Two patients with normal ascorbic acid levels (45 and 62 micrommol/L) had consumed multivitamins. In 2 patients with deficient ascorbic acid, plasma levels returned to normal after phlebotomy treatment. Of the 8 patients studied during remission, 4 had normal ascorbic acid values and 4 were deficient (5 to 8 micromol/L). Plasma ascorbic acid values were normal for all patients who had HCV but no PCT. These data suggest that plasma ascorbic acid concentrations are commonly low in PCT, but this decrease is unrelated to HCV infection. Ascorbic acid deficiency may be one of the factors that contributes to the pathogenesis of PCT.

Adult↗