Faculty Bibliography

Psoriasis is a common, chronic, inflammatory disease. Psoriasis has been hypothesized to be associated with an increased risk of lymphoma due to its pathophysiology, its treatments, or a combination of these factors. We performed a large population-based cohort study of the risk of lymphoma in psoriasis patients using the General Practice Research Database. We identified 153,197 patients with psoriasis and 765,950 corresponding subjects without psoriasis. Psoriasis patients who received a systemic treatment consistent with extensive disease were classified as severe (N=3,994) and those who did not receive systemic therapies were classified as mild (N=149,203). The analyses were adjusted for age, gender, and person-time using a Cox proportional hazards model. For mild and severe psoriasis patients, the respective adjusted relative risks for lymphoma and its subtypes were as follows: all lymphoma 1.34 (1.16, 1.54) and 1.59 (0.88, 2.89); non-Hodgkin's lymphoma 1.15 (0.97, 1.37) and 0.73 (0.28, 1.96); Hodgkin's lymphoma (HL) 1.42 (1.00, 2.02) and 3.18 (1.01, 9.97); cutaneous T-cell lymphoma (TCL) 4.10 (2.70, 6.23) and 10.75 (3.89, 29.76). Psoriasis is associated with an increased risk of lymphoma. The association is strongest for HL and CTCL. The excess risk of lymphoma attributed to psoriasis was 7.9/100,000 psoriasis patients per year. Although patients with psoriasis have an increased relative risk of lymphoma, the absolute risk attributable to psoriasis is low given that lymphoma is a rare disease and the magnitude of association is modest

BACKGROUND: Sunburn is a major preventable risk factor for skin cancer. OBJECTIVE: We investigated risk factors for sunburn in the United States based on the 2003 Behavioral Risk Factor Surveillance System. DESIGN AND METHODS: A random sample of 207,776 respondents provided data for the population-based survey. The main outcome measure was any report of sunburn within the previous 12 months. RESULTS: Overall, 39% of respondents had at least one sunburn. The strongest factors associated with sunburn were age and socioeconomic factors. Sunburn prevalence was greatest in respondents 18 to 24 years old (61%). This group was more likely to have a sunburn than respondents 45 to 54 years of age (odds ratio [OR] = 2.76). Higher income and higher levels of education were positively associated with sunburn (OR 1.67 and 1.63, respectively). Individuals reporting recent binge drinking had a higher prevalence of sunburn (OR = 1.33). LIMITATIONS: The Behavioral Risk Factor Surveillance System does not include data on skin type or sun protection behavior; therefore the impact of these factors was not assessed. CONCLUSION: Sunburn occurs at a very high rate in the United States.

BACKGROUND: Unopposed estrogen replacement therapy is associated with increased risk of endometrial cancer. To investigate the mechanism of this association, we evaluated whether risk of endometrial cancer was associated with the genotypes involved in steroid hormone metabolism and the duration of exogenous hormone use. METHODS: A population-based case-control study in nine counties of the Philadelphia metropolitan area was undertaken with 502 case patients with endometrial cancer and 1326 age- and race-matched control subjects. Data regarding exogenous hormone use were obtained by interview, and genotypes of the genes COMT, CYP1A1, CYP1A2, CYP1B1, CYP3A4, PGR, SULT1A1, SULT1E1, and UGT1A1 were obtained by polymerase chain reaction techniques. Conditional logistic regression was used to examine the relationship among genotype, hormone use, and endometrial cancer risk. RESULTS: Associations were observed between the risk of endometrial cancer and genotypes of the following steroid hormone metabolism genes: CYP1A1*2C (adjusted odds ratio [OR] = 1.68, 95% confidence interval [CI] = 1.08 to 2.61); SULT1A1*3 (adjusted OR = 0.51, 95% CI = 0.29 to 0.92); and the G --> A variant in the promoter of SULT1E1 at position -64 (adjusted OR = 1.45, 95% CI = 1.06 to 1.99). We observed a statistically significant interaction between estrogen replacement therapy use and SULT1A1*2 genotype: the SULT1A1*2 allele and long-term use of estrogen replacement therapy were associated with statistically significantly higher risk of endometrial cancer (adjusted OR = 3.85, 95% CI = 1.48 to 10.00) than that of the SULT1A1*2 allele and no estrogen replacement therapy use. CONCLUSIONS: Among women with long-term use of estrogen replacement therapy or combined hormone replacement therapy, the risk of endometrial cancer may be associated with functionally relevant genotypes that regulate steroid hormone sulfation.

In this paper we consider longitudinal studies in which the outcome to be measured over time is binary, and the covariates of interest are categorical. In longitudinal studies it is common for the outcomes and any time-varying covariates to be missing due to missed study visits, resulting in non-monotone patterns of missingness. Moreover, the reasons for missed visits may be related to the specific values of the response and/or covariates that should have been obtained, i.e. missingness is non-ignorable. With non-monotone non-ignorable missing response and covariate data, a full likelihood approach is quite complicated, and maximum likelihood estimation can be computationally prohibitive when there are many occasions of follow-up. Furthermore, the full likelihood must be correctly specified to obtain consistent parameter estimates. We propose a pseudo-likelihood method for jointly estimating the covariate effects on the marginal probabilities of the outcomes and the parameters of the missing data mechanism. The pseudo-likelihood requires specification of the marginal distributions of the missingness indicator, outcome, and possibly missing covariates at each occasions, but avoids making assumptions about the joint distribution of the data at two or more occasions. Thus, the proposed method can be considered semi-parametric. The proposed method is an extension of the pseudo-likelihood approach in Troxel et al. to handle binary responses and possibly missing time-varying covariates. The method is illustrated using data from the Six Cities study, a longitudinal study of the health effects of air pollution.

OBJECTIVES: Prolonged activation of pain centers is a proposed cause of chronic pain syndromes. Women are at particular risk for chronic pain as they tend to more readily detect pain and to attenuate it less than men. We set out to determine whether sex affected pain and recovery after major surgery by analyzing data originally collected to determine the effect of the timing of epidural analgesia on long-term outcome after thoracotomy. METHODS: Patients presenting for lobectomy, segmentectomy, or bilobectomy, but not pneumonectomy or chest wall resection, were enrolled. Pain, physical activity, and the extent that pain interfered with activities after surgery were prospectively assessed with standard questionnaires (Brief Pain Inventory and physical component score of SF-36) on postoperative days 1 to 5, and at postoperative weeks 4, 8, 12, 24, 36, and 48 by a blinded research assistant. Perioperative care was standardized and included patient-controlled thoracic epidural analgesia until thoracostomy tube removal. RESULTS: Fifty eight men and 62 women were enrolled. Women reported more pain than men throughout the entire study period, and they had a higher rate of nonsteroidal anti-inflammatory drug use, but not opioid use. This increased pain was not explained by incision type, surgeon, tumor type, or tumor stage. Older patients reported less pain after discharge than younger patients. Postoperative physical activity levels were significantly less than those reported preoperatively, but did not differ by sex. DISCUSSION: Women have a distinctly different pain experience than men after thoracic surgery and probably require novel and/or multimodal analgesic regimens to improve their comfort.

Reactive and redox-active polycyclic aromatic hydrocarbon (PAH) o-quinones produced by Aldo-Keto Reductases (AKRs) have the potential to cause depurinating adducts leading to the formation of abasic sites and oxidative base lesions. The aldehyde reactive probe (ARP) was used to detect these lesions in calf thymus DNA treated with three PAH o-quinones (BP-7,8-dione, 7,12-DMBA-3,4-dione, and BA-3,4-dione) in the absence and presence of redox-cycling conditions. In the absence of redox-cycling, a modest amount of abasic sites were detected indicating the formation of a low level of covalent o-quinone depurinating adducts (>3.2 x 10(6) dNs). In the presence of NADPH and CuCl2, the three PAH o-quinones increased the formation of abasic sites due to ROS-derived lesions destabilizing the N-glycosidic bond. The predominant source of AP sites, however, was revealed by coupling the assay with human 8-oxoguanine glycosylase (hOGG1) treatment, showing that 8-oxo-dGuo was the major lesion caused by PAH o-quinones. The levels of 8-oxo-dGuo formation were independently validated by HPLC-ECD analysis. Apyrimidinic sites were also revealed by coupling the assay with Escherichia coli (Endo III) treatment showing that oxidized pyrimidines were formed, but to a lesser extent. Different mechanisms were responsible for the formation of the oxidative lesions depending on whether Cu(II) or Fe(III) was used in the redox-cycling conditions. In the presence of Cu(II)-mediated PAH o-quinone redox-cycling, catalase completely suppressed the formation of the lesions, but mannitol and sodium benzoate were without effect. By contrast, sodium azide, which acts as a *OH and 1O2 scavenger, inhibited the formation of all oxidative lesions, suggesting that the ROS responsible was 1O2. However, in the presence of Fe(III)-mediated PAH o-quinone redox-cycling, the *OH radical scavengers and sodium azide consistently attenuated their formation, indicating that the ROS responsible was *OH.

BACKGROUND: Urban minority groups, such as those living in northern Manhattan and the South Bronx, are generally underserved with regard to breast cancer prevention and screening practices. Primary care physicians are critical for the recommendation of mammography and clinical breast examinations to their patients. DESIGN: Two medically underserved communities were matched and block randomized. The aim of the study was to assess the efficacy of academic detailing in increasing recommendations for breast cancer screening in community-based primary care physicians. SETTING/PARTICIPANTS: Ninety-four primary care community-based (ie, not hospital-based) physicians in northern Manhattan were compared with 74 physicians in the South Bronx who received no intervention. INTERVENTION: INTERVENTION participants received multicomponent physician-directed education, academic detailing, using the American Cancer Society guidelines for the early detection of breast cancer. MAIN OUTCOME MEASURES: We administered interviews to ask about primary care physicians' recommendation of mammography and clinical breast examination. They were also queried about their knowledge of major risk factors and perceived barriers to breast cancer screening. We conducted medical audits of 710 medical charts 2 years before and after the intervention. RESULTS: Using a mixed models linear analysis, we found a statistically significant intervention effect on the recommendation of mammography and clinical breast examination (according to medical audit) by female patients age 40 and over. INTERVENTION group physicians correctly identified significantly more risk factors for breast cancer, and significantly fewer barriers to practice, than did comparison physicians. CONCLUSIONS: We found some evidence of improvement in breast cancer screening practices due to academic detailing among primary care physicians practicing in urban underserved communities.

Optimization of oxygen tolerance extension by intermittent exposure was studied in groups of 20 rats exposed to systematically varied patterns of alternating oxygen and normoxic breathing periods at 4.0, 2.0, and 1.5 ATA. Oxygen periods of 20, 60, and 120 min were alternated with normoxic intervals that provided oxygen-to-normoxia ratios of 4:1, 2:1, 1:1, and 1:3. In general, median survival times had nearly linear relationships to increasing normoxic intervals with oxygen period held constant. Exceptions occurred at 4.0 and 2.0 ATA where a 5-min normoxic interval was too short for adequate recovery even with a 20-min oxygen period, and an oxygen period of 120 min was too long even with a normoxic interval of 30 min. These exceptions did not occur at 1.5 ATA. Survival time for many intermittent exposure patterns was equivalent to that for continuous exposure to an oxygen pressure definable as a time-weighted average of the alternating oxygen and normoxia periods. However, this predictive method underestimated the degree of protection achieved by several of the intermittent exposure patterns, especially those performed at 4.0 ATA. Results provided guidance for selection of intermittent exposure patterns for direct evaluation in humans breathing oxygen at 2.0 ATA. Definition of intermittent exposure patterns and conditions that produced prominent gains in oxygen tolerance can also facilitate the performance of future experiments designed to study potential mechanisms for oxygen tolerance extension by intermittent exposure. Heat shock and oxidation-specific stress proteins that are induced by exposure to oxidant injury are suggested for emphasis in such investigations.

Where and how one lives is associated with cancer survival. This study was designed to assess geographical region of residence, race/ethnicity, and clinical and socioeconomic factors as predictors of survival in a population based cohort of women with breast cancer followed for up to 12 years. In a cohort of 218,879 breast cancer patients >20 years of age at diagnosis, registered in the database of the US National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program between 1990 and 2001, we analyzed the association of breast cancer-specific survival with SEER region; age; stage; histology; hormone receptor status; race/ethnicity; and census data on educational attainment, income, employment, and insurance coverage. We compared Kaplan-Meier survival curves by region and race/ethnicity. We used Cox proportional hazards regression models to assess the association of mortality with region, race/ethnicity, and the other variables. Women who lived in Detroit had significantly higher mortality than those living in most other SEER regions. In most regions, black women had the poorest survival. The association of mortality with race did not differ significantly across regions, but it was significantly stronger among women 50-64 years of age than among women 65 and older. The SEER data document the association of breast cancer mortality with region, race, and socioeconomic status. Black race was a strong predictor of mortality in each region even after controlling for socioeconomic factors. The diminishing effect of race with age, which may only partially be explained by insurance in those over 65, suggests a need for research on the role of other factors, such as comorbid conditions or access to care, in breast cancer mortality.

CONTEXT: Through medical decision making, physicians in the U.S. influence the spending of >$1.3 trillion or 15% of the gross domestic product. U.S. physicians are challenged to identify areas of clinical practice to improve while cutting cost and increasing access. Primary screening for colorectal cancer is a good example to illustrate this point. OBJECTIVE: To apply a population-based method of medical decision making in the area of primary screening for colorectal cancer in order to illustrate a reduction in health care costs while increasing access and maintaining quality of care. DESIGN: We used a combination of (a) census population data, (b) National Cancer Institute Survey data on screening rates, and (c) charge data to estimate the current costs of colorectal cancer screening. We also estimated cost and capacity increases that would occur under various other screening scenarios. These included all currently screened subjects receiving annual fecal occult blood testing (FOBT), all currently unscreened individuals undergoing either colonoscopy every decade or annual FOBT, and all eligible subjects undergoing annual FOBT. MAIN OUTCOME MEASURES: Cost and access differences between current screening activity and other potential scenarios compliant with guidelines. RESULTS: Screening for colorectal cancer with yearly, six-window, rehydrated FOBT for all normal-risk individuals over the age of 50 has the potential to screen 3,813,095 more Americans for colon cancer yearly than are currently being screened, while costing $8.7 billion less per decade than what is currently being spent on screening a fraction of the population. Looking into the future, it is possible to increase screening rates from 50% to 100%, while saving almost $10 billion per decade by using FOBT for all eligible Americans. In practice, some proportion of these benefits would be realized as the calculations assume a 100% patient compliance rate. CONCLUSIONS: Considering a population-based approach and the balance among quality, accessibility, and cost parameters, we recommend primary screening for colorectal cancer to be based on yearly six-window, rehydrated FOBT. Colonoscopy due to cost and access issues should be relegated to secondary screening and case finding.