James S. Goodwin

Regulation of the immune response by prostaglandins

Of all the arachidonic acid metabolites, only prostaglandin E (PGE) has been shown to have a clear role in the regulation of cellular and humoral immune responses. In cellular immune responses such as T cell proliferation, lymphokine production, and cytotoxicity, PGE usually acts as a feedback inhibor of the response. This is also true of macrophage and natural killer cytotoxicity. In some instances PGE is responsible for cellular activation rather than inhibition. This is clearest in the control of humoral immunity, where PGE production is a necessary component in the generation of some type of T suppressor cells. Disturbances in immune function found in several human conditions and diseases have been linked to changes in PGE mediated immunoregulation. Either increased production of PGE or increased sensitivity to PGE results in depressed cellular immunity. Conversely drugs which inhibit PGE production act as stimulants of cellular immune functionin vitro andin vivo.

Geographic Variation in the Use of Breast-Conserving Treatment for Breast Cancer

BACKGROUND In the past decade there has been an increase in the use of treatment designed to conserve the breast for women with breast cancer. The extent to which such treatment has been adopted in various regions of the country and whether characteristics of hospitals and patients predict its use is not known, however. METHODS We used national data on Medicare claims for inpatient care provided in 1986 to study 36,982 women 65 to 79 years of age, who had local or regional breast cancer and underwent either mastectomy or breast-conserving treatment (local excision, quadrantectomy, or subtotal mastectomy). Information about the hospitals at which these women were treated was obtained from an American Hospital Association survey. RESULTS Of the 36,982 women, 12.1 percent had breast-conserving surgery and 87.9 percent had a mastectomy. The frequency of breast-conserving surgery ranged from 3.5 percent to 21.2 percent in various states. The highest rate of use was in the Middle Atlantic states (20.0 percent) and New England (17.2 percent), and the lowest was in the East South Central states (5.9 percent) and the West South Central states (7.3 percent). Breast-conserving treatment was used more often in urban than in rural areas, in teaching hospitals than in nonteaching hospitals, in large hospitals than in small hospitals, and in hospitals with on-site radiation therapy or geriatric services than in others. Most of the geographic variation persisted after adjustment for the characteristics of hospitals and patients for which data were available. CONCLUSIONS There is substantial geographic variation in the use of breast-conserving surgery, which cannot be explained by differences in hospital characteristics. Hospital characteristics that were independently redictive of greater use of breast-conserving surgery were the size of the metropolitan area, the status of the institution as a teaching hospital, and the availability of radiation therapy and geriatric services.

Regulation of the immune response by prostaglandins.

This paper reviews work on the regulation of humoral and cellular immunity by prostaglandins. A substantial body of evidence implicates prostaglandins E1 and E2 as local feedback inhibitors of T-cell activation in vitro and in vivo. Blockade of prostaglandin synthesis in vitro or in vivo results in an enhanced cellular immune response in a number of different experimental systems. Prostaglandins of the E and F series also modulate humoral immune responses such as B-cell activation or antibody production. Several disease states are discussed where disordered regulation by prostaglandins might have a role in the altered immune responses.

Prostaglandin-Producing Suppressor Cells in Hodgkin's Disease

We examined the role of a prostaglandin-producing suppressor cell in the hyporesponsiveness to phytohemagglutinin seen in Hodgkins disease. Addition of indomethacin to phytohemagglutinin cultures of lymphocytes from six patients with Hodgkins disease resulted in an increase of 182 +/- 60 per cent in 3H-thymidine incorporation versus a 44 +/- 18% increase in 29 controls (mean +/- S.D., P less than 0.001). Without indomethacin the mean response of the lymphocytes in Hodgkins disease was 48% of that of control. With indomethacin it was 94% of the control value. Phytohemagglutinin cultures of Hodgkin-disease lymphocytes produced approximately fourfold more prostaglandin E2 after 48 hours than did normal lymphocytes (P less than 0.02). Removal of glass-adherent cells markedly decreased the enhancement seen with indomethacin; it reduced prostaglandin E2 production by more than 80% and eliminated the differences in response to phytohemagglutinin between Hodgkin-disease and normal lymphocytes. Thus, a glass-adherent, prostaglandin-producing suppressor cell is responsible for the hyporesponsiveness to phytohemagglutinin seen with Hodgkin-disease lymphocytes.

Congestive Heart Failure in Older Women Treated With Adjuvant Anthracycline Chemotherapy for Breast Cancer

PURPOSE Limited data are available on long-term cardiac safety of adjuvant anthracycline chemotherapy in breast cancer patients over age 65 years. We evaluated rates and predictors of congestive heart failure (CHF) in this population. PATIENTS AND METHODS We used the Surveillance, Epidemiology, and End Results Medicare database and included women with no history of CHF who were age 66 to 80 years and diagnosed with stage I to III breast cancer from 1992 to 2002. Cumulative rates of CHF were estimated, and multivariable Cox regression analysis was used to determine factors associated with the development of CHF. RESULTS A total of 43,338 women were included. Anthracycline-treated women were younger, with fewer comorbidities and more advanced disease than women who received nonanthracycline or no chemotherapy (P < .001 for each). The adjusted hazard ratio (HR) for CHF was 1.26 (95% CI, 1.12 to 1.42) for women aged 66 to 70 treated with anthracycline compared with other chemotherapy. For women aged 71 to 80, adjuvant chemotherapy type was not associated with CHF. The following baseline characteristics were significant predictors of CHF: age (HR, 1.79 per 10 years; 95% CI, 1.66 to 1.93), black race (HR, 1.40; 95% CI, 1.30 to 1.50), trastuzumab treatment (HR, 1.46; 95% CI, 1.21 to 1.77), hypertension (HR, 1.45; 95% CI, 1.39 to 1.52), diabetes (HR, 1.74; 95% CI, 1.66 to 1.83), and coronary artery disease (HR, 1.58; 95% CI, 1.39 to 1.79). Left-sided radiotherapy did not confer an elevated risk of CHF (HR, 1.04; 95% CI, 0.98 to 1.11). CONCLUSION Women aged 66 to 70 years who received adjuvant anthracyclines had significantly higher rates of CHF. The difference in rates of CHF continued to increase through more than 10 years of follow-up.

Emotional Well-Being Predicts Subsequent Functional Independence and Survival

OBJECTIVE: To determine whether positive affect has an independent effect on functional status, mobility, and survival in an older Mexican American sample.

The association between emotional well-being and the incidence of stroke in older adults

Objective Individuals with high levels of depressive symptoms have an increased risk of many illnesses, including stroke. Measures of depressive symptoms include questions about the presence of negative affect, such as sadness, as well as the absence of positive affect, such as happiness and optimism. We assessed whether positive or negative affect, or both, predicted risk of stroke. Methods Data were from a 6-year prospective cohort study of a population-based sample of 2478 older whites and blacks from five counties in North Carolina who reported no history of stroke at the baseline interview. Baseline, in-person interviews were conducted to gather information on sociodemographic, psychosocial, and health-related characteristics of subjects. Thereafter interviews were conducted annually for 6 years. Results Increasing scores on the modified version of the Center for Epidemiological Studies Depression Scale (CES-D) were significantly associated with stroke incidence for the overall sample (relative risk [RR] = 1.04 for each one-point increase, 95% confidence interval [CI] = 1.01–1.09) over the 6-year follow-up period after adjusting for sociodemographic characteristics, blood pressure, body mass index, smoking status, and selected chronic diseases. Positive affect score demonstrated a strong inverse association with stroke incidence (RR = 0.74, 95% CI = 0.62–0.88). Conclusions Increasing scores on the modified CES-D are related to an increased risk of stroke, whereas high levels of positive affect seem to protect against stroke in older adults.

Use and outcomes of adjuvant chemotherapy in older women with breast cancer

PURPOSE This study was undertaken to determine patterns and outcomes of adjuvant chemotherapy use in a population-based cohort of older women with primary breast cancer. PATIENTS AND METHODS Women were identified from the Surveillance, Epidemiology, and End Results-Medicare-linked database who met the following criteria: age > or = 65 years, stage I to III breast cancer, and diagnosis between 1991 and 1999. Adjuvant chemotherapy use was ascertained by Common Procedural Terminology J codes. Logistic regression analysis was performed to determine factors associated with chemotherapy use. Multivariate Cox proportional hazards models were used to calculate the hazard of death for women with and without chemotherapy. RESULTS A total of 41,390 women met study criteria, of whom 4,500 (10.9%) received chemotherapy. The use of adjuvant chemotherapy more than doubled during the 1990s, from 7.4% in 1991 to 16.3% in 1999 (P < .0001), with a significant shift toward anthracycline use. Women who were younger, white, with lower comorbidity scores, more advanced stage disease, and estrogen receptor (ER) -negative disease were significantly more likely to receive chemotherapy. Chemotherapy was not associated with improved survival among women with lymph node-negative (LN) disease or LN-positive, ER-positive disease (hazard ratio [HR], 1.05; 95% CI, 0.85 to 1.31). However, among women with LN-positive, ER-negative breast cancer, chemotherapy was associated with a significant reduction in breast cancer mortality (HR, 0.72; 95% CI, 0.54 to 0.96). A similar significant benefit of chemotherapy was seen in the subset of women age 70 years or older (HR, 0.74; 95% CI, 0.56 to 0.97). CONCLUSION In this observational cohort, chemotherapy was associated with a significant reduction in mortality among older women with ER-negative, LN-positive breast cancer.

Prostaglandin Suppression of Mitogen-Stimulated Lymphocytes In Vitro: CHANGES WITH MITOGEN DOSE AND PREINCUBATION

In this study we further characterize the properties of the prostaglandin-producing suppressor cell. Overnight preincubation of peripheral blood mononuclear cells results in an increased response of the cells to phytohemagglutinin or Concanavalin A compared to the response of fresh cells. This increase in mitogen response with preincubation was similar in magnitude to the increase in mitogen response of fresh cells after the addition of indomethacin. The two manipulations were not additive; that is, after preincubation, indomethacin caused much less enhancement of mitogen stimulation of peripheral blood mononuclear cells (100 +/- 12% increase before preincubation vs. 12 +/- 6% after preincubation; mean+/-SEM, P < 0.001). Preincubated cells also lose sensitivity to inhibition by exogenous prostaglandin E(2). It requires the addition of 100- to > 1,000-fold more exogenous PGE(2) to produce comparable inhibition of phytohemagglutinin-stimulated preincubated cells than is required for inhibition of phytohemagglutinin-stimulated fresh cells. The enhancing effect of indomethacin increases with decreasing doses of phytohemagglutinin. Indomethacin causes a 1,059+/-134% increase in [(3)H]thymidine incorporation at the lowest dose of phytohemagglutinin (0.2 mug/ml), and a 4+/-3% increase at the highest dose (20 mug/ml). This increase in response to indomethacin with a lower dose of phytohemagglutinin is due to increased sensitivity to inhibition by PGE(2) at lower mitogen doses. The prostaglandin-producing suppressor cell assay and the short-lived suppressor cell assay measure over-lapping phenomena. The increased suppressive effect of the prostaglandin-producing suppressor at suboptimal mitogen dose must be taken into account in the interpretation of any study where the response to a range of mitogen doses is studied.

Physician behaviors that correlate with patient satisfaction.

The behavior of 15 internal medicine residents, each with 10 patients, was observed through a one-way mirror. Ratings by the patients of satisfaction with their physicians were also obtained. Patient satisfaction correlated strongly with ratings for physician courtesy and information-giving, Nonverbal behaviors such as eye contact, bodily positioning, and physical contact did not correlate with patient satisfaction. The correlations between physician behavior and patient satisfaction did not hold for the four women physicians studied.