Nahida H. Gordon

Socioeconomic factors and breast cancer in black and white Americans

The incidence of breast cancer in the US is known to be higher among white than black women and among women of higher socioeconomic status (SES), but once a woman, either black or white, has the disease, she is more likely to have a recurrence and to die of breast cancer if she is of lower socioeconomic status. Explanations for these observed differences are varied and inconsistent making it clear that these reported differentials are not sufficiently understood. In understanding breast cancer in a multicultural setting, delay in diagnosis, follow-up, and treatment are frequently the focus of attention. However these factors do not sufficiently explain the observed differences between blacks and whites. A review of recent literature reveals an increasing focus on the role of SES in breast cancer etiology and progression; however, the confounding of SES with race/ethnicity (black vs. white) contributes to the insufficient understanding of the effect of these two factors. This report will focus on the interplay between race/ethnicity and SES and their relative effects upon analyses of survival from breast cancer. Findings are based on prospective clinical trial data. SES factors have been associated with most of the known or suspected risk factors for breast cancer incidence and progression. In addition to race/ethnicity, SES is also associated with diet, lifestyle factors, physical characteristics, and tumor characteristics. Without controlling for other risk factors, the ratios of risk for blacks with respect to whites for disease-free survival and overall survival were 1.30 (95% CI: 1.04–1.61) and 1.42 (95% CI: 1.15–1.76), respectively. However, after controlling for patient risk factors, such as the number of positive lymph nodes, tumor diameter, estrogen receptor status and socioeconomic factors, these differences decrease and are not statistically significant. Socioeconomic status is associated both with race/ethnicity and estrogen receptor status. A loglinear analysis demonstrates that the apparent association of race/ethnicity with estrogen receptor status is mediated by socioeconomic status. An implication of this finding is that environmental and lifestyle components rather than genetic factors associated with race may explain the observed differentials between black and white breast cancer patients. Knowledge of environmental factors associated with SES have the potential for providing important clues about the prevention and control of breast cancer.

Mortality Trends During a Program That Publicly Reported Hospital Performance

Background. It is unclear whether publicly reporting hospitals’ risk-adjusted mortality leads to improvements in outcomes. Objectives. To examine mortality trends during a period (1991–1997) when the Cleveland Health Quality Choice program was operational. Research Design. Time series. Subjects. Medicare patients hospitalized with acute myocardial infarction (AMI; n = 10,439), congestive heart failure (CHF; n = 23,505), gastrointestinal hemorrhage (GIH; n = 11,088), chronic obstructive pulmonary disease (COPD; n = 8495), pneumonia (n = 23,719), or stroke (n = 14,293). Measures. Risk-adjusted in-hospital mortality, early postdischarge mortality (between discharge and 30 days after admission), and 30-day mortality. Results. Risk-adjusted in-hospital mortality declined significantly for all conditions except stroke and GIH, with absolute declines ranging from –2.1% for COPD to –4.8% for pneumonia. However, the mortality rate in the early postdischarge period rose significantly for all conditions except COPD, with increases ranging from 1.4% for GIH to 3.8% for stroke. As a consequence, the 30-day mortality declined significantly only for CHF (absolute decline 1.4%, 95% CI, −2.5 to −0.1%) and COPD (absolute decline 1.6%, 95% CI, −2.8–0.0%). For stroke, risk-adjusted 30-day mortality actually increased by 4.3% (95% CI, 1.8–7.1%). Conclusion. During Cleveland’s experiment with hospital report cards, deaths shifted from in hospital to the period immediately after discharge with little or no net reduction in 30-day mortality for most conditions. Hospital profiling remains an unproven strategy for improving outcomes of care for medical conditions. Using in-hospital mortality rates to monitor trends in outcomes for hospitalized patients may lead to spurious conclusions.

Effectiveness Trial of an Intensive Communication Structure for Families of Long-Stay ICU Patients

BACKGROUND Formal family meetings have been recommended as a useful approach to assist in goal setting, facilitate decision making, and reduce use of ineffective resources in the ICU. We examined patient outcomes before and after implementation of an intensive communication system (ICS) to test the effect of regular, structured formal family meetings on patient outcomes among long-stay ICU patients. METHODS One hundred thirty-five patients receiving usual care and communication were enrolled as the control group, followed by enrollment of intervention patients (n = 346), from five ICUs. The ICS included a family meeting within 5 days of ICU admission and weekly thereafter. Each meeting discussed medical update, values and preferences, and goals of care; treatment plan; and milestones for judging effectiveness of treatment. RESULTS Using multivariate analysis, there were no significant differences between control and intervention patients in length of stay (LOS), the primary end point. Similarly, there were no significant differences in indicators of aggressiveness of care or treatment limitation decisions (ICU mortality, LOS, duration of ventilation, treatment limitation orders, or use of tracheostomy or percutaneous gastrostomy). Exploratory analysis suggested that in the medical ICUs, the intervention was associated with a lower prevalence of tracheostomy among patients who died or had do-not-attempt-resuscitation orders in place. CONCLUSIONS The negative findings of the main analysis, in combination with preliminary evidence of differences among types of unit, suggest that further examination of the influence of patient, family, and unit characteristics on the effects of a system of regular family meetings may be warranted. Despite the lack of influence on patient outcomes, structured family meetings may be an effective approach to meeting information and support needs. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT01057238 ; URL: www.clinicaltrials.gov.

Synergistic efficacy of O6benzylguanine and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in a human colon cancer xenograft completely resistant to BCNU alone

The DNA repair protein O6-alkylguanine-DNA alkyltransferase (alkyltransferase) repairs cytotoxic DNA damage formed by 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). High levels of this repair protein cause tumor drug resistance to nitrosoureas. To investigate the ability of a direct alkyltransferase inhibitor, O6-benzylguanine, to reverse the nitrosourea resistance of human colon cancer cells, we studied the VACO 6 cell line which has high alkyltransferase and is completely resistant to BCNU at maximal tolerated doses in the xenograft model. O6-Benzylguanine at 0.5 microgram/mL for 1 hr inactivated VACO 6 alkyltransferase by > 98% and reduced the IC50 of BCNU by 3- to 4-fold. Further analysis indicated that these two agents act in a highly synergistic fashion. In xenograft bearing athymic mice, dose-dependent depletion of hepatic and tumor alkyltransferase was noted. To maintain alkyltransferase depletion in the xenograft for at least 24 hr, two doses of 60 mg/kg O6-benzylguanine were given 1 hr prior and 7 hr after BCNU. Under these conditions, VACO 6 xenografts became responsive to BCNU with significant reductions (P < 0.001) in the tumor growth rate. The combination increased toxicity to the host, reducing the maximum tolerated dose of BCNU by approximately 50%. This study provides definitive evidence that high alkyltransferase activity is responsible for BCNU resistance in human colon cancer xenografts and that with careful drug scheduling, O6-benzylguanine can sensitize a tumor which is completely unresponsive to BCNU alone. Further studies which optimize the therapeutic index of BCNU and O6-benzylguanine in vivo will define the schedule to be used in broader preclinical studies.

Photodynamic therapy of human breast cancer xenografts lacking caspase-3.

The human breast cancer cell line MCF-7 is deficient in procaspase-3 and in caspase-3-dependent steps in apoptosis due to deletion of the CASP-3 gene. We previously found that the cells transfected with empty vector (MCF-7v cells) were considerably less sensitive to photodynamic treatment in vitro with the phthalocyanine photosensitizer Pc 4 than were the cells stably transfected with human procaspase-3 cDNA (MCF-7c3 cells); however, overall cell killing, as determined by a clonogenic assay, was not affected by the presence of procaspase-3. The present study was undertaken to determine whether photodynamic therapy (PDT) in vivo was dependent on the ability of the cells to carry out the late steps in apoptosis that are catalyzed by this caspase. Xenografts of MCF-7 cells and the isogenic-derived MCF-7v and MCF-7c3 cells were generated in female athymic nude mice implanted with an estrogen pellet. MCF-7c3 xenografts, but not those of the other two lines, continued to express procaspase-3, as revealed by Western blots of proteins from the cells and the xenografts. When the xenografts reached 50-120 mm(3), some were treated with PDT (1mg/kg Pc 4 i.v. followed 48 h later by 150 J/cm(2) light at 672 nm and 150 mW/cm(2)), while others served as controls (no treatment, light alone, or Pc 4 alone). All Pc 4-PDT-treated tumors and none of the controls exhibited either complete or strong partial responses, and complete responses were durable for the entire observation period of 16 days. The responses were not dependent upon the presence of procaspase-3 in the xenografts. The results indicate that the rapid response of Pc 4-PDT-treated tumors in vivo is not due to their ability to carry out the major caspase-3-mediated late steps in apoptosis.

Rehospitalization in a National Population of Home Health Care Patients with Heart Failure

OBJECTIVE Patients with heart failure (HF) have high rates of rehospitalization. Home health care (HHC) patients with HF are not well studied in this regard. The objectives of this study were to determine patient, HHC agency, and geographic (i.e., area variation) factors related to 30-day rehospitalization in a national population of HHC patients with HF, and to describe the extent to which rehospitalizations were potentially avoidable. DATA SOURCES Chronic Condition Warehouse data from the Centers for Medicare & Medicaid Services. STUDY DESIGN Retrospective cohort design. DATA EXTRACTION The 2005 national population of HHC patients was matched with hospital and HHC claims, the Provider of Service file, and the Area Resource File. PRINCIPAL FINDINGS The 30-day rehospitalization rate was 26 percent with 42 percent of patients having cardiac-related diagnoses for the rehospitalization. Factors with the strongest association with rehospitalization were consistent between the multilevel model and Cox proportional hazard models: number of prior hospital stays, higher HHC visit intensity category, and dyspnea severity at HHC admission. Substantial numbers of rehospitalizations were judged to be potentially avoidable. CONCLUSIONS The persistently high rates of rehospitalization have been difficult to address. There are health care-specific actions and policy implications that are worth examining to improve rehospitalization rates.

Hormone Receptors: An Update and Application

The introduction of measurements of hormone receptors in breast cancer tumor specimens provides a major advance in selection of patients likely to have hormone-dependent cancers. Endocrine adjuvant treatment for estrogen-positive breast cancers in both pre- and postmenopausal women has been shown to be effective in delaying recurrence. Whenever possible, estrogen and progesterone receptors should be measured in tumor tissue from all patients with breast cancer.

Modulation of O6-alkylguanine alkyltransferase-directed DNA repair in metastatic colon cancers.

PURPOSE Carmustine (BCNU) resistance has been correlated with tumor expression of the DNA repair enzyme O6-alkylguanine-DNA alkyltransferase (AT). It has been shown that streptozotocin will deplete AT activity of human colon cancer cells in vitro and potentiate BCNU cytotoxicity. This clinical trial was conducted to determine whether streptozotocin can be used as a modulator of AT in metastatic colorectal cancers and thereby overcome clinical resistance to BCNU. PATIENTS AND METHODS Fifteen patients with fluorouracil-resistant metastatic colon or rectal cancers were treated sequentially with 2 g/m2 of streptozotocin followed 5 1/2 hours later by BCNU. Sequential biopsies of metastases before and after streptozotocin were conducted to determine whether streptozotocin depletes tumor AT. Peripheral-blood mononuclear cells (PBMCs) were evaluated as a surrogate tissue for prediction of baseline AT levels and streptozotocin posttreatment modulation of the AT in metastases. RESULTS Streptozotocin treatment led to a 78% (range, 69% to 89%) decrease in the AT levels in colon cancer metastases; however, myelosuppression and hepatic toxicity limited the BCNU dose to 130 mg/m2. A similar decrease in AT levels of PBMCs was found; however, the absolute levels of AT in PBMCs at baseline and following streptozotocin were not predictive of the levels expressed in metastases from the same patient. Despite the decrease in tumor levels of AT, no clinical responses were observed. CONCLUSION Streptozotocin decreases but does not fully deplete AT activity in metastatic colorectal cancers and the residual AT level in metastases is sufficient to maintain clinical resistance to BCNU. We have also demonstrated that sequential computed tomography (CT)-directed biopsies of colorectal cancer metastases can be used to evaluate strategies to investigate modulators of AT-directed repair. AT levels of PBMCs do not predict for the AT level or degree of modulation achieved in the metastatic tumor.

Endocrine versus endocrine plus five-drug chemotherapy in postmenopausal women with stage II estrogen receptor-positive breast cancer

Postmenopausal women who underwent modified radical mastectomy for Stage II, estrogen receptor (ER)‐positive breast cancer were randomized to receive endocrine treatment (tamoxifen [T], 40 mg daily for 3 years) alone versus endocrine treatment plus five‐drug chemotherapy (Cytoxan [cyclophosphamide, C], methotrexate [M], 5‐fluorouracil [F], vincristine [V], and prednisone [P], CMFVP, for 1 year). Chemotherapy consisted of oral P (1 month), oral C (12 months), and intravenous MFV weekly for the first 3 months, biweekly for 3 months, and triweekly for 6 months. Patients were entered into the study from October 1979, to October 1985, and the median follow‐up is 55 months. Results show that with 94 postmenopausal women, disease‐free survival (DFS) is significantly greater (P = 0.04, log‐rank test; P = 0.03, multivariate analysis) in patients receiving CMFVPT as compared to those receiving T alone. These results suggest that intensive chemotherapy combined with T is more effective in delaying recurrence than T alone in postmenopausal patients.

An Exploratory Study of Relational, Persuasive, and Nonverbal Communication in Requests for Tissue Donation

This study explores the effects of tissue requesters’ relational, persuasive, and nonverbal communication on families’ final donation decisions. One thousand sixteen (N = 1,016) requests for tissue donation were audiotaped and analyzed using the Siminoff Communication Content and Affect Program, a computer application specifically designed to code and assist with the quantitative analysis of communication data. This study supports the important role of communication strategies in health-related decision making. Families were more likely to consent to tissue donation when confirmational messages (e.g., messages that expressed validation or acceptance) or persuasive tactics such as credibility, altruism, or esteem were used during donation discussions. Consent was also more likely when family members exhibited nonverbal immediacy or disclosed private information about themselves or the patient. The results of a hierarchical log-linear regression revealed that the use of relational communication during requests directly predicted family consent. The results provide information about surrogate decision making in end-of-life situations and may be used to guide future practice in obtaining family consent to tissue donation.