Publications

PURPOSE

Resistance to topoisomerase (topo) I inhibitors has been related to down-regulation of nuclear target enzyme, whereas sensitization to topo II inhibitors may result from induction of topo II by topo I inhibitors. Here, we evaluated a sequence-specific administration of a topo I inhibitor followed by a topo II inhibitor.

EXPERIMENTAL DESIGN

Twenty-five patients with advanced or metastatic malignancies were treated with increasing doses (0.75, 1.0, 1.25, 1.5, 1.75, or 2.0 mg/m(2)) of 9-nitrocamptothecin (9-NC) on days 1 to 3, followed by etoposide (100 or 150 mg/d) on days 4 and 5. At the maximally tolerated dose, 20 additional patients were enrolled. The median age was 60 years (range, 40-84 years). Endpoints included pharmacokinetic analyses of 9-NC and etoposide, and treatment-induced modulations of topo I and II expression in peripheral blood mononuclear cells.

RESULTS

Neutropenia, thrombocytopenia, nausea, vomiting, diarrhea, and fatigue were dose-limiting toxicities and occurred in six patients. Despite a median number of four prior regimens (range 1-12), 2 (4%) patients had an objective response and 13 (29%) patients had stable disease. In contrast to the expected modulation in topo I and IIalpha levels, we observed a decrease in topo IIalpha levels, whereas topo I levels were not significantly altered by 9-NC treatment.

CONCLUSIONS

Sequence-specific administration of 9-NC and etoposide is tolerable and active. However, peripheral blood mononuclear cells may not be a predictive biological surrogate for drug-induced modulation of topo levels in tumor tissues and should be further explored in larger studies.

PURPOSE

In phase I studies with oral CI-1033, dose-limiting toxicities were primarily gastrointestinal, supporting the exploration of i.v. dosing to achieve optimal drug exposures by increasing bioavailability.

EXPERIMENTAL DESIGN

Fifty-three patients with advanced nonhematologic malignancies received i.v. CI-1033 via 30-minute infusions (10-500 mg) on a thrice-weekly schedule. Pharmacokinetic samples were collected on days 1 and 8 and evaluated using noncompartmental analysis.

RESULTS

Dose levels evaluated were 10, 20, 30, 45, 67.5, 100, 150, 225, 337.5, and 500 mg. The maximum administered dose was 500 mg, whereas the maximum tolerated dose was 225 mg. The most common treatment-related grade 1 to 2 adverse events were rashes (38% of patients), nausea (17%), vomiting (17%), stomatitis (14%), and diarrhea (13%). Most common grade 3 adverse events were hypersensitivity reactions (7.5%), rashes (3.8%), and diarrhea (3.8%). No grade 4 toxicities were observed. Ten of the 53 (19%) patients had disease stabilization at their first efficacy evaluation visit (including two with minor responses). A 5- to 10-fold increase in i.v. C(max) was noted with a 3-fold increase in AUC compared with oral CI-1033 at equivalent doses. Treatment-related gastrointestinal adverse events were notably less frequent with this i.v. regimen.

CONCLUSIONS

CI-1033 was safely given i.v. up to 225 mg/dose on a thrice-weekly schedule, with evidence of antitumor activity. At equivalent doses, the bioavailability of i.v. CI-1033 is thrice that of the oral formulation. Treatment with i.v. CI-1033 is feasible and may be warranted when increased drug exposures are desired.

BACKGROUND

Little is known about patient characteristics associated with comprehension of consent information, and whether modifications to the consent process can promote understanding.

OBJECTIVE

To describe a modified research consent process, and determine whether literacy and demographic characteristics are associated with understanding consent information.

DESIGN

Descriptive study of a modified consent process: consent form (written at a sixth-grade level) read to participants, combined with 7 comprehension questions and targeted education, repeated until comprehension achieved (teach-to-goal).

PARTICIPANTS

Two hundred and four ethnically diverse subjects, aged > or = 50, consenting for a trial to improve the forms used for advance directives.

MEASUREMENTS

Number of passes through the consent process required to achieve complete comprehension. Literacy assessed in English and Spanish with the Short Form Test of Functional Health Literacy in Adults (scores 0 to 36).

RESULTS

Participants had a mean age of 61 years and 40% had limited literacy (s-TOHFLA<23). Only 28% of subjects answered all comprehension questions correctly on the first pass. After adjustment, lower literacy (P=.04) and being black (P=.03) were associated with requiring more passes through the consent process. Not speaking English as a primary language was associated with requiring more passes through the consent process in bivariate analyses (P<.01), but not in multivariable analyses (P>.05). After the second pass, most subjects (80%) answered all questions correctly. With a teach-to-goal strategy, 98% of participants who engaged in the consent process achieved complete comprehension.

CONCLUSIONS

Lower literacy and minority status are important determinants of understanding consent information. Using a modified consent process, little additional education was required to achieve complete comprehension, regardless of literacy or language barriers.

BACKGROUND

While limited literacy is common and its prevalence increases with age, no prospective study has assessed whether limited literacy is associated with mortality in older adults.

OBJECTIVE

To assess the association of limited literacy with mortality.

DESIGN AND SETTING

Five-year prospective study from 1999 to 2004 of community-dwelling elders from Memphis, TN, and Pittsburgh, PA, who were from the Health, Aging, and Body Composition study. Subjects' literacy was assessed with the Rapid Estimate of Adult Literacy in Medicine. Scores were categorized into limited (0 to 8th grade reading level) or adequate literacy (> or = 9th grade reading level).

PARTICIPANTS

Two thousand five hundred and twelve black and white elders without baseline functional difficulties or dementia.

MEASUREMENTS

Time to death.

RESULTS

Participants' mean age was 75.6 years, 48% were male, 38% were black, and 24% had limited literacy; the median follow-up time was 4.2 years. Compared with those with adequate literacy, those with limited literacy had a higher risk of death (19.7% vs 10.6%) with a hazard ratio (HR) of 2.03 (95% confidence intervals [CI], 1.62 to 2.55). After adjusting for demographics and socioeconomic status, co-morbid conditions, self-rated health status, health-related behaviors, health care access measures, and psychosocial status, limited literacy remained independently associated with mortality (HR 1.75; 95% CI, 1.27 to 2.41).

CONCLUSIONS

Limited literacy is independently associated with a nearly 2-fold increase in mortality in the elderly. Given the growth of the aging population and the prevalence of chronic diseases, the mechanisms by which limited literacy is associated with mortality in the elderly warrant further investigation.

OBJECTIVES

To describe patterns of home health and hospice use by older cancer patients and a comparison group of older persons without cancer. To identify predictors of home care and hospice utilization.

DESIGN

Retrospective analysis using the Surveillance, Epidemiology and End Results (SEER)-Medicare Database, a linkage of the SEER Program of the National Cancer Institute (an epidemiological surveillance system of population-based tumor registries) and Medicare Claims.

SETTING

The SEER data used in this paper cover a service area that includes approximately 14% of the U.S. population, including the states of Connecticut, Hawaii, Iowa, and New Mexico and the metropolitan areas of Detroit, San Francisco-Oakland, Atlanta, Seattle-Puget Sound, Los Angeles County, and San Jose-Monterey.

PARTICIPANTS

Five analytical samples were drawn. The first consisted of all cases with a diagnosis of cancer in 1997 to 1999 who were eligible for services in calendar year 1999 (n=120,072). The second and third were subsamples of these and consisted of cases with a new cancer diagnosis in 1999 (n=46,373) and cases who died in 1999 (n=41,483). The fourth consisted of a comparison sample without cancer (n=160,707). The fifth was a subsample of this and consisted of those who died in 1999 (n=6,639).

MEASUREMENTS

Utilization rates of home health and hospice services.

RESULTS

Twenty-nine percent of cancer patients used home health services, and 10.7% used hospice services, compared with 7.8% of noncancer patients who used home health and less than 1% who used hospice. Half (51.4%) of cancer patients who used home health did not have cancer listed as an admitting diagnosis for the use of those services. Home health utilization was lowest for unmarried men.

CONCLUSION

This is the first study to evaluate community-based home health and hospice utilization by older cancer patients. Future studies must begin to address what constitutes appropriate utilization.

INTRODUCTION

Most medical schools are remiss in preparing physicians in end-of-life communication skills. As a result, many residents are uncomfortable with approaching the patient, have not developed the skills required to discuss the patients' wishes, and avoid end-of-life conversations.

OBJECTIVE

To evaluate an educational intervention focused on teaching residents skills to discuss advance directives.

METHODS

Medicine Residents attended a morning report consisting of both didactic training and participation in a role-play exercise. Charts of inpatients were audited ten days prior to and five days subsequent to the intervention to ascertain if there was a documented do-not-resuscitate (DNR) discussion.

RESULTS

Seventy-nine records of patients assigned to eight physicians who attended the intervention and who were responsible for patients before and after the intervention were reviewed. Of the patients assigned to these residents before the intervention, 32% had a documented DNR discussion. Thirty-four (34%) of the physicians had discussions after the intervention, demonstrating only minimal improvement.

CONCLUSIONS

A single intervention may be inadequate to affect physician practices related to DNR discussions. Physicians may need more interactive, experiential learning opportunities and related supervision over the course of their training in order to improve these communication skills. A chart review that only records if a DNR discussion was documented in the medical record may not be the best tool to evaluate the success of this educational intervention. Improvement in attitudes and knowledge were not able to be measured.

OBJECTIVE

To examine the association of heart disease with depression and the impact of treatment with anti-depressants on this association in older males with type 2 diabetes.

RESEARCH DESIGN AND METHODS

In this cross-sectional study, data were collected from the electronic medical record system of the Veterans Affairs Medical Center (VAMC) in a large mid-western city in the United States. Subjects were 8185 males older than 40, with a history of type 2 diabetes, who had visited the VAMC within the previous 6 years. Odds ratios were used to measure bivariate associations; multivariate logistic regression was used to adjust for potential confounding factors.

RESULTS

After adjustments for confounding variables, significant associations were found between depression and any adverse heart event (OR=1.34, p=0.001), coronary artery disease (OR=1.23, p=0.039), myocardial infarction (MI; OR=1.77, p<0.001), and angioplasty (OR=1.36, p=0.034). Examination of the interaction between depression and anti-depressant prescription status indicated that, except for MI, these associations were no longer significant among those who had been prescribed anti-depressants, but remained significant and were increased in magnitude among those who had not been prescribed anti-depressants.

CONCLUSIONS

These findings support the premise that co-morbid depression in diabetics is associated with the occurrence of adverse heart events, and further suggest that treatment of depression with anti-depressants moderates this association.

BACKGROUND

Obese Zucker rats demonstrate increased susceptibility to hepatic ischemia-reperfusion injury. This study evaluates the effect of mild systemic hypothermia on ischemia-induced acute fulminant necrosis during warm ischemia and reperfusion, and investigates blood metabolic profiles under normothermic and mildly hypothermic conditions.

METHODS

The left and median hepatic lobes of male, obese, Zucker rats were exposed to 75 minutes of ischemia under either normothermic (36.9 +/- 0.3 degrees C) or mildly hypothermic (33.3 +/- 0.1 degrees C) conditions followed by 8 hours of reperfusion. Animals were killed and tissue and blood were harvested for analysis of histology, liver enzymes, and metabolic 1H-NMR spectroscopy.

RESULTS

Liver enzyme activities were significantly higher in the normothermic group when compared with mildly hypothermic animals. Histologic analysis showed greater than 75% necrosis in the normothermic group, whereas in the mildly hypothermic group necrosis was less than 25%. Blood from normothermic animals contained greater concentrations of lactate (190%, P = .001) and lower concentrations of glucose (60%, P = .01) than hypothermic animals; hepatic osmolyte betaine was also increased in blood from the normothermic group (220%, P = .0002). In addition, normothermic rats had increased concentrations of circulating fatty acids, triglycerides, glutamate, succinate, and acetate when compared with the hypothermic.

CONCLUSION

Mild hypothermia decreased hepatic necrosis in obese rats. NMR blood profiles indicate that hypothermia protects hepatic metabolism.

Several animal models of atrial fibrillation (AF) have been developed that demonstrate either atrial structural remodeling or atrial electrical remodeling, but the characteristics and spatiotemporal organization of the AF between the models have not been compared. Thirty-nine dogs were divided into five groups: rapid atrial pacing (RAP), chronic mitral regurgitation (MR), congestive heart failure (CHF), methylcholine (Meth), and control. Right and left atria (RA and LA, respectively) were simultaneously mapped during episodes of AF in each animal using high-density (240 electrodes) epicardial arrays. Multiple 30-s AF epochs were recorded in each dog. Fast Fourier transform was calculated every 1 s over a sliding 2-s window, and dominant frequency (DF) was determined. Stable, discrete, high-frequency areas were seen in none of the RAP or control dogs, four of nine MR dogs, four of six CHF dogs, and seven of nine Meth dogs in either the RA or LA or both. Average DFs in the Meth model were significantly greater than in all other models in both LA and RA except LA DFs in the RAP model. The RAP model was the only one with a consistent LA-to-RA DF gradient (9.5 +/- 0.2 vs. 8.3 +/- 0.3 Hz, P < 0.00005). The Meth model had a higher spatial and temporal variance of DFs and lower measured organization levels compared with the other AF models, and it was the only model to show a linear relationship between the highest DF and dispersion (R(2) = 0.86). These data indicate that structural remodeling of atria (models known to have predominantly altered conduction) leads to an AF characterized by a stable high-frequency area, whereas electrical remodeling of atria (models known to have predominantly shortened refractoriness without significant conduction abnormalities) leads to an AF characterized by multiple high-frequency areas and multiple wavelets.

In patients requiring mechanical ventilation for acute lung injury or acute respiratory distress syndrome (ARDS), tidal volume reduction decreases mortality, but the mechanisms of the protective effect have not been fully explored. To test the hypothesis that alveolar macrophage activation is an early and critical event in the initiation of ventilator-induced lung injury (VILI), rats were ventilated with high tidal volume (HV(T)) for 10 min to 4 h. Alveolar macrophage counts in bronchoalveolar lavage (BAL) fluid decreased 45% by 20 min of HV(T) (P < 0.05) consistent with activation-associated adhesion. Depletion of alveolar macrophages in vivo with liposomal clodronate significantly decreased permeability and pulmonary edema following 4 h of HV(T) (P < 0.05). BAL fluid from rats exposed to 20 min of HV(T) increased nitric oxide synthase activity nearly threefold in naïve primary alveolar macrophages (P < 0.05) indicating that soluble factors present in the air spaces contribute to macrophage activation in VILI. Media from cocultures of alveolar epithelial cell monolayers and alveolar macrophages exposed to 30 min of stretch in vitro also significantly increased nitrite production in naïve macrophages (P < 0.05), but media from stretched alveolar epithelial cells or primary alveolar macrophages alone did not, suggesting alveolar epithelial cell-macrophage interaction was required for the subsequent macrophage activation observed. These data demonstrate that injurious mechanical ventilation rapidly activates alveolar macrophages and that alveolar macrophages play an important role in the initial pathogenesis of VILI.