Citations

The General Well-being Schedule is a brief indicator of subjective feelings of psychological well-being and distress. It is easy to administer, reliable, and valid, although its validity with American Indians has not been established. This study then assessed reliability, validity, and factor structure for a sample of 88 diabetic American Indians, who sought care for diabetes at an Indian Health Service hospital. Cronbach alpha was .89. A factor analysis indicated four dimensions. Adequate concurrent and divergent validity were noted in association with scores on the Beck Depression Inventory-Second Edition, the depression scale on the Symptom Checklist-90-Revised, and Family-Adaptation, Partnership, Growth, Affection, & Resolve. These results suggest that the General Well-being Schedule is a reliable and valid measure of general well-being for this population of American Indians.

Abstract Chemotherapy-related myeloid neoplasia (t-MN) is a significant late toxicity concern after cancer therapy. In the randomized intergroup phase 3 E2997 trial, initial therapy of chronic lymphocytic leukemia with fludarabine plus cyclophosphamide (FC) compared with fludarabine alone yielded higher complete and overall response rates and longer progression-free, but not overall, survival. Here, we report t-MN incidence in 278 patients enrolled in E2997 with a median 6.4-year follow-up. Thirteen cases (4.7%) of t-MN occurred at a median of 5 years from initial therapy for chronic lymphocytic leukemia, 9 after FC and 4 after fludarabine alone. By cumulative incidence methodology, rates of t-MN at 7 years were 8.2% after FC and 4.6% after fludarabine alone (P = .09). Seven of the 9 cases of t-MN after FC occurred without additional therapy. Abnormalities involving chromosomes 5 or 7 were found in 10 cases, which suggests alkylator involvement. These data suggest that FC may induce more t-MN than fludarabine alone.

Abstract A phase I trial of ABT-888 (veliparib), a PARP inhibitor, in combination with topotecan, a topoisomerase I–targeted agent, was carried out to determine maximum tolerated dose (MTD), safety, pharmacokinetics, and pharmacodynamics of the combination in patients with refractory solid tumors and lymphomas. Varying schedules and doses of intravenous topotecan in combination with ABT-888 (10 mg) administered orally twice a day (BID) were evaluated. Plasma and urine pharmacokinetics were assessed and levels of poly(ADP-ribose) (PAR) and the DNA damage marker γH2AX were measured in tumor and peripheral blood mononuclear cells (PBMC). Twenty-four patients were enrolled. Significant myelosuppression limited the ability to coadminister ABT-888 with standard doses of topotecan, necessitating dose reductions. Preclinical studies using athymic mice carrying human tumor xenografts also informed schedule changes. The MTD was established as topotecan 0.6 mg/m2/d and ABT-888 10 mg BID on days one to five of 21-day cycles. Topotecan did not alter the pharmacokinetics of ABT-888. A more than 75% reduction in PAR levels was observed in 3 paired tumor biopsy samples; a greater than 50% reduction was observed in PBMCs from 19 of 23 patients with measurable levels. Increases in γH2AX response in circulating tumor cells (CTC) and PBMCs were observed in patients receiving ABT-888 with topotecan. We show a mechanistic interaction of a PARP inhibitor, ABT-888, with a topoisomerase I inhibitor, topotecan, in PBMCs, tumor, and CTCs. Results of this trial reveal that PARP inhibition can modulate the capacity to repair topoisomerase I–mediated DNA damage in the clinic. Cancer Res; 71(17); 5626–34. ©2011 AACR.

The fine structure of the microvasculature in areas of focal cerebral ischemia was studied in squirrel monkeys and the changes in areas of impaired and unimpaired microvascular filling, as defined by carbon perfusion, were compared. Microcirculatory obstruction became evident three hours following middle cerebral artery (MCA) occlusion and appeared to be partly the result of compression of capillaries by perivascular glial swelling and developing cerebral edema. Slight endothelial swelling was a common finding. Intraluminal membrane-bound bodies were occasionally identified but they did not appear to be producing significant obstruction. The tight endothelial junctions remained intact and there was no evidence of accelerated micropinocytosis. Severe neuronal injury frequently preceded the development of the microvascular obstruction and was more widespread than the zones of impaired perfusion.

The sequential synaptic alterations which occur during the early phase of developing cortical infarction in the squirrel monkey were studied with the electron microscope. Mild swelling of a few dendritic terminals and clumping of synaptic vesicles were the earliest detectable changes, being present at 45 minutes. The two basic patterns of degeneration of the terminal boutons were shrinkage and swelling, with shrinkage being the predominant response. Many of the shrunken boutons became electron-dense, resembling the changes present in anterograde axonal degeneration. The alterations which developed in the dendritic terminals were relatively unimpressive. Disruption of axosomatic synapses occurred at an earlier stage and was more severe than that of axodendritic synapses. Reduction in the number of synaptic vesicles was first observed at six hours and appeared to be progressive. The edema which developed was morphologically distinct from both "vasogenic" and "cytotoxic" edema in that there was early and progressive enlargement of the extracellular space.

We reviewed surrogate calls (i.e. those made on behalf of the patient) to a national triage call centre to determine whether there were differences between calls made by surrogates and self calls. During a three-year period there were 14,646 calls (14% of the total) made by a surrogate on behalf of the patient. Surrogate calls, as a percentage of total calls, increased with the age of the patient from 12% in the 18–34 year age group to 43% in the 80 and over age group ( P < 0.0001). The symptoms of vomiting or nausea and dizziness or light-headedness were significantly more likely to be reported by surrogate callers than self callers. Surrogates reported a higher original intention of taking patients to the hospital emergency department (ED) compared with self callers across all adult age groups (OR 1.64; 95% CI 1.57 to 1.71). A higher proportion (38%) of surrogate calls ended with the nurse recommending an ED visit compared with only 26% of self calls (OR 1.72; 95% CI 1.66 to 1.79). Calls about men accounted for 54% of surrogate calls but only 26% of self calls (OR 3.3; 95% CI 3.2 to 3.4), suggesting that surrogate calls may be a way of increasing medical access for men.

Abstract The diazeniumdiolate O2-(2,4-dinitrophenyl)-1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2diolate (JS-K, NSC 724771) is a nitric oxide (NO)-donating prodrug that was designed to release NO upon reaction with glutathione-S-transferase which is overexpressed in some tumors. We demonstrated that JS-K reacts with nucleophiles in biological fluids and has an extremely short half-life in mice. The purpose of the study was to test the hypothesis that liposomal encapsulation improves the in vivo half-life, tissue distribution and acute toxicity profile of JS-K. We investigated the pharmacokinetics of [3H]JS-K in CD mice administered the drug in DMSO or DMPC (dimyristoylphosphatidylcholine) liposomes (20:1 molar ratio of DMPC: JS-K) and in tumor-bearing athymic nu/nu NCr mice administered the radiolabeled drug in DMPC liposomes. The terminal elimination half-life of total radioactivity (2 hours) was similar for both formulations. We did not detect [3H]JS-K in any plasma or red blood cell samples from mice administered 6 mg/kg JS-K in DMSO and only trace amounts of [3H]JS-K were detected in samples collected at the earliest time-points from mice administered 6 mg/kg JS-K in DMPC liposomes. Small amounts of radioactivity, presumably associated with JS-K metabolites, were detected at the solvent front of HPLC chromatograms. Very little radioactivity and no JS-K was detected in tumor samples. Finally, we developed an LC/MS/MS assay to investigate formation of JS-K metabolites in biological samples and used that method to measure concentrations of JS-K and its metabolites in plasma, red blood cells, liver tissue and tumor tissue collected from tumor-bearing mice administered 3 mg/kg or 6 mg/kg JS-K in DMPC liposomes. We confirmed extremely rapid in vivo degradation of JS-K in the systemic circulation following intravenous administration and rapid formation of several expected metabolites including high concentrations of the glutathione conjugate of the dinitrophenol moiety and piperazine. Supported by NCI Contract NO1-CM-52206. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2662.

Declines in heart disease and stroke mortality rates are conventionally attributed to reductions in cigarette smoking, recognition and treatment of hypertension and diabetes, effective medications to improve serum lipid levels and to reduce clot formation, and general lifestyle improvements. Recent evidence implicates these and other cerebrovascular factors in the development of a substantial proportion of dementia cases. Analyses were undertaken to determine whether corresponding declines in age‐specific prevalence and incidence rates for dementia and cognitive impairment have occurred in recent years. Data spanning 1 or 2 decades were examined from community‐based epidemiological studies in Minnesota, Illinois, and Indiana, and from the Health and Retirement Study, which is a national survey. Although some decline was observed in the Minnesota cohort, no statistically significant trends were apparent in the community studies. A significant reduction in cognitive impairment measured by neuropsychological testing was identified in the national survey. Cautious optimism appears justified.