A phase I study of decitabine with pegylated interferon α-2b in advanced melanoma: impact on DNA methylation and lymphocyte populations.

BACKGROUND: Melanoma cell lines treated with decitabine show upregulation of cancer antigens, and interferon-α upregulates MHC Class I antigens in cancer cells, leading to enhanced T-cell recognition and T-cell mediated tumor apoptosis. We evaluated the synergy between the hypomethylating effects of decitabine and the immunomodulatory effects of interferon in a combination regimen administered to advanced melanoma patients in a phase 1 trial. METHODS: Patients with one prior systemic therapy were eligible. Using a modified 3 + 3 design, patients received escalating doses of decitabine and pegylated interferon α-2b (PEG-IFN) during every 28-day treatment cycle. Global DNA methylation was measured on days 1 and 5 of cycles 1 and 3. Cytokine profiling and quantification of T-cell subpopulations by FACS were performed at baseline and cycle 3. RESULTS: Seventeen patients were assigned to one of four dose levels. Decitabine 15 mg/m2/d + PEG-IFN 3 µg/kg was the maximum tolerated dose (MTD). Grade 3/4 cytopenias were seen across all dose levels: anemia (1), neutropenia (7), and thrombocytopenia (2). One patient remained progression-free for 37 weeks. The other 16 patients progressed at or before 12 weeks. Median overall survival was 39 weeks. Hypomethylation was seen at all dose levels. Due to treatment-induced lymphocytopenia, absolute changes in T-cell populations post-treatment were too small to be meaningfully interpreted. CONCLUSIONS: The response to this combination regimen was characterized by significant myelosuppression, particularly neutropenia. Although disappointing efficacy and slow accrual led to early closure of the trial, hypomethylation showed pharmacodynamic evidence of a therapeutic effect of decitabine at all dose levels.

Physical and pharmacologic restraint of nursing home patients with dementia. Impact of specialized units.

This case-control study of 31 specialized dementia units and 32 traditional units in five states investigated use of physical and pharmacologic restraints among 625 patients with the diagnosis of dementia. Physical restraints were observed in use on 18.1% of dementia unit patients and on 51.6% of comparison unit patients who were out of bed during the day (adjusted odds ratio, 0.283;95% confidence interval, 0.129 to 0.619). Pharmacologic restraints were routinely given to 45.3% of dementia unit patients and 43.4% of comparison unit patients (adjusted odds ratio, 0.950; 95% confidence interval, 0.611 to 1.477). We used multivariate logistic regression to identify residence in a nonspecialized nursing home unit, nonambulatory status, transfer dependency, mental status impairment, hip fracture history, and a high nursing staff-to-patient ratio, which we found to be independent predictors of physical restraint use. Physically abusive behavior, severe mental status impairment, and frequent family visitation were found to be significant predictors of pharmacologic restraint use, while advanced patient age, large nursing home size, and patient nonambulatory status were protective against such use. These results support the conclusion that physical and pharmacologic restraint constitute separate treatment modalities with different risk factors for use, and indicate that specialized dementia units are successful in reducing the use of physical but not pharmacologic restraints.

KIE: This report discusses the results of a study of the use of physical and pharmacologic restraints in the management of patients with dementia among 307 residents in specialized dementia units and 318 residents receiving traditional nursing home care. The authors note the prevalence and types of restraints used among these patients. They also identify those factors such as nonambulatory status, mental status impairment, and physically abusive behavior that were associated with the use of physical and pharmacologic restraints, and they estimate the effect of special dementia units on restraint use.