Three-hundred and twenty-four patients were enrolled in an open-label, multicenter, international study in which pre- and post-liver transplantation (LT) patients with recurrent chronic hepatitis B (CHB) and evidence of lamivudine-resistant HBV were treated with adefovir dipivoxil 10 mg once daily. In the pre- and post-LT cohorts, 128 and 196 patients were treated for a median duration of 18.7 and 56.1 weeks, respectively. In patients who received 48 weeks of treatment, 81% of the pre-LT and 34% of the post-LT cohort achieved undetectable serum hepatitis B virus (HBV) DNA (Roche Amplicor Monitor polymerase chain reaction [PCR] assay lower limit of quantification [LLQ] < 400 copies/mL) with a median change in serum HBV DNA from baseline of -4.1 log(10) and -4.3 log(10) copies/mL, respectively. Serum alanine aminotransferase (ALT), albumin, bilirubin, and prothrombin time normalized in 76%, 81%, 50%, and 83% of pre-LT patients and 49%, 76%, 75%, and 20% of post-LT patients. The Child-Pugh-Turcotte (CPT) score improved in over 90% of patients in both cohorts. Genotypic analysis of 122 HBV baseline samples revealed that 98% of these patients had lamivudine-resistant mutant HBV. No adefovir resistance mutations were identified in patients after 48 weeks of therapy. One-year survival was 84% for pre-LT and 93% for post-LT patients (Kaplan-Meier analysis). Treatment-related adverse effects associated with adefovir dipivoxil in this setting were primarily mild to moderate in severity. In conclusion, 48 weeks of adefovir dipivoxil resulted in significant improvements in virologic, biochemical, and clinical parameters in CHB patients pre- and post-LT with lamivudine-resistant HBV.
Purpose To investigate SGI-110 as a “chemosensitizer” in ovarian cancer (OC) and to assess its effects on tumor suppressor genes (TSG) and chemo-responsiveness associated genes silenced by DNA methylation in OC. Experimental Design Several OC cell lines were used for in vitro and in vivo platinum resensitization studies. Changes in DNA methylation and expression levels of TSG and other cancer-related genes in response to SGI-110 were measured by pyrosequencing and RT-PCR. Results We demonstrate in vitro that SGI-110 resensitized a range of platinum-resistant OC cells to cisplatin (CDDP) and induced significant demethylation and reexpression of TSG, differentiation-associated genes and putative drivers of OC cisplatin resistance. In vivo, SGI-110 alone or in combination with CDDP was well tolerated and induced anti-tumor effects in OC xenografts. Pyrosequencing analyses confirmed that SGI-110 caused both global (LINE1) and gene specific hypomethylation in vivo, including TSGs (RASSF1A), proposed drivers of OC cisplatin resistance (MLH1 and ZIC1), differentiation-associated genes (HOXA10 and HOXA11), and transcription factors (STAT5B). Furthermore, DNA damage induced by CDDP in OC cells was increased by SGI-110, as measured by ICP-mass spectrometry analysis of DNA adduct formation and repair of cisplatin-induced DNA damage. Conclusions These results strongly support further investigation of hypomethylating strategies in platinum-resistant OC. Specifically, SGI-110 in combination with conventional and/or targeted therapeutics warrants further development in this setting.
OBJECTIVE: To assess the potential benefit of a pharmacist performing in‐home medication evaluations on frail older people. DESIGN: Prospective analysis with pre‐post comparison. SETTING: A hospital‐based home care program at the Sepulveda Veterans Affairs Medical Center. PARTICIPANTS: Male veterans in a home care program who live within 15 miles of the medical center and take three or more prescription medications (N = 20, mean age: 75.1 years). MEASURES: Prescribed medications were documented from the medical records and compared with regimens actually being followed in the home. In addition, the home was inspected, patients were educated, and recommendations were made to the prescribing physicians when necessary. RESULTS: At first visit, patients had a mean of 6.0 prescribed daily medications but were only taking 4.7 of these regularly. Also noted were many potentially unnecessary medications (70% of subjects) and multiple problems with the medication regimen (e.g., incorrect drug frequency or dosage, expired medications, medication omission). Follow‐up visit revealed a significant decrease in medication discrepancies and problems (P ≤ .05). CONCLUSION: An in‐home pharmacy assessment reveals many problems with drug administration not otherwise detected easily. These assessments can lead to potentially useful interventions that can improve medication regimens and compliance. Determination of long‐term effects must await controlled trials.
Background:Upregulation of PIM kinase expression has been reported in many malignancies, suggesting that inhibition of PIM kinase activity may be an attractive therapeutic strategy. We hypothesised that inhibition of PIM kinase activity with SGI-1776, a novel small molecule inhibitor of PIM kinase activity, would reduce the viability of renal cell carcinoma (RCC) cells and enhance the activity of sunitinib.Methods:Immunoblotting, qRT–PCR, and gene expression arrays were carried out to identify genes modulated by SGI-1776 treatment. The anticancer activity of SGI-1776 and sunitinib was determined by viability and apoptosis assays and in tumour xenografts in vivo.Results:Treatment with SGI-1776 led to a decrease in phosphorylated and total c-Myc levels, which resulted in the modulation of c-Myc target genes. SGI-1776 in combination with sunitinib induced a further reduction in c-Myc levels, which was associated with enhanced anticancer activity. siRNA-mediated knockdown of c-Myc demonstrated that its expression has a key role in regulating the sensitivity to the combination of SGI-1776 and sunitinib. Importantly, the combination significantly reduced tumour burden in two RCC xenograft models compared with single-agent therapy and was very well tolerated.Conclusion:These data indicate that targeting PIM kinase signalling is a promising treatment strategy for RCC.
Amuvatinib was well tolerated, modulated RAD51, and showed antitumor activity when combined with paclitaxel/carboplatin and carboplatin/etoposide in NE, NSCLC, and SCLC tumors.
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