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Background: Viral loads (VLs) frequently are followed during treatment of symptomatic congenital cytomegalovirus disease, but their predictive value is unclear.Methods: Post hoc analysis of 2 antiviral studies was performed. Seventy-three subjects were treated for 6 weeks and 47 subjects were treated for 6 months. Whole blood VL was determined by real-time polymerase chain reaction before and during therapy.Results: Higher baseline VL was associated with central nervous system involvement (3.82 log, range 1-5.65 vs 3.32 log, range 1-5.36; P = .001), thrombocytopenia (3.68 log, range 1-5.65 vs 3.43 log, range 1-5.36; P = .03), and transaminitis at presentation (3.73 log, range 1-5.60 vs 3.39 log, range 1-5.65; P = .009), but with overlap in the amount of virus detected between groups. In subjects treated for 6 months, lower VL at presentation correlated with better hearing outcomes at 12 months, but VL breakpoints predictive of hearing loss were not identified. Sustained viral suppression during 6 months of therapy correlated with better hearing outcomes at 6, 12, and 24 months (P = .01, P = .0007, P = .04), but a majority without viral suppression still had improved hearing.Conclusions: In infants with symptomatic congenital cytomegalovirus disease, higher whole blood VL before initiation of antiviral therapy has no clinically meaningful predictive value for long-term outcomes. [ABSTRACT FROM AUTHOR]

TRA-8, a monoclonal antibody to death receptor 5 induces apoptosis in various cancer cells; however, the degree of sensitivity varies from highly sensitive to resistant. We have previously shown that resistance to TRA-8 can be reversed by using chemotherapeutic agents, but the mechanism underlying this sensitization was not fully understood. Here, we examined the combination of TRA-8 with doxorubicin or bortezomib in breast cancer cells. In TRA-8-resistant BT-474 and T47D cells, both chemotherapy agents synergistically sensitized cells to TRA-8 cytotoxicity with enhanced activation of apoptosis shown by cleavage of caspases and PARP, reduced Bid, increased proapoptotic Bcl-2 proteins, and increased mitochondrial membrane depolarization. Doxorubicin or bortezomib combined with TRA-8 also reduced Bcl-XL and X-linked inhibitors of apoptosis (XIAP) in treated cells. Furthermore, targeting these proteins with pharmacologic modulators, AT-101, BH3I-2' and AT-406, produced sensitization to TRA-8. TRA-8 combined with AT-101 or BH3I-2', inhibitors of antiapoptotic Bcl-2 proteins, produced synergistic cytotoxicity against ZR-75-1, BT-474, and T47D cells. The IAP-targeting compound, AT-406, was synergistic with TRA-8 in BT-474 cells, and to a lesser extent T47D cells. Activation of the intrinsic apoptotic pathway was a common mechanism associated with sensitization of TRA-8-resistant breast cancer cell lines. Collectively, these studies show that the Bcl-2 and IAP families of proteins are involved in TRA-8 and chemotherapy resistance via their modulation of the intrinsic apoptotic pathway. Targeting these proteins with novel agents sensitized TRA-8-resistant breast cancer cells, suggesting this approach may represent a potent therapeutic strategy in the treatment of breast cancer., (©2011 AACR.)

Purpose: To determine the maximum tolerated dose (MTD), toxicity spectrum, clinical activity, and biological effects of the tropism-modified, infectivity-enhanced conditionally replicative adenovirus (CRAd), Ad5-Δ24-Arg-Gly-Asp (RGD), in patients with malignant gynecologic diseases., Experimental Design: Cohorts of eligible patients were treated daily for 3 days through an i.p. catheter. Vector doses ranged from 1 × 10(9) to 1 × 10(12) viral particles per day. Toxicity was evaluated using CTCv3.0. CA-125 and Response Evaluation Criteria in Solid Tumors (RECIST) criteria were used to determine clinical efficacy. Corollary biological studies included assessment of CRAd replication, wild-type virus generation, viral shedding, and neutralizing antibody response., Results: Twenty-one patients were treated. Adverse clinical effects were limited to grade 1/2 fever, fatigue, or abdominal pain. No vector-related grade 3/4 toxicities were noted. No clinically significant laboratory abnormalities were noted. The maximum tolerated dose was not reached. Over a 1 month follow-up, 15 (71%) patients had stable disease and six (29%) had progressive disease. No partial or complete responses were noted. Seven patients had a decrease in CA-125; four had a >20% drop. RGD-specific PCR showed the presence of study vector in ascites of 16 patients. Seven revealed an increase in virus after day 3, suggesting replication of Ad5-Δ24-RGD. Minimal wild-type virus generation was detected. Viral shedding studies showed insignificant shedding in the serum, saliva, and urine. Anti-adenoviral neutralizing antibody effects were prevalent., Conclusions: This study, the first to evaluate an infectivity-enhanced CRAd in human cancer, shows the feasibility, safety, potential antitumor response, and biological activity of this approach in ovarian cancer. Further evaluation of infectivity enhanced virotherapy approaches for malignant gynecologic diseases is warranted., (©2010 AACR.)