Adaptive designs for dual-agent phase I dose-escalation studies.

Anticancer agents used in combination are fundamental to successful cancer treatment, particularly in a curative setting. For dual-agent phase I trials, the goal is to identify drug doses and schedules for further clinical testing. However, current methods for establishing the recommended phase II dose for agents in combination can fail to fully explore drug interactions. With increasing numbers of anticancer drugs requiring testing, new adaptive model-based trial designs that improve on current practice have been proposed, although uptake has been minimal. We describe the methods available and discuss some of the opportunities and challenges faced in dual-agent phase I trials, as well as giving examples of trials in which adaptive designs have been implemented successfully. Improving the design and execution of phase I trials of drug combinations critically relies on collaboration between the statistical and clinical communities to facilitate the implementation of adaptive, model-based designs.

Persistent neuropsychological impairment associated with West Nile virus infection.

West Nile virus infection can result in prolonged subjective complaints of cognitive and functional decline even in the absence of a neuroinvasive form of infection. Persistent cognitive and functional complaints could be a result of general somatic symptoms, emotional distress, or residual central nervous system damage or dysfunction. Most studies of cognition in postacute West Nile virus infection rely on self-report. This descriptive study aimed to document cognitive deficits in a sample of the 2003 infected population reported in New Mexico. Patients with clinically defined neuroinvasive disease or who were impaired on brief mental status screening were seen for comprehensive neuropsychological assessment. We found that one year after symptom onset, more than half of the sample had objectively measurable neuropsychological impairment in at least two cognitive domains. Impairment was not related to subjective complaints of physical or emotional distress, or premorbid intellectual abilities. Persistent cognitive impairment in West Nile virus infection may be due to prolonged or permanent damage to the central nervous system.

West Nile virus neuroinvasive disease.

Since 1999, there have been nearly 20,000 cases of confirmed symptomatic West Nile virus (WNV) infection in the United States, and it is likely that more than 1 million people have been infected by the virus. WNV is now the most common cause of epidemic viral encephalitis in the United States, and it will likely remain an important cause of neurological disease for the foreseeable future. Clinical syndromes produced by WNV infection include asymptomatic infection, West Nile Fever, and West Nile neuroinvasive disease (WNND). WNND includes syndromes of meningitis, encephalitis, and acute flaccid paralysis/poliomyelitis. The clinical, laboratory, and diagnostic features of these syndromes are reviewed here. Many patients with WNND have normal neuroimaging studies, but abnormalities may be present in areas including the basal ganglia, thalamus, cerebellum, and brainstem. Cerebrospinal fluid invariably shows a pleocytosis, with a predominance of neutrophils in up to half the patients. Diagnosis of WNND depends predominantly on demonstration of WNV-specific IgM antibodies in cerebrospinal fluid. Recent studies suggest that some WNV-infected patients have persistent WNV IgM serum and/or cerebrospinal fluid antibody responses, and this may require revision of current serodiagnostic criteria. Although there is no proven therapy for WNND, several vaccines and antiviral therapy with antibodies, antisense oligonucleotides, and interferon preparations are currently undergoing human clinical trials. Recovery from neurological sequelae of WNV infection including cognitive deficits and weakness may be prolonged and incomplete.