Effect of HSV-IL12 Loaded Tumor Cell-Based Vaccination in a Mouse Model of High-Grade Neuroblastoma.

We designed multimodal tumor vaccine that consists of irradiated tumor cells infected with the oncolytic IL-12-expressing HSV-1 virus, M002. This vaccine was tested against the syngeneic neuroblastoma mouse model Neuro 2a injected into the right caudate nucleus of the immunocompetent A/J mice. Mice were vaccinated via intramuscular injection of multimodal vaccine or uninfected irradiated tumor cells at seven and 14 days after tumor establishment.

A Randomized, Double-Blind, Placebo-Controlled Trial of Pleconaril for the Treatment of Neonates With Enterovirus Sepsis.

Background: Neonatal enterovirus sepsis has high mortality. Antiviral therapy is not available.

Methods: Neonates with suspected enterovirus sepsis (hepatitis, coagulopathy, and/or myocarditis) with onset at ≤15 days of life were randomized 2:1 to receive oral pleconaril or placebo for 7 days.

Herpes Simplex Encephalitis: Lack of Clinical Benefit of Long-term Valacyclovir Therapy.

Background: Despite the proven efficacy of acyclovir (ACV) therapy, herpes simplex encephalitis (HSE) continues to cause substantial morbidity and mortality. Among patients with HSE treated with ACV, the mortality rate is approximately 14%-19%. Among survivors, 45%-60% have neuropsychological sequelae at 1 year.

Dynamics of Circulating γδ T Cell Activity in an Immunocompetent Mouse Model of High-Grade Glioma.

Human γδ T cells are potent effectors against glioma cell lines in vitro and in human/mouse xenograft models of glioblastoma, however, this effect has not been investigated in an immunocompetent mouse model. In this report, we established GL261 intracranial gliomas in syngeneic WT C57BL/6 mice and measured circulating γδ T cell count, phenotype, Vγ/Vδ repertoire, tumor histopathology, NKG2D ligands expression, and T cell invasion at day 10-12 post-injection and at end stage. Circulating γδ T cells transiently increased and upregulated Annexin V expression at post-tumor day 10-12 followed by a dramatic decline in γδ T cell count at end stage.

CMV-independent lysis of glioblastoma by ex vivo expanded/activated Vδ1+ γδ T cells.

Vδ2(neg) γδ T cells, of which Vδ1+ γδ T cells are by far the largest subset, are important effectors against CMV infection. Malignant gliomas often contain CMV genetic material and proteins, and evidence exists that CMV infection may be associated with initiation and/or progression of glioblastoma multiforme (GBM). We sought to determine if Vδ1+ γδ T cells were cytotoxic to GBM and the extent to which their cytotoxicity was CMV dependent.

Improving the quality of manuscript reviews: impact of introducing a structured electronic template to submit reviews.

Objective: The purpose of this study is to evaluate the impact of structured electronic templates on the quality of manuscript reviews.

Materials And Methods: Twenty-five gastrointestinal and genitourinary reviewers for the American Journal of Roentgenology were included in this investigation. Reviewers were selected and anonymized on the basis of having reviewed one or more manuscripts during period 1 (January 2008 through December 2009).

Oseltamivir pharmacokinetics, dosing, and resistance among children aged <2 years with influenza.

Background: Children <2 years of age are at high risk of influenza-related mortality and morbidity. However, the appropriate dose of oseltamivir for children <2 years of age is unknown.

Methods: The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group evaluated oseltamivir in infants aged <2 years in an age-de-escalation, adaptive design with a targeted systemic exposure.

Oral acyclovir suppression and neurodevelopment after neonatal herpes.

Background: Poor neurodevelopmental outcomes and recurrences of cutaneous lesions remain unacceptably frequent among survivors of neonatal herpes simplex virus (HSV) disease.

Methods: We enrolled neonates with HSV disease in two parallel, identical, double-blind, placebo-controlled studies. Neonates with central nervous system (CNS) involvement were enrolled in one study, and neonates with skin, eye, and mouth involvement only were enrolled in the other.

Preclinical evaluation of ex vivo expanded/activated γδ T cells for immunotherapy of glioblastoma multiforme.

We have previously shown that expanded/activated γδ T cells from healthy donors are cytotoxic to GBM cell lines and primary GBM explants. In this report, we examined the therapeutic effect of intracranial infusion of expanded/activated γδ T cells on human minimal and established U251 tumor xenografts in athymic nude mice. Immunohistochemistry was used to determine the presence of NKG2D ligands on cell lines and tumors, and blocking studies were used to determine the effect of these ligands on γδ T cell recognition.

Substance abuse treatment in an urban HIV clinic: who enrolls and what are the benefits?

Substance abuse treatment (SAT) is important for HIV medical care. Characteristics of those who choose SAT and effects of SAT on HIV clinical outcomes are not understood. We compared patients who enrolled and did not enroll in a SAT program offered within an HIV clinic, and evaluated the effect of SAT on CD4 T-cell counts and HIV plasma viral load (VL).

Safety of oseltamivir compared with the adamantanes in children less than 12 months of age.

Background: When oseltamivir is administered in extremely high doses (500-1000 mg/kg) to young juvenile rats, central nervous system toxicity and death occurred in some animals. Mortality was not observed in older juvenile rats, suggesting a possible relationship between neurotoxicity and an immature blood-brain barrier. To assess potential neurologic adverse effects of oseltamivir use in infants, a retrospective chart review was performed in infants less than 12 months of age who received oseltamivir, amantadine, or rimantadine.

Neurodevelopmental outcomes following ganciclovir therapy in symptomatic congenital cytomegalovirus infections involving the central nervous system.

Background: Ganciclovir protects against hearing deterioration in infants with symptomatic congenital cytomegalovirus (CMV) disease involving the central nervous system (CNS).

Objectives: To assess the neurodevelopmental impact of ganciclovir therapy in this population.

Study Design: 100 neonates were enrolled into a controlled Phase III study of symptomatic congenital CMV involving the CNS, and were randomized to either 6 weeks of intravenous ganciclovir or no treatment.

Vaccine prevention of maternal cytomegalovirus infection.

Background: Congenital infection with cytomegalovirus (CMV) is an important cause of hearing, cognitive, and motor impairments in newborns.

Methods: In this phase 2, placebo-controlled, randomized, double-blind trial, we evaluated a vaccine consisting of recombinant CMV envelope glycoprotein B with MF59 adjuvant, as compared with placebo. Three doses of the CMV vaccine or placebo were given at 0, 1, and 6 months to CMV-seronegative women within 1 year after they had given birth.

Intensive anti-inflammatory therapy with dexamethasone in patients with non-small cell lung cancer: effect on chemotherapy toxicity and efficacy.

Background: Our preclinical and clinical data suggest that pretreatment with dexamethasone 4 days prior to chemotherapy increased the efficacy and decreased the toxicity of carboplatin and gemcitabine. To translate these findings to patients, we have undertaken a Phase 1/2 clinical trial.

Methods: Thirty patients with advanced non-small cell lung cancer (NSCLC) received gemcitabine, 1,000 mg/m(2) on days 1 and 8, and carboplatin, AUC 5.

Protective immunosurveillance and therapeutic antitumor activity of gammadelta T cells demonstrated in a mouse model of prostate cancer.

In contrast to Ag-specific alphabeta T cells, gammadelta T cells can kill malignantly transformed cells in a manner that does not require the recognition of tumor-specific Ags. Although such observations have contributed to the emerging view that gammadelta T cells provide protective innate immunosurveillance against certain malignancies, particularly those of epithelial origin, they also provide a rationale for developing novel clinical approaches to exploit the innate antitumor properties of gammadelta T cells for the treatment of cancer. Using TRAMP, a transgenic mouse model of prostate cancer, proof-of-concept studies were performed to first establish that gammadelta T cells can indeed provide protective immunosurveillance against spontaneously arising mouse prostate cancer.

Pharmacokinetic and pharmacodynamic assessment of oral valganciclovir in the treatment of symptomatic congenital cytomegalovirus disease.

Background: Intravenous ganciclovir administered for 6 weeks improves hearing outcomes in infants with symptomatic congenital cytomegalovirus (CMV) disease involving the central nervous system.

Methods: Twenty-four subjects received antiviral therapy for 6 weeks. Serial pharmacokinetic assessments were performed after administration of valganciclovir oral solution and of intravenous ganciclovir.

Predictors of distant brain recurrence for patients with newly diagnosed brain metastases treated with stereotactic radiosurgery alone.

Purpose: To ascertain predictors of distant brain failure (DBF) in patients treated initially with stereotactic radiosurgery alone for newly diagnosed brain metastases. We hypothesize that these factors may be used to group patients according to risk of DBF.

Methods And Materials: We retrospectively analyzed 100 patients with newly diagnosed brain metastases treated from 2003 to 2005 at our Gamma Knife radiosurgery facility.

Safety, tolerance, and efficacy of posaconazole therapy in patients with nonmeningeal disseminated or chronic pulmonary coccidioidomycosis.

Background: Coccidioidomycosis can be difficult to treat with available therapies, particularly in patients with progressive or disseminated disease. Posaconazole is a new azole antifungal with potent activity against Coccidioides species, the causative agent of coccidioidomycosis.

Methods: Twenty patients with chronic pulmonary or nonmeningeal disseminated coccidioidomycosis were enrolled in a multicenter trial to study the safety and tolerability of posaconazole therapy, with efficacy as a secondary end point.

Phase I and correlative biology study of cilengitide in patients with recurrent malignant glioma.

Purpose: This multi-institutional phase I trial was designed to determine the maximum-tolerated dose (MTD) of cilengitide (EMD 121974) and to evaluate the use of perfusion magnetic resonance imaging (MRI) in patients with recurrent malignant glioma.

Patients And Methods: Patients received cilengitide twice weekly on a continuous basis. A treatment cycle was defined as 4 weeks.

Prevalence of inducible clindamycin resistance among community- and hospital-associated Staphylococcus aureus isolates.

Methicillin-resistant Staphylococcus aureus (MRSA) infections have become common among both hospitalized and nonhospitalized patients. Optimal outpatient therapy for MRSA infections has yet to be determined, but this matter is complicated by the possibility of inducible macrolide-lincosamide-streptogramin B resistance (MLSBi). We studied the prevalence of MLSBi in community- and hospital-associated S.

Distribution of health care expenditures for HIV-infected patients.

Background: Health care expenditures for persons infected with human immunodeficiency virus (HIV) in the United State determined on the basis of actual health care use have not been reported in the era of highly active antiretroviral therapy.

Methods: Patients receiving primary care at the University of Alabama at Birmingham HIV clinic were included in the study. All encounters (except emergency room visits) that occurred within the University of Alabama at Birmingham Hospital System from 1 March 2000 to 1 March 2001 were analyzed.

A randomized study of the use of fluconazole in continuous versus episodic therapy in patients with advanced HIV infection and a history of oropharyngeal candidiasis: AIDS Clinical Trials Group Study 323/Mycoses Study Group Study 40.

Background: In human immunodeficiency virus (HIV)-infected patients, fluconazole prophylaxis is associated with reductions in the rate of fungal infection. However, concerns exist with regard to the use of fluconazole prophylaxis and the risk of development of fluconazole treatment-refractory infections.

Methods: We performed a randomized, open-label trial that compared oral fluconazole given continuously (200 mg 3 times weekly; the "continuous fluconazole arm") with fluconazole that was provided only for episodes of orophayngeal candidiasis (OPC) or esophageal candidiasis (EC) (the "episodic fluconazole arm") in HIV-infected persons with CD4+ T cell counts of <150 cells/mm3 and a history of OPC.

Phase I evaluation of the safety and pharmacokinetics of murine-derived anticryptococcal antibody 18B7 in subjects with treated cryptococcal meningitis.

A promising approach to improving outcomes in patients with cryptococcal meningitis is to use adjunctive passive immunotherapy with a monoclonal antibody (MAb) directed against the capsular polysaccharide of Cryptococcus neoformans. This is the first application of MAb therapy for the treatment of a fungal disease in humans. We determined the safety and maximum tolerated dose of the murine anticryptococcal MAb 18B7 in a phase I dose-escalation study.

Detection of cytomegalovirus (CMV) DNA by polymerase chain reaction is associated with hearing loss in newborns with symptomatic congenital CMV infection involving the central nervous system.

Objective: The study sought to determine the relationship between cytomegalovirus (CMV) viremia during early infancy and clinical and laboratory outcome events, particularly hearing loss in infants with symptomatic congenital CMV infection involving the central nervous system (CNS).

Study Design: A total of 147 infant patients were enrolled prospectively in 2 clinical trials evaluating ganciclovir for the treatment of symptomatic congenital CMV infection involving the CNS. Aliquots of serum collected at enrollment in either of the 2 trials were available from 50 of the infants, and the degree of viremia was determined by real-time quantitative polymerase chain reaction.

Assessment of brain tumor angiogenesis inhibitors using perfusion magnetic resonance imaging: quality and analysis results of a phase I trial.

Purpose: To determine thresholds of quality for a T2*-weighted perfusion magnetic resonance imaging (MRI) study and evaluate the effects of an angiogenesis inhibitor on relative blood flow and volume changes in brain tumor patients in a multi-institution setting.

Materials And Methods: A total of 36 volunteers from four participating institutions with clinically diagnosed malignant gliomas were studied using perfusion MRI protocols. These included a baseline study and follow-up studies every eight weeks to evaluate the effect of an anti-angiogenic agent on tumor perfusion.