Cancer vaccine strategies: translation from mice to human clinical trials.

We translated two cancer vaccine strategies from mice into human clinical trials. (1) In preclinical studies on TARP, an antigen expressed in most prostate cancers, we mapped epitopes presented by HLA-A*0201, modified them to increase affinity and immunogenicity in HLA transgenic mice, and induced human T cells that killed human cancer cells ("epitope enhancement"). In a clinical trial, HLA-A2+ prostate cancer patients with PSA biochemical recurrence (Stage D0) were vaccinated with two peptides either in Montanide-ISA51 or on autologous dendritic cells (DCs). In stage D0, the Prostate-Specific Antigen (PSA) slope is prognostic of time to radiographic evidence of metastases and death. With no difference between arms, 74% of combined subjects had a decreased PSA slope at 1 year compared to their own baseline slopes (p = 0.0004). For patients vaccinated with DCs, response inversely correlated with a tolerogenic DC signature. A randomized placebo-controlled phase II trial is underway. (2) HER2 is a driver surface oncogene product expressed in multiple tumors. We made an adenoviral vector vaccine expressing the extracellular and transmembrane domains of HER2 and cured mice with large established HER2+ tumors, dependent on antibodies to HER2, not T cells. The mechanism differed from that of trastuzumab. We tested a human version in advanced metastatic cancer patients naïve to HER2-directed therapies. At the second and third dose levels, 45% of evaluable patients showed clinical benefit. Circulating tumor cells also declined in some vaccinated patients. Thus, cancer vaccines developed in mice were successfully translated to humans with promising early results.

A Randomized Controlled Trial of Two Ready-to-Use Supplementary Foods Demonstrates Benefit of the Higher Dairy Supplement for Reduced Wasting in Mothers, and Differential Impact in Infants and Children Associated With Maternal Supplement Response.

BACKGROUND: There is no consensus over best approaches to reliably prevent malnutrition in rural communities in low-income countries. OBJECTIVE: We compared the effectiveness of 2 lipid-based ready-to-use supplementary foods (RUSFs) differing in dairy protein content to improve the nutritional status of mothers and at-risk infants and young children in rural Guinea-Bissau. METHODS: A 3-month cluster-randomized controlled pilot trial of 2 RUSFs was conducted with 692 mothers and 580 mildly or moderately malnourished infants (6-23 months) and children (24-59 months) from 13 villages. The RUSFs contained either 478 (mothers, children) or 239 kcal/d (infants) with 15% or 33% of protein from dairy and were distributed at community health centers 5 d/wk. Controls were wait-listed to receive RUSF. Primary outcomes were mid-upper arm circumference (MUAC) in mothers, and weight-for-age and height-for-age z-scores (WAZ and HAZ) in infants and children. RESULTS: There was a significant effect of the RUSF-33% on MUAC in mothers ( P = .03). The WAZ and HAZ increased substantially, by ≈1 z-score, in infants and children ( P < .01) independent of group randomization. In children, but not infants, baseline WAZ and change in maternal MUAC were associated with change in WAZ (ß = .07, P = .02). CONCLUSION: Ready-to-use supplementary foods with higher dairy protein content had a significant benefit in village mothers, supporting a comparable recent finding in preschool children. In addition, supplementation of children <2 years resulted in improved growth independent of family nutritional status, whereas success in older children was associated with change in maternal nutrition, suggesting the need for community-level education about preventing malnutrition in older, as well as younger, children.

Limitations of the National Comprehensive Cancer Network® (NCCN®) Guidelines for Prediction of Limited Life Expectancy in Men with Prostate Cancer.

PURPOSE: National Comprehensive Cancer Network prostate cancer guidelines for the prediction of life expectancy recommend subtracting 50% of life table predicted longevity for those in the lowest quartile of health. However, it is unclear how to identify these men and if their survival is uniform. MATERIALS AND METHODS: We sampled records of 1,482 men diagnosed with prostate cancer from 1998 to 2004 at 2 VA hospitals. We identified men in the lowest quartile of health by age using Charlson scores, calculated their NCCN predicted life expectancy, and compared this with observed median survival in aggregate and across comorbidity subgroups. RESULTS: Men with Charlson scores of 2+ (age less than 75 years) and 3+ (age 75 years or older) comprised the lowest quartile of health. Among those younger than 65, 65 to 69, 70 to 74, 75 to 79 and 80 years or older, observed survival vs NCCN predicted life expectancy in years was similar at 10.4 vs 11.1, 10.0 vs 7.8, 6.2 vs 6.4, 4.4 vs 4.9 and 3.7 vs 3.3, respectively. Yet within the lowest quartile there was significant heterogeneity in survival among men with differing Charlson scores. For example, men age 65 to 69 years with Charlson scores 2, 3 and 4+ had an observed median survival greater than 13.3, 9.4 and 4.3 years, respectively. NCCN guidelines misclassified 10-year life expectancy in 24% and 56% of men age less than 65 and 65 to 69 years, and 5-year life expectancy in 18% of men age 70 to 74 years. CONCLUSIONS: While NCCN predictions matched observed survival on average for the lowest quartile of health, there was substantial heterogeneity in survival by Charlson scores. More granular assessments of life expectancy should be used for those at highest risk for mortality.

A Randomized Controlled Trial Offering Higher- Compared with Lower-Dairy Second Meals Daily in Preschools in Guinea-Bissau Demonstrates an Attendance-Dependent Increase in Weight Gain for Both Meal Types and an Increase in Mid-Upper Arm Circumference for the Higher-Dairy Meal.

BACKGROUND: Controversy remains over the most effective approaches to prevent childhood malnutrition. OBJECTIVES: We tested the feasibility and effectiveness of delivering ready-to-use supplementary foods (RUSFs) as a second daily meal in preschool children aged 3-5 y in Guinea-Bissau, and compared RUSFs with different levels of dairy protein. METHODS: This study was a 3 mo cluster-randomized controlled pilot trial of 2 RUSFs differing in dairy protein in 533 boys and girls from 9 preschools. Children receiving RUSFs were compared with wait-listed controls, and all students received a daily school lunch. The RUSFs were delivered 5 d/wk for 3 mo and contained 478 kcal and 11.5 g protein per 92-g daily serving. Deliveries included a ready-to-use supplementary food with 15% of protein from dairy sources (RUSF-15%) or one with 33% of protein from dairy sources (RUSF-33%). Intention-to-treat (ITT) and per-protocol analyses (>50 d of RUSF consumption) were conducted. Changes in the weight-for-age z score (WAZ) and height-for-age z score were primary outcomes. Additional outcomes included changes in mid-upper arm circumference (MUAC), hemoglobin, and retinol binding protein. RESULTS: Baseline anthropometry was not different between groups (WAZ, -0.48 ± 1.04) and increased significantly over time (P < 0.01) with no effects of the RUSFs in ITT analyses. However, children consuming RUSFs for >50 d had a significantly greater increase in WAZ relative to the increase in controls (+0.40 and +0.32 for RUSF-15% and RUSF-33%, respectively, compared with +0.24 in controls, P < 0.01 and P < 0.05, respectively). RUSF-33%, but not RUSF-15%, also eliminated a decrease in MUAC observed in controls (-0.01 cm in RUSF-33% compared with -0.34 cm in controls, P < 0.05). The only difference between RUSF-15% and RUSF-33% was a mean decrease in hemoglobin in children receiving RUSF-15% (-0.5 compared with -0.002 g/dL, P = 0.05). CONCLUSIONS: Implementation of 2-meal preschool feeding programs is feasible in low-income countries, and there are measurable benefits relative to 1-meal programs in children attending preschool regularly. In addition, MUAC and hemoglobin measurements indicate that meals with 33% compared with 15% of protein from dairy may help prevent wasting and anemia.

Urinary incontinence in women.

Urinary incontinence affects women of all ages. History, physical examination, and certain tests can guide specialists in diagnosing stress urinary incontinence, urgency urinary incontinence, and mixed urinary incontinence. First line management includes lifestyle and behavior modification, as well as pelvic floor strength and bladder training. Drug therapy is helpful in the treatment of urgency incontinence that does not respond to conservative measures. In addition, sacral neuromodulation, intravesical onabotulinumtoxinA injections, and posterior tibial nerve stimulation can be used in select patient populations with drug refractory urgency incontinence. Midurethral synthetic slings, including retropubic and transobturator approaches, are safe and efficacious surgical options for stress urinary incontinence and have replaced more invasive bladder neck slings that use autologous or cadaveric fascia. Despite controversy surrounding vaginal mesh for prolapse, synthetic slings for the treatment of stress urinary incontinence are considered safe and minimally invasive.

Pharmacokinetics and tissue distribution of 14C-labeled grape polyphenols in the periphery and the central nervous system following oral administration.

Grape polyphenols confer potential health benefits, including prevention of neurodegenerative diseases. To determine the absorption and tissue distribution of the complex grape polyphenol mixture, (14)C-labeled polyphenols were biosynthesized by grape cell suspension cultures, during co-incubation with radioisotopically labeled sucrose, and fractionated into polyphenolic subfractions. The pharmacokinetics and distribution of grape polyphenols into blood, brain, and peripheral interstitial fluid were determined by tracking the (14)C label. The blood peak (14)C concentration of the fractions ranged from 15 minutes to 4 hours. Absorption and tissue distribution varied greatly between fractions. Concentrations in interstitial fluid were lower than in blood. The amount of residual label in the brain at 24 hours ranged from 0.1% to 1.7% of the dose, depending on the fraction. (14)C label found in the brain tissue and brain microdialysate indicated that grape polyphenols or their metabolites are able to cross the blood-brain barrier. Using (14)C-labeled plant polyphenols it is possible to track the compounds or their metabolic products into any tissue and determine distribution patterns in spite of low concentrations. A central question regarding the potential role of dietary polyphenolics in neurodegenerative research is whether they are bioavailable in the brain. Our observations indicate that some grape-derived polyphenolics do reach the brain, which suggests their potential value for applications in neurodegenerative disorders.

Safety, pharmacokinetics, and pharmacodynamics of cyclodextrin itraconazole in pediatric patients with oropharyngeal candidiasis.

The safety, pharmacokinetics, and pharmacodynamics of cyclodextrin itraconazole (CD-ITRA) oral suspension were investigated in an open sequential dose escalation study with 26 human immunodeficiency virus (HIV)-infected children and adolescents (5 to 18 years old; mean CD4(+)-cell count, 128/microl) with oropharyngeal candidiasis (OPC). Patients received CD-ITRA at either 2.5 mg/kg of body weight once a day (QD) or 2.5 mg/kg twice a day (BID) for a total of 15 days. Pharmacokinetic sampling was performed after the first dose and for up to 120 h after the last dose, and antifungal efficacy was evaluated by standardized scoring of the oropharynx. Apart from mild to moderate gastrointestinal disturbances in three patients (11.5%), CD-ITRA was well tolerated. Two patients (7.6%) discontinued treatment prematurely due to study drug-related adverse events. After 15 days of treatment, the peak concentration of drug in plasma (C(max)), the area under the plasma concentration-time curve (AUC) from 0 to 24 h (AUC(0-24)), the concentration in plasma at the end of the dosing interval (predose) (C(min)), and the terminal half-life of itraconazole (ITRA) were (means and standard deviations) 0.604 +/- 0.53 microg/ml, 6.80 +/- 7.4 microg. h/ml, 0.192 +/- 0.06 microg/ml, and 56.48 +/- 44 h, respectively, for the QD regimen and 1.340 +/- 0.75 microg/ml, 23.04 +/- 14.5 microg. h/ml, 0.782 +/- 0.19 microg/ml, and 104.22 +/- 94 h, respectively, for the BID regimen. The mean AUC-based accumulation factors for ITRA on day 15 were 4.14 +/- 0.9 and 3.53 +/- 0.6, respectively. A comparison of the dose-normalized median AUC of the two dosage regimens revealed a trend toward nonlinear drug disposition (P = 0.05). The mean metabolic ratios (AUC of hydroxyitraconazole/AUC of ITRA) at day 15 were 1.96 +/- 0.1 for the QD regimen and 1.29 +/- 0.2 for the BID regimen, respectively (P < 0.05). The OPC score (range, 0 to 13) for all 26 patients decreased from a mean of 7.46 +/- 0.8 at baseline to 2.8 +/- 0.7 at the end of therapy (P < 0.001), demonstrating antifungal efficacy in this setting. The relationships among C(max), C(min), AUC(0-12), C(max)/MIC, C(min)/MIC, AUC(0-12)/MIC, time during the dosing interval when the plasma drug concentrations were above the MIC for the infecting isolate, and the residual OPC score at day 15 for the entire study population fit inhibitory effect pharmacodynamic models (r, 0.595 to 0.421; P, <0.01 to <0.05). All patients with fluconazole-resistant isolates responded to treatment with CD-ITRA; however, there was no clear correlation between the MIC of ITRA and response to therapy. In conclusion, CD-ITRA was well tolerated and efficacious for the treatment of OPC in HIV-infected pediatric patients. Pharmacodynamic modeling revealed significant correlations between plasma drug concentrations and antifungal efficacy. Based on this documented safety and efficacy, a dosage of 2.5 mg/kg BID can be recommended for the treatment of OPC in pediatric patients > or =5 years old.