Tumor‐induced angiogenesis is essential for malignant growth. This mini review focuses on the role of vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) and their receptors in this process, and the rationale to combine inhibitors of these growth factors as anticancer therapy. Concomitantly, targeting the VEGF(R) and the EGF(R) signaling pathway may circumvent the problem of acquired resistance to EGFR inhibitors. By targeting both pathways, the antiangiogenic effect may be more pronounced, which may lead to greater antitumor activity. Preliminary efficacy data from clinical trials encourage further exploration of this combined anticancer strategy. © 2005 Wiley‐Liss, Inc.
Purpose: A disturbed myeloid lineage development with abnormally abundant neutrophils and impaired dendritic cell (DC) differentiation may contribute to tumor immune escape. We investigated the effect of sunitinib, a tyrosine kinase inhibitor of fms-like tyrosine kinase-3, KIT, and vascular endothelial growth factor receptors, on myeloid differentiation in renal cell cancer (RCC) patients. Experimental Design: Twenty-six advanced RCC patients were treated with sunitinib in a 4-week on/2-week off schedule. Enumeration and extensive phenotyping of myeloid subsets in the blood was done at baseline and at weeks 4 and 6 of the first treatment cycle. Baseline patient data were compared with sex-and age-matched healthy donor data. Results: Baseline frequencies of DC subsets were lower in RCC patients than in healthy donors. After 4 weeks of sunitinib treatment, a generalized decrease in myeloid frequencies was observed. Whereas neutrophils and monocytes, which were both abnormally high at baseline, remained low during the 2-week off period, DC rates recovered, resulting in a normalized myeloid lineage distribution. Subsequent to sunitinib treatment, an increase to high levels of myeloid DC (MDC) subset frequencies relative to other myeloid subsets, was specifically observed in patients experiencing tumor regression. Moreover, high CD1c/BDCA-1 + MDC frequencies were predictive for tumor regression and improved progression-free survival. Conclusion: The sunitinib-induced myeloid lineage redistribution observed in advanced RCC patients is consistent with an improved immune status. Immunologic recovery may contribute to clinical efficacy as suggested by the finding of highly increased MDC frequencies relative to other myeloid subsets in patients with tumor regression.
The degree and dynamics of cytomegalovirus (CMV) replication were investigated in blood samples that were prospectively collected in the context of a placebo-controlled study evaluating the efficacy of preemptive oral ganciclovir for the prevention of CMV disease after liver transplantation. The degree of viral replication was strongly associated with progression to CMV disease or viremia (risk ratio, 8.8 and 51.5 among patients with virus loads < or =2860 and >2860 copies/10(6) peripheral blood leukocytes, respectively). Preemptive oral ganciclovir therapy diminished the incidence of CMV disease or viremia but did not completely suppress higher levels of CMV replication. Six (21%) of 29 patients had persistent CMV replication during preemptive oral ganciclovir therapy; 2 patients subsequently developed "breakthrough" CMV syndrome. This study identifies a relative cutoff virus load that predicts subsequent development of CMV disease and highlights the inability of oral ganciclovir to suppress CMV replication in a subset of patients.
We investigated the effect of beta-herpesviruses on allograft failure and mortality, hepatitis C virus (HCV) replication, and liver histologic characteristics among 92 HCV-infected liver transplant recipients. Reactivation of cytomegalovirus (CMV) but not of human herpesvirus 6 (HHV-6) was independently associated with allograft failure and mortality (risk ratio, 3.71; 95% confidence interval, 1.64-8.39); allograft failure and mortality was observed in 48% of patients with CMV disease, 35% of patients with subclinical CMV infection, and 17% of patients without CMV infection (P=.0275). CMV reactivation was highly predictive of mortality (P<.001), regardless of whether it remained subclinical or evolved into CMV disease. Patients with CMV disease had a higher fibrosis stage (P=.05) and had a trend toward a higher hepatitis activity index (P=.10) and HCV load (P=.10) at 16 weeks after liver transplantation. The pathogenesis of HCV is influenced by its interaction with CMV but not with HHV-6.
Human herpesvirus (HHV)-6 and HHV-7 are increasingly being recognized as emerging pathogens among transplant recipients. Using quantitative polymerase chain reaction assays, we demonstrate the presence of HHV-6 and/or HHV-7 in 18 of 20 episodes of clinically presumed or microbiologically confirmed cytomegalovirus (CMV) infection. Seventeen (89%) of 19 microbiologically confirmed cytomegalovirus (CMV)-infected patients had concomitant HHV-6 variant B (47%) and/or HHV-7 (63%) infection. The degree of HHV-6 coinfection was significantly correlated with hyperbilirubinemia while HHV-7 coinfection demonstrated a non-significant trend toward cytopenias. In one of the 20 episodes described herein, the 'viral syndrome' was due solely to HHV-7 infection; clinical and virological response was observed during intravenous ganciclovir therapy in this patient. While this study emphasizes the significance of HHV-6 and/or HHV-7 coinfection during episodes of CMV infection, it significantly highlights the novel observation of the causal role of HHV-7 (in the absence of HHV-6 and CMV) in a clinical illness presumed to be caused CMV. Thus, HHV-7 (and HHV-6) should be considered as a pathogen (or copathogen) in the viral syndromes following organ transplantation.
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