Citations

Purpose We conducted a pediatric phase I trial of the vascular endothelial growth factor (VEGF)–neutralizing antibody bevacizumab (BV). Primary aims included estimating the maximum-tolerated dose (MTD) and determining the dose-limiting toxicities (DLTs), pharmacokinetics, and biologic effects of BV in children with cancer. Patients and Methods BV (5, 10, 15 mg/kg) was administered intravenously every 2 weeks in 28-day courses to children with refractory solid tumors. Results Twenty-one patients enrolled, 20 (median age, 13 years) were eligible, and 18 completed one course and were fully assessable for toxicity. A total of 67 courses were administered (median, three courses per patient; range, one to 16 courses). Treatment was well tolerated with no DLTs observed. Non-DLTs included infusional reaction, rash, mucositis, proteinuria, and lymphopenia. Increases in systolic and diastolic blood pressure not meeting Common Terminology Criteria for Adverse Events (CTCAEv3) pediatric-specific criteria for hypertension were observed. There was no hemorrhage or thrombosis. Growth perturbation was not detected in a limited sample over the first course. The serum exposure to BV as measured by area under the concentration-time curve (AUC) seemed to increase in proportion to dose. The median clearance of BV was 4.1 mL/d/kg (range, 3.1 to 15.5 mL/d/kg), and the median half-life was 11.8 days (range, 4.4 to 14.6 days). No objective responses were observed. Exploratory analyses on circulating endothelial mobilization and viability are consistent with the available adult data. Conclusion BV is well tolerated in children. Phase II pediatric studies of BV in combination with chemotherapy in dosing schedules similar to adults are planned.

OBJECTIVE—Birth weight is a risk factor for both diabetes and mortality. Diabetes is a risk factor for mortality. Whether the excess mortality observed for diabetes varies with birth weight is unclear. RESEARCH DESIGN AND METHODS—Among all 2,508 Rochester, Minnesota, residents who first met research criteria for adult-onset diabetes in 1960–1995, 171 were born locally in-hospital after 1922 (i.e., birth weights available) as singleton, term infants. Each case subject and two age- and sex-matched nondiabetic control subjects (born locally, residing locally when the case subject met the criteria for diabetes) were followed through 31 December 2000 for vital status. RESULTS—Of the diabetic case subjects, 16% (27 of 171) died vs. 7% (25 of 342) of control subjects (P = 0.004). The difference was less for normal-birth-weight (NBW) (2,948–<3,856 g) individuals (12% [12 of 102] vs. 8% [20 of 246], P = 0.31) than for abnormal-birth-weight individuals (low birth weight [LBW] 20% [8 of 39] vs. 2% [1 of 46], P = 0.01; high birth weight [HBW] 23% [7 of 30] vs. 8% [4 of 50], P = 0.16), as confirmed with age- and sex-adjusted Cox proportional hazards (diabetes-associated hazard ratio 1.4 [95% CI 0.69–2.90] for NBW vs. 4.8 [1.7–13.3] for abnormal birth weight, test for interaction P = 0.056). The observed diabetes deaths were greater than expected, based on mortality for the general population (27 vs. 13.3, P < 0.001), with 70% of excess deaths occurring among LBW (8 vs. 2.2, P < 0.001) and HBW (7 vs. 3.1, P = 0.03) individuals. CONCLUSIONS—The excess mortality observed for diabetes appears disproportionately concentrated among abnormal-birth-weight individuals, thus identifying a subset of at-risk diabetic individuals and reinforcing the importance of NBW deliveries.

BACKGROUND: The application of vascularized rib grafts in spine surgery has been limited to the treatment of kyphosis with anterior placement of the rib graft to facilitate anterior spine arthrodesis. The outcomes following use of vascularized rib grafts in complex spinal reconstruction have not been adequately evaluated. The purpose of this study was to determine the results, including the time to osseous union and complications, following anterior or posterior placement of pedicled vascularized rib grafts for complex spinal reconstruction. METHODS: The medical records and images of all patients in whom a vascularized rib graft had been used for a multisegmental spine reconstruction at a single institution between 1994 and 2004 were retrospectively reviewed. Eighteen patients (mean age, 45.3 years) who had been followed for an average of 31.8 months were identified. Details regarding indications, the levels that were spanned, the graft length, the time to union, and complications were evaluated. RESULTS: The preoperative diagnoses included metastatic or primary tumor (thirteen patients) and progressive kyphosis secondary to chronic osteomyelitis (two), injury (one), congenital anomalies (one), or implant failure (one). On the average, 4.4 levels were fused and 1.9 vertebral bodies were excised. All eighteen arthrodeses included various forms of allograft and/or autograft material, and instrumentation was used, in addition to the vascularized rib graft, in twelve patients. The mean rib length was 16.1 cm, and a rib between the fifth and eleventh ribs, inclusive, was used, depending on the location of the spinal reconstruction. The average time to union was 6.8 months, and all rib grafts united. There were no complications specific to the rib-harvesting procedure. CONCLUSIONS: The use of a vascularized rib graft in complex spinal reconstruction adds little time to the overall procedure, is associated with low morbidity, and appears to offer substantial benefits to the patient.

Abstract NKX3.1 is a homeobox gene located at chromosome 8p21.2, and one copy is frequently deleted in prostate carcinoma. Prior studies of NKX3.1 mRNA and protein in human prostate cancer and prostatic intraepithelial neoplasia (PIN) have been conflicting, and expression in focal prostate atrophy lesions has not been investigated. Immunohistochemical staining for NKX3.1 on human tissue microarrays was decreased in most focal atrophy and PIN lesions. In carcinoma, staining was inversely correlated with Gleason grade. Fluorescence in situ hybridization showed that no cases of atrophy had loss or gain of 8p, 8 centromere, or 8q24 (C-MYC) and only 12% of high-grade PIN lesions harbored loss of 8p. By contrast, NKX3.1 staining in carcinoma was correlated with 8p loss and allelic loss was inversely related to Gleason pattern. Quantitative reverse transcription-PCR for NKX3.1 mRNA using microdissected atrophy revealed a concordance with protein in five of seven cases. In carcinoma, mRNA levels were decreased in 6 of 12 cases but mRNA levels correlated with protein levels in only 4 of 12 cases, indicating translational or post-translational control. In summary, NKX3.1 protein is reduced in focal atrophy and PIN but is not related to 8p allelic loss in these lesions. Therefore, whereas genetic disruption of NKX3.1 in mice leads to PIN, nongenetic mechanisms reduce NKX3.1 protein levels early in human prostate carcinogenesis, which may facilitate both proliferation and DNA damage in atrophic and PIN cells. Monoallelic deletions on chromosome 8p are associated with more advanced invasive and aggressive disease. (Cancer Res 2006; 66(22): 10683-90)

Abstract Glial tumors progress to malignant grades by heightened proliferation and relentless dispersion throughout the central nervous system. Understanding genetic and biochemical processes that foster these behaviors is likely to reveal specific and effective targets for therapeutic intervention. Our current report shows that the fibroblast growth factor-inducible 14 (Fn14), a member of the tumor necrosis factor (TNF) receptor superfamily, is expressed at high levels in migrating glioma cells in vitro and invading glioma cells in vivo. Forced Fn14 overexpression stimulates glioma cell migration and invasion, and depletion of Rac1 by small interfering RNA inhibits this cellular response. Activation of Fn14 signaling by the ligand TNF-like weak inducer of apoptosis (TWEAK) stimulates migration and up-regulates expression of Fn14; this TWEAK effect requires Rac1 and nuclear factor-κB (NF-κB) activity. The Fn14 promoter region contains NF-κB binding sites, which mediate positive feedback causing sustained overexpression of Fn14 and enduring glioma cell invasion. Furthermore, Fn14 gene expression levels increase with glioma grade and inversely correlate with patient survival. These results show that the Fn14 cascade operates as a positive feedback mechanism for elevated and sustained Fn14 expression. Such a feedback loop argues for aggressive targeting of the Fn14 axis as a unique and specific driver of glioma malignant behavior. (Cancer Res 2006; 66(19): 9535-42)

ABSTRACTThe goal of this study was to determine the roles of eosinophils and neutrophils in innate and adaptive protective immunity to larvalStrongyloides stercoralisin mice. The experimental approach used was to treat mice with an anti-CCR3 monoclonal antibody to eliminate eosinophils or to use CXCR2−/−mice, which have a severe neutrophil recruitment defect, and then determine the effect of the reduction or elimination of the particular cell type on larval killing. It was determined that eosinophils killed theS. stercoralislarvae in naïve mice, whereas these cells were not required for the accelerated killing of larvae in immunized mice. Experiments using CXCR2−/−mice demonstrated that the reduction in recruitment of neutrophils resulted in significantly reduced innate and adaptive protective immunity. Protective antibody developed in the immunized CXCR2−/−mice, thereby demonstrating that neutrophils were not required for the induction of the adaptive protective immune response. Moreover, transfer of neutrophil-enriched cell populations recovered from either wild-type or CXCR2−/−mice into diffusion chambers containing larvae demonstrated that larval killing occurred with both cell populations when the diffusion chambers were implanted in immunized wild-type mice. Thus, the defect in the CXCR2−/−mice was a defect in the recruitment of the neutrophils and not a defect in the ability of these cells to kill larvae. This study therefore demonstrated that both eosinophils and neutrophils are required in the protective innate immune response, whereas only neutrophils are necessary for the protective adaptive immune response to larvalS. stercoralisin mice.