Combinatorial antiangiogenic gene therapy by nonviral gene transfer using the sleeping beauty transposon causes tumor regression and improves survival in mice bearing intracranial human glioblastoma.

Glioblastoma is a fatal brain tumor that becomes highly vascularized by secreting proangiogenic factors and depends on continued angiogenesis to increase in size. Consequently, a successful antiangiogenic therapy should provide long-term inhibition of tumor-induced angiogenesis, suggesting long-term gene transfer as a therapeutic strategy. In this study a soluble vascular endothelial growth factor receptor (sFlt-1) and an angiostatin-endostatin fusion gene (statin-AE) were codelivered to human glioblastoma xenografts by nonviral gene transfer using the Sleeping Beauty (SB) transposon. In subcutaneously implanted xenografts, co-injection of both transgenes showed marked anti-tumor activity as demonstrated by reduction of tumor vessel density, inhibition or abolition of glioma growth, and increase in animal survival (P = 0.003). Using luciferase-stable engrafted intracranial gliomas, the anti-tumor effect of convection-enhanced delivery of plasmid DNA into the tumor was assessed by luciferase in vivo imaging. Sustained tumor regression of intracranial gliomas was achieved only when statin-AE and sFlt-1 transposons were coadministered with SB-transposase-encoding DNA to facilitate long-term expression. We show that SB can be used to increase animal survival significantly (P = 0.008) by combinatorial antiangiogenic gene transfer in an intracranial glioma model.     

Cytogenetic abnormalities in PHA-stimulated lymphocytes from patients with Langerhans cell histocytosis. AIEOP-Istiocitosi Group

The aetiopathogenesis of Langerhans cell histiocytosis (LCH) is still undefined. Constitutional abnormalities in LCH have rarely been reported. One study showed chromosomal instability in lesional cells from three patients. No chromosomal studies are available on peripheral blood lymphocytes. Peripheral blood lymphocytes were analysed for the presence of chromatid and/or chromosomal breaks and structural rearrangements. A fluorescence in situ hybridization (FISH) painting technique was also applied in two cases. Sixteen patients with multisystem (MS, n = 11) or single system (SS, n = 5) LCH were studied, either at the diagnosis (n = 8), during treatment (n = 2) or during follow‐up, when asymptomatic (n = 6). Thirteen patients had chromosomal abnormalities. Eleven patients (69%) had chromatid and chromosomal breaks in 7–45% of cells. Overall, chromosome and chromatid breaks were significantly more frequent in the 11 patients with MS disease than in the five patients with SS disease: the mean percentage of cells showing chromosome and chromatid breaks was 13·4% in MS patients vs. 6·2% in SS patients (P = 0·003). Chromosomal abnormalities may be found in phytohaemagglutinin (PHA)‐stimulated peripheral blood lymphocytes of LCH patients at diagnosis, during the disease course and even during long‐term follow‐up, more frequently in MS disease. Chromosome instability may be considered as either a basic genetic instability or as a landmark of reaction to an environmental agent (viral?) that, through genome alteration, may play a role in histiocyte proliferation and, in some cases, also in the increased risk of malignancy.     

Five-Year Outcomes in Patients With Chronic Total Coronary Occlusion Treated With Drug-Eluting vs Bare-Metal Stents: A Case-Control Study

Background

Limited data exist on long-term safety and effectiveness of drug-eluting stents (DESs) in true chronic total coronary occlusion (CTO) settings. We evaluated 5-year clinical outcomes of patients with CTO treated successfully with DES vs bare-metal stent (BMS).

Methods

We compared the 5-year clinical outcomes of 156 patients treated with DES implantation with outcomes of a historical cohort of 159 patients treated with BMS. Primary end point was freedom from major adverse cardiac events (MACEs; defined as death, myocardial infarction [MI], and target lesion revascularization [TLR]); secondary end points were freedom from target vessel failure (TVF; combination of target vessel revascularization, MI, and cardiac death) and TLR at 5 years.

Results

After 5 years, the DES group had significantly superior event-free survival from MACE (84% vs 69%; log rank P < 0.001), TVF (71% vs 84%; P = 0.002), and TLR (77% vs 92%; P = 0.0001), compared with the BMS group. The Cox proportional hazards model identified BMS vs DES (adjusted hazard ratio [HR] = 3.37; 95% confidence interval [CI], 1.85-6.17; P = 0.001), final minimal lumen diameter (HR, 0.27; 95% CI, 0.14-0.52; P = 0.0001), and stent length (HR, 1.01; 95% CI, 1.00-1.03; P = 0.03) as independent predictors of MACE at 5-year follow-up. Twelve (7%) and 7 (4%) stent thromboses occurred in the DES and BMS groups (P = 0.23), respectively.

Conclusions

After 5 years, DESs were superior to BMSs in reducing MACE, TVF, and TLR in patients with CTO and should be the preferred strategy.     

Phase 2 trial of linifanib (ABT‐869) in patients with unresectable or metastatic hepatocellular carcinoma

BACKGROUND:

The efficacy and safety of linifanib (ABT‐869), a selective inhibitor of vascular endothelial growth factor and platelet‐derived growth factor receptor tyrosine kinases, were assessed in this phase 2, single‐arm, open‐label, multicenter trial.

METHODS:

Eligible patients had unresectable or metastatic hepatocellular carcinoma and had received ≤ 1 prior systemic therapy. Patients received oral linifanib at a fasting dose of 0.25 mg/kg,. The primary endpoint was the progression‐free rate at 16 weeks. Tumor response was assessed every 8 weeks. Secondary endpoints included the time to disease progression, overall survival, and objective response rate. Safety was also assessed.

RESULTS:

Of the 44 patients enrolled, the majority were Asian (89%), had received no prior systemic therapy (82%), had Child‐Pugh class A hepatic function (86%), and had hepatitis B virus infection (61%). The estimated progression‐free rate at 16 weeks was 31.8% (34.2% for patients with Child‐Pugh class A hepatic function), the estimated objective response rate was 9.1% (10.5% for patients with Child‐Pugh class A hepatic function), the median time to disease progression was 3.7 months (3.7 months for patients with Child‐Pugh class A hepatic function), and the median overall survival was 9.7 months (10.4 months for patients with Child‐Pugh class A hepatic function). The most common linifanib‐related adverse events were diarrhea (55%) and fatigue (52%). The most common linifanib‐related grade 3/4 adverse events were hypertension (25%) and fatigue (14%). Serum levels of biomarkers cancer antigen (CA) 125, cytokeratin fragment (CYFRA)21.1, and protein induced by vitamin K absence or antagonist II (PIVKA) demonstrated potential as prognostic indicators of patient response or outcome.

CONCLUSIONS:

Single‐agent linifanib was found to be clinically active in patients with advanced hepatocellular carcinoma, with an acceptable safety profile. Cancer 2013. © 2012 American Cancer Society.