The possibility that cytokine administration could enhance the antitumor effects of proteasome inhibition was explored. It was found that coadministration of bortezomib and interferon-? (IFN-?) induced synergistic apoptosis in human melanoma cell lines and prolonged survival in a murine model of melanoma. A phase I study was conducted to determine the tolerability and the maximum tolerated dose of bortezomib when administered in combination with IFN-?-2b to patients with metastatic melanoma. Patients were treated on a 5-week cycle. In week 1 of cycle 1, patients received 5 million U/m(2) IFN-? subcutaneously thrice weekly. During weeks 2-4 of cycle 1, bortezomib was administered intravenously weekly along with IFN-? thrice weekly. There was a treatment break during week 5. After cycle 1, bortezomib was administered in combination with IFN-?. Bortezomib was administered in escalating doses (1.0, 1.3, or 1.6 mg/m) to cohorts of 3 patients. Sixteen patients were treated (8 women, 8 men; median age 59 y). Common grade 3 toxicities included fatigue (5), vomiting (3), and diarrhea (3). Grade 4 toxicities included fatigue (3) and lymphopenia (1). The maximum tolerated dose for bortezomib was 1.3 mg/m(2). One patient had a partial response, and 7 had stable disease. Progression-free survival was 2.5 months, and overall survival was 10.3 months. Bortezomib administration did not augment the ability of IFN-? to induce phosphorylation of STAT1 in circulating immune cells; however, it did lead to reduced plasma levels of proangiogenic cytokines. The combination of bortezomib and IFN-? can be safely administered to melanoma patients.
Correlation exists between people who engage in academic dishonesty as students and unethical behavior once in practice. Previously, we assessed the attitudes of general surgery residents and ethical practices in test taking at a single institution. Most residents had not participated in activities they felt were unethical, yet what constituted unethical behavior was unclear. We sought to verify these results in a multi-institutional study.
Gastrointestinal stromal tumors (GIST) are a unique class of mesenchymal tumors identified within the past decade. Intense molecular and genetic study has been used to characterize these tumors and develop treatment strategies. Although the mainstay of treatment remains surgical resection, therapy targeted at inhibiting tyrosine kinases has had dramatic results. Because of the rapid accumulation of information about the diagnosis and treatment of these tumors, the National Comprehensive Cancer Network convened a GIST task force to provide updated recommendations in 2010. As understanding of these tumors advances, rapid changes in recommendations will continue and should warrant regular updates in tumor management.
Bevacizumab is a humanized recombinant monoclonal antibody that neutralizes vascular endothelial growth factor, an agent with proangiogenic effects in melanoma. Interferon alpha (IFN-?) has antiangiogenic properties through its ability to downregulate basic-fibroblast growth factor levels. We hypothesized that the coadministration of these agents would lead to tumor regression. Patients with metastatic melanoma received bevacizumab 15 mg/kg intravenously on day 1 of the 2-week cycle. IFN-? was administered thrice weekly at 5 MU/m subcutaneously during cycle 1 and was increased to 10 MU/m during cycle 2. Patients were restaged every 6 cycles. Patients with stable disease or a response continued with therapy. Baseline serum vascular endothelial growth factor and fibroblast growth factor were measured. Twenty-five patients were accrued. Mean age was 58.4 years. Eleven patients required IFN-? dose reductions due to toxicity. Common grade 3 toxicities associated with IFN-? included fatigue and myalgia. Bevacizumab administration was associated with grade 2-3 proteinuria in 6 patients. Grade 4 adverse events were pulmonary embolus (1), myocardial infarction (1), and stroke (1). Six patients had a partial response, and 5 patients exhibited stable disease that lasted more than 24 weeks (range: 30 to 122 wk). Median progression-free survival and overall survival were 4.8 and 17 months, respectively. Significantly lower fibroblast growth factor levels were observed in patients with a partial response compared to those with stable or progressive disease (P=0.040). Administration of bevacizumab with IFN led to a clinical response in 24% of patients with stage IV melanoma and stabilization of disease in another 20% of patients. This regimen has activity in advanced melanoma.
The clinical management of locally recurrent or unresectable malignant melanoma continues to pose a significant challenge. These lesions are typically painful and currently available treatments, such as repeated intratumoral injections of interferon-alpha (IFN-?), are costly and inconvenient. Nanotechnology offers promise as a novel means of drug delivery. A capsule-like nanoporous miniature device (NMD) based on a biodegradable polymer, poly(polycaprolactone) (PCL) was developed for controlling the local delivery of immunological agents to the tumor microenvironment. The device consists of a nanoporous release gate, a fabricated drug reservoir loaded with IFN-? and a protective layer. To improve the biocompatibility of the device, a hydrophilic poly(ethylene glycol) monoacrylate was applied to the outside wall of the device via covalent bonding techniques. Microscopic visualization of the nanoporous gate from in vitro experiments exhibited good pore stability over a two-month period. In vitro experiments demonstrated a constant release rate of IFN-? from the NMD and showed that the release rate could be regulated by the gate area. The released IFN-? was biologically functional. Cytokine-containing supernatants from release experiments phosphorylated signal transducer and activator of transcription (STAT1) in peripheral blood mononuclear cells. Subcutaneous implantation of the NMDs was well tolerated and associated with an anti-tumor effect in a human xenograft model of melanoma. There was no evidence of a significant inflammatory response to the NMD or encapsulation of the NMD by fibrosis. These experiments show that the NMD can be fabricated and employed in vivo as a versatile drug delivery platform.
Interleukin-29 (IL-29) is a member of the type III IFN family that has been shown to have antiviral activity and to inhibit cell growth. Melanoma cell lines were tested for expression of the IL-29 receptor (IL-29R) and their response to IL-29. Expression of IL-28R1 and IL-10R2, components of IL-29R, was evaluated using reverse transcription-PCR. A combination of immunoblot analysis and flow cytometry was used to evaluate IL-29-induced signal transduction. U133 Plus 2.0 Arrays and real-time PCR were used to evaluate gene expression. Apoptosis was measured using Annexin V/propridium iodide staining. In situ PCR for IL-29R was done on paraffin-embedded melanoma tumors. Both IL-28R1 and IL-10R2 were expressed on the A375, 1106 MEL, Hs294T, 18105 MEL, MEL 39, SK MEL 5, and F01 cell lines. Incubation of melanoma cell lines with IL-29 (10-1,000 ng/mL) led to phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT2. Microarray analysis and quantitative reverse transcription-PCR showed a marked increase in transcripts of IFN-regulated genes after treatment with IL-29. In the F01 cell line, bortezomib-induced and temozolomide-induced apoptosis was synergistically enhanced following the addition of IL-29. In situ PCR revealed that IL-10R2 and IL-28R1 were present in six of eight primary human melanoma tumors but not in benign nevi specimens. In conclusion, IL-29 receptors are expressed on the surface of human melanoma cell lines and patient samples, and treatment of these cell lines with IL-29 leads to signaling via the Jak-STAT pathway, the transcription of a unique set of genes, and apoptosis.
A correlation exists between people who engage in academic dishonesty as students and unethical behaviors later as professionals. Academic dishonesty has been assessed among medical students, but not among general surgery residents. We sought to describe the attitudes of general surgery residents with regard to ethical practices in test taking.
Herein we describe the development and implementation of a nanoporous cell-therapy device with controllable biodegradation. Dopamine-secreting PC12 cells were housed within newly formulated alginate-glutamine degradable polylysine (A-GD-PLL) microcapsules. The A-GD-PLL microcapsules provided a 3-D microenvironment for good spatial cell growth, viability and proliferation. The microcapsules were subsequently placed within a poly(ethylene glycol) (PEG)-coated poly(?-caprolactone) (PCL) chamber covered with a PEG-grafted PCL nanoporous membrane formed by phase inversion. To enhance PC12 cell growth and to assist in controlled degradation of both the PC12 cells and the device construct, small PCL capsules containing neural growth factor (PCL-NGF) and a poly(lactic-co-glycolic acid) pellet containing glutamine (PLGA-GLN) were also placed within the PCL chamber. Release of NGF from the PCL-NGF capsules facilitated cell proliferation and viability, while the controlled release of GLN from the PLGA-GLN pellet resulted in A-GD-PLL microcapsule degradation and eventual PC12 cell death following a pre-specified period of time (4 weeks in this study). In vivo, our device was found to be well tolerated and we successfully demonstrated the controlled release of dopamine over a period of four weeks. This integrated biodegradable device holds great promise for the future treatment of a variety of diseases.
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