On-line re-optimization of prostate IMRT plans for adaptive radiation therapy

For intermediate and high risk prostate cancer, both the prostate gland and seminal vesicles are included in the clinical target volume. Internal motion patterns of these two organs vary, presenting a challenge for adaptive treatment. Adaptive techniques such as isocenter repositioning and soft tissue alignment are effective when tumor volumes only exhibit translational shift, while direct re-optimization of the intensity-modulated radiation therapy (IMRT) plan maybe more desirable when extreme deformation or differential positioning changes of the organs occur. Currently, direct re-optimization of the IMRT plan using beamlet (or fluence map) has not been reported. In this study, we report a novel on-line re-optimization technique that can accomplish plan adjustment on-line. Deformable image registration is used to provide position variation information on each voxel along the three dimensions. The original planned dose distribution is used as the 'goal' dose distribution for adaptation and to ensure planning quality. Fluence maps are re-optimized via linear programming, and a plan solution can be achieved within 2 min. The feasibility of this technique is demonstrated with a clinical case with large deformation. Such on-line ART process can be highly valuable with hypo-fractionated prostate IMRT treatment.     

Giant bilateral renal angiomyolipomas associated with tuberous sclerosis

Renal angiomyolipomas in patients with tuberous sclerosis can be associated with significant morbidity, mostly related to complications from bleeding. We describe a patient with tuberous sclerosis and massive bilateral renal angiomyolipomas (total tumor burden 5500 g) who presented with acute right renal hemorrhage. She was treated with right renal artery embolization followed immediately by right nephrectomy and left partial nephrectomy. The patient had a creatinine nadir of 1.3 mg/dL postoperatively. We demonstrate that nephron-sparing surgery is feasible, even in the setting of very large angiomyolipomas, such as the one presented here, currently the largest such tumor by weight reported.     

Paclitaxel (taxol) and taxoid derivates for lung cancer treatment: potential for aerosol delivery

Paclitaxel (PTX, Taxol) has revolutionized cancer treatment in the past decade and is recognized as one of the biggest advances in oncology medicine. In spite of the good clinical efficacy shown by PTX, there is still a growing need to achieve better safety and pharmacokinetic profile of PTX in patients. The standard delivery modalities of intravenous infusion result in multiple side effects, and targeting of the drug to specific areas within the body can result in better efficacy and lower toxicity. Aerosol delivery of therapeutic agents has the potential of localizing the drugs specifically to the lung tissue, with a comparable or better pharmacokinetics as compared to intravenous, oral or intraperitoneal delivery. Aerosol delivery of PTX has not been studied extensively, however, it holds immense potential for improving the efficacy against lung tumors. Early pre-clinical studies in mice and dogs have shown good promise, both for pharmacokinetics of PTX, safety and efficacy in lung cancer models. This review looks at the still developing approach of aerosol delivery of PTX for lung cancer, documents the progress so far and the future directions that can bring this approach to clinical reality.     

Camptothecins and lung cancer: improved delivery systems by aerosol

Lung cancer is the largest and the most common cause of cancer-related deaths worldwide. The cure rate for lung cancer remains lowest among all malignancies. The discovery of new chemical agents with activity in first onset and recurrent disease is crucial for advancing treatment of patients with pulmonary tumors. Camptothecins are known as inhibitors of topoisomerase I, one of the key enzymes for DNA replication and subsequent cell proliferation. Preclinical and clinical studies had shown that the camptothecins are active against lung cancer and other solid malignancies. In this paper, we review the status of camptothecin and derivatives for treatment of pulmonary cancers, including the development of new formulations and, particularly, novel aerosol routes of drug administration, and their application in combination therapy.     

Cyclosporin A aerosol improves the anticancer effect of paclitaxel aerosol in mice.

The objective of this study was to assess the effect of cyclosporin A liposome aerosol on the anticancer activity of paclitaxel (PTX) liposome aerosol against renal cell carcinoma (Renca) pulmonary metastases in mice. Cyclosporin A (CsA) was administered as a liposome aerosol for one-half hour before starting one-half hour treatment with PTX liposome aerosol (CsA/PTX), and in a second groups of animals cyclosporin A liposome aerosol was given before PTX for one-half hour and also later by mixing a second dose of cyclosporin A aerosol with PTX aerosol and extending the treatment period to one hour (CsA/PTX + CsA). In one experiment, PTX and CsA/PTX aerosols were significantly more effective compared to untreated controls against renal cell cancer as measured by lung weights and tumor surface areas. CsA/PTX was significantly better that PTX alone as measured by lung weights and tumor area. In a second experiment, tumor areas of PTX and CsA/PTX treated mice were significantly reduced compared to untreated controls and CsA/PTX treated mice had significantly smaller tumor areas than PTX treated mice. In contrast, tumor numbers were not significantly fewer than controls in either therapeutic group. In a third experiment, tumor numbers and tumor areas were significantly fewer in mice treated with CsA/PTX and CsA/PTX + CsA compared to untreated controls. Mice treated with CsA/PTX + CsA had significantly fewer tumors and less tumor area than mice receiving CsA/PTX. While PTX treated mice were not different than untreated controls with respect to tumor numbers or tumor volumes, PTX treated mice had significantly greater tumor numbers and tumor areas than CsA/PTX and CsA/PTX + CsA treated mice. Co-administration of CsA with PTX demonstrated significant dose dependent anticancer effects against renal cell pulmonary metastases in mice. Toxicity manifested by weight loss was associated with the highest dose of CsA.     

Improved respiratory delivery of the anticancer drugs, camptothecin and paclitaxel, with 5% CO2-enriched air: pharmacokinetic studies

PURPOSE: To increase pulmonary deposition of anticancer liposome aerosols in mice by modulation of respiratory physiology through the addition of 5% CO2 to the air source used to generate the aerosols. Breathing CO2-enriched aerosol increases pulmonary ventilation with concurrent increased deposition of inhaled particles. METHODS: Dilauroylphosphatidylcholine liposome formulations of two anticancer drugs, paclitaxel (PTX) and camptothecin (CPT), were investigated. The aerosol droplet size was measured using an Andersen cascade impactor. Drug concentrations in aerosol droplet fractions and tissues were determined by HPLC analysis. ICR mice were exposed to each liposome aerosol for 30 min. For each drug, one group of mice inhaled the drug-liposome aerosol generated with a mixture of 5% CO2 in air and another group inhaled the drug-liposome aerosols produced with normal air. Tissue distribution and pharmacokinetics were determined for both drug delivery systems. RESULTS: Significantly higher concentrations of PTX and CPT were found in organs of mice exposed to 5% CO2-air aerosols compared to organs of mice exposed to normal air aerosols. The highest concentrations of drug were detected in the lungs and were two- to fourfold higher with 5% CO2-air aerosols than with aerosols generated with normal air. Higher concentrations were also detected in liver, spleen, kidneys, blood, and brain. CONCLUSION: 5% CO2 enrichment of air increased respiratory tract deposition of inhaled aerosol particles containing PTX and CPT.     

Body mass index predicts risk of complications in lumbar spine surgery based on surgical invasiveness

Background Context

Obesity as a comorbidity in spine pathology may increase the risk of complications following surgical treatment. The body mass index (BMI) threshold at which obesity becomes clinically relevant, and the exact nature of that effect, remains poorly understood.

RNAi-dependent and -independent antiviral phenotypes of chromosomally integrated shRNA clones: Role of VASP in respiratory syncytial virus growth

Stable RNA interference (RNAi) is commonly achieved by recombinant expression of short hairpin RNA (shRNA). To generate virus-resistant cell lines, we cloned a shRNA cassette against the phosphoprotein gene of respiratory syncytial virus (RSV) into a polIII-driven plasmid vector. Analysis of individual stable transfectants showed a spectrum of RSV resistance correlating with the levels of shRNA expressed from different chromosomal locations. Interestingly, resistance in a minority of clones was due to mono-allelic disruption of the cellular gene for vasodilator-stimulated phosphoprotein (VASP). Thus, pure clones of chromosomally integrated DNA-directed RNAi can exhibit gene disruption phenotypes resembling but unrelated to RNAi.

The Effect of Sintering Temperature on the Phase Composition,Microstructure, and Mechanical Properties of Yttria-Stabilized Zirconia

It is known that the yttria-stabilized zirconia (YSZ) material has superior thermal, mechanical, and electrical properties. This material is used for manufacturing products and components of air heaters, hydrogen reformers, cracking furnaces, fired heaters, etc. This work is aimed at searching for the optimal sintering mode of YSZ ceramics that provides a high crack growth resistance. Beam specimens of ZrO₂ ceramics doped with 6, 7, and 8 mol% Y₂O₃ (hereinafter: 6YSZ, 7YSZ, and 8YSZ) were prepared using a conventional sintering technique. Four sintering temperatures (1450 °C, 1500 °C, 1550 °C, and 1600 °C) were used for the 6YSZ series and two sintering temperatures (1550 °C and 1600 °C) were used for the 7YSZ and 8YSZ series. The series of sintered specimens were ground and polished to reach a good surface quality. Several mechanical tests of the materials were performed, namely, the microhardness test, fracture toughness test by the indentation method, and single-edge notch beam (SENB) test under three-point bending. Based on XRD analysis, the phase balance (percentages of tetragonal, cubic, and monoclinic ZrO₂ phases) of each composition was substantiated. The morphology of the fracture surfaces of specimens after both the fracture toughness tests was studied in relation to the mechanical behavior of the specimens and the microstructure of corresponding materials. SEM-EDX analysis was used for microstructural characterization. It was found that both the yttria percentage and sintering temperature affect the mechanical behavior of the ceramics. Optimal chemical composition and sintering temperature were determined for the studied series of ceramics. The maximum transformation toughening effect was revealed for ZrO₂-6 mol% Y₂O₃ ceramics during indentation. However, in the case of a SENB test, the maximum transformation toughening effect in the crack tip vicinity was found in ZrO₂-7 mol% Y₂O₃ ceramics. The conditions for obtaining YSZ ceramics with high fracture toughness are discussed.