Preparation, characterization, and in vivo evaluation of triamcinolone acetonide microspheres after intravitreal administration

Abstract Purpose: The aim of this study was to evaluate the intraocular pressure (IOP) increasing effect and bioavailability of triamcinolone acetonide (TA) microspheres, as a novel drug delivery system, after intravitreal administration. Methods: Microspheres loaded by TA were prepared by the solvent evaporation method. After encapsulation, the final microspherical formulation was tested in an animal model. The left eyes of rabbits received microspherical TA and the right eyes were injected with conventional TA suspension. The drug concentration in the vitreous samples at days 7, 14, 28, and 56 after the injection was determined by high-performance liquid chromatography. The IOP was also checked at the same days with the Schiotz tonometer. Results: There was no statistically significant (P>0.05) difference between mean concentration of TA in the vitreous of right and left eyes at the different sampling times except day 56. Mean IOP of eyes that received microspherical TA was increased less than that of the eyes injected with TA suspension, and the difference was statistically significant (P<0.05) for each measurement day. TA was detectable in both eyes after 8 weeks. Both TA microsphere and suspension showed the sustained release profile. Conclusion: The results of this study showed less IOP increasing effect of triamcinolone microspheres in comparison with suspension form.     

Correlation of MR diffusion tensor imaging parameters with ASIA motor scores in hemorrhagic and nonhemorrhagic acute spinal cord injury

This study investigated correlations between American Spinal Injury Association (ASIA) clinical injury motor scores in patients with traumatic cervical cord injury and magnetic resonance (MR) diffusion tensor imaging (DTI) parameters. Conventional imaging and DTI were performed to evaluate 25 patients (age, 39.7±13.9 years; 4 women, 21 men) with blunt spinal cord injury and 11 volunteers (age, 31.5±10.7 years; 3 women, 8 men). Cord contusions were hemorrhagic (HC) in 13 and non-hemorrhagic (NHC) in 12 patients. The spinal cord was divided into three regions to account for spatial and pathological variation in DTI parameters. Comparisons of regional and injury site mean diffusivity (MD), fractional anisotropy (FA), radial diffusivity ( λ(⊥)), and longitudinal diffusivity ( λ(‖)) were made with control subjects. ASIA motor scores were correlated with DTI using linear regression analysis. HC and NHC patients showed significant reduction (p<0.001) in MD and λ(‖) in all three regions. At the injury site, significant decreases in FA and λ(‖) were seen for both injury groups (p<0.001). λ(⊥) values were significantly increased only for patients with NHC (p<0.05). Significant reduction in FA and λ(‖) (p<0.0001) was observed at the whole cord level between the injured (NH and NHC) and control groups. Within the NHC group, strong correlations were observed between ASIA motor scores and average MD, FA, λ(⊥), and λ(‖) at the injury site. However, no correlation was observed within the HC group between any of the DTI parameters and ASIA motor scores. DTI parameters reflect the severity of spinal cord injury and correlate well with ASIA motor scores in patients with NHC.     

Co-overexpression of Met and Hepatocyte Growth Factor Promotes Systemic Metastasis in NCI-H460 Non-Small Cell Lung Carcinoma Cells

Complete resection of early-stage non-small cell lung cancer (NSCLC) is potentially curative, yet approximately 50% of patients are at risk for developing metastatic recurrence. Met, the receptor for hepatocyte growth factor (HGF) is a receptor tyrosine kinase with demonstrated roles in regulating cellular proliferation, motility, morphogenesis, and apoptosis. Met receptor and its ligand, HGF, are commonly overexpressed in NSCLC, and their overexpression has been associated with poor prognosis, which could potentially involve a paracrine and/or autocrine activation loop. However, there is as yet no direct evidence that HGF-Met signaling directly promotes metastasis in NSCLC cells. Using retroviral transduction, we overexpressed the human c-met and hgf complementary DNA, alone or in combination in the NCI-H460 human large cell carcinoma cell line. The HGF/Met co-overexpressing (H460-HGF/Met) cells demonstrated enhanced tumorigenicity in xenograft SCID mice. When these cells are implanted orthotopically into the lungs of nude rats, only the H460-HGF/Met cells showed higher spontaneous metastases to distant organs including bone, brain, and kidney. These results provide evidence that autocrine overactivation of the Met- HGF loop enhances systemic metastases in NSCLC. Targeted interference of this loop may potentially be an effective adjuvant therapy to improve survival of early-stage NSCLC patients.     

Increased intra-abdominal, intrathoracic, and intracranial pressure after severe brain injury: multiple compartment syndrome

OBJECTIVES: Fluid therapy and/or acute lung injury may increase intra-abdominal pressure (IAP) and intrathoracic pressure, thereby increasing intracranial pressure (ICP) after traumatic brain injury (TBI). Further fluid administration to support cerebral perfusion or increasing ventilatory support to treat acute lung injury further increases ICP. This can create a cycle that ultimately produces multiple compartment syndrome (MCS). Both decompressive craniectomy (DC) and decompressive laparotomy (DL) decrease ICP. DL can also decrease IAP and ICP. We evaluated the serial application of DC and DL to treat MCS. METHODS: Data were analyzed for 102 consecutive patients with severe TBI who underwent DC alone to decrease ICP or in combination with DL to treat MCS. RESULTS: All 102 patients sustained blunt injury. Seventy percent were men with a mean age of 29.5 years, an Injury Severity Score of 34.4, and admission Glasgow Coma Scale score of 7.1. Fifty-one patients had diffuse brain injury and 51 had mass lesions. Seventy-eight patients (76%) underwent DC alone. Twenty-four (22%) had both therapies for MCS. Fifteen patients had DC before DL and nine had DL before DC. Mean time between DC and DL was 3.4 +/- 6 days. The mean IAP before DL was 28 +/- 5 mm Hg. Twenty-four-hour cumulative mean intrathoracic pressure decreased significantly after DL in the MCS group (p = 0.01). Mean ICP decreased significantly after both DC and DL (p < 0.05). CONCLUSION: Increased ICP may be from primary TBI or MCS. Patients with MCS have a higher Injury Severity Score, ICP, and fluid requirements, but no increase in mortality. Both DC and DL reduce ICP and can be used in sequence. MCS should be considered in multiply injured patients with increased ICP that does not respond to therapy.     

A study of CD117 expression in dermatofibrosarcoma protuberans and cellular dermatofibroma

BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) is a relatively uncommon spindle cell tumor of the skin. It is locally aggressive and can be a therapeutic challenge. There are case reports of partial response of DFSP to the tyrosine kinase inhibitor STI571 (Imatinib), despite the reported negativity of the tumor cells for CD117. At least one publication reported focal CD117 positivity of DFSP cells, and we would like to clarify the issue. Cellular dermatofibroma (CDF) can mimic DFSP, but typical cases are easily differentiated from DFSP by their staining pattern for CD34 and factor 13a. We also report our experience with CD117 staining of typical CDFs. METHODS: Thirty-seven cases of clear-cut DFSP and 13 cases of clear-cut CDF were retrieved from the archives of Sunnybrook Health Sciences Center between 2000 and 2005. RESULTS: All DFSPs were CD34 (+), factor 13a (-) and CD117 (-). All CDFs were factor 13a (+), CD34 (-) and CD117 (-). CONCLUSIONS: Our study on a relatively large number of cases confirms the negativity of DFSP and CDF for CD117. Therefore, if adjuvant therapy is attempted with drugs such as STI571 (Imatinib), the eligibility of patients should not be based on immunohistochemical assessment of CD117 expression.