166Ho-DOTMP radiation-absorbed dose estimation for skeletal targeted radiotherapy.

166Ho-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene-phosphonate (DOTMP) is a tetraphosphonate molecule radiolabeled with 166Ho that localizes to bone surfaces. This study evaluated pharmacokinetics and radiation-absorbed dose to all organs from this beta-emitting radiopharmaceutical. METHODS: After two 1.1-GBq administrations of 166Ho-DOTMP, data from whole-body counting using a gamma-camera or uptake probe were assessed for reproducibility of whole-body retention in 12 patients with multiple myeloma. The radiation-absorbed dose to normal organs was estimated using MIRD methodology, applying residence times and S values for 166Ho. Marrow dose was estimated from measured activity retained after 18 h. The activity to deliver a therapeutic dose of 25 Gy to the marrow was determined. Methods based on region-of-interest (ROI) and whole-body clearance were evaluated to estimate kidney activity, because the radiotracer is rapidly excreted in the urine. The dose to the surface of the bladder wall was estimated using a dynamic bladder model. RESULTS: In clinical practice, gamma-camera methods were more reliable than uptake probe-based methods for whole-body counting. The intrapatient variability of dose calculations was less than 10% between the 2 tracer studies. Skeletal uptake of 166Ho-DOTMP varied from 19% to 39% (mean, 28%). The activity of 166Ho prescribed for therapy ranged from 38 to 67 GBq (1,030-1,810 mCi). After high-dose therapy, the estimates of absorbed dose to the kidney varied from 1.6 to 4 Gy using the whole-body clearance-based method and from 8.3 to 17.3 Gy using the ROI-based method. Bladder dose ranged from 10 to 20 Gy, bone surface dose ranged from 39 to 57 Gy, and doses to other organs were less than 2 Gy for all patients. Repetitive administration had no impact on tracer biodistribution, pharmacokinetics, or organ dose. CONCLUSION: Pharmacokinetics analysis validated gamma-camera whole-body counting of 166Ho as an appropriate approach to assess clearance and to estimate radiation-absorbed dose to normal organs except the kidneys. Quantitative gamma-camera imaging is difficult and requires scatter subtraction because of the multiple energy emissions of 166Ho. Kidney dose estimates were approximately 5-fold higher when the ROI-based method was used rather than the clearance-based model, and neither appeared reliable. In future clinical trials with 166Ho-DOTMP, we recommend that dose estimation based on the methods described here be used for all organs except the kidneys. Assumptions for the kidney dose require further evaluation.     

The molecular and clinical impact of hepatocyte growth factor, its receptor, activators, and inhibitors in wound healing

Wound healing involves a number of cellular and molecular events, many of which are controlled by soluble growth factors. In the process of healing, hepatocyte growth factor, a cytokine known to act as mitogen, motogen, and morphogen, has been postulated to play multiple roles during several stages of this complex biological process. Produced primarily by stromal fibroblasts, hepatocyte growth factor regulates angiogenesis, vascular permeability, cell migration, matrix deposition and degradation, and other biological processes. The current article discusses recent progress in understanding the multiple roles played by this growth factor in tissue repair.     

Use of an in vitro model of tissue-engineered human skin to study keratinocyte attachment and migration in the process of reepithelialization

To produce a stable epidermis, keratinocytes need to be firmly attached to the basement membrane. However, following wounding, keratinocytes are required to develop a migratory phenotype in order to reepithelialize the wound. To investigate some of the issues underlying reepithelialization, we have developed a three-dimensional in vitro model of tissue-engineered skin, comprising sterilized human dermis seeded with human keratinocytes and dermal fibroblasts. Using this model, we have shown that the inclusion of fibroblasts within the model increases the stability of keratinocyte attachment. We have also demonstrated that keratinocyte migration occurs most effectively in the absence of a basement membrane and following the inclusion of fibroblasts in the model. In addition, subjecting the keratinocyte layer to mechanical trauma induces a migratory phenotype. We conclude that this three-dimensional in vitro wound model can be used to increase our understanding of the factors that enhance keratinocyte migration and hence wound healing in vivo.     

Prevention of Descending Pneumonia in Rats with Perflubron-delivered Tobramycin

OBJECTIVES: Patients undergoing emergent endotracheal intubation are at increased risk for developing pneumonia. Although numerous strategies have been investigated to reduce ventilator-associated pneumonia (VAP), the incidence of VAP and its associated mortality remains high. This investigation tested the hypothesis that LiquiVent (Alliance Pharmaceutical, San Diego, CA-LV) delivered antibiotics (via spray-dried microspheres-SDM) would improve survival in a rat model of descending gram-negative pneumonia. METHODS: Wistar rats (n = 49) were randomized to receive prophylaxis with 1). nothing (controls); 2). intramuscular (IM) tobramycin, 3). intratracheal LV plus SDM shells (vehicle), 4). intratracheal LV plus SDM shells plus IM tobramycin, or 5). intratracheal LV plus SDM containing 1 mg/kg of tobramycin. All interventions were given 24 hours before a bacterial challenge with 10(8) colony-forming units of intratracheal Klebsiella pneumoniae. Mortality at ten days was the sole outcome measure. Survival in individual groups was compared with controls by Fisher's exact test with Bonferroni correction for multiple comparisons. RESULTS: All animals in the control group died of pneumonia within ten days of bacterial inoculation (0% survival). Prophylaxis with either IM tobramycin or SDM vehicle plus IM tobramycin provided no protection (0% survival). This is in sharp contrast to the cohort receiving pretreatment with tobramycin-containing SDM delivered via LV, in which 60% of the animals survived to study completion (p < 0.05). CONCLUSIONS: Prophylaxis with SDM containing antibiotics delivered in low-dose LV provided significant protection in a rat model of descending gram-negative pneumonia. These data support the hypothesis that perfluorocarbon-delivered intratracheal antimicrobials may be useful in the prevention of VAP.     

Intrapulmonary metastasis developing eighteen years after complete resection of thymoma

We present a case of intrapulmonary metastasis developing 18 years after complete resection of thymoma. An 8 mm nodule in the lower lobe of the left lung was noted on chest X-ray in a 76-year-old woman who had undergone complete resection of Masaoka’s stage II thymoma 18 years earlier. Since the nodule grew to 17 mm during a 2-year follow-up, wedge resection was performed. The lesion was histologically diagnosed as an intrapulmonary metastasis from thymoma. Extremely late recurrence after complete resection of thymoma is discussed.