Richard H. Simon

Wound Geometry and the Kinetics of Wound Contraction

Contraction of an excisional wound can be described by a decaying exponential with a non-zero asymptote between days 6 and 39 after wounding. Regardless of size or shape, the contraction-rate constant is invariant within age- and species-matched animals. Differently shaped wounds of the same size contract at the same rate during the exponential period. Shape exerts its effect prior to the onset of contraction by defining the size of the wound entering the exponential period. Perimeter is the factor by which shape determines size.

Facet “denervation” in the treatment of low back syndrome

&NA; Long‐term pain relief occurred in 21% of patients with low back and leg pain who underwent injection or radiofrequency rhizotomy. When pain was accompanied by unequivocal limitation of straight leg raising, neither injection nor rhizotomy produced long‐term relief. Leg pain improved more than low back pain. Improvement was limited to pain relief as reported to the physician and reduction of medication. There was no improvement in work or activity status. Despite the low success rate, facet “denervation” is uncommonly safe and seems to be of some usefulness in the treatment of patients with low back pain and sciatica.

Treatment of recurrent malignant gliomas with stereotactic intensity modulated radiation therapy.

Malignant gliomas are usually refractory to aggressive combined-modality therapy, and the incidence of recurrence and death after treatment is very high. State-of-the-art techniques such as stereotactic intensity-modulated radiation therapy (IMRT) are now available to deliver a high dose of radiation to the tumor with relative preservation of surrounding tissues to achieve optimal tumor coverage with minimal toxicity. We report 10 patients (median age 48 years) with recurrent malignant gliomas that were treated with stereotactic directed IMRT. Initial tumor histologies included one low grade glioma (upgraded to anaplastic astrocytoma at recurrence), four anaplastic astrocytomas, and four glioblastomas multiforme. One patient was originally presumed to have a brain metastasis secondary to renal cell carcinoma but was pathologically confirmed as having glioblastoma multiforme at the time of recurrence. Before recurrence, all patients had been treated with external beam radiation therapy (median 59.7 Gy). All recurrences were confirmed by a subtotal resection (5/10) or by imaging (5/10). The median Karnofsky performance score at the time of IMRT was 80. The median tumor volume was 34.69 cm3. Treatment was delivered on a 10-MV linear accelerator with a mini-multileaf collimator, MIMiC, and planned with Peacock/Corvus software. Radiation was delivered in daily fractions of 5 Gy, to a total median dose of 30 Gy at the 71% to 93% median isodose line. Median overall survival time was 10.1 months from the date of stereotactic treatment, with 1- and 2-year survival rates of 50% and 33.3%, respectively. Fractionated stereotactic intensity modulated radiation therapy is a novel technique used in the treatment of recurrent malignant gliomas, which produces results comparable to other currently used stereotactic techniques.

An application of fractal dimension to the detection of transients in the electroencephalogram

It is sometimes desirable to identify a brief seizure, occasional spike, single evoked potential, or other transient in the EEG. Transient detection in an EEG can be a difficult task, often requiring prior knowledge of the characteristics of the transient. A fractal is a shape which retains structural detail despite magnification (scaling). The complexity of the structure of such a set, invariant under this scaling, can be characterized by a single number: the fractal dimension. Regarding the EEG as a fractal, we have shown that transient deterministic data in the EEG have a fractal dimension different from the quasirandom background. An extensive introduction to fractals is presented with the assumption that the reader is unfamiliar with the theory. In the preliminary results presented here, analysis by fractal dimension is shown to be a promising method of transient detection, requiring no prior knowledge of the characteristics of the transient. Possible applications of the technique to evoked potential technology and epilepsy surgery are discussed. Other applications to biology, neuroscience and medicine are reviewed.

Spectral analysis of photic stimulation in migraine

In seeking an electrophysiologic discriminator of migraine, we applied computer technology to power spectral analysis of the EEG with photic stimulation. In 11 normal volunteers and 11 migraineurs (both classic and common) we were able to classify all migraineurs and misclassified only one normal based on the spectral analysis. The discriminator contained 5 elements: the increased driving power of migraineurs with photic stimulation at 24 flashes/sec, 34 flashes/sec, and 38 flashes/sec; and the increased power in the alpha band in both parietal and occipital leads at 20 flashes/sec. Power spectral analysis in conjunction with photic stimulation may provide the necessary data for effective discrimination of migraine from non-migraine states.

Lipid-coated ultrastable microbubbles as a contrast agent in neurosonography.

Lipid-coated microbubbles can be synthesized from selected lipid monolayer systems for use as ultrasonic contrast. These microbubbles have the property of longevity of weeks in vitro (ultrastability) and longevity of hours in vivo. The bubbles can be manufactured with a mean diameter of approximately 2 microns in a tight diameter distribution; all are less than 6 microns and 99% are smaller than 4.5 microns. The current study compared the in vivo survival characteristics of these lipid-coated microbubbles with microbubbles produced by saline. The comparison was made in the rat brain using direct intraparenchymal injections and injections into a previously created cyst/coagulum. The echogenic enhancement by the lipid-coated microbubbles persisted in vivo for over 24 hours in both the intraparenchymal environment and in the cyst/coagulum. The saline bubble echos were not detectable by 3 hours in a cyst/coagulum, and not detectable in the parenchyma after 2 hours. The sonographic characteristics and longevity of lipid-coated microbubbles make this agent a potentially useful clinical contrast material for neurosonography.

Evaluation of lipid-coated microbubbles as a delivery vehicle for taxol in brain tumor therapy

OBJECTIVE This work evaluates the potential of lipid-coated microbubbles (LCM) as a delivery vehicle for lipid-soluble antineoplastic agents. We have shown, in rats, the selective affinity of intravenously administered LCM for tumor cells. They are internalized by the tumor cells both in vitro and in vivo. The specificity of LCM for tumors and subsequent incorporation into the cytoplasm could significantly reduce the systemic effects of an agent incorporated into the bubbles, such as Taxol. METHODS The in vitro methods were as follows. C6 cells (10(5) cells) were treated with Taxol-LCM (6 micrograms/ml), Taxol-Cremophore (6 micrograms/ml), or LCM alone for 8 or 24 hours. Cell death was determined by staining the cells with nuclear staining. Abnormalities of microtubule structures were ascertained by confocal microscopy. The in vivo methods were as follows. Two rat tumor models (C6 and 9L) were used. Rats were treated with single bolus injections or with repetitive (two or three) treatment courses, with respective control animals. Each course consisted of one daily tail vein injection for 5 consecutive days and then 2 days of rest. RESULTS When compared with either a saline control group or a group receiving Taxol in an oil vehicle, Taxol-LCM reduced tumor progression in Fischer 344 rats inoculated with 9L glioma. The most profound effect was observed with rats treated with three treatment cycles (five daily injections/cycle) separated by two rest periods (2 d/period). CONCLUSION Both in vitro and in vivo data indicate that Taxol can be incorporated into LCM, can be delivered to the tumor site, and can exert a measurable antitumor biological effect.

Internalization of microbubbles by tumor cellsin vivo andin vitro

SummaryLipid-coated microbubbles (LCM) administered intravenously (i.v.) to rats bearing brain tumor, specifically enhance tumor visualization by ultrasound [1]. In order to understand the basis for this observation, we have examined the interactions of LCM with glioblastoma (C6) and gliosarcoma (9L) tumor cellsin vivo andin vitro. LCM and LCM labeled with the fluorescent lipophilic dye 3,3′-dioctadecyloxacarbocyanine perchlorate (diO) were administered to rats bearing brain tumor. LCM and diO-labeled LCM were found principally at the tumor site with no evidence of label in the surrounding normal brain tissue. Analysis of the tumor by confocal laser scanning microscopy revealed that labeled LCM were inside the tumor cells. Similar analysis of LCM interactions with C6 and 9L cells in culture showed that LCM first adsorb at the surface of the cells, and with time became localized inside the cells. Binding and internalization proceeded faster at 37° C than at room temperature (RT). Staining of live cells with N-(3-((2,4-dinitrophenyl)amino)propyl)-N-(3-aminopropyl) methylamine dihydrochloride (DAMP), a dye that recognizes acidic compartments, showed that the majority of internalized LCM was associated with compartments containing DAMP. If the same uptake mechanism were operativein vivo, it would indicate that a portion of LCM bypasses the reticuloendothelial system and become endocytosed directly by tumor cells.

Applications of lipid-coated microbubble ultrasonic contrast to tumor therapy

Lipid-coated microbubbles (LCM) make an excellent diagnostic ultrasonic contrast agent in experimental tumor systems. LCM have been shown to aggregate in brain tumors and subcutaneous tumors after intravenous administration, and to provide persistent image enhancement for many minutes. In this work, experimental subcutaneous Walker Carcinosarcoma is insonated after the bubbles are given intravenously. Selective necrosis, lymphocyte proliferation and hemorrhage within the tumor can be demonstrated. Preliminary data are given to demonstrate this phenomenon. The mechanism of the effect is discussed in the context of both heating and cavitation.

Morphine increases metastatic tumor growth

Walker 256 carcinosarcoma cells produce subpleural pulmonary metastases when given intravenously to the Sprague-Dawley rat. The number of metastases increases when the rat is given morphine subsequent to the tumor load. The increase in the number of metastases can be blocked be pretreatment with the opiate antagonist naloxone. Naloxone itself does not influence the number of metastases. Pentazocine is an opiate that is agonistic to the endorphin kappa-type opiate receptor and partially antagonistic to the mu-type receptor, where morphine acts primarily. While pentazocine alone has no influence on metastases and may decrease the number when given early, pentazocine partially blocks the metastatic inducing effect of morphine.