Feasibility of lung cancer hyperthermia using breathable perfluorochemical (PFC) liquids. Part I: Convective hyperthermia.

Clinical studies have shown that hyperthermia in combination with radiotherapy and/or chemotherapy may be effective in the treatment of advanced cancer. No method of lung hyperthermia, however, has been accepted as standard or superior. This investigation sought to demonstrate in animals the thermal and physiologic feasibility of lung hyperthermia induced using heated breathable perfluorochemical (PFC) liquids, a method termed liquid-filled lung convective hyperthermia (LCHT). The ability to use LCHT is rooted in the development of both PFC liquid ventilation, now in clinical development with the PFC perflubron (LiquiVent), and a PFC blood substitute also in late Phase III trials (Oxygent). As LCHT background, the PFC technologies and biology are first reviewed. The physical properties of a variety of PFCs were evaluated for LCHT and it was concluded that more than one liquid is suitable based on such properties. Using total liquid ventilation type devices, LCHT was shown to deliver successfully localized (lobar) lung heating in sheep, and bilateral whole lung heating and whole-body hyperthermia in rabbits, cats and lambs. During LCHT, lung parenchymal temperatures were uniform (<1 degree C) across heated regions. In addition, based on patterns relating lung tissue temperatures to inspiratory and expiratory PFC liquid temperatures in the endotracheal tube, LCHT may minimize invasive thermometry requirements in the lung. Based on acute experiments, it was concluded that LCHT appears feasible and may simplify lung hyperthermia. It was recommended that potentially synergistic combinations of LCHT with other whole-body hyperthermia or local heating modalities, and with chemotherapeutic lung drug delivery, also be explored in the future.

Feasibility of lung cancer hyperthermia using breathable perfluorochemical (PFC) liquids. Part II: Ultrasound hyperthermia.

Enhanced local control of disease in lung cancer has been shown to improve survival, and controlled clinical trials of hyperthermia adjunctive to radiotherapy in other cancers have shown improved disease control and survival over radiotherapy alone. The challenge of lung hyperthermia, however, persists. This investigation sought to demonstrate the feasibility of localized lung hyperthermia at depth via therapeutic ultrasound. The method is based on using breathable perfluorochemical liquids as acoustic coupling media in the lung, liquids that have also been shown to enable controlled liquid-filled lung convective hyperthermia (LCHT). The ability to use both lung convective hyperthermia and liquid-filled lung ultrasound hyperthermia (LUHT) provides potential flexibility in heating patterns for the hyperthermic treatment of lung cancer with concurrent radiotherapy and/or chemotherapy. Using custom ultrasound transducers designed and built for these studies, the acoustic properties of three candidate perfluorochemicals were characterized over a range of temperatures, gas contents and ultrasound frequencies and acoustic intensities. Both sound speed and attenuation were measured in the neat liquids and in isolated lungs filled with the perfluorochemicals. Successful ultrasound hyperthermia at depth was demonstrated in vivo in sheep lung lobes in intraoperative conditions. In addition, the use of ultrasound diagnostic imaging was explored as a tool for use in conjunction with lung ultrasound hyperthermia.

Dose maintenance for Partial Liquid Ventilation: passive heat-and-moisture exchangers.

Partial Liquid Ventilation (PLV), a promising method for the treatment of acute lung failure, has been evaluated in many animal studies. It has recently progressed to the point of controlled clinical trials in which patients of all ages on conventional mechanical ventilation (CMV) have their lungs substantially filled with a perfluorochemical (PFC) liquid, perflubron (PFB). During PLV, it is desirable to both maintain humidification and minimize the evaporation of PFB in order to maintain a desired dose in the lung and to reduce dose consumption and redosing effort. Heat-and-moisture exchangers (HMEs) have been used for years as a passive means of minimizing water vapor loss from the respiratory tract during CMV support of intensive care and surgical patients. In the current study, research was undertaken to leverage the operating principles of existing HMEs such that specialized "fluorophilic" HMEs (FHMEs), devices optimized for both water and PFB conservation, could be realized. A patient simulator (involving both water vapor and PFB vapor sources) was constructed and used in the in-vitro evaluation of various FHME concepts. Dose-retention efficiencies were determined with the aid of an infrared instrument and a digital thermohygrometer. Although no larger than commercial HMEs in terms of dead space (gas-occupying volume), efficient FHMEs resulted, offering less flow resistance (delta P) than their commercial counterparts. Additionally, the presence of PFB vapor did not appear to compromise the water-exchange efficiency of certain HME configurations. One promising FHME design was also tested in swine undergoing 12-hour PLV treatments. A mean conservation efficiency of 63% at an average tidal volume of 550 mL was shown, although somewhat lower efficiencies may result in adult patients because efficiency was found to trend downward with increasing tidal volume. The use of an FHME is expected to sustain dose levels in patients for longer periods with less frequent dosing and reduced dose consumption, saving treatment labor and cost.

Bilateral elastofibroma: a case report and review of the literature.

Elastofibroma, or elastofibroma dorsi as it was first described, is an uncommon tumor-like process that characteristically appears as an ill-defined mass in the infrascapular region of elderly patients. This lesion can occur bilaterally and may appear asynchronously. The occurrence of elastofibroma in other anatomic sites has been reported, although with much less frequency. Elastofibromas display typical diagnostic histologic, cytologic, and electron microscopic features. The use of magnetic resonance imaging can lead to a presumptive diagnosis in elderly individuals with suprascapular lesions. It is important to differentiate this lesion from other soft-tissue lesions, such as sarcomas and desmoid tumors. This study presents a case of bilateral elastofibromas in a 72-year-old man and a review of the literature.

Thermal quantification of region myocardial perfusion and heat generation.

A technique for experimental determination of regional myocardial blood flow and heat generation has been developed, based on a heat-clearance method. This method allows repetitive and frequent measurements of regional blood flow without necessity for biopsy or microspheres. Testing was performed on a pedicle preparation, an intact segment of left ventricular myocardium dependent on a single diagonal coronary artery and situated in situ in the left ventricular free wall. Total blood flow to the pedicle was measured by an electromagnetic flow probe. A specially designed 3-thermistor microprobe was positioned in the pedicle to continuously sense temperature changes in the subepicardium, midmyocardium, and subendocardium. The theory underlying this method is based on a heat balance that includes local myocardial heating, conduction, and convection. Comparison of the predicted time- and position-dependent temperature with that measured experimentally allows extraction of the local myocardial blood flow and heating rates. This method allows resolution of differential flows in subendocardial, midmyocardial, and subepicardial myocardium and provides quantification of dynamic flow changes in each layer in response to various stimuli such as ischemia or pressor agents, without in itself causing damage to the myocardial microvasculature. Our data show total flow, based on summation of thermally calculated regional flows, to have correlation coefficients of 0.88 with both the flowmeter and microsphere results. Resting flow values for Nembutal-anaesthetized, open-chest dogs of 0.66 ml/(g . min) compare favorably with values obtained by microsphere studies. Infusion of norepinephrine increased total flow and all layer flows, but the increase in subendocardial flow with norepinephrine was less than the increase of the other layers, perhaps accounting for the vulnerability of this region during catecholamine stress. Local myocardial heating rates in subepicardial, midendocardial, and subendocardial layers are shown to follow the same dependence on local myocardial blood flow in response to anoxic stress or norepinephrine-induced vasodilation. Specifically, local heating rate increases to a factor of 10 at flow below resting level.

Surface chemistry characteristics of human umbilical vein used as chronic canine arteriovenous fistulas.

Six bilateral loop arteriovenous fistulas from the femoral artery to the femoral vein were constructed in dogs using Dacron-mesh-coated human umbilical vein. Each graft was punctured twice weekly with a 16 gauge needle for up to 36 weeks, and biopsies were done every four to eight weeks. The long-term patency was 83% at 24 weeks. There was no thrombosis from the needle puncture. Serial histologic examination revealed progressive transmural fibrous cell ingrowth and progressive neointimal cell formation. Scanning electron microscopy demonstrated areas of disrupted basement membrane covered with laminar fibrin meshes, probably representing sites of needle puncture. With multiple attenuated internal reflection spectroscopy of the graft lumens, minimal to moderate lipid deposition was observed to a depth of 1 micrometer at 32-36 weeks. No abnormal amounts of minerals were found within the graft walls with energy-dispersive x-ray analysis. Critical surface tensions remained within the biocompatible range of 20-30 dynes/cm. Human umbilical vein possesses many of the surface chemistry qualities of an ideal vascular prosthesis, has excellent long term patency, and is suitable for use where angioaccess with repeated needle puncture is needed.