Intraprostatic Ethanol Injection Using a Porous Needle in an Acute and Chronic Canine Study, Heart-Beating Cadaveric Organ Donors, and a Murine Xenograft Model of Human Prostate Cancer
Kevin C. DiBona, B.S.1, Jan Svihra, Jr., M.D.2, Megan N. Eubank, B.S.1, Jan Strnadel, B.S.3, Benjamin J. King, M.D.1, Mark K. Plante, M.D.1, Jan Luptak, M.D.2, Mads Hvid Aaberg Poulsen, M.D.4, Masatoshi Kida, M.D.5, Eduard Baco, M.D.6, Jan Svihra, M.D.2, Peter Zvara, M.D.7.
1Department of Surgery, Larner College of Medicine, University of Vermont Medical Center, Burlington, VT, USA, 2Department of Urology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Bratislava, Slovakia, 3Biomedical Center, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Bratislava, Slovakia, 4Department of Urology, Odense University Hospital, Odense, Denmark, 5Department of Pathology and Laboratory Medicine, University of Vermont Medical Center, Burlington, VT, USA, 6Department of Urology, Oslo University Hospital, Oslo, Norway, 7Biomedical Laboratory and Research Unit of Urology, University of Southern Denmark, Odense, Denmark.
Over the last 10 years, focal therapies have been developed with a goal of eradicating localized prostate cancer, while limiting side effects and complications associated with whole organ therapies. Provided that targeted intraprostatic drug delivery techniques will be developed, intraprostatic injection of a therapeutic agent could develop into an alternative nonmorbid treatment that would halt the progression and delay or eliminate the need for radical prostatectomy or whole organ radiation. We aimed to develop a safe, efficacious, and precise method for intraprostatic injection and establish correlation between the volume of the injectate and the volume of infiltrated area of the prostate.
Materials and Methods:
We performed intraprostatic injection of 96% ethanol using a needle which has a segment of its wall made of a capillary membrane with hundreds of pores. The intraprostatic injection was performed in an acute and chronic canine experiment, in heartbeating cadaveric organ donors, and in a murine xenograft model of human prostate cancer (PCa). Whole mount sections of the prostates were used for 3D reconstruction of the necrotic lesions.
In the acute experiments, ethanol injection resulted in lesions of well delineated coagulative necrosis with significant alteration of native histological architecture including shrinkage of cell nuclei and disruption of glandular columnar epithelium. In both healthy human and canine prostates, the prostatic pseudocapsule and neurovascular bundle remained intact without evidence of disruption. There was a linear correlation between administered volume of ethanol and the necrotic lesion volume. Regression analysis demonstrated strong correlation in the acute canine and xenografts of human PCa experiments (R2 = 0.85 and R2 = 0.85 respectively), and moderate correlation in the cadaveric organ donor experiment (R2 = 0.48). A formula was calculated for each experiment to estimate the relationship between the injected volume and the volume of infiltrated prostate tissue area.
This study proposes a new method that would allow for effective and predictable tissue distribution of injectate in the prostate, while limiting side effects. In the acute experiments, we documented well delineated areas of coagulative necrosis. Four weeks post injection, ablation of prostate tissue was documented. In both instances, EtOH injection did not cause any disruption to the prostatic pseudocapsule or evidence of injury to the periprostatic anatomical structures. Through varying the volume of the agent injected and use of needles with a different length of the porous segment, the infiltrated tissue could be adjusted allowing for targeted focal treatment. With the development of PCa therapeutics, alternative targeted therapies could be delivered using a similar injection protocol, achieving enhanced outcomes, and preventing complications.
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