Surgery – Diagnostic testing – Detecting nuclear – electromagnetic – or ultrasonic radiation
Reexamination Certificate
2000-06-19
2002-08-06
Jaworski, Francis J. (Department: 3737)
Surgery
Diagnostic testing
Detecting nuclear, electromagnetic, or ultrasonic radiation
Reexamination Certificate
active
06428479
ABSTRACT:
The present invention relates to a method of diagnosing and characterising prostate abnormalities using ultrasound contrast agent-enhanced ultrasonography, e.g. transrectal ultrasonography. In particular, the invention relates to determination of the kinetics of contrast agent in-flow and thus the state of vascularisation in the prostate as a means for such diagnosis and characterisation.
Abnormalities of the prostate gland, in particular cancer of the prostate, affect a large number of men, particularly in middle age and beyond. It is now the second leading cause of male cancer death in the USA and is becoming increasingly prevalent as longevity increases, resulting in an increased number of men of older years. Around one third of men over the age of 50 years in the USA are thought to have cancer of the prostate and approximately one tenth of these will die as a result of it.
Prostate abnormalities are primarily investigated by a combination of digital rectal examination (DRE) and evaluation of serum prostate specific antigen (PSA), possibly augmented by ultrasound or magnetic resonance imaging (MRI) techniques. Although sometimes used as an aid to diagnosis, transrectal ultrasonography (TRUS), whether or not it is augmented by the use of contrast-enhancing agents, cannot at present be relied upon to provide unequivocal diagnostic or characterising information about any prostate abnormality.
Regardless of the findings of DRE, PSA evaluation and TRUS or MRI studies, actual diagnosis of prostate abnormalities, the most common of which are cancer, prostatitis, granulomatous prostatitis, tuberculous prostatitis, prostatic intra-epithelial neoplasia, infarcts and cysts, can at present only be reliably based on samples taken from the prostate by needle biopsy. Currently, up to 10 biopsy sites are chosen randomly throughout the prostate for sampling by the clinician. This is an unsatisfactory situation since the random choice of sampling sites does not preclude the possibility of missing a cancerous lesion and thus failing to diagnose a potentially fatal disease. Furthermore, such a procedure requires detailed laboratory analysis of a large number of samples and is therefore costly and labour intensive. Needles to say, such an invasive practice is unpleasant for the patient.
Much effort has been invested in trying to improve TRUS techniques and contrast-enhancing agents so that they may, at the very least, be able to differentiate normal from abnormal tissue sufficiently well to act as a guide to the clinician in his choice of biopsy site.
Despite improvements in the enhancing ability of contrast agents and advances in imaging methods themselves, TRUS is still widely regarded as being non-specific in nature and as having made a disappointing clinical impact in this field (Downey (1997) Current Opinion in Urology 7: 93-99). also, because 25-40% of prostate tumours are isoechoic and therefore not amenable to ultrasound detection with current methods, some experts still feel that the contribution to date of ultrasonography to the diagnosis and characterisation of prostate abnormalities is minimal and disappointing (Downey supra; Bude & Rubin (1996) Radiology 200: 21-25).
Change in vascular architectured due to the induction of angiogenesis by tumour cells is known to accompany the establishment of all solid tumours, and is necessary to allow tumour development and metastasis. Studies of the changes in vascularisation which accompany tumour establishment and development quantitate the number of microvessels present in a defined area of the tissue or organ of interest, and use this to assess the degree of angiogenesis. This has been shown to correlate with disease progression in such conditions as melanoma, non-small cell lung cancer and breast cancer and can be used in predicting metastic disease.
Microvessel counts (MVCs) performed microscopically on samples taken from biopsy or prostatectomy samples have revealed a positive correlation between high MVCs and increasingly pathological stages of prostate disease (Fregene et al. (1993) Anticancer Research 13: 2377-2382). Such studies indicate that MVC determination can effectively discriminate between benign and malignant tumours and can be used to estimate confidently the likelihood of cancerous lesions in the prostate becoming metastatic.
Generally speaking, malignant tissue in the prostate, as with other body parts, has more microvessels associated with it, and hence a higher MVC, than does normal or hyperplastic tissue. Thus, determination of the state of vascularisation in defined areas of the prostate gland correlates with the state of the tissue examined. The correlation between altered vascular geometry and tissue abnormality is sufficiently close that analysis of vascularisation could be used in the diagnosis, characterisation, monitoring and prognosis of tissue abnormalities in the prostate. Unfortunately, the determination of vascular constitution or MVCs in prostate tissue may only be performed ex vivo on samples taken from a patient by biopsy.
Attempts to visualise vascular architecture in situ using TRUS have failed to generate the detail and resolution necessary to allow this technique to be reliably used for the diagnosis/monitoring of prostate abnormalities.
There is therefore a substantial need for a reliable, non-invasive method of assessing in detail the state of vascularisation in the prostate gland, in a manner which is amenable to routine clinical investigation and interpretation.
The present invention is based on the unexpected finding that abnormalities in vascular state may be assessed by ultrasonically determining certain flow parameters of contrast agent-containing blood as it traverses the prostate gland.
Thus according to one aspect, the present invention provides a method for assessing the state of vascularisation of the prostate gland by ultrasonographically determining the in-flow kinetics of an intravascularly administered ultrasound contrast agent into at least one area of the prostate.
The ultrasound image data so obtained may be used to assess one or more of blood flow, blood volume or blood perfusion in the area or areas of the prostate being imaged, so that information in respect of the whole of the prostate may be acquired.
The volume and flow rate of blood passing through the tissues of the prostate are largely determined by the number and nature of blood vessels carrying the blood. Deviations from normal vascular architecture of the prostate, even in tiny areas thereof, for example resulting from injury or tumour-induced angiogenesis, result in alterations to blood flow patterns such as the volume and flow rate and/or the number, size and compliance of the blood vessels within the organ. These changes are reflected in the flow parameters and degree or perfusion of the tissues and thus the in-flow kinetics of an ultrasound contrast agent passing through the vascular network of the prostate.
Viewed from another aspect, the present invention provides the use of an ultrasound contrast agent as an in the manufacture of an image-enhancing composition for use in the above method.
Within the contest of the present invention, the term “perfusion” may be defined as a measurement of blood volume/tissue weight/unit time. This is a difficult parameter to quantify directly, and with respect to the prostate gland probably cannot be measured in situ by any currently known technology. The degree of regional perfusion may, however, be assessed in accordance with the present invention by monitoring the temporal development of contrast effect in different regions of tissue upon arrival of the injected bolus. The arrival of contrast to tissue regions of high perfusion is expected to take place earlier than in areas of lower perfusion. However, if key variables such as the volume of conducting vessels to different tissue regions are known, the results can be directly interpreted as a quantitative measure of perfusion.
The relative degree of regional perfusion may also be assessed by power Doppler (also named “Doppler
Aksnes Anne Kirsti
Eriksen Morten
Hagen Else Kruger
Tornes Audun
Chisholm Robert F.
Jaworski Francis J.
Nycomed Imaging AS
Ronning, Jr. Royal N.
Ryan Stephen G.
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