WO2009036566A1 - Procédés pour détecter des anomalies dans le tissu mammaire à l'aide d'inhibiteurs de l'aromatase - Google Patents

Procédés pour détecter des anomalies dans le tissu mammaire à l'aide d'inhibiteurs de l'aromatase Download PDF

Info

Publication number
WO2009036566A1
WO2009036566A1 PCT/CA2008/001651 CA2008001651W WO2009036566A1 WO 2009036566 A1 WO2009036566 A1 WO 2009036566A1 CA 2008001651 W CA2008001651 W CA 2008001651W WO 2009036566 A1 WO2009036566 A1 WO 2009036566A1
Authority
WO
WIPO (PCT)
Prior art keywords
breast
subject
aromatase inhibitor
image
breast tissue
Prior art date
Application number
PCT/CA2008/001651
Other languages
English (en)
Inventor
Robert Casper
Mohamed Mitwally
Pavel Crystal
Noha Ahmed Al-Sayed Mousa
Original Assignee
Mount Sinai Hospital
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Mount Sinai Hospital filed Critical Mount Sinai Hospital
Publication of WO2009036566A1 publication Critical patent/WO2009036566A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
    • A61K49/10—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/05—Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radio waves 
    • A61B5/055—Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radio waves  involving electronic [EMR] or nuclear [NMR] magnetic resonance, e.g. magnetic resonance imaging
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids

Definitions

  • the invention generally relates to methods and formulations for detecting abnormalities in breast tissue.
  • MRI Magnetic resonance imaging
  • a method of the invention generally comprises administering to a subject an effective amount of one or more aromatase inhibitor (AI) to reduce breast density and/or vascularity in the subject prior to making an image of the breast tissue.
  • AI aromatase inhibitor
  • the invention relates to a method for reducing breast density and/or vascularity in a subject comprising administering to the subject an effective amount of one or more AI to reduce breast density and/or vascularity prior to making an image of breast tissue of the subject.
  • the invention provides a method for detecting an abnormality in breast tissue in a subject comprising administering to the subject an effective amount of one or more AI to reduce the density and/or the vascular perfusion of the breast tissue in the subject, and making an image of the breast tissue such that the abnormality in the breast is capable of being, or is detected.
  • an abnormality in breast tissue includes without limitation, a mass, a cyst, a microcalcification, a fibrous finding, an architectural distortion, and/or other abnormal findings related to benign or malignant abnormalities.
  • the abnormality in the breast tissue is a breast lesion, more particularly a tumor, which may be benign or malignant.
  • the abnormality in the breast tissue is a high grade tumor.
  • An image of breast tissue may be made using techniques known in the art, including, without limitation, film mammography, digital mammography, magnetic resonance imaging (MRI), dynamic contrast-enhanced MRI, or alternative techniques for visualizing breast tissue such as ultrasonography, thermography, computed tomography, positron emission tomography, transillumination, or radionucleotide imaging.
  • MRI magnetic resonance imaging
  • MRI dynamic contrast-enhanced MRI
  • ultrasonography thermography
  • computed tomography computed tomography
  • positron emission tomography positron emission tomography
  • transillumination or radionucleotide imaging.
  • the invention also relates to a packaged formulation for reducing breast density and/or vascularity in a subject prior to making an image of the subject's breast tissue comprising one or more AI packaged with instructions for using the AI(s) for reducing breast density and/or vascularity in the subject prior to making an image of the subject's breast tissue.
  • the invention involves the use of one or more AI, either alone or in combination with other pharmaceutical agents (e.g. hormone replacement therapy) for reducing breast density and/or vascularity in a subject before making an image of the subject's breast tissue.
  • other pharmaceutical agents e.g. hormone replacement therapy
  • the invention also involves the use of one or more AI for preparation of a packaged formulation for reducing breast density and/or vascularity in a subject prior to making an image of the subject's breast tissue.
  • the invention relates to the use of an aromatase inhibitor for use in combination with mammography or MRI or for use in the manufacture of a medicament for use in combination with mammography or MRI in a subject.
  • FIGURES Figure 1 shows scanned images acquired through three different sources, a. Digital image acquired by Direct Digital Acquisition (DDA); b. Image scanned with Kodak L S85 film digitizer; and c. Image scanned with Agfa DuoScan Flatbed scanner.
  • DDA Direct Digital Acquisition
  • Figure 2 shows the editing tools included in the ImageQuant 5 program.
  • Figure 3 shows selection and background correction in respect to a comparison of scanned images using the ImageQuant 5 program.
  • Figure 4 shows the outlining of the total area of glandular tissue and the densest glandular region of a scanned image using the ImageQuant 5 program.
  • Figure 5 shows a visual representation of breast density using the "Surface Plot" function of the Image J program.
  • Figure 6 shows a 3d interactive surface plot of breast density that is available as a plugin of the Image J program.
  • Figure 7 shows a display of a greyscale image in colors through the "lookup tables" tool of the Image J program.
  • Greyscale images are displayed using a color lookup table which describes the color to be used for each of 256 possible displayed pixel values.
  • Figure 8 shows a comparison of breast density for a patient receiving an aromatase inhibitor pre- or post- mammogram.
  • Figure 9 shows a comparison of breast density for a patient receiving an aromatase inhibitor pre- or post- mammogram.
  • Figure 10 shows a 3-D interactive surface plot of pixel density of images taken from a patient before and after receiving an aromatase inhibitor.
  • Figure 11 shows a comparison of breast density in a subject receiving an aromatase inhibitor pre- or post- mammogram.
  • Figure 12 shows MRI-Tl : A pre-contrast, B post-contrast and C subtraction views.
  • Figure 13 shows benign background enhancement in MRI and its Image J interactive surface plotting, a) MRI benign breast tissue with no background enhancement after gadolinium injection, b) Interactive surface plotting of Image J representation of the breast in picture a), c) MRI stippled foci of benign background enhancement in the same patient, d) Interactive surface plotting of Image J representation of the breast in picture c) assigning lighter gradient of color corresponding to the increased pixel intensity caused by the stippled foci of enhancement. - A -
  • the invention is related to methods, formulations and compositions for improved detection of breast abnormalities, in particular breast abnormalities in dense breast tissue.
  • the methods of the invention generally comprise administering to a subject an effective amount of one or more AI to reduce breast density and/or vascularity in the subject prior to making an image of the subject's breast tissue.
  • the term "subject” refers to a warm-blooded animal such as a mammal, which requires a reduction in breast density and/or vascularity, and/or is being subjected to methods for imaging breast tissue, for example, mammography or MRI.
  • the term refers to a human, more particularly a female human.
  • the subject is a menopausal female, in particular a menopausal female receiving hormone replacement therapy.
  • the subject is a postmenopausal female.
  • the term includes male humans.
  • a subject is a BRCA mutation carrier.
  • the subject has multiple cancerous foci in breast tissue.
  • the subject has a high incidence of interval breast malignancies (Komenaka, 2004).
  • an “aromatase inhibitor” refers to a substance that inhibits or inactivates aromatase, an enzyme of the cytochrome P-450 superfamily and a product of the CYPl 9 gene.
  • the enzyme synthesizes estrogens from androgenic substrates, for example, estrone is synthesized from the preferred substrate androstenedione and estradiol from testosterone.
  • the inhibitors have been classified as first-, second- and third- generation inhibitors according to the chronologic order of their clinical development, and as type 1 or type 2 inhibitors according to their mechanism of action. (See, for example, Smith, M.D., I.E.
  • Type 1 aromatase inhibitors are steroidal analogues of androstenedione that bind irreversibly to aromatase to thereby inactivate the enzyme
  • Type 2 aromatase inhibitors are nonsteroidal and bind reversibly to the heme group of the enzyme by way of a basic nitrogen.
  • the aromatase inhibitors for use in the methods of the present invention include the compounds described in U.S. Patent Nos. 4,808,616, 4,904,650 and 4,322,416; EP Patent Publication Nos. EP-A-165904, EP-A-236940, EP-A- 408509, EP 91810110.6, EP-A-114033, EP-A-166692, EP-A-356673, EP-A-337929, EP- A-337928, EP-A-340153, EP-A-293978, EP-A-250198, EP-A-281283, EP-A-296749, EP- A-299683, EP-A-299684, EP-A-316097, EP-A-354689, EP-A-354683, andEP-A-181287; Swiss Patent Application Nos.
  • aromatase inhibitors include: 6-methylenandrosta-l,4-diene-3,17- dione; 1 -methyl-6-methylenandrosta- 1 ,4-diene-3 , 17-dione; 1 -ethyl-6-methylenandrosta- l,4-diene-3,l 7-dione; 4-methyl-6-methylenandrosta-l,4-diene-3,l 7-dione; 4-ethyl-6- methylenandrosta- 1 ,4-diene-3 , 17-dione; 4-fluoro-6-methylenandrosta- 1 ,4-diene-3 , 17- dione; 4-chloro-6-methylenandrosta- 1 ,4-diene-3 , 17-dione; 6-ethylidenandrosta- 1 ,4-diene- 3 , 17-dione; 6-propylidenandrosta- 1 ,4-diene-3 , 17-dione; 4-fluor
  • an aromatase inhibitor is 6-methylenandrosta-l ,4-diene- 3,17-dione, also known as exemestane (Aromasin®). 6-Methylenandrosta-l,4-diene-3,17- dione may be synthesized using the process of Example 1 in U.S. Patent Nos. 4,808,616 and 4,904,650.
  • Patent 4,978,672 and marketed as Femara®; 6-[(4- chlorophenyl)- 1 H- 1 , 2,4- triazol- 1 -ylmethyl]- 1 -methyl- 1 H- benzotriazole, also known as vorozole; and 4- [N-(4-bromobenzyl)-N-(4-cyanophenyl)amino]-4H-l ,2,4- triazole.
  • An aromatase inhibitor may be formulated with a pharmaceutically acceptable carrier, excipient or vehicle.
  • pharmaceutically acceptable carrier, excipient, or vehicle refers to a medium which does not interfere with the effectiveness or activity of an active ingredient and which is not toxic to the hosts to which it is administered.
  • a carrier, excipient, or vehicle includes diluents, binders, adhesives, lubricants, disintegrates, bulking agents, wetting or emulsifying agents, pH buffering agents, and miscellaneous materials such as absorbants that may be needed in order to prepare a particular composition.
  • diluents binders, adhesives, lubricants, disintegrates, bulking agents, wetting or emulsifying agents, pH buffering agents, and miscellaneous materials such as absorbants that may be needed in order to prepare a particular composition.
  • Suitable pharmaceutical carriers, excipients, and vehicles are described in the standard text, Remington: The Science and Practice of Pharmacy, [(formerly called Remington's Pharmaceutical Sciences), Editor: University of the Sciences in Philadelphia (USIP), 21 st Edition, May, 2005].
  • aromatase inhibitors may be administered to a subject as a pharmaceutically acceptable salt, prodrug, or a salt of a prodrug.
  • the aromatase inhibitors may also be in the form of hydrates or their crystals and may include the solvent used for crystallization. Further the aromatase inhibitors may occur in the form of R- or S- enantiomers and as enantiomeric mixtures thereof, for example in the form of a racemate. Isomers of aromatase inhibitors, mixtures of at least two isomers (e.g.
  • the aromatase inhibitor is a sustained release formulation, i.e, a formulation that allows for the continuous delivery of an AI to a subject over a period of time (e.g., 1-2 days, 1-3 days, 1-5 days, 1-7 days, 1-2 weeks, 1-3 weeks, 1- 4 weeks, 1-5 weeks, 1-7 weeks, 1-10 weeks, 1-12 weeks, 1-9 weeks, 1-6 weeks, 1 -12 months, 1-9 months, 1-6 months or 1-3 months).
  • a sustained release formulation i.e, a formulation that allows for the continuous delivery of an AI to a subject over a period of time (e.g., 1-2 days, 1-3 days, 1-5 days, 1-7 days, 1-2 weeks, 1-3 weeks, 1- 4 weeks, 1-5 weeks, 1-7 weeks, 1-10 weeks, 1-12 weeks, 1-9 weeks, 1-6 weeks, 1 -12 months, 1-9 months, 1-6 months or 1-3 months).
  • breast density refers to the appearance of the breast parenchyma produced using techniques for imaging breast tissue.
  • Breast density can be classified using the system proposed by Wolfe, JN, Cancer, 37:2486-2492, 1976 which is based on the appearance of four breast parenchyma patterns in mammograms (i.e., the categories Nl, Pl, P2 and DY).
  • Nl the breast consists of mostly fatty tissue with no ducts visible and it represents an essentially normal breast.
  • the Pl category represents a fatty breast, with predominant ducts in the anterior portion occupying up to a quarter of the breast area.
  • the breast In P2, the breast is involuted, with prominent duct patterns of moderate to severe degree, occupying more than a quarter of the breast, and the visible duct pattern may occupy the entire breast.
  • the breast parenchyma In DY, the breast parenchyma is dense, which usually denotes connective tissue hyperplasia, and it may appear homogeneous due to the overall increased density.
  • Breast tissues classified as P2 or DY using the Wolfe system are generally considered to be "dense breasts".
  • the American College of Radiology has proposed a modified version of the Wolfe patterns for the BI-RADS [American College American College of Radiology. Illustrated Breast Imaging Reporting and Data System (BI-RADS), The American College of Radiology, third edition, 1998].
  • the classification scheme is generally as follows:
  • the breast is heterogeneously dense. This may lower the sensitivity of mammography.
  • the breast tissue is extremely dense, which could obscure a lesion in mammography.
  • pattern classifications include, without limitation the six-category classification (SCC) and others (see, for example, Marias K, et al, Conf Proc IEEE Eng Med Biol Soc. 6:6394-8, 2005; and Jeffreys, M., Br J Radiol. 76(908):561-3, 2003 and Table 3 herein).
  • SCC six-category classification
  • vascularity includes vessel permeability, vascular volume and perfusion of breast tissue.
  • the phrases "to reduce breast density and/or vascularity" or “for reducing breast density and/or vascularity” refer to methods and compositions that result in a change in breast density and/or vascularity.
  • the terms include a change in the breast parenchyma classification of a subject to a less dense or more lucent appearance and/or a change in the vascularity of breast tissue of a subject, relative to the breast density and/or vascularity observed in the subject in the absence of a treatment with a method or formulation of the invention.
  • the terms may include a reduction in baseline enhancement of contrast material (e.g. Gadolinium dye) uptake by the blood vessels.
  • contrast material e.g. Gadolinium dye
  • the terms “making an image of breast tissue”, “imaging breast tissue” and “making an image of the subject's breast tissue” refer to one of a variety of techniques known in the art for visualizing breast tissue. Suitable techniques include, without limitation, film mammography, digital mammography, ultrasonography, thermography, computed tomography, positron emission tomography, transillumination, magnetic resonance imaging, contrast-enhanced MRI, or radionucleotide imaging (see for example, Jackson, VP et al, Radiology 188:297-301, 1993; Braeuning, MP et al, Breast Cancer Res. Treat.
  • an image is made using film mammography.
  • an image is made using digital mammography.
  • an image is made using MRI.
  • abnormality of the breast refers to any abnormality in breast tissue that may be detected by making an image of the breast tissue.
  • An abnormality in breast tissue includes without limitation, a mass, a cyst, a microcalcification, a fibrous finding, an architectural distortion, and/or other abnormal findings related with benign or malignant abnormalities.
  • the abnormality in the breast tissue is a breast lesion, more particularly a tumor, which may be benign or malignant.
  • the abnormality is a high grade tumor.
  • the invention relates to a method for reducing breast density and/or vascularity in a subject prior to making an image of breast tissue of the subject. The method involves administering an effective amount of one or more AI to reduce breast density in the subject.
  • the invention also relates to methods for detecting an abnormality of the breast of a subject.
  • the methods comprise administering to the subject an effective amount of one or more AI to reduce breast density and/or vascularity of the subject's breast tissue, and making an image of the breast tissue such that an abnormality of the breast can be or is detected.
  • the abnormality is a malignant or benign tumor.
  • the image of the breast tissue is made by standard film mammography.
  • the image of the breast tissue is made by digital mammography.
  • the image of the breast tissue is made by MRI.
  • the invention relates to a method for diagnosing breast cancer in a subject comprising administering an effective amount of an aromatase inhibitor to the subject and making an image of breast tissue of the subject to detect an abnormality of the breast tissue.
  • a method for diagnosing breast cancer in a subject comprising administering an effective amount of an aromatase inhibitor to the subject and subjecting the subject to mammography.
  • a method for diagnosing breast cancer in a subject comprising administering an effective amount of an aromatase inhibitor to the subject and subjecting the subject to MRI.
  • the invention relates to a method of preparing a female subject for mammography comprising the step of, prior to performing the mammography, administering to the subject one or more doses of at least one aromatase inhibitor, either alone or in conjunction with another pharmaceutical agent, in an effective amount to reduce breast density in the subject.
  • the invention relates to a method of preparing a female subject for breast MRI comprising the step of, prior to performing the breast MRI, administering to the subject one or more doses of at least one aromatase inhibitor, either alone or in conjunction with another pharmaceutical agent, in an effective amount to reduce breast vascularity in the subject.
  • the subject is a BRCA mutation carrier.
  • the subject has multiple cancerous foci in breast tissue.
  • the subject has a high grade tumor.
  • the subject has a high incidence of interval breast malignancies (Komenaka, 2004).
  • an "effective amount” relates to the amount or dose of AI(s) that is sufficient to result in a desired reduction in breast density and/or to improve detection of an abnormality of the breast.
  • the effective amount may vary with the particular subject involved, the density and/or vascularity of the breast tissue prior to treatment, the particular AI(s), and/or the intended result.
  • the amount of AI to reduce breast density and/or vascularity in a subject is in a dosage range of about 0.01 mg/kg to about 2000 mg/kg, 0.01 mg/kg to about 1000 mg/kg, 0.01 to about 500 mg/kg, 0.01 to about 250 mg/kg, 0.01 to about 200 mg/kg, 0.01 to about 100 mg/kg, 0.01 to about 75 mg/kg, 0.01 to about 60 mg/kg, 0.01 to about 50 mg/kg, 0.01 to about 25 mg/kg, or 0.01 to about 20 mg/kg, once, twice or three times daily.
  • the amount of AI to reduce breast density and/or vascularity in a subject is in a dose of about 1 to about 500 mg, 10 to about 500 mg, 1 to about 100 mg, 1 to about 75 mg, 1 to 60 mg, 1 to about 50 mg, 2 to about 75 mg, 2 to about 60 mg, 2 to about 50 mg, 5 to about 75 mg, 5 to about 60 mg, 5 to about 50 mg, or 2 to about 20 mg once, twice or three times daily, preferably once daily.
  • the dose of AI is about 0.01 mg/kg/day to about 400 mg/kg/day, 0.01 mg/kg/day to about 250 mg/kg/day, 0.01 mg/kg/day to about 200 mg/kg/day, 0.01 mg/kg/day to about 100 mg/kg/day, 0.01 mg/kg/day to about 75 mg/kg/day, 0.01 mg/kg/day to about 60 mg/kg/day, 0.01 mg/kg/day to about 50 mg/kg/day, 0.01 mg/kg/day to about 30 mg/kg/day, 0.01 mg/kg/day to about 20 mg/kg/day or 0.01 mg/kg/day to about 10 mg/kg/day.
  • aminoglutethimide (marketed as Cytadren® and available as 250 mg oral tablets) may be administered initially at a dose of 250 mg given at 8-hour intervals and the dosage may be increased to a daily dose of 2 grams.
  • Other commercially available aromatase inhibitors include letrozole, marketed as Femara®, which is available as a 2.5 mg oral tablet; anastrazole, marketed as Arimidex®, which is available as a 1 mg oral tablet and exemestane, marketed as Aromasin®, which is available as a 25 mg oral tablet.
  • the aromatase inhibitor is letrozole which is administered in a daily dose of from about 2.5 mg to about 50 mg or 5 mg to about 20 mg, in particular 5 mg, 12.5 mg, or 20 mg. In an embodiment letrozole is administered for 1 to 3 days, preferably 3 days.
  • the aromatase inhibitor is anastrozole which is administered in a daily dose of from about 1 mg to about 100 mg, 1 mg to about 75 mg, or 1 mg to about 60 mg. In an embodiment anastrozole is administered for 1 to 3 days, preferably 3 days. In other aspects, the aromatase inhibitor is vorozole which is administered in a daily dose of from about 4 mg to about 100 mg, 4 mg to about 75 mg, 1 mg to about 60 mg or 4 mg to about 60 mg.
  • the aromatase inhibitor is exemestane which is administered in a daily dose of from about 25 mg to about 500 mg, 25 mg to about 250 mg, 10 mg to about 100 mg, 10 mg to about 50 mg, 25 mg to about 100 mg or 25 mg to about 50 mg.
  • the treatment regimen of an AI may vary depending on the particular subject involved, the density of the breast tissue and/or vascularity prior to treatment, the particular AI(s), and/or the intended result.
  • the administration of one or more AI may be given as a single dose for one day or multiple days, or as multiple doses for one day or multiple days.
  • Other pharmaceutical agents e.g. hormone replacement therapy
  • Administration of the AI(s) alone or in conjunction with other medications can start at least about 1 to about 2 days, 1 to about 3 days, 1 to about 5 days, 1 to about 7 days, 1 to about 10 days, 1 to about 14 days, 1 to about 20 days, 1 to about 30 days, 1 to about 60 days, 1 to about 120 days, 1 to about 180 days, 1 to about 200 days, 1 to about 210 days, 1 to 240 days, 1 week to 2 weeks, 1 week to 4 weeks, 1 week to 6 weeks, 1 week to 8 weeks, 1 week to 10 weeks, 1 week to 3 months, 1 week to 6 months, 1 week to 9 months, 1 week to 12 months, 1 month to 3 months, 1 month to 4 months, 1 month to 6 months, 1 month to 9 months, 1 month to 12 months, 4 months to 6 months, 4 months to 9 months, 6 months to 12 months, or 12 months prior to making an image of the breast.
  • the period of time that a subject is administered an AI(s) may vary depending on factors such as the particular subject involved, the density and/or vascularity of the breast tissue prior to treatment, the AI(s) used, and the desired degree of breast density and/or vascularity reduction.
  • a subject may be treated with an AI(s) prior to making an image of the subject's breast tissue continuously for about 1 to about 2 days, 1 to about 3 days, 1 to about 5 days, 1 to about 7 days, 1 to about 10 days, 1 to about 14 days, 1 to about 20 days, 1 to about 30 days, 1 to about 60 days, 1 to about 120 days, 1 to about 180 days, 1 to about 200 days, 1 to about 210 days, 1 to about 240 days, 1 week to 2 weeks, 1 week to 4 weeks, 1 week to 6 weeks, 1 week to 8 weeks, 1 week to 10 weeks, 1 week to 3 months, 1 week to 6 months, 1 week to 9 months, 1 week to 12 months, 1 month to 3 months, 1 month to 6 months, 1 month to 9 months, 1 month to 12 months, 6 months to 12 months, 12 months to 24 months, or 12 months to 48 months or longer, or periodically.
  • an AI(s) prior to making an image of the subject's breast tissue continuously for about 1 to about 2 days, 1 to about 3 days, 1 to about 5 days
  • the invention further relates to a packaged formulation for reducing breast density in a subject prior to making an image of breast tissue of a subject.
  • a packaged formulation of the invention comprises one or more AI packaged with instructions for using the one or more AI for reducing breast density and/or vascularity in a subject prior to making an image of the breast tissue of the subject.
  • the packaged formulation comprises an effective amount of one or more AI.
  • the AI in the packaged formulation may be in a form suitable for oral administration.
  • the AI in the packaged formulation may be in a form suitable for systemic administration.
  • the AI in the packaged formulation may be in a form suitable for subcutaneous or intravenous injection.
  • the AI in the packaged formulation may be in a form suitable for continuous infusion.
  • the AI in the packaged formulation is in a sustained release formulation.
  • a packaged formulation may be provided in a single dosage unit or multiple dosage units (i.e., tablets or capsules) having about 1 to about 1000 mg, 1 to about 500 mg, 1 to about 300 mg, 1 to about 250 mg, 1 to about 200 mg, 1 to about 150 mg, 1 to about 100 mg, 1 to about 75 mg, 1 to about 70 mg, 1 to about 60 mg, 1 to about 50 mg, 5 to about 60 mg, 5 to about 25 mg, 5 to about 20 mg, 10 to about 20 mg, 12 to about 25 mg, 15 to about 25 mg, or 15 to about 20 mg of an AI.
  • a single dosage unit or multiple dosage units i.e., tablets or capsules having about 1 to about 1000 mg, 1 to about 500 mg, 1 to about 300 mg, 1 to about 250 mg, 1 to about 200 mg, 1 to about 150 mg, 1 to about 100 mg, 1 to about 75 mg, 1 to about 70 mg, 1 to about 60 mg, 1 to about 50 mg, 5 to about 60 mg, 5 to about 25 mg, 5 to about 20 mg, 10 to about 20 mg,
  • the methods and formulations of the invention may be used with or comprise any of a variety of aromatase inhibitors.
  • a single aromatase inhibitor or a combination of aromatase inhibitors, in particular aromatase inhibitors with different half lives, may be used in the methods and formulations of the invention.
  • An aromatase inhibitor may be selected that has a half-life of about 2 hours to about 1 day, 2 hours to about 3 days, 2 hours to about 4 days, 2 hours to about 2 days, 1 to about 5 days, 1 to about 3 days, 1 to about 2 days, or in particular 1 , 2, or 3 days.
  • aromatase inhibitors that may be used in the methods of the invention include non-steroidal and reversible aromatase inhibitors or steroidal and non-reversible aromatase inhibitors.
  • an oral aromatase inhibitor in particular a commercially available oral aromatase inhibitor is employed, including without limitation anastrozole (ArimidexTM), letrozole (FemaraTM), vorozole and/or exemestane (AromasinTM).
  • letrozole Preferably letrozole (FemaraTM) is employed in the present invention.
  • Control mammograms were chosen from available mammograms of the same patients while they were on HRT alone prior to starting the AI. Additionally, mammograms of an age matched group of postmenopausal women using HRT alone were used. After obtaining the consents, all of the past and the present medical history were reviewed carefully and the data related to the study was collected and entered to coded electronic sheets.
  • Analog mammograms obtained by the conventional Film- based X-ray systems using an analog acquisition technique.
  • CDs Digital mammograms
  • DDA Direct Digital Acquisition
  • PACS picture archiving and communication systems
  • the next step was to transform the mammograms available only in hard copies into digital forms that can be further analyzed by image analysis software.
  • image analysis software Two different pieces of equipment were used: a) Kodak LS85 film digitizer (Eastman Kodak Co., Rochester, NY). This is a high-resolution film digitizer which has a laser beam to illuminate scanned films and produce digital signals as accurate as 0.001 optical density through a logarithmic amplifier. The resolution and densities in the digital images produced by this digitizer are closely representative of the original image.
  • the Kodak LS85 film digitizer Specifications are shown in Table 1.
  • Agfa DuoScan Flatbed scanner (Agfa-Gevaert Group- Mortsel, Belgium).
  • the scanner incorporates TwinPlate Scanning Technology to enable scanning of transparencies and reflective work on independent scan beds in a single integrated unit. Films are placed on a tray, which slides into the body of the scanner. A single carriage carrying light sources, optics, and a CCD sensor, traverses between the upper glass plate for reflective work and the transparency tray below. A rotation of a single mirror occurs upon switching from reflective to transparency scanning.
  • the Agfa DuoScan Flatbed scanner specifications are shown in Table 2. Scanning of the films Preparation and placement of the films: In order to have an equal scanning environment necessary for comparison, each patient's mammograms were compared using the same scanner.
  • each scanner's software was set to the same scanning parameters. Differences in the equipment or in any of these parameters would result in differences in the measurements of the breast density.
  • Each patch of films was carefully arranged and labelled serially with a coded obscure name that could be interpreted only by the investigators into patient's ID, date of mammogram, laterality and view of the original film.
  • Each film was then cleaned and placed inside the digitizer or inside the tray of the scanner. In the case of the Agfa scanner, proper application was important to make sure that no air is entrapped between the film and the glass tray which could create background noise that might affect the quality of the produced image.
  • the Kodak digitizer needed at least 30 minutes to warm up before starting the process of scanning and it takes approximately 30 seconds to scan a single image while the Agfa scanner usually takes around 1 minute. After finishing the scanning process, the scanned images are saved by file names using a naming convention of the same labels tagged earlier on the X-rays; then each patient's files are stored in a single directory.
  • Mammograms Scanning Software :
  • Lumisys Scan program is used with the Kodak LS85 film digitizer
  • .iv2 is created at 260 microns per pixel and is 12 bits.
  • a .iv2 is 1.2 MB and for large films (24 cm x 30 cm) an .iv2 is 2.05 MB.
  • the bmp format is in 8 bits and is 0.6 MB for the small and 1.2 MB for the large films.
  • the scanned image files are in RGB (red green blue) format which needs further transformation before computer assisted image analysis.
  • B. Fotolook FL 3.6 is used with Agfa DuoScan Scanner: This is used to preview, adjust and set up the profile of the scanned films.
  • the images could be acquired directly in grayscale mode and the images could be cropped in a preview mode if desired.
  • TIFF "Tagged Image File Format"
  • Produced file sizes were approximately 78MB.
  • the scan parameters were set as follows: Original: Transparent; Size: Max. area; Mode : Gray Scale; Input: 800ppi; Scale to: 100%; 16 bit; Range: Automatic; Tone curve: None; Sharpness: high; Descreen: None; Flavor: none; and w ⁇ point: none.
  • the radiologist reviewed the mammograms after their digitization and not in hard copies.
  • the radiologist was totally blinded to any information related to the patients, the dates of the mammograms or if a specific film was obtained before or after the investigated protocol.
  • the file names of the images appearing on the screen were all in an obscure code that could not be interpreted by the radiologist as identifying data.
  • Films were also shown by the investigator to the radiologist randomly without specific order.
  • the radiologist analyzed each image separately and comments were recorded by the investigator. In order to make for intraobserver reliability, randomly taken samples of the films were reblinded and shown again to a breast-imaging specialist.
  • BI-RADS Breast Imaging Reporting and Data System
  • ACR which provides a standard classification for mammographic breast density estimations and facilitates the reporting of patients' results and the communication among health providers.
  • Table 3 shows the interpretation of BI-RADS scores
  • Quantitative Computer Assisted Image analysis In total, there were 3 different sources of the images that were eventually collected as shown in Figure 1. There were well visible differences in the quality and resolution of the produced images among the three methods. The highest quality being for digitally acquired films followed by films scanned by the Kodak LS85 digitizer and the least quality was produced by the Agfa Duoscan flatbed scanner. Additionally, a previous study found that breast density was significantly lower in mammograms originally acquired in digital format compared to those digitized after being obtained by the conventional film screen (Harvey, J. 2004). However, as mentioned above each patient's group of films assigned for comparison were screened and scanned using the same equipment.
  • ImageQuant then assigns each pixel a numerical value according to the absorbance of the image at this spot. Eventually, it presents the summation of all those numerical values in what is termed : the integrated pixel intensity (IPI) (Palomares, MR et al, 2006).
  • IPI integrated pixel intensity
  • the whole breast was outlined using the mouse. Different tools are available for region selection; the polygonal tool was chosen which provided better control and more accurate outline of the breast edge. Chest wall structures, when present, were excluded from the outline.
  • the copy- paste tool the polygon drawn above is pasted over the breast in the second image.
  • the smaller breast is outlined first and copied and pasted to the larger breast starting from the nipple side to avoid biased measurements based on patient positioning which might happen during the original film screen. ( Figure 3). Then, in order to avoid the effect of the background noise on the measured (IPI), background correction tools available in ImageQuant were used.
  • the background correction option was used when the background value is zero as in the digitally acquired films.
  • “Local Average” option value was selected when the background is heterogeneous allover the film surface, and this option calculates a background value which is equal to the average of all the points beneath the outline. Background correction can be also done using an Object Average option, which should be best used when the background noise is homogenous.
  • Image J is a free public domain Java image processing program offered by the NIH (NIH, Image J). It can be used, either as an online applet or can be downloaded to any computer. This system should have Java 1.4 (Sun Microsystems, Inc.) or later versions installed. It also has more than 300 plugins that can be downloaded and added to enhance its function. Using image J, the average intensities of the pixels inside an outlined area similar to ImageQuant were measured; however there was no volume measurement feature. On the other hand, Image J provided a more visual representation of the breast density by its "Surface Plot" function (Figure 5). Interactive surface plot is also available as a plugin ( Figure 6).
  • Grayscale images can be also displayed in colors through the "lookup tables" tool which allows for a broad selection of colors and patterns that can be assigned for each of 256 possible displayed pixel values ( Figure 7).
  • ImageQuant data output was exported to Excel software (Microsoft Office Excel 2003). The statistical tests were then performed using SPSS 14.00 for Windows (Release 14.01, SPSS Inc., Chicago, IL, USA). Both the paired samples t-test and the non parametric Wilcoxon's test were used to analyze related continuous variables and the independent student's Mest and the non-parametric Mann- Whitney Latest were used to analyze continuous independent variables. P ⁇ 0.05 was considered statistically significant. Results:
  • the main difference between MRI and other imaging techniques is the accompanying intravenous injection of a contrast material, commonly Gadolinium, which is a non radioactive material specifically up-taken by highly vascular tissues, especially cancer, leading to enhancement or brightness of this particular tissue.
  • the malignant tissue is typically able to enhance more markedly and quickly than normal tissue or benign lesions possibly due to an abnormal and extremely high vascularity.
  • the primary objectives of this study are to determine the effectiveness of the aromatase inhibitor Letrozole in increasing the sensitivity and specificity of MRI in healthy postmenopausal women with diagnostic difficulties. Secondary obj ectives are to determine the tolerability and side effects of this intervention at different doses.
  • Study Design Pilot prospective study with a clinically similar retrospective cohort as control group.
  • Eligibility Age eligibility: 35 years old and over. Gender eligibility. Female. Target population: Healthy postmenopausal who have had one or repeated MRIs for diagnostic difficulties.
  • FSH follicle-stimulating hormone
  • Implants with any implant including pacemakers, vagus nerve stimulators, implantable cardioverter-defibrillators (ICD), loop recorders, insulin pumps, cochlear implants, deep brain stimulators, surgical prostheses, aneurysm clips or any other implant.
  • ICD implantable cardioverter-defibrillators
  • loop recorders insulin pumps
  • cochlear implants deep brain stimulators
  • surgical prostheses aneurysm clips or any other implant.
  • Osteoporosis defined as a bone mineral density T-score > -2.5 on dual-energy x- ray absorptiometry. History of pathological or fragility fractures.
  • Drug Formulation Femara TM Novartis Pharmaceuticals Canada Inc., Dorval, QC). Oral Tablets 2.5 mg.
  • SERMs Selective estrogen receptor modulators
  • Gonadotrophin releasing hormone analogues GnRh agonists and antagonists
  • Phytoestrogens Other aromatase inhibitors
  • MRIs are obtained and archived through the Picture Archiving and Communication Systems (PACS).
  • PACS Picture Archiving and Communication Systems
  • the MRIs will be burned on CDs with a DICOM viewer (eFilm (TM) Lite (TM) software Copyright ⁇ 1998-2005, Merge eMed, Milwaukee, WI USA) that allowed manipulation of the images and exporting them to other computer programs.
  • Transverse sections will be used for the purpose of this study.
  • the level of the nipple will be taken as a landmark to compare the corresponding sections in both the pre and post treatment films.
  • the MRI series (Tl) will be used for the evaluation and comparison of enhancement in all study subjects and controls.
  • SI postcontrast will be determined at 3 time points after Gadolinuim injection.
  • a clinically similar retrospective cohort will be chosen as a control group. Similarity is based on age, body mass index, hormone therapy status and breast cancer risk. Breast cancer risk is based on familial and genetic risk factors as well as Gail risk score. The same outcome measures mentioned above will be applied for the retrospective cohort of MRI. Two successive MRIs with 4 months or less apart will be compared to see if there is a difference between the change of MRI pattern of enhancement and density with time and without an intervention being applied.
  • Statistical Analysis will include the analysis of a subject's base line clinical features, risk indicators as well as the baseline and after treatment endpoints.
  • the non- parametric Mann-Whitney U-test and repeated measures ANOVA will be used to analyze independent and related continuous variables respectively, Wilcoxon's signed-rank test to analyze related continuous variables, the chi-square ( ⁇ 2) test to analyze categorical variables and Spearman's test in measuring bivariate correlations.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Physics & Mathematics (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Radiology & Medical Imaging (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Surgery (AREA)
  • Chemical & Material Sciences (AREA)
  • High Energy & Nuclear Physics (AREA)
  • Biophysics (AREA)
  • Pathology (AREA)
  • Medicinal Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Medical Informatics (AREA)
  • Molecular Biology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

L'invention concerne des procédés améliorés pour détecter des anomalies dans le tissu mammaire, en particulier le tissu mammaire dense. Un procédé de l'invention comporte, d'une manière générale, l'administration à un sujet d'une quantité efficace d'un ou de plusieurs inhibiteurs de l'aromatase pour réduire la densité et/ou la vascularisation du sein chez le sujet avant d'effectuer une image du tissu mammaire.
PCT/CA2008/001651 2007-09-21 2008-09-19 Procédés pour détecter des anomalies dans le tissu mammaire à l'aide d'inhibiteurs de l'aromatase WO2009036566A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US99483207P 2007-09-21 2007-09-21
US60/994,832 2007-09-21

Publications (1)

Publication Number Publication Date
WO2009036566A1 true WO2009036566A1 (fr) 2009-03-26

Family

ID=40467455

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CA2008/001651 WO2009036566A1 (fr) 2007-09-21 2008-09-19 Procédés pour détecter des anomalies dans le tissu mammaire à l'aide d'inhibiteurs de l'aromatase

Country Status (1)

Country Link
WO (1) WO2009036566A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016061615A1 (fr) * 2014-10-22 2016-04-28 Chavah Pty Ltd Procédé de réduction de densité mammaire monographique et/ou de risque de cancer du sein
US9616072B2 (en) 2005-10-19 2017-04-11 Chavah Pty Ltd. Reduction of side effects from aromatase inhibitors used for treating breast cancer
WO2017066827A1 (fr) * 2015-10-22 2017-04-27 Havah Therapeutics Pty Ltd Procédés de réduction de la densité mammaire à la mammographie et/ou du risque de cancer du sein
US11524014B2 (en) 2019-06-03 2022-12-13 Havah Therapeutics Pty Ltd. Pharmaceutical formulations and systems for delivery of an androgenic agent and an aromatase inhibitor with sustained multi-phasic release profiles and methods of use
CN117257994A (zh) * 2023-11-21 2023-12-22 北京大学人民医院 动物模型的构建方法及应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2329352A1 (fr) * 1998-04-27 1999-11-04 Marc B. Garnick Methodes de detection de lesion dans le tissu mammaire dense au moyens d'antagonistes de la luliberine.

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2329352A1 (fr) * 1998-04-27 1999-11-04 Marc B. Garnick Methodes de detection de lesion dans le tissu mammaire dense au moyens d'antagonistes de la luliberine.

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BRISSON J. ET AL.: "Tamoxifen and Mammographic Breast Densities", CANCER EPIDEMIOL. BIOMARKERS PREV., vol. 9, September 2000 (2000-09-01), pages 911 - 91515 *
GOSS P.E. ET AL.: "Aromatase Inhibitors in the Treatment and Prevention of Breast Cancer", J. CLIN. ONCOL., vol. 19, no. 3, 1 February 2001 (2001-02-01), pages 881 - 894, XP003022842 *
MOUSA N.A. ET AL.: "Aromatase inhibitors and mammographic breast density in postmenopausal women receiving hormone therapy", MENOPAUSE, vol. 15, no. 5, 2008, pages 875 - 884 *
OLSON J.E. ET AL.: "A Comprehensive Examination of CYP19 Variation and Breast Density", CANCER EPIDEMIOL. BIOMARKERS PREV., vol. 16, no. 3, March 2007 (2007-03-01), pages 623 - 625 *

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9616072B2 (en) 2005-10-19 2017-04-11 Chavah Pty Ltd. Reduction of side effects from aromatase inhibitors used for treating breast cancer
US10765684B2 (en) 2005-10-19 2020-09-08 Havah Therapeutics Pty Ltd. Reduction of side effects from aromatase inhibitors used for treating breast cancer
US10525063B2 (en) 2014-10-22 2020-01-07 Havah Therapeutics Pty Ltd. Methods of reducing mammographic breast density and/or breast cancer risk
US10588912B2 (en) 2014-10-22 2020-03-17 Havah Therapeutics Pty Ltd Methods of reducing mammographic breast density and/or breast cancer risk
JP2017531685A (ja) * 2014-10-22 2017-10-26 ハバフ セラピューティクス ピーティーワイ エルティーディー マンモグラフィ乳房密度及び／又は乳癌リスクを低下させる方法
CN107405353A (zh) * 2014-10-22 2017-11-28 哈瓦赫治疗有限公司 降低乳房摄影乳腺密度和/或乳腺癌风险的方法
US11883414B2 (en) 2014-10-22 2024-01-30 Havah Therapeutics Pty Ltd. Methods of reducing mammographic breast density and/or breast cancer risk
US10064874B2 (en) 2014-10-22 2018-09-04 Havah Therapeutics Pty Ltd. Methods of reducing mammographic breast density and/or breast cancer risk
US10155005B2 (en) 2014-10-22 2018-12-18 Havah Therapeutics Pty Ltd. Methods of reducing mammographic breast density and/or breast cancer risk
JP7269200B2 (ja) 2014-10-22 2023-05-08 ハバフ セラピューティクス ピーティーワイ エルティーディー マンモグラフィ乳房密度及び／又は乳癌リスクを低下させる方法
WO2016061615A1 (fr) * 2014-10-22 2016-04-28 Chavah Pty Ltd Procédé de réduction de densité mammaire monographique et/ou de risque de cancer du sein
CN107405353B (zh) * 2014-10-22 2021-07-30 哈瓦赫治疗有限公司 降低乳房摄影乳腺密度和/或乳腺癌风险的方法
US9351977B2 (en) 2014-10-22 2016-05-31 Chavah Pty Ltd. Methods of reducing mammographic breast density and/or breast cancer risk
JP2020183394A (ja) * 2014-10-22 2020-11-12 ハバフ セラピューティクス ピーティーワイ エルティーディー マンモグラフィ乳房密度及び／又は乳癌リスクを低下させる方法
AU2015336929B2 (en) * 2014-10-22 2021-03-18 Havah Therapeutics Pty Ltd Methods of reducing mammographic breast density and/or breast cancer risk
US11040044B2 (en) 2014-10-22 2021-06-22 Havah Therapeutics Pty Ltd. Methods of reducing mammographic breast density and/or breast cancer risk
WO2017066827A1 (fr) * 2015-10-22 2017-04-27 Havah Therapeutics Pty Ltd Procédés de réduction de la densité mammaire à la mammographie et/ou du risque de cancer du sein
CN108472302A (zh) * 2015-10-22 2018-08-31 哈瓦赫治疗有限公司 降低乳房摄影乳腺密度和/或乳腺癌风险的方法
US10471073B2 (en) * 2016-04-19 2019-11-12 Havah Therapeutics Pty Ltd. Methods of reducing mammographic breast density and/or breast cancer risk
US11524014B2 (en) 2019-06-03 2022-12-13 Havah Therapeutics Pty Ltd. Pharmaceutical formulations and systems for delivery of an androgenic agent and an aromatase inhibitor with sustained multi-phasic release profiles and methods of use
CN117257994A (zh) * 2023-11-21 2023-12-22 北京大学人民医院 动物模型的构建方法及应用
CN117257994B (zh) * 2023-11-21 2024-03-01 北京大学人民医院 动物模型的构建方法及应用

Similar Documents

Publication Publication Date Title
Padhani et al. METastasis reporting and data system for prostate cancer: practical guidelines for acquisition, interpretation, and reporting of whole-body magnetic resonance imaging-based evaluations of multiorgan involvement in advanced prostate cancer
Padhani et al. Rationale for modernising imaging in advanced prostate cancer
Harvey et al. Quantitative assessment of mammographic breast density: relationship with breast cancer risk
Closmann et al. The use of cone beam computed tomography as an aid in evaluating and treatment planning for mandibular cancer
Borson-Chazot et al. Guidelines for the management of differentiated thyroid carcinomas of vesicular origin: recommandations pour la prise en charge des cancers thyroïdiens différenciés de souche vésiculaire
Gombos et al. Intraoperative supine breast MR imaging to quantify tumor deformation and detection of residual breast cancer: preliminary results
WO2009036566A1 (fr) Procédés pour détecter des anomalies dans le tissu mammaire à l'aide d'inhibiteurs de l'aromatase
Di Maggio State of the art of current modalities for the diagnosis of breast lesions
Crecco et al. Retromolar trigone tumors: evaluation by magnetic resonance imaging and correlation with pathological data
Wu et al. Retroperitoneal neoplasms within the perirenal space in infants and children: differentiation of renal and non-renal origin in enhanced CT images
Schäfgen et al. Evaluation of the FUSION-X-US-II prototype to combine automated breast ultrasound and tomosynthesis
Tziakouri et al. Value of ultrasonography, CT and MR imaging in the diagnosis of primary hyperparathyroidism
de Ru et al. The location of parotid gland tumors in relation to the facial nerve on magnetic resonance images and computed tomography scans
Mousa et al. Aromatase inhibitors and mammographic breast density in postmenopausal women receiving hormone therapy
Hatzipanagiotou et al. Feasibility of ABUS as an alternative to handheld ultrasound for response control in neoadjuvant breast cancer treatment
Taketomi et al. Solitary neurofibroma of the hard palate: A case report and literature review
Surana et al. Radio-Morphometric Analysis of Sella Turcica in Relation to Age and Gender in Sri Ganganagar Population: A Prospective Cephalometric Study
Dresel et al. [18 F] FDG imaging of head and neck tumours: comparison of hybrid PET and morphological methods
Gamba et al. Keratocystic odontogenic tumor: role of cone beam computed tomography and magnetic resonance imaging
Slieker et al. Detecting bone invasion of the maxilla by oral squamous cell carcinoma: diagnostic accuracy of preoperative computed tomography versus magnetic resonance imaging
Turlakow et al. Local detection of prostate cancer by positron emission tomography with 2-fluorodeoxylglucose: Comparison of filtered back projection and iterative reconstruction with segmented attenuation correction
Diamanti-Kandarakis et al. Brown tumor of the fibula: unusual presentation of an uncommon manifestation. Report of a case and review of the literature
Yücesoy et al. Conventional galactography and MR contrast galactography for diagnosing nipple discharge: preliminary results
Liu et al. Dental implant in anterior mandible according to mandibular lingual foramens and lingual mucosal vessels: using fusion volumetric images from computed tomography and magnetic resonance imaging
Gil-Arnaiz et al. Skull metastasis from rectal gastrointestinal stromal tumours

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08800352

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08800352

Country of ref document: EP

Kind code of ref document: A1