PROCEDURE FOR THE ACQUISITION OF DATA FOR THE DETECTION OF ANGIOGENESIS IN LOWER LIMBS

Abstract

The invention relates to a method for obtaining useful data about the angiogenesis in a patient's lower limbs, and particularly in the lower limbs of patients with diabetes subjected to treatment.

Claims

1. A method for obtaining useful data about the angiogenesis in a patient's lower limbs after injecting a contrast agent in the patient, characterized in that it comprises the following steps: taking at least one time series of successive transverse slices in at least one position of the patient's limb by means of a CT scanner; obtaining a perfusion CT image corresponding to said at least one time series of successive transverse slices; selecting an analysis region in said at least one perfusion CT image; calculating the perfusion parameters BF and/or BV and PS corresponding to the analysis region selected in the preceding perfusion CT image; and comparing said calculated perfusion parameters with previously obtained perfusion parameters in order to determine if angiogenesis is taking place.

2. The method according to claim 1, where taking the time series of transverse slices starts between 13 seconds and 15 seconds after injecting the contrast agent.

3. The method according to claim 2, where taking the time series of transverse slices starts 14 seconds after injecting the contrast agent.

4. The method according to claim 1, were taking the time series of transverse slices comprises acquiring between 20 and 30 CT images during a total time of between 100 seconds and 150 seconds.

5. The method according to claim 4, where taking the time series of transverse slices comprises acquiring 25 CT images during a total time of 120 seconds.

6. The method according to claim 1, which comprises taking a plurality of time series of transverse slices corresponding to several positions along the patient's limb.

7. The method according to claim 1, where the selection of the analysis region is done by manually selecting the contour of said analysis region.

8. The method according to claim 1, where the selection of the analysis region is done automatically by selecting only those pixels the perfusion value of which is above a minimum threshold value.

9. The method according to claim 1, where the selection of the analysis region in a perfusion CT image corresponding to a slice position is extrapolated to the rest of the perfusion CT images corresponding to the rest of the slice positions.

10. The method according to claim 1, where the analysis region is split into an anterior portion essentially corresponding to the area of the tibial muscle and a posterior portion essentially corresponding to the area of the calf muscle and the soleus muscle.

11. The method according to claim 1, where an increase in BF and/or BV combined with an increase in PS is interpreted as being indicative of the presence of angiogenesis.

12. The method according to claim 1, where a decrease in BF and/or BV combined with a decrease in PS is interpreted as being indicative of the presence of necrosis.

13. The method according to claim 1, where a decrease in BF and/or BV combined with an increase in or lack of variation in PS is interpreted as being indicative of the presence of inflammation, granulation or early fibrosis.

14. The method according to claim 1, where a decrease in or lack of variation in BF and/or BV combined with a steep increase in PS is interpreted as being indicative of poor compartmentalization of the contrast agent.

15. The method according to claim 1, further comprising the step of calculating the perfusion parameter TTM corresponding to the analysis region selected in the perfusion CT image.

16. The method according to claim 15, where an improvement of at least two of the parameters BF, BV, PS and TTM is interpreted as being indicative of the presence of angiogenesis, improvement being defined as an increase of at least 5% for parameters BF, BV and PS and a decrease of at least 5% for parameter TTM.

17. The method according to claim 1, further comprising the step of calculating the number of blood vessels from the obtained perfusion CT image.

18. A computer program comprising program instructions for making a computer carry out the method according to claim 1.

19. The computer program according to claim 18, incorporated in storage media.

20. The computer program according to claim 18, supported in a carrier signal.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0054] FIGS. 1a-1e show a example of images obtained by means of conventional arteriography of the lower limbs according to the prior art, respectively corresponding to an early or initial arterial phase, an advanced arterial phase, a late arterial phase (precapillary), an early venous phase, and an advanced venous phase.

[0055] FIG. 2 shows the positions corresponding to 16 respective time series of transverse slices of a patient's lower limbs.

[0056] FIG. 3 shows an example of a raw image corresponding to a transverse slice of the lower limbs taken by means of a CT scanner.

[0057] FIG. 4 shows an example of a perfusion CT image corresponding to the preceding transverse slice, where a color code represents the blood perfusion value at each point.

PREFERRED EMBODIMENT OF THE INVENTION

[0058] An example of the method according to the present invention is described below in reference to the attached drawings. The study conducted to determine the relationship between the parameters BF, BV and PS and the onset or absence of angiogenesis is then described. Finally, several specific examples are described.

[0059] Method of the Invention

[0060] Positioning [0061] Firstly, a prior procedure aimed at precisely positioning the block of slices of the CT scan is performed to take transverse slices of the patient's lower limbs. To that end, once the patient is introduced in the CT gantry, the block of slices is centered on both legs and a planning scanogram is performed in a coronal plane that includes from the tibial plateau to the foot. In the obtained image, which is shown in FIG. 2, the distance existing between the lower end of the tibia (tibial condyle) and the upper end of the tibia (tibial plateau) is measured, and the block of slices is moved until being located at the midpoint between both. In this specific example the midpoint is taken as a reference because it is an area of the leg where there is a sufficient amount of soft tissue to perform the method of the invention. [0062] Once the position of the midpoint is determined, the block of slices can be located at several parallel positions along the patient's lower limb in order to take a number of series of transverse slices. In this example, 16 time series of transverse slices corresponding to the 16 positions shown in FIG. 2 will be performed.

[0063] Injection of the Contrast Agent [0064] The intravenous injection can be performed in an arm of the patient, for example using an automatic injector. The administered contrast agent will spread to the right heart cavities to subsequently return through the pulmonary veins to the left atrium and left ventricle. From here, the distribution of the contrast agent will be an arterial distribution to end up reaching the patient's lower limbs. [0065] More specifically, in this example 0.5 ml of iodinated contrast of 370 mg/mL per kg of the patient's weight are injected by intravenous route. Subsequently, 30 ml of physiological serum are injected. The injection is performed at a rate of 5 ml/s.

[0066] Taking CT Images [0067] The start of CT imaging is preferably performed with a delay of between 13 and 15 seconds in relation to the time of the injection of the contrast agent, more preferably 14 seconds. This delay specific has been determined through several tests with different patients to assure that the first CT image that is acquired is immediately prior to the arrival of the contrast agent to the patient's lower limb. Therefore each time series of transverse slices covers the times immediately prior to the arrival of the contrast agent and the tissue perfusion phase of the soft tissues in infrapopliteal region. [0068] As mentioned above, 16 time series of transverse slices corresponding to 16 different positions along the patient's lower limb are taken in this example. According to a preferred embodiment of the invention, each time series can comprise the acquisition of between 20 and 30 CT images for a total approximate time of between 100 seconds and 150 seconds. For example, in this case specific 25 CT images have been acquired during a total approximate time of 120 seconds. In other words, approximately one CT image has been acquired in each position every 5 seconds. [0069] The obtained CT images are similar to FIG. 3, in which a cross section of the different internal structures of the patient's lower limb can be seen. The patient's tibia and fibula are seen in a light color, almost white, the patient's soft tissues are seen in grey; and again, the contrast agent going through the patient's blood vessels can be seen in a light color, almost white. Each blood vessel is seen in this image almost as a point, which differs from the branched structure that was obtained while obtaining images of coronal slices according to the prior art. Actually, by taking a complete series of CT images in 120 seconds, the white points corresponding to the vessels would start to appear as the contrast agent reaches them and would fade away after a few seconds.

[0070] Obtaining Perfusion CT Images [0071] Based on each of the 16 time series of CT images obtained corresponding to each of the 16 positions, the necessary calculations for determining the blood perfusion value in each point of the image are performed. Starting from that information, an image like the one shown in FIG. 4, corresponding to a slice where the values of the perfusion obtained by the CT scan are represented through a color code, is built for each of the 16 time series. [0072] Due to the provisions of Patent Law November 1986 currently in force, FIG. 4 is shown in black and white, although it must be taken into account that in the original image the points where the perfusion is high are seen in red and the points with low perfusion are seen in blue. In this example, arrows indicate the position of the three most visible arteries in each limb, although it must be understood that the color image allows identifying arteries with even further clarity, because they are red colored areas immersed in a blue colored background. [0073] This operation results in obtaining 16 perfusion CT images similar to that of FIG. 4 corresponding to each of the 16 positions of the transverse slices, where each point of each image corresponds to the blood perfusion value in that point.

[0074] Calculation of the Parameters [0075] In this example, the parameters BF, BV, MTT and PS defined are calculated. To that end, the user must only select the analysis region in at least one of the 16 perfusion CT images obtained in the preceding step. The analysis region must include all the soft tissue of the patient's limb except the bones. The selection of the analysis region can preferably be done manually by the physician or user. Alternatively, the selection step can be performed automatically by means of a computer program. The selection of said analysis region is extrapolated to each of the 15 remaining images, and then the parameters BF, BV, MTT and PS corresponding to said analysis region are calculated.

[0076] Interpretation of the Obtained Values [0077] Finally, once the parameters BF, BV, MTT and PS have been calculated, the obtained values are compared with those that were obtained at another time, for example before starting treatment, which allows determining not only if angiogenesis has taken place, but also additional data helping to interpret what is happening in the tissue.

[0078] Study in Patients

[0079] The study was conducted in 11 patients in which the parameters BF, BV, MTT and PS were determined according to the described method. This process was carried out a first time before starting treatment (month 0) and a second time three months after treatment (month 3). Patterns in the variation of the parameters were evaluated taking into account the Rutherford-Becker classification.

[0080] The result was the following:

TABLE-US-00003 BF/BV (generally coupled) PS Interpretation ↑ ↑ Formation of new vessels (angiogenesis) with varying degrees of maturation ↓ ↓ Necrosis ↓  or ↑ Inflammation/granulation tissue/early fibrosis  or ↓ ↑↑ Poor compartmentalization of the contrast agent. Very immature vessels

Examples

[0081] A series of examples corresponding to the patients included in the described study are presented below. The calculated values of BF, BV, MTT and PS in month 0 and in month 3, as well as the conclusion reached according to the present method, are shown for each of them.

[0082] Patient 1

TABLE-US-00004 BF BV MTT PS Soft tissues Soft tissues Soft tissues Soft tissues Month 0 351 11.7 1.99 1.89 Month 3 360 14.9 6.54 1.88 Conclusion ↑ ↑ ↑ [0083] Since BF/BV increased and PS was maintained, it is concluded that angiogenesis exists. [0084] It is verified that this is consistent with an improvement in the clinical picture, with an increase in the ABI (Ankle-brachial Index) and the TcO2P (Transcutaneous Oxygen Pressure), and with an improvement in the Rutherford-Becker classification.

[0085] Patient 2 (Lower Right Limb)

TABLE-US-00005 BF BV MTT PS Soft tissues Soft tissues Soft tissues Soft tissues Month 0 7.52 0.816 16.4 2.10 Month 3 9.58 1.77 18.3 3.61 Conclusion ↑ ↑ ↑ ↑ [0086] Since the BF/BV increased and PS also increased, it is therefore determined that angiogenesis exists. [0087] It is verified that this is consistent with an improvement in the clinical picture, with an increase in ABI and TcO2P, and with an improvement in the Rutherford-Becker classification.

[0088] Patient 2 (Lower Left Limb)

TABLE-US-00006 BF BV MTT PS Soft tissues Soft tissues Soft tissues Soft tissues Month 0 7.03 0.800 19.2 1.35 Month 3 9.11 1.28 20.9 2.15 Conclusion ↑ ↑ ↑ ↑ [0089] Since the BF/BV increased and PS also increased, it is therefore determined that angiogenesis exists. [0090] It is verified that this is consistent with an improvement in the clinical picture, with an increase in ABI and TcO2P, and with an improvement in the Rutherford-Becker classification.

[0091] Patient 3

TABLE-US-00007 BF BV MTT PS Soft tissues Soft tissues Soft tissues Soft tissues Month 0 6.84 0.457 13.9 0.60 Month 3 5.09 0.378 12.7 0.791 Conclusion ↑ ↑ [0092] Since BF/BV decreased or were maintained and PS was maintained, it is therefore determined that angiogenesis does not exist. [0093] This is consistent with the need for subsequent amputation of this patient's limb.

Additional Examples

[0094] Additional examples are described below where the analysis region has been split into an anterior portion and an anterior portion, and where to assess the presence of angiogenesis an alternative method with respect to the method described above is used. In the following additional examples it is considered that there is presence of angiogenesis if an improvement of at least two of the parameters BF, BV, PS and TTM is observed, improvement being defined as an increase of at least 5% for parameters BF, BV and PS and a decrease of at least 5% for parameter TTM.

[0095] Patient 4 [0096] The data corresponding to the posterior and anterior areas of both legs of one and the same patient is shown below:

TABLE-US-00008 BF BV TTM PS Soft Soft tissues Soft tissues Soft tissues tissues LOWER RIGHT LIMB Posterior area 33.3 2.65 14.3 3.69 (initial) Posterior area 32.5 2.91 16.3 6.32 (final) Conclusion ↑ ↑ ↑ Anterior area 12.0 3.21 23.1 4.55 (initial) Anterior area 10.7 2.35 24.7 5.38 (final) Conclusion ↓ ↓ ↑ ↓ LOWER LEFT LIMB Posterior area 31.7 2.27 12.1 3.55 (initial) Posterior area 62.7 6.4 13.9 16.0 (final) Conclusion ↑ ↑ ↓ ↑ Anterior area 1.91 1.69 13.6 3.22 (initial) Anterior area 11.0 1.28 16.5 3.66 (final) Conclusion ↑ ↑ ↓ ↑ [0097] According to this data, it can be seen that in the posterior area of the lower right limb there was an improvement of two parameters, specifically parameters BV and PS. Therefore, it is interpreted that angiogenesis exists in this area. The same happens with both the anterior and posterior areas of the lower left limb, because an improvement in all the parameters can be seen.

[0098] Patient 5

TABLE-US-00009 LOWER LEFT BF BV TTM PS LIMB Soft tissues Soft tissues Soft tissues Soft tissues Posterior area 10.5 1.44 19.6 3.81 (initial) Posterior area 34.4 4.66 15.8 10.5 (final) Conclusion ↑ ↑ ↓ ↑ Anterior area 13.1 2.08 17.3 8.55 (initial) Anterior area 39.8 4.53 15.1 14.3 (final) Conclusion ↑ ↑ ↓ ↑ [0099] In view of this data, it is concluded that there is improvement in both the anterior and posterior areas of the patient's analyzed lower limb, because all the analyzed parameters have experienced improvement.