JP2005040606A - Hepatic perfusion separation method - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a hepatic perfusion separation method for increasing tumor/liver intake rate of artery dosage medicine. <P>SOLUTION: This blood vessel separation method for liver makes it possible to perform local treatment of a patient whose region causing metastasis to the liver cannot be surgically removed. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  This invention relates to a liver perfusion separation method for the treatment of liver metastases, and more particularly to a liver perfusion separation method with minimally invasive techniques.

  This application claims the benefit of US Provisional Application No. 60 / 488,163, Jul. 18, 2003.

  Liver perfusion separation (IHP) involves a method of complete isolation of liver blood vessels that allows local treatment of patients with unresectable liver metastases. Because the dose for most cytostatic compounds is limited by systemic toxicity, hepatic perfusion separations also allow drug administration in amounts that cause fatal complications when delivered systemically. In addition, effective anti-tumor compounds such as tumor necrosis factor (TNF) that cannot be administered systemically due to systemic toxicity can be used in the liver perfusion separation method.

  Since the development of the liver perfusion separation method (Non-patent Document 1), several types of clinical studies have been conducted. For example, Non-Patent Document 2, Non-Patent Document 3, Non-Patent Document 4, Non-Patent Document 5, Non-Patent Document 6, Non-Patent Document 7, Non-Patent Document 8, Non-Patent Document 9, Non-Patent Document 10, and Non-Patent Document Reference 11 is available. Recent studies, including liver perfusion separation with melphalan and tumor necrosis factor, refer to a response rate of up to 77% and a median survival of up to 27.7 months. In this regard, Non-Patent Document 4 and Non-Patent Document 9 are known.

  Treatment of 71 patients with colorectal cancer metastases by the inventors with liver perfusion separation combined with high-dose melphalan treatment resulted in a response rate of up to 60% and a median survival of up to 28.8 months. showed that. There is Non-Patent Document 11 on this point. These data indicate that liver perfusion separation is highly effective in treating colorectal cancer metastasis. Furthermore, promising results were obtained with liver perfusion separation for liver metastasis from uveal melanoma. This applies to Non-Patent Document 3.

  The current hepatic perfusion isolation method is a major drawback in that it is a demanding and technically difficult procedure, with significant morbidity and mortality, mainly related to the invasive nature of the surgical procedure. is there. Furthermore, this procedure produces non-repeatable adhesion tissue. The 1 hour treatment with liver perfusion separation combined with melphalan is already very effective, as shown by the high response rate in current studies such as Non-Patent Document 4 and Non-Patent Document 11, and so on. Repeated treatment with separation methods would be very attractive. This may increase antitumor response and survival. Development of a minimally invasive and repeatable liver perfusion separation method is needed to reduce the difficulty and perform the current liver perfusion separation method and expand the applicability of the liver perfusion separation method.

  One approach to minimally invasive liver perfusion isolation has been tried with Yorkshire pigs (60 kilograms) and the liver was isolated from the systemic circulatory system using a stented flap closure and a balloon catheter. As for the intrahepatic pressure, the blood flow through the liver is reversed during the liver perfusion separation method, that is, it flows in through the hepatic vein, flows out through the portal vein (PV), and negative pressure (suction pressure) into the portal vein. Was controlled by applying.

  Tests performed with varying blood pressure applied to the portal vein showed a clear relationship between suction pressure at the outflow site (PV), intrahepatic pressure, and systemic leakage of 99 technetium. A leak-free liver perfusion separation method was obtained in seven different experiments.

  The latest results from Phase 1 / Phase 2 studies, including surgical liver perfusion separation as a treatment for unresectable liver metastases, show good response rates: median and number of life expectancy at about 30 months 5 survivors were shown. Thus, liver perfusion separation using minimally invasive techniques can be performed in pigs where intrahepatic pressure is controlled. This technique can be used for human patients. However, since the liver perfusion separation method is invasive and technically difficult and is a non-repeatable and demanding procedure, a modification of the less invasive liver perfusion separation method is preferred.

SUMMARY OF THE INVENTION Current surgical hepatic perfusion separation methods require extensive surgical examination for the compression of the superior hepatic vena cava (SCV) and the insertion of a cannula into the intrahepatic vena cava (ICV). It takes a lot of time. Occlusion of the superior hepatic vena cava (SCV) due to occlusion of the stent graft flap and occlusion of the intrahepatic vena cava (ICV) with a balloon catheter alleviates some of the treatment time constraints. In addition, occlusion techniques with stent graft flaps and balloon catheters contribute to liver perfusion separation methods that eliminate leakage, are minimally invasive, and can ensure a flow rate comparable to known surgical liver perfusion separation procedures.

  Unfortunately, due to the presence of many collateral veins, complete vessel separation cannot be achieved even by occluding almost all of the liver vessels. An increase in intrahepatic pressure during the implementation of the liver perfusion separation inevitably results in unacceptable leakage from the isolated circulatory system through the collateral system to the systemic circulatory system. These collaterals can be easily ligated during the performance of surgical liver perfusion separation, but are clearly not easy with minimally invasive techniques.

  In order to achieve a leak-free minimally invasive liver perfusion separation method with the system and method of the present invention, intrahepatic pressure is controlled. Leakage into the systemic circulatory system via the liver subimmediate system can be prevented if the liver internal pressure is kept low. Applying negative pressure (suction pressure) to the outflow site helps to achieve the desired low intrahepatic pressure. An unpublished experiment by the present inventor has shown that the reverse flow of blood flow through a separated liver allows better control of the liver pressure compared to the normal perfusion direction. Therefore, the present invention reverses the blood flow through the separated liver (ie, flows in via the hepatic vein and flows out through the portal vein (PV)), and negative pressure (suction pressure) at the outflow site (PV). To control liver pressure. An additional benefit of reversing blood flow through the liver during the performance of liver perfusion separation is to increase the tumor / liver uptake of arterial drugs, which reduces liver toxicity associated with liver perfusion separation. There is a possibility to reduce. In this regard, Rothbarth J. et al., “Decreased liver intake of melphalan infused by arteries during hepatic perfusion in degenerative rats with liver tumor intake unaffected.” A medical journal, Vol. 303, pages 736 to 740, 2002, is known.

“Development of Liver Perfusion Separation Technology” by Osman R.K., New York State University Medical Journal, Volume 61, pages 3393 to 3397, 1961 "Phase I clinical and pharmacological evaluation of high-dose melphalan treatment for patients with liver metastasis from colorectal cancer" by Vahmeijer AL, et al. ~ 1546, 2000 "Phase 1 of the liver perfusion separation method used with or without melphalan in combination with tumor necrosis factor in patients with liver metastasis of eyeball melanoma, by Alexander HR et al. , Phase II study "Clinical Cancer Research Vol. 6, pages 3062-3070, 2000 “A liver perfusion separation method using melphalan and tumor necrosis factor for the metastasis of unresectable cancer to the liver” by Alexander HR et al., Clinical Oncology, Vol. 16 1479-1489, 1998 "Liver perfusion separation using mitomycin C / 5-FU: pharmacokinetic surgical method, clinical outcome" by Aigner KR, et al., Control Oncology, Vol. 29, pages 229-246. 1988 “High-temperature liver perfusion separation combined with chemotherapy for malignant liver” by Hafstrom LR et al., Surgical Oncology Vol. 3, pp. 103-108, 1994 Marinelli A. et al., “Liver Perfusion Separation Method Using Mitomycin C in Treatment of Metastasis of Colorectal Cancer to the Liver,” Japanese Journal of Clinical Oncology 26: 341-350, 1996 "First Experience and Technical Aspects of Liver Perfusion Separation for Extensive Metastasis of Liver" by Oldhafer K. J. et al., Surgical Research Vol. 123, pp. 622-631, 1998 Bartlett D.L. et al., “Liver Perfusion Separation for Unresectable Liver Metastasis from Colorectal Cancer,” Surgical Research Vol. 129, pp. 176-187, 2001 De Vries MR, et al. “Liver Perfusion Separation Using Tumor Necrosis Factor Alpha and Melphalan: Experimental Study on Phase 1 Data from Pigs and Humans” Cancer Research Latest Achievement Vol.147, pp.107-119, 1998 Rothbarth J. et al. "Liver perfusion separation combined with high-dose melphalan treatment for colorectal cancer metastasis to the liver" Submitted to Brown University Surgical Journal

  An object of the present invention is to provide a liver perfusion separation method in which the tumor / liver uptake rate of an arterial drug is increased.

  The invention according to claim 1 of the present invention is a liver perfusion separation method, wherein the step of separating the liver from the systemic circulation system, the step of controlling the internal pressure of the liver, and the injection of a chemotherapeutic agent for treating liver metastasis Including the step of performing.

  According to the present invention, it is possible to reverse the blood flow through the separated liver and to apply a negative pressure to the outflow site to control the internal pressure of the liver. Drugs that cannot be administered can be administered, and the effect of increasing the tumor / liver uptake rate of arterial drugs can be obtained.

  The above embodiments, other embodiments, aspects and advantages of the present invention will be better understood with reference to the appended claims and drawings.

  Surgical liver perfusion separation with melphalan, that is, treatment of liver metastases during complete blood separation, has proved effective in treating liver metastases in colorectal cancer. In accordance with the present invention, a minimally invasive and repeatable liver perfusion separation method has been developed to reduce the difficulty and perform the current liver perfusion separation method and to expand the applicability of the liver perfusion separation method. With liver perfusion separation using percutaneous balloon catheterization for pigs, the portal vein (PV) is surgically compressed and the liver is hypoxic via the hepatic artery (HA) using the hepatic vein for outflow. Perfusion is known. Van Ijken MG, et al., “Hypoxic liver perfusion separation using tumor catheter necrosis factor alpha, melphalan and mitomycin C using balloon catheter technology: Pharmacokinetics in pigs Journal of Surgical Society, Vol. 228, pages 763 to 770, 1998 is known.

  The present invention provides a unique method in which liver perfusion separation using extracorporeal vein-venous bypass is accomplished using balloon catheters and occlusive stent-grafts instead of extensive surgical examination. Thus, the method and apparatus used by this invention is another minimally invasive liver perfusion separation method. A leak-free liver perfusion separation method can be performed with the method of this invention by controlling the intrahepatic pressure. In order to achieve this control of intrahepatic pressure, the blood flow through the liver is reversed (ie, it flows in via the hepatic vein and flows out through the portal vein (PV)), and the negative pressure ( Apply suction pressure). Thus, the backflow of blood flow through the liver allows good blood pressure control in the liver. Blood pressure control in the liver helps to minimize drug leakage, i.e. ideally prevents drug leakage into the systemic circulatory system via the collateral system resulting from excessive pressure in the isolated circulatory system .

  The regurgitation of blood flow through the liver is different from the methods used in treatment by known surgical liver perfusion separation methods. The lack of vascular valves in the hepatic vein and portal vein allows for a short partial regurgitation of this blood flow. Liver function (AST: aspartate aminotransferase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, PNP: purine nucleoside phosphate adductase) and the amount of glutathione depend on the blood flowing through the liver. It was not significantly adversely affected by partial backflow. There is known a document by Compagnon P. et al. "Effect of hypothermic perfusion on rat liver function depending on the perfusion route" Transplantation Journal Vol. 72, pp. 606-614, 2001. Furthermore, non-physiological blood pressure changes can be prevented, such as intrahepatic pressure that can be controlled during the implementation of liver perfusion separation. Thus, the safety and efficacy of short-term reflux of blood flow through the liver is enhanced.

  Melphalan is injected into the hepatic artery (HA) during the performance of conventional surgical liver perfusion separation. When almost all liver tumors become arterial, reversing venous blood flow through the liver does not adversely affect tumor response or exposure to chemotherapy, ie, maintain antitumor efficacy It will be. This was confirmed in a study in rats that showed that tumor ingestion of arterial infused melphalan was independent of the direction of perfusion. Rothbarth J. et al., “Decrease in liver intake of melphalan injected into the arteries during liver perfusion in degenerative rats under conditions where liver tumor intake was not affected,” Journal of Pharmacology Experiments and Treatments, 303. A volume of 736 to 740, 2002 is known. Furthermore, the above research results showed that the intake in the liver was significantly reduced after partial reflux of blood flow. This outcome is probably due to the fact that only melphalan reaches the periportal region during reverse perfusion. Therefore, the regurgitation of blood flow combined with hepatic artery injection of a chemotherapeutic agent can reduce liver toxicity, even if there is a possibility that the liver intake of the cytostatic agent is decreased.

  The method of the present invention is ready for a Phase 1 study on patients. For the hepatic artery (HA) and portal vein (PV), a percutaneous method may be incorporated to achieve a fully percutaneous liver perfusion separation. Since these methods are well known in interventional radiology, percutaneous applications to the hepatic artery (HA) and portal vein (PV) in liver perfusion separation are also feasible and easily understood by those skilled in the art. And is expected to be legitimately evaluated. “Resecting unresectable liver metastases of colorectal cancer after percutaneous portal embolization” by Azoulay D. et al., Journal of Surgical Society, Vol. 231, pages 480-486, 2000; “Interventional Radiology” by Casteneda-Zuniga WR, et al., Published by Williams End Wilkins, Baltimore, Maryland, USA, 1991 is known.

  The experimental protocol related to liver isolation for treatment according to this invention was approved by the Leiden University Animal Research Committee. The approved experimental protocol used Dutch Yorkshire pigs weighing approximately 60 kilograms. General anesthesia was maintained with an oxygen / nitrogen dioxide (50/50) gas mixture containing 1% to 2% isoflurane (Isoflurane®). Breathing was facilitated by the muscle relaxant Pavlon® and the anesthetic agent Finadyne®.

  Each of the femoral artery and internal jugular vein was accessible via a small incision formed in the right inguinal region and neck of the pig. Following abdominal transection, the portal vein (PV) and the intrahepatic vena cava (ICV) were exposed. Prior to cannulation, pigs were heparinized with 3 mg heparin per kilogram body weight.

  As shown in FIG. 1A, all six devices in this experiment required liver perfusion separation to be provided with extracorporeal venous-venous bypass by ensuring liver isolation and venous return. Six devices include a surgically placed upper liver clamp (1a), an in-house balloon catheter (2) to occlude the intrahepatic vena cava (ICV), and stop the inflow to the liver and between the intestines Depressurized balloon catheter (3) for draining membrane outflow, catheter (4) for draining internal portal vein system, catheter (5) for draining outflow from lower limbs, systemic circulation from extracorporeal vein-venous bypass A catheter (6) that returns blood to the system was implemented. The hepatic artery (HA) was embolized with histoacryl®. In a phase 2 liver perfusion separation experiment, the surgically placed upper liver clamp (1a) has been replaced by a recoverable occlusive stent graft flap (1b) as shown in FIG. 1B. .

  Three catheters were placed in the portal system. That is, a decompression balloon catheter that stops the inflow to the liver and drains the mesenteric outflow (3) (manufactured by Terumo Cardiovascular System, Ann Arbor, Michigan, USA) French size 13), catheter for draining the internal portal vein system (4) (Cook, Amsterdam, Netherlands, 12F Sarquick) and blood pressure monitoring catheter (5) (Netherlands Rodin, heart pigtail, French size) 5). Contrary to the surgical introduction of catheter (3), catheters (4) and (5) were introduced by the Seldinger method. The splenic vein was ligated just before entering the portal vein body.

  For the intrahepatic vena cava (ICV), a large-diameter balloon catheter (2) that blocks physiological venous blood flow and provides inflow to the hepatic vein via a large lumen, close to the tail of the hepatic vein Occluded. A balloon catheter (2) (Boston Scientific, Maastricht, The Netherlands, French size 18) was surgically introduced into the intrahepatic vena cava (ICV) above the renal vein level.

  For the superior hepatic vena cava (SCV), from the cervical approach, it can be surgically compressed as shown in FIG. 1A or can be recovered as shown in FIG. Borg's JOME, Inc., French size 22, Wall Street with standard implants). In order to simplify the procedure and because the cannulation of the hepatic artery (HA) is insignificant for the purpose of the experiment, to achieve hypoperfusion with a balloon catheter, as is actually done in a clinical setting. Instead, the hepatic artery (HA) was occluded. For the common hepatic artery (HA), the proximal side is Histoacryl (registered trademark: Brown, Mersungen, Germany) and Lipiodol (registered trademark: Galebe Institute, Allnaisboa, France). Embolized with 3 ml of a 1: 1 mixture with. The splenic artery (not shown) was embolized in the same manner to prevent spleen congestion.

  The balloon catheter (2) in the intrahepatic vena cava (ICV) and the balloon catheter (3) in the portal vein (PV) are taken from two independent roller pumps (Cove / Stuckart, Munich, Germany, model 10-30-00). Respirator (10) (Cove VPCML oxygen generator, Cove Cardiovascular Company, Alberta, Colorado, USA). Mesenteric outflow catheter (3) and catheter (5) in the left femoral vein (Edwards Life Sciences LLC, LLC, Irvine, Calif., USA) (DIITF022L), French size 22) Was connected to a catheter (6) in the right axillary vein (Lifestream International, The Woodlands, Texas, USA 7326 perfusion cannula, French size 18) to establish an extracorporeal vein-venous bypass. A centrifugal pump (20) (Medtronic BIO-Medicus, Eden Prairie, Minn., USA) was used to assist venous-venous bypass and priming with 700 ml saline (0.9%).

  The perfusion medium consisted of the pooled intrahepatic blood and 700 ml of Gelofusion (registered trademark, Vifor medical SA, Sempach, Switzerland). Only materials appropriate for the patient were used. One skilled in the art should appreciate that all interventional radiology techniques can be guided by fluoroscopy (Best Philippe Medical Systems, The Netherlands, VV300 Plus).

All balloons were expanded after insertion. Once hemodynamic stability is ensured and maintained, a contrast agent (Gelebe Laboratories, Telebrix 350, Allnaisboa, France) is injected into the mesenteric bed and the separated liver perfusion separation segment The initial leakage was visually inspected. "Continuous Measurement of Leakage During Liver Perfusion Separation Using a Radiotracer", above and by Runia RD, et al., International Radio Application Society Journal B, Vol. 14, pp. 113-118, 1987 As described in detail in the yearly literature, 2 × 10 MBq mass number 99 technetium pertechnetate ( ^99m Tc) is added to the separation circulatory system to monitor the leakage of perfusate into the systemic circulatory system. The amount of radioactivity in both the systemic circulatory system and the separated circulatory system was then measured.

  In these experiments, as shown in FIG. 1A, the superior liver vena cava (SCV) was surgically compressed to eliminate room for leakage from this site. In order to achieve control of the liver pressure, the blood flow through the liver (L) is reversed (inflow through the intrahepatic vena cava (ICV) and out through the portal vein (PV)), negative pressure (suction Pressure) was applied to the portal vein (PV). The negative pressure was varied from 0 mmHg to 30 mmHg to monitor the effects of intraportal pressure during liver perfusion separation, display of intrahepatic pressure, and leakage of 99 technetium into the systemic circulatory system. The experiment was stopped after obtaining data from liver perfusion separation with surgical compression.

  After completing the first phase of the experiment, the second phase of the experiment was started with the same settings as shown in FIG. 1A. However, after confirming zero leakage in liver perfusion with mass 99 technetium and upward compression of the liver, the clamp (1a) was replaced with the occlusive stent graft flap (1b) of FIG. 1B. Subsequently, in order to confirm whether the occluding stent graft flap (1b) can occlude the upper liver vena cava (SCV) and whether hepatic pressure and leakage data can be obtained, mass 99 technetium Was administered at a second dose. In addition, to ascertain whether effective flushing can be achieved with the device and method according to the present invention, 2 liters of saline was applied to the liver for about 10 minutes after perfusion.

  Other experiments were conducted using pigs. One experiment is an ectopic inferior hepatic vein anatomy that does not involve cannulation of the intrahepatic vena cava (ICV) (ie, the intrahepatic vena cava (ICV) is blocked with half continuity). I stopped for a reason. In other experiments, all newly developed minimally invasive materials could be introduced without difficulty. The liver after separation from the systemic circulatory system was perfused at a flow rate of 300 ml / min. The venous-venous bypass flow rate ranged from 0.9 l / min to 1.6 l / min. The perfused pig was hemodynamically stable.

  Referring to FIG. 2, the first setting of the experiment (n = 4) showed that the balloon (2) occluded under the liver did not show any leakage as observed with contrast injection. When the upper liver vena cava (SCV) is surgically compressed so as not to leave room for leakage from the upper liver vena cava (SCV) (FIG. 1A), the blood pressure applied to the portal vein (PV) is changed. The test showed a clear relationship between the suction pressure at the outflow site and the internal portal pressure. As shown in FIG. 3, a negative pressure of 30 mmHg applied to the portal vein (PV) sufficiently reduced the internal portal pressure to an average of 2.4 mmHg (P <0.05). Experiments with such a configuration showed no leakage of liver perfusion in the experiment, but only when a negative pressure of 30 mmHg was applied to the portal vein (PV). Other negative pressure values, such as values between 25 mmHg and 35 mmHg, may be applied to the portal vein (PV), and those skilled in the art should appreciate that a negative pressure of 30 mmHg is most preferred. As a result, as shown in FIG. 4, the internal portal pressure, ie, the liver internal pressure, is kept low, whereas when no negative pressure is applied (FIG. 4), leakage occurs almost instantaneously. .

  In the second set of experiments, a surgically placed clamp (1a) that occludes the superior liver vena cava (SCV) was replaced with a retrievable occlusive stent-graft (1b) (FIG. 1B). The occlusive stent graft flap (1b) did not show any leakage, as can be seen with contrast injection (FIG. 5). As shown in FIG. 5, in the upper liver vena cava (SCV: thick arrow), no contrast agent is visible, indicating that there is no leakage that occurs via the stent graft flap for upper liver occlusion. It is shown. These series of experiments confirmed the data from the leak-free liver perfusion separation using the surgically placed clamp (1a) that occludes the superior liver vena cava (SCV), ie the first stage of the experiment. As shown in FIG. 6, almost ideal intrahepatic pressure and leakage data were obtained as produced by clamp (1a) (FIG. 4) with a recoverable occlusive stent graft flap. In any case, no significant leakage could be detected. Washing with physiological saline for 10 minutes eliminates almost all of the 99 technetium having a mass of separation (FIG. 6).

  As shown in FIG. 6, (I) the systemic circulatory system after the upper liver vena cava (SCV) is occluded with a clamp and mass 99 technetium is administered into the isolated circulatory system at a first dose. (II) replacing the clamp with a recoverable occlusive stent graft flap and dispersing 99 technetium in both the separate circulatory system and the systemic circulatory system at a first dose; III) Leakage into the systemic circulatory system after the upper hepatic vena cava (SCV) is occluded with a recoverable occlusive stent graft flap and at the same time 99 technetium is administered into the isolated circulatory system at a second dose (IV) After applying 2 liters of physiological saline to the liver for about 10 minutes, almost all mass 99 technetium is removed from the liver.

  As shown in FIG. 7, the diameter of the occlusion catheter for the intrahepatic vena cava (ICV) and the upper hepatic vena cava (SCV) placed in various veins ranges from 20 mm to 40 mm, The diameter of the portal vein (PV) catheter ranges from 15 mm to 25 mm. The length of the catheter for the upper hepatic vena cava (SCV) is in the range of 20 mm to 30 mm, whereas the length for the intrahepatic vena cava (ICV) is 80 mm for the portal vein (PV) The length of is 10 mm. The distance between the intrahepatic vena cava (ICV) catheter (2) and the clamp (1a) or stent graft flap (1b) is in the range of 8 mm to 12 mm. The flow rates in the various blood vessels range from a minimum value of 50 ml / min in the hepatic artery (HA) to a maximum value of 3000 ml / min in the femoral vein to the axillary vein bypass. Other figures relating to the invention are evident in the table of FIG.

  The hub design of any catheter or stent graft flap according to the present invention preferably does not limit the flow rate. The catheter is preferably resistant to chemotherapeutic agents. Early contraction is undesirable and standard percutaneous transcatheter angioplasty is acceptable. Since a heart-lung machine is used, high blood pressure should not be generated. Negative pressure is preferably applied to the portal vein site so as not to disrupt the catheter wall.

  While what is believed to be the most practical and preferred embodiment of this invention has been shown and described, it will be apparent to those skilled in the art that the starting point from the particular design and method described and shown in this specification is It should be suggested that it can be used without departing from the spirit of the invention. The present invention is not limited to the particular construction described and illustrated, but should be construed as consistent with all modifications that may fall within the scope of the appended claims.

Specific embodiments of the present invention are as follows.
(1) The method according to claim 1, wherein the step of controlling the intrahepatic pressure further includes a step of reversing a blood flow passing through the liver and a step of applying a negative pressure to the liver in the portal vein.
(2) The method according to embodiment (1), wherein the step of controlling intrahepatic pressure further comprises preventing the intrahepatic pressure from exceeding a physiological intrahepatic pressure level.
(3) The embodiment in which the step of reversing the blood flow through the liver further includes the step of causing inflow that occurs through the intrahepatic vena cava (ICV) and the step of causing outflow that occurs through the portal vein (PV). 2) The method described.
(4) Compressing the upper hepatic vena cava (SCV), occluding the intrahepatic vena cava, and combining the compression, occlusion and negative pressure to minimize blood leakage from the liver, thereby The method according to embodiment (3), further comprising the step of separating from the systemic circulatory system.
(5) The method according to embodiment (4), wherein the step of separating the liver from the systemic circulatory system includes the step of creating a venous-to-venous bypass of the systemic circulatory system using the compression, occlusion and negative pressure.

(6) The method according to embodiment (4), wherein the blockage of the intrahepatic vena cava further includes a step of placing a balloon catheter in the intrahepatic vena cava.
(7) The method according to embodiment (6), further comprising the step of occluding the upper liver vena cava at the compression site.
(8) The method according to embodiment (7), wherein the occlusion of the upper liver vena cava is constituted by occluding a stent-graft flap in the upper liver vena cava.
(9) The method according to embodiment (6), wherein the negative pressure applied to the portal vein is in the range of 25 to 35 mmHg, preferably 30 mmHg.
(10) The method according to embodiment (8), wherein the negative pressure applied to the portal vein is in the range of 25 to 35 mmHg, preferably 30 mmHg.

It is a schematic diagram which shows the 1st phase liver perfusion isolation | separation experiment for pigs. It is a schematic diagram which shows the obstruction | occlusion state of the stent graft flap by this invention. A cast cast of balloon catheter dilated in the intrahepatic vena cava (ICV: thick arrow) and portal vein (PV: thin arrow), and histoacryl (R) and Lipiodol (R) in the hepatic and splenic arteries It is a projection photograph which shows (arrow head). It is a graph which shows the internal portal pressure (± standard deviation) (n = 5) when the suction pressure is applied to the portal vein and when it is not applied. The statistical difference between the liver perfusion separation method when applied and the liver perfusion separation method when not applied is shown. The upper liver vena cava (SCV) is occluded by a surgically placed clamp, and it is detected that no mass 99 technetium has leaked into the systemic circulatory system when suction pressure is applied to the portal vein (PV). However, during an experiment in which a mass leakage of 99 technetium occurs when no suction pressure is applied to the portal vein (PV), 99 technetium counts / second in the isolated circulatory system (left Y axis) ) And 99 technetium counts / second (right Y axis) in the systemic circulatory system. FIG. 5 is a projected photograph showing the distal end of a retrievable occlusive stent graft flap (thin arrow) sealing the upper liver vena cava (SCV), with the hepatic vein and separated portion of the upper liver vena cava (SCV) up It shows a state filled with a contrast medium (thin arrow head) injected via a balloon catheter placed in the liver vena cava (SCV: thick arrow). In an experiment in which a surgically placed clamp occluding the superior hepatic vena cava (SCV) was replaced by a recoverable occlusive stent-graft, a mass count of 99 technetium / It is a graph which shows the count number / second of mass number 99 technetium in a second and a systemic circulation system. 4 is a table showing numerical values relating to balloon catheters according to the present invention, occluding stent-grafts and other aspects.

Explanation of symbols

1a surgical clamp 1b stent graft flap 2 balloon catheter 3 catheter 4 catheter 5 catheter 6 catheter 10 cardiopulmonary device 20 biomedical pump

Claims (1)

  A liver perfusion separation method comprising the steps of separating the liver from the systemic circulatory system, controlling the intrahepatic pressure, and injecting a chemotherapeutic agent to treat liver metastases.

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