Metastatic Liver Carcinoma Research Articles

A prospective evaluation of the treatment of primary or metastatic liver carcinoma with hepatic arterial infusion chemotherapy.

The efficacy of hepatic arterial infusion chemotherapy (HAICT) in the treatment of primary or metastatic liver carcinoma was evaluated in 37 patients. The infusions were administered through a catheter that was placed in the hepatic artery, either surgically or by percutaneous puncture of the femoral artery. A complete response was observed in four patients. A partial response was observed in six patients and a minor response in another six. In nine patients the disease had stabilized, while a progression of the disease had developed in 12 patients. After a mean of 4.7 cycles per patient, the response rate (complete, partial and minor responses) was 43.2% and median survival 12.0 months. Seventeen Grade III toxicities were observed in a total of 174 cycles, but none of them were fatal. HAICT has demonstrated a successful palliation with minimal toxicity in patients with unresectable liver carcinoma.

経皮的深部凝固用電極を用いた肝悪性腫瘍に対する治療経験

The microwave coagulo-necrotic therapy with perctaneousmicrowave needle for deep lesion were performed in 7 tumor lesions of 4 patients. They were 2 hepatoceller carcinomas and 2 metastatic liver carcinomas. Each 7 lesions existed in inside from liver surface. At laparotomy, monopolar electrodes were inserted with an ultrasonic guide. One round of coagulation lasted for 30 seconds at 60w. Except for one patient (Esophageal cancer with liver metastasis), 3 patients are alive for 12-16 months. Almost of complications were not observed after this therapy. This method acts directly on tumors and is simple and safe. In this time, microwave coagulation for liver tumor were underwent, because of hepatic dysfunction, multiple liver tumor or absolute unresection of primary lesion. Therefore, it seems to expect as a useful means for regional treatment of tumors. But, through the repeated experience of various cases, we must decide the indication of this therapy.

Serum response factor enhances liver metastasis of colorectal carcinoma via alteration of the E-cadherin/β-catenin complex

Serum response factor (SRF) is a transcription factor that controls cell growth, differentiation, and tumor progression as well as muscle development and function. Reduced expression of cell adhesion molecules has been reported to be associated with tumor metastasis. The aim of this study was to evaluate the expression and a role of SRF in liver metastasis of primary colorectal carcinomas. We examined the expression of SRF, E-cadherin, and beta-catenin by the use of immunochemical staining in 43 cases as a set of primary colorectal carcinomas and liver metastases. We also examined the role of SRF in colorectal carcinoma by overexpression of SRF in a colon cancer cell line. In metastatic carcinoma surgical samples, there was a marked increased expression of SRF as compared to expression in primary colorectal carcinoma surgical samples (P<0.05). E-cadherin expression was significantly decreased in metastatic liver carcinoma samples as compared to primary colorectal carcinoma samples (P<0.001). Frequent nuclear translocation of beta-catenin protein in primary and metastatic carcinoma cells was observed. Overexpression of SRF in SW480 cells resulted in a decreased expression of E-cadherin and an increased expression of non-phosphorylated nuclear beta-catenin. Overexpression of SRF in colorectal carcinoma cells enhanced cell motility and invasiveness. These results indicate that overexpression of SRF in colorectal carcinoma cells is associated with modulation of E-cadherin/beta-catenin expression and may play an important role in colorectal cancer metastasis.

Preoperative and postoperative cytokines in patients with cancer.

Changes in tumor necrosis factor-alpha (TNF-alpha), interleukin-1 alpha (IL-1 alpha), interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), and granulocyte macrophage-colony-stimulating factor (GM-CSF) were investigated before and after operation in patients with hepatocellular carcinoma (HCC), metastatic liver carcinoma, and gastrointestinal carcinoma. Serum levels of TNF-alpha, IL-1 alpha, and IL-1 beta were high in patients with liver carcinoma (HCC and metastatic liver carcinoma) before operation in comparison with those of normal controls (P less than 0.01). In patients with gastrointestinal carcinoma, serum levels of cytokines, except those of TNF-alpha, were the same as in patients with liver carcinoma. The level of TNF-alpha in patients with gastrointestinal carcinoma was low compared with that in patients with liver carcinoma. Within 1 day after operation, the peak level of TNF-alpha was observed at 15 hours, IL-1 alpha at 18 hours, IL-1 beta at 21 hours, and IL-6 at 24 hours after operation. Subsequently, these cytokine levels peaked again: TNF-alpha at 48 hours, IL-1 alpha at 72 hours, IL-1 beta at 120 hours, and IL-6 at 168 hours after operation. GM-CSF levels increased gradually after operation. Moreover, in HCC, serum levels of TNF-alpha were high in patients with recurrence compared with those without recurrence (P less than 0.01). The difference in IL-1 alpha and IL-1 beta levels between patients with recurrence and those without recurrence can be regarded as significant (P less than 0.01). These results suggest that TNF-alpha, IL-1, IL-6, and GM-CSF may play an important role in the pathogenesis of cancers; TNF-alpha may be especially important as a tumor marker in HCC and metastatic liver carcinoma.

Thomsen-Friedenreich (t)-active glycoproteins, blood group N antigen precursor glycoproteins and N antigen precursor glycoproteins with T activity from ascitic fluids of liver cancer patients

1. 1. Five perchloric acid-soluble fractions (PASFs) obtained from ascitic fluids of three patients with primary hepatocellular carcinoma (HCC), a patient with liver metastatic carcinoma (LUC) from ureteral carcinoma and human normal serum (NS) were subjected to DEAE-cellulose column chromatography to separate seven glycoprotein fractions, respectively. 2. 2. In this chromatography, two HCC-PASFs gave a Thomsen-Friedenreich (T)-active glycoprotein, respectively. 3. 3. Other HCC-PASF gave a T-active glycoprotein, two blood group N antigen precursor glycoproteins and an N antigen precursor glycoprotein with T activity. 4. 4. LUC-PASF gave two T-active glycoproteins and an N antigen precursor glycoprotein with T activity. 5. 5. NS-PASF did not give these serologically active glycoproteins.

Monoclonal Antibodies in the Treatment of Metastatic Carcinoma to the Liver

Thirteen patients with metastatic liver carcinoma were treated with hepatic irradiation, leukopheresis and monoclonal antibodies to test the tumoricidal effects of murine 17-1A immunoglobulin G (IgG) Mab. A significant increase in survival for this group of patients was identified.

Clinical evaluation of monoclonal antibodies against aldolase-a in the diagnosis of hepatocellular carcinoma

Serum ALD-A of 57 patients with HCC and 43 of other diseases were measured by ALD-A-McAb linked with125I-staphylococcus A protein. The results showed that the ALD-A in patient with HCC was significantly elevated as compared with controls and that in patients with cholangiocarcinoma, gastrointestinal cancer without hepatic metastasis, cirrhosis, CAH and benign GI diseases. There was no statistical difference between ALD-A in patients with HCC and that in cases of cirrhosis with liver failure and that in cases of metastatic liver carcinoma. It was noted that diagnostic sensitivity of ALD-A in AFP (+) HCC was 73.9% and that in AFP (−) HCC was 81.8% 1–6 patients with HCC were treated by hepatic arterial embolization combined with chemotherapy. ALD-A in patients after the treatment decreased significantly than that before treatment, furthermore, advantages of the method are discussed.

水素ガスクリアランス法による肝組織血流量測定 実験的ならびに臨床的研究

In this study, the author intended to examine the validity of the inhaled hydrogen gas clearance method (i-H2) for determination of the hepatic blood flow (HBF), and also to show some applicabilities of the method in experimental animals and patients with liver diseases. Simultaneous determinations of HBF by i-H2 and electromagnetic flowmetry in rabbits revealed an excellent correlation between the values obtained by the two methods. Moreover, HBF in rabbits measured by i-H2 varied in parallel with that by thermocouple flowmetry or laser Doppler velocimetry after administration of norepinephrine, propranolol or glucagon. In carbon tetrachloride-treated rats, HBF measured by i-H2 correlated better with the severity of damage in the sinusoidal structure than the severity of hepatic cell injury or the serum levels of transaminases. HBF as determined by i-H2 was significantly decreased in acute hepatitis (AH), chronic inactive hepatitis (CIH), chronic active hepatitis (CAH), liver cirrhosis (LC) and fatty liver. Reduced HBF in AH returned to normal during recovery of the disease. The ratio of HBF in tumor/normal tissue was greater than 1.0 for hepatocellular carcinoma in contrast to the ratio of less than 1.0 for metastatic liver carcinoma. Propranolol caused a decrease in HBF by 31%, and vasopressin by 39% in patients with CIH or LC. In contrast, glucagon induced its increase by 65%, 35% and 17%, respectively, in patients with CIH, AH and LC.

Specific diagnosis of hepatocellular carcinoma by delayed hepatobiliary imaging

For assessment of the value of delayed hepatobiliary imaging with technetium 99m (99mTc)-(Sn)-N-pyridoxyl-5-methyltryptophan (99mTc-PMT) for specific diagnosis of hepatocellular carcinoma, 88 patients with various malignant and benign liver diseases (49 with hepatocellular carcinoma, 4 with cholangiocellular carcinoma, 10 with metastatic liver carcinoma, 2 with liver cysts, 2 with liver hemangioma, 1 with liver abscess, 2 with intrahepatic lithiasis, 12 with liver cirrhosis, and 6 with chronic hepatitis) were studied. In 20 (41%) of the 49 patients with hepatocellular carcinoma, greater uptake of 99mTc-PMT by the tumor than by the surrounding liver tissue was seen in delayed hepatobiliary images, whereas in eight patients (16%), equilibrated uptake was seen. No increased uptake of the radioisotope by hepatic lesions was seen in 21 patients with localized liver diseases other than hepatoma. Moreover, in 18 patients with diffuse liver diseases, no focal accumulation of the radioisotope was seen in delayed 99mTc-PMT images. In addition, of 28 patients with hepatocellular carcinoma in whom the serum alpha-fetoprotein level showed little or no increase, 12 showed increased uptake of 99mTc-PMT by the tumor. In assessing delayed 99mTc-PMT images, however, it was necessary to consider following complications: accumulation of tracer in obstructed and dilated biliary trees; retention of radioactivity in nonneoplastic liver tissues; difficulties in evaluating 99mTc-PMT uptake by small hepatic tumors; overlapping of radioactivity in the gut and gallbladder in delayed 99mTc-PMT images of tumors. This study indicates that delayed 99mTc-PMT images can be useful in the diagnosis of hepatocellular carcinoma.

Hepatic resection in 125 patients.

Hepatic resection was performed in 125 patients. Ninety-three of the 125 patients had malignant neoplasms; primary liver carcinoma in 61, metastatic liver carcinoma in 15, carcinoma of the bifurcation of the hepatic ducts in 16, and carcinoma of the gallbladder in one. Performance of hepatic resection was complicated by the presence of liver cirrhosis and jaundice in 42 and 19 patients, respectively. Nine of the 125 patients died within 30 days of the operations, with an operative mortality of 7.2%. Eight of the nine deaths were due to liver failure in the cirrhotic patients who underwent resection of more than two segments of the liver. None of the jaundiced patients died postoperatively. The three-year actuarial survival rates of the patients with hepatocellular carcinoma, metastatic liver carcinoma, and carcinoma of the bifurcation of the hepatic ducts were 31%, 56%, and 21% respectively.

Serum alpha-L-fucosidase: a new marker for the diagnosis of primary hepatic carcinoma?

alpha-L-fucosidase, a lysosomal enzyme which catabolizes fucoproteins, was studied in sera from 30 controls, 32 patients with primary hepatic carcinomas, 24 patients with secondary metastatic liver carcinomas and 36 patients with cirrhosis. Serum alpha-L-fucosidase was increased in primary hepatic carcinomas (145.5 +/- 12 nkat per liter) with a high statistical significance versus controls (51.4 +/- 4.5 - p less than 10(-7], secondary metastatic liver carcinomas (58.9 +/- 6.4 - p less than 10(-5] and cirrhotics (71.3 +/- 6 - p less than 10(-5). A level exceeding 110 was a useful marker for the diagnosis of primary hepatic carcinoma with 75% sensitivity and 90% specificity.

Hepatic arterial chemotherapy and occlusion for palliation of primary hepatocellular and unknown primary neoplasms in the liver.

Eighteen patients with malignant liver disease were treated with hepatic arterial infusion (HAI) of floxuridine (FUDR), Adriamycin (doxorubicin), and mitomycin C (FUDRAM). Twelve of the patients had primary hepatocellular carcinoma and six had metastatic liver carcinoma originating from an unknown primary site. One complete remission and seven partial remissions (greater than or equal to 50% reduction in tumor size) were observed among 12 hepatocellular cancer patients, while only one partial remission was achieved among six patients with unknown primary liver neoplasms. When arterial occlusion was added to HAI of FUDRAM, a prolongation of median survival to 14 months as opposed to six months in patients with an intact arterial tree was observed (P = 0.02). Arterial occlusion had its effect on survival particularly among patients who failed to respond to HAI of FUDRAM. Thus, among nonresponding patients, the addition of arterial occlusion resulted in a median survival of 10.5 months while median survival in those without arterial occlusion was six months (P = 0.08). With procedure-related morbidity being minimal, we conclude that arterially administered FUDRAM offers a notable palliation to patients with primary hepatocellular carcinoma. In patients with unknown primary liver neoplasms and those with hepatocellular cancer who fail HAI of FUDRAM, arterial occlusion can offer additional palliation.

Aldolase A Isoenzyme Levels in Serum and Tissues of Patients With Liver Diseases

A radioimmunoassay specific for human aldolase A was used to measure human aldolase A levels in human tissue and serum of patients with various liver diseases. The method was a double-antibody technique using radio-iodinated purified aldolase A, chicken antibody to aldolase A, and rabbit antibody to chicken immunoglobulin G. Normal liver tissue contains only a small amount of aldolase A. In contrast, aldolase A predominates in liver cell carcinoma tissue. Aldolase A levels in the sera of normal subjects were 171 +/- 39 ng/ml (mean +/- 2 SD). In almost all of the nonmalignant liver diseases, the aldolase A levels remained less than 210 ng/ml. The serum aldolase A levels increased remarkable only in fulminant hepatitis. in contrast, 32 of 34 patients with liver cell carcinoma and all of 29 patients with metastatic liver carcinoma showed clearly increased serum aldolase A levels. More patients with primary liver cell carcinoma had increased serum aldolase A levels than elevations of serum alpha-fetoprotein. These results suggest that the determination of aldolase A by radioimmunoassay may be useful to differentiate malignant form nonmalignant liver diseases.

A Comparative Diagnostic Study of Malignant Lesions of the Liver by Infusion Angiography and Percutaneous Transhepatic Portography

The diagnostic effectiveness of percutaneous transhepatic portography (PTP) was evaluated in 21 patients with primary and metastatic liver carcinoma, who also had infusion hepatic angiography. The findings at PTP were compared with unequivocal tumor changes demonstrated at infusion hepatic angiography in all cases. PTP revealed tumors in 14 of 21 cases. The location, size and number of the tumor(s) were decisive for their detectability at PTP. Solitary lesions smaller than 2 cm in the central parts of the liver escaped detection, whereas lesions larger than 7 cm in the left lobe and 6 cm in the right lobe were demonstrated in all cases. Multiple metastases of 1--2 cm were detected in most cases. Lesions smaller than 4 cm were better shown by the sinusoidal phase at PTP, where lesions larger than 5 cm were better delineated by the portal venous phase.

Serum glutamic oxalacetic transaminase/glutamic pyruvic transaminase ratios in hepatocellular carcinoma

Serum enzyme activities were studied in 131 cases of hepatocellular carcinoma (HCC), 76 cases of metastatic liver carcinomas (MLC) and 234 cases of hepatic cirrhosis. SGOT was elevated above SGPT in most of the time in these patients, SGOT/SGPT was greater in HCC compared with other groups, and that this ratio increased during the preterminal period more markedly in patients with HCC because of the significant increase of SGOT in the face of relatively stable SGPT. Preterminal rises of alkaline phosphatase and LDH activities were more pronounced in MLC. Leucine aminopeptidase activity exhibited no characteristic feature of diagnostic value. Of the five enzymes, SGOT changes were more closely correlated with the growth of HCC; SGPT reflected more of the liver parenchymal damage while SGOT was probably accounted for in part by tumor-derived GOT. Other clinical and pathological implications are discussed.

Intrahepatic arterial infusion of combination of mitomycin-C and 5-fluorouracil in treatment of primary and metastatic liver carcinoma

Improvement in drug response and reduction of toxicity were observed after continuous intrahepatic arterial infusion of mytomycin-C (MMC) and 5-fluorouracil (5-FU) in 15 of 26 patients with primary or metastatic carcinoma of the liver. Serum bilirubin values of 10 mg/100 ml absence of ascites, extreme cachexia and impending hepatic failure were used as the criteria for admission of these patients into the study. The patients were given MMC in a dose of 0.08 mg/kg on day 1,5-FU in a dose of 8-10 mg/kg on days 2-5, and MMC on day 6. This schedule was reinitiated on days 8 and 15 for total mean duration of 18 days. Maintenance therapy was carried out by the administration of these drugs at induction dosage alternated each week as a single 24 hourly intravenous infusion. Objective response to combination therapy was defined as decrease of at least 50% in the liver size and in the abnormal levels of serum alkaline phosphatase and glutamic oxaloacetic transaminase (SGOT), and near normal levels of serum bilirubin for a minimum period of 2 months. The duration of objective response ranged from 3-16 months with a median of 8.2 months. The median survival time for the responders was 7.2 months for patients with primary carcinoma and 9.4 months for patients with metastatic carcinoma of the liver as compared to 2 months for patients who failed to respond to the treatment. Five out of 12 patients who were refractory to MMC or 5-FU by intravenous infusion responded to the present combination drug therapy. Of four patients who died during induction therapy, three had liver failure and the fourth suffered pulmonary embolism. These studies provide evidence that combination therapy with MMC and 5-FU increases the survival time of patients with hepatic cancer, presumably due to the synergistic action of these drugs which permits the use of a low dosage schedule and has less toxic effects.

Localized submassive liver cell necrosis as a terminal event of liver carcinoma

Six cases of hepatocellular carcinoma (HCC) and one case of metastatic liver carcinoma in which SGOT, SGPT, and SLDH were suddenly and markedly elevated immediately before death are described. All had a large blood loss and systemic hypotension in the preterminal period; autopsy disclosed irregularly shaped, patchy necrotic areas or infarcts, often clearly demarcated by hemorrhagic rims, in the noncancerous liver parenchyma. Tumor growths in the intrahepatic portal branches were extensive in all six cases with HCC; in the metastatic case, invasion and narrowing of the portal branches were extensive. The incidence of this terminal catastrophe was 3.3% (6 of 184 cases) for HCC and 1.15% (1 of 87) for metastatic carcinoma. The terminal liver necrosis was probably a result of sudden reduction in portal perfusion which had been inadequate because of tumor thrombosis, combined with hypotension of hepatic arteries.

A new technique for in situ hepatic isolation and perfusion in the rabbit

A method for isolation and in situ perfusion of rabbit liver is presented which allows for the separation of hepatic and systemic circulation without requiring shunting of inferior vena caval blood around the liver, via an extracorporeal bypass. In the present procedure caval circulation is shunted intracorporeally through the liver by a specially designed double lumen catheter, having an occlusive balloon attachment. The catheter is inserted into the inferior vena cava and passed through the liver so that the occlusive balloon attachment is just past the emptying of the hepatic veins. Perforations in the outer lumen at the junction of the renal veins allow for shunting of blood from the vena cava through the liver and to the right atrium. When the system is in operation inflation of the balloon attachment prevents mixing of caval and hepatic circulation. Vena caval circulation is shunted through the bypass catheter while hepatic venous effluent surrounds the bypass catheter and is collected through a small catheter situated at the emptying of the hepatic veins. This catheter passes through the inner lumen of the bypass catheter and exits independently. Good perfusion flow rates were obtained and the metabolic status of the liver was well maintained. The present in situ isolated perfusion procedure provides a useful technique for the study of liver metabolic processes. When the normal circulatory relationships are restored liver-peripheral tissue interrelationships may be further studied. This technique may also be utilized in the administration of chemotherapeutic agents and other drugs in localized treatment of metastatic liver carcinoma and other hepatic disorders.

Eicosatrienoic acid ω9 in serum lipids of patients with hepatocellular carcinoma

Eicosatrienoic acid ω9 was detected in the serum lipids of patients with hepatocellular carcinoma. This unusual fatty acid was identified by argentation thin-layer chromatography followed by hydrogenation and a combination of gas—liquid chromatography and mass spectrometry of the trimethylsilyloxy derivatives of the methyl esters. The incidence of eicosatrienoic acid ω9-positive cases in serum lipids was 37.5% in hepatocellular carcinoma ( 9 24 ), while there were no eicosatrienoic acid ω9-positive cases in metastatic liver carcinoma ( 0 14 ), liver cirrhosis ( 0 10 ) or in healthy controls ( 0 105 ). Positive correlations were found between the presence of this fatty acid and α 1-fetoprotein in serum. In eicosatrienoic acid ω9-positive hepatocellular carcinoma, the limited distribution of eicosatrienoic acid cu9 to tumor tissue and serum was shown by the analysis of tissues of tumor, non-invasive cirrhotic liver, lung, spleen, heart muscle, skeletal muscle, adipose tissue, pancreas, intestine and serum. The possibility was discussed that eicosatrienoic acid ω9 is one of the metabolic products of hepatocellular carcinoma.

Chemotherapy for metastatic colorectal liver carcinoma by intra-aortic infusion

Over a 9-year period (1960–1968), 243 patients with liver metastases from colorectal carcinoma were treated by the continuous infusion of fluorouracil, methotrexate, cyclophosphamide, vinblastine, and vincristine, singly or in combination, into the aorta at a level above the celiac artery for a period of 14 days or longer. The common femoral, and on occasion the brachial, artery was percutaneously cannulated with the employment of an 18-gauge thin-wall needle through which was introduced a catheter, preferably teflon, and the distal catheter-tip critically positioned into the aorta as determined by fluorescein dye injection or, if necessary, by radiologic visualization. This study was designed to determine the response of metastatic liver carcinoma to the infusion of cytotoxic agents into the critical aortic level on the premise that total abdominal infusion is more effective than selective hepatic infusion because of the common presence of other intra-abdominal metastases and because the liver has two major arterial pathways (from the celiac and superior mesenteric arteries) with frequent variations. Eighty-eight (36.2%) of the 243 patients obtained an objective response of 6 to 30 months' duration. The median survival time of the responders with colon carcinoma was 12.0 months as opposed to 4.0 months for the non-responders. The rectal carcinoma responders had a median survival time of 12.2 and the non-responders 3.2 months. No major complications occurred. The minor complication rate was 9.1%. This simplified bedside procedure for liver and intra- abdominal drug infusion has produced significant clinical results without serious infusion complications or major adverse drug effects in the dosage regimens used. It has increased survival (the significant parameter for evaluation) threefold over that of the non-responders. This modality of chemotherapy can be utilized in the treatment of any metastatic liver neoplasm.