Ryoichi Kanashima

The natural history of hepatocellular carcinoma. A study of 100 untreated cases

The natural course of hepatocellular carcinoma (HCC) was evaluated in 100 untreated patients who were seen during recent 13 years. There were 80 males and 20 females. The macroscopic type of tumor was massive in 58, nodular in 35, and diffuse in 7 cases. Liver cirrhosis was associated with in 80% of patients. The mean survival time of overall patients was 4 months from the onset of initial symptoms to death and 2 months from admission to death. Occult and cirrhotic types of HCC showed a longer survival than frank and febrile types that had a mean survival time of all patients. The prognosis of icteric and metastatic types was poorest. Sex, tumor type, or associated cirrhosis did not substantially affect the natural course of HCC. The tumor stage and clinical stage were grossly correlated to the prognosis. In terms of symptoms, severe jaundice and ascites were the most dismal prognostic signs.

Effect of 5-fluorouracil on liver regeneration and metabolism after partial hepatectomy in the rat

The effects of 5‐fluorouracil (5‐FU) on regenerating liver were studied after two thirds hepatectomy in rats. In Group I, 68% hepatectomy was performed. In Group II, 5‐FU in a dose of 20 mg/kg was administered intravenously immediately after, 24 and 48 hours after the same hepatectomy. In Group III, the same amount of 5‐FU was given after sham‐operation. The mortality rates were 4.5% in Group I, 28.0% in Group II, and 0% in Group III. The treatment with 5‐FU following hepatectomy caused not only suppression but delay of liver cell division. Histologic changes such as cellular degeneration, liver steatosis and dilatation of the sinusoidal space were marked and prolonged in the hepatectomy‐5‐FU group. The metabolic abnormalities in albumin, cholesterol, triglycedides, and phospholipids were further more profound in Group II compared to those in Group I. In Group III, moderate derangements in albumin, triglycerides and phopholipids were observed. The results may indicate that adjuvant chemotherapy with 5‐FU or similar drugs immediately after partial hepatectomy in hepatoma patients should be performed with great care if necessary. Otherwise, it should not be carried out until hepatic regeneration is almost completed.

Effect of doxorubicin on liver regeneration and host survival after two–thirds hepatectomy in rats

The effects of doxorubicin (Adriamycin) on regenerating liver were studied after two‐thirds hepatectomy in rats. In Group I, standard two‐thirds hepatectomy was performed. Doxorubicin in a dose of 2 mg/kg (Group II) and 6 mg/kg (Group III) was given intravenously immediately after the same hepatectomy. In Group IV, 6 mg/kg doxorubicin was given after sham operation. Animal survival, body weight restoration, wet weight and mitotic activity of remnant livers, and serum albumin concentrations were examined 1–14 days after operation. The survival rates were 95.5% in Group I, 76.8% in Group II, 10.3% in Group III, and 96.7% in Group IV. Although there were no differences in the residual liver weights among the hepatectomized groups, treatment with doxorubicin induced substantial, dose‐dependent suppression and delay of liver cell division. Serum albumin levels dropped considerably in hepatectomized, doxorubicin‐treated rats. Light microscopy showed degenerative changes with a single cell necrosis of hepatocytes in Group III. Death among rats hepatectomized and treated with doxorubicin was considered to be mainly due to the failure of residual livers since albumin synthesis was impaired and no marked changes were seen in vital organs other than the liver. For patients with hepatoma, the present results may indicate that the administration of adjuvant chemotherapy with doxorubicin, when necessary immediately after hepatectomy, should be performed with great care. In the absence of such necessity, doxorubicin should be withheld until life‐sustaining liver regeneration has taken place.

Serum alpha-fetoprotein in patients following partial hepatectomy

Serum alpha-fetoprotein (AFP) concentrations were estimated postoperatively at weekly intervals with the radioimmunoassay in eight adult patients. Seven patients underwent partial hepatectomies of up to 80% of the liver. Surgical drainage was carried out in one individual who had a huge pyogenic abscess in the right hepatic lobe. Despite evidence of clinical and biochemical recovery associated with normal liver regeneration, none of the sera were positive for AFP during the period 4–12 weeks after operation. This study does not support the hypothesis that the elevation of serum AFP in benign liver diseases reflects the extent of liver regeneration.

Ranitidine as an inhibitor of liver regeneration

The effects of ranitidine, a new H2-receptor antagonist, on liver regeneration were investigated using a protocol described previously. The animals in Group I had standard two-thirds hepatectomy. In Group II, the rats received an 8 mg/kg intramuscular dose of ranitidine immediately and 24 and 48 hours after two-thirds hepatectomy. In Group III, the rats had the same amounts of ranitidine after a sham operation. Mortality rate, liver weight restoration, mitotic activities of the residual livers, and serum levels of aminotransferases were examined from 24 hours to 14 days after operation. The mortality was very high in Group II (45 percent), whereas no rats died in Group I, and only 1 of 35 animals died in Group III. Administration of ranitidine after hepatectomy resulted in suppression not only of liver restoration, but also of the mitotic activities of hepatocytes. The serum aminotransferase levels in Group II had a tendency to increase after hepatectomy, compared with the levels in Group I. Using light microscopy, we detected that the hepatectomized group treated with ranitidine (Group II) underwent profound liver steatosis and marked dilatation of sinusoidal spaces. The present and previous observations by us indicate that ranitidine also inhibits, like cimetidine, liver regeneration after hepatectomy. The causes of the inhibitory effects of both cimetidine and ranitidine on hepatocyte cell division have also been discussed herein.

Serum activities of lysosomal enzymes in patients with liver cell carcinoma.

Serum activities of two lysosomal enzymes, β-glucuronidase and acid phosphatase, were estimated in 66 patients with liver cell carcinoma, 10 with secondary liver cancer, 14 with cirrhosis of the liver, and 9 normal controls. A substantial increase in the enzyme activities was found in patients with liver cell carcinoma but not in those with secondary liver cancer. The degree of the enzyme elevations paralleled the stage of hepatoma. Although the serum activities of both enzymes were also elevated in patients with liver cirrhosis, the elevations were significantly higher in hepatoma than in liver cirrhosis. Possible mechanisms for the elevation of serum lysosomal enzyme activities in hepatoma are discussed, but further studies are necessary to elucidate the biological and clinicopathological significance of estimating serum lysosomal acid hydrolases in patients with primary liver cell carcinoma.

Platelet aggregability after splenectomy in patients with normosplenism and hypersplenism

The relationship between platelet count and aggregability was serially evaluated after splenectomy in patients with normosplenism and hypersplenism, and the results were compared with those found in patients undergoing only upper abdominal surgery. The preoperative count and aggregability of platelets were significantly suppressed in patients with cirrhosis of the liver, idiopathic portal hypertension, and prehepatic portal obstruction. However, the platelet aggregability of these patients markedly increased in accordance with the platelet counts after splenectomy. In the patients with normal splenic function preoperatively, splenectomy caused a simultaneous increase in platelet count and aggregability. The platelet function was not always reflected by the count in the patients with idiopathic thrombocytopenic purpura. On the other hand, in the control patients undergoing only laparatomy the platelet count substantially increased two weeks after operation, but platelet aggregability did not differ from the preoperative value. The present results suggest that additional factors for thromboembolism such as hypotension, acidosis, or stagnant blood flow should be avoided during the peak period of reactive thrombocytosis after splenectomy, and that an appropriate use of anticoagulants or inhibitors of platelet aggregation is recommended if and when necessary.

Tumor embolism in the right atrium after hepatic artery ligation for hepatoma.

A case of tumor embolism in the right atrium after hepatic artery ligation for hepatoma was reported. Patient was a 55 year old male complaining of upper abdominal pain. Preoperative angiogram and scintigram revealed multinodular hepatomas in the right and middle lobes of the liver. During the first week after the ligation of the right and middle hepatic arteries, the patient progressed satisfactorily. But his condition gradually deteriorated thereafter and sudden hypotension occurred on the 22nd postoperative day with a fatal sequela. At autopsy, the orifice of the right atrium was impacted by a tumor embolus. The cause of death seemed to be attributable to this embolus liberated from the hepatic veins. Accordingly, we emphasize the necessity of careful angiographic evaluation not only of the hepatic inflow but of the outflow tract in performing hepatic artery ligation as a treatment of nonresectable hepatoma.

Remnant liver function during surgery for extensive hepatic resection

True functional reserve of remnant liver should be determined at the same condition that contemplated hepatectomy has been performed, and this condition can be achieved before resection by temporary lamping of the inflow vessels of hepatic lobes to be removed. Using indocyanine green (ICG), the remnant liver function (RLF) was evaluated whether or not the method can be a useful indicator for or against hepatomy. In the study of healthy dogs, the RLF proved to be a reliable indicator to prospect hepatic failure which may occur after extensive resection of the liver. Then, the method was employed in nine patients who underwent 40 to 70 per cent hepatectomy. The results indicated that the RLF with ICG during surgery, if performed under stable hemodynamics, is a beneficial tool to decide the resectability in equivocal cases.

Treatment of hepatoma accompanying esophageal varices

過去12年間に経験した食道静脈瘤合併肝癌の治療経験を検討した.この著しく治療困難な疾病の治療方針に関しては,まだ多くの解決すべき問題点があるが,現時点での我々の見解は以下の通りである.(1) 食道静脈瘤合併肝癌でも,肝癌を早期に診断できれば小範囲肝切除で満足すべき成績をおさめうる.この際,吐血の既往を有する静脈瘤あるいはGradeの高い静脈瘤に対しては同時に静脈瘤手術を併施しうる.(2) 40%以上の硬変肝切除を行なうと,約40%の門脈圧上昇を来すので,特にGradeの高い食道静脈瘤では症例に応じて静脈瘤手術を考慮すべきである.術式としては,手術時間,肝癌再発によるシャントの閉塞の可能性などを考えた場合,遠位脾腎静脈吻合術が好ましいと考える.(3) 肝癌が切除されない症例での静脈瘤手術は必ずしも吐血を防止しえず,今後,検討されるべき課題である.