[Preoperative CEA level predicts outcomes of hepatic resection for liver metastases from colorectal cancer].

We analyzed patients receiving hepatic resection for liver metastases from colorectal cancer to determine prognostic factors. Seventy-one patients underwent curative hepatic resection for liver metastases and 32 of them were treated with arterial infusion chemotherapy (AIC) using implantable port. Five-year survival rates in the AIC group and non-AIC group calculated by the method of Kaplan-Meier were 43% and 22%, respectively (p < 0.01, logrank test). By multivariate analysis calculated by the Cox proportional hazard model, the preoperative CEA level (cut point 10 ng/dl) and existence of AIC predicted survival.

[Three cases of Pseudomyxoma peritonei treated with intraperitoneal inoculation of cisplatin through an implantable port system].

Three patients with Pseudomyxoma peritonei were treated with intraperitoneal chemotherapy through an implantable port system which had been used subcutaneously. Three patients were given 100 mg of cisplatin for intraperitoneal chemotherapy and adjuvant chemotherapy was needed for only one of them. An adjuvant chemotherapy through an implantable port is an easy method and a useful therapy.

[Evaluation of hepatic resection and hepatic arterial infusion chemotherapy for multiple liver metastases from colon cancer].

We examined the significance of hepatic resection and hepatic infusion chemotherapy for multiple liver metastases from colon cancer. Twelve patients underwent curative hepatic resection for multiple liver metastases (more than five), and 10 of them received arterial infusion chemotherapy. The number of metastases ranged 5 to 30 (mean 9.4). Recurrence rates in the remnant liver were 50%, and five-year survival rates were 31%.

[Liver abscess caused by hepatic artery infusion chemotherapy].

A 48-year-old man underwent left hemicolectomy and right extended hepatectomy for colon cancer and its synchronous multiple liver metastasis. Sixteen months after, multiple metastases in the remnant liver were found, so he was given bolus hepatic infusion of 5-FU 1,000 mg/week, total amount, 25 g. The response was CR, but he developed a liver abscess in segment 4.

[Indication of prophylactic hepatic arterial-infusion chemotherapy after hepatic resection for liver metastases from colorectal cancer].

The purpose of this study was to clarify the indication of prophylactic hepatic arterial-infusion chemotherapy (PHAIC) after hepatic resection for liver metastases from colorectal cancer. Sixty-one patients underwent curative hepatectomy, and 27 of them were treated with PHAIC using implantable port. According to clinicopathological factors of primary colorectal cancer and liver metastases, the prognoses were analyzed. In conclusion, PHAIC was not useful for patients who had distant lymph node metastases (paraaortic lymph node) from primary cancer.

[Common bile duct fistula caused by hepatic arterial infusion chemotherapy].

We often use hepatic arterial infusion chemotherapy to control recurrence of metastatic cancer of liver. Recently, we encountered a case of common bile duct fistula caused by hepatic arterial infusion chemotherapy. A 61-year-old man had undergone right hepatic lobectomy for liver metastasis of gastric cancer, 7 months after total gastrectomy. A hepatic arterial infusion catheter was placed. Since then he has received continuous and/or bolus hepatic artery infusion of 5-FU, ADR and CDDP+5-FU. There was a recurrence of gastric cancer in segment 2 of the liver. On his second admission, when we administered contrast medium to the infusion port, a common bile duct was found.

[Study of hepatic arterial infusion chemotherapy for prophylaxis of liver metastases of colorectal cancer after hepatic resection].

We examined the significance of hepatic arterial infusion chemotherapy (HAIC) for prophylaxis of liver metastases of colorectal cancer after hepatic resection using an implantable port. Fifty-five patients operated at the hospital from August 1988 to December 1994 were divided into two groups consisting of 23 patients with HAIC group: (HAIC (+)), and 32 patients without HAIC group: (HAIC (-)) retrospectively. The cumulative survival rates and recurrent rates of cancer free in remnant liver of HAIC (+) were improved, compared with HAIC (-). This suggests that HAIC was effective in improving the prognosis and preventing recurrence in remnant liver.

[Sclerosing cholangitis-induced biliary cyst formation: complication of hepatic artery infusion chemotherapy].

A 60-year-old man underwent resection of a sigmoid colon adenocarcinoma, left hepatic lobe, part of segment 6 and 8, due to its metastasis. He received hepatic artery infusions of 5-FU total amount, 15.5 g. There was no recurrence in the liver, but he developed sclerosing cholangitis, and a large biliary cyst formed in segment 8. After drainage of the cyst by percutaneous-trans-hepatic approach, bile leakage persisted, and liver dysfunction was progressive. Sclerosing cholangitis-induced biliary cyst formation is rare. Occlusion, or necrosis of the peripheral bile duct may be the cause.

[Two cases of catheter tip dislocation to the duodenal bulb: a rare complication of hepatic arterial infusion chemotherapy].

Case 1: A 63-year-old woman underwent transverse colectomy and hepatectomy for colonic cancer and liver metastasis. A hepatic arterial infusion port (HAIP) was implanted. Continuous infusion of 5-FU (total amount, 7,500 mg) caused a hemorrhagic duodenal ulcer 15 months after. Follow-up endoscopy revealed the catheter tip was in the duodenal bulb. Case 2: A 62-year-old man underwent abdominoperineal resection for rectal cancer. Repeated hepatectomy for liver metastases was performed at 3 and 5 years after the first operation. HAIP was implanted at the last operation, but was not available at all due to the wound infection. The port was removed, but the catheter remained. Three years after, the catheter tip was found in the duodenal bulb by endoscopy.

Pharmacology of a non-selective ETA and ETB receptor antagonist, TAK-044 and the inhibition of myocardial infarct size in rats.

1. The aims of the present study were to characterize the pharmacological profile of a new endothelin (ET) receptor antagonist, TAK-044 and to consider whether it limits the extension of myocardial infarct size in rats. 2. Binding of [125I]-ET-1 to ET receptors on rabbit ventricular and cerebellar membrane fractions was inhibited by TAK-044 with IC50 values of 3.8 nM and 130 nM, respectively. 3. It inhibited ET-1, ET-2 and ET-3-induced vasoconstriction of porcine isolated coronary arteries in a competitive (ET-1, ET-2) and a non-competitive (ET-3) manner. 4. In the rat in vivo, the ET-1-induced blood pressure changes including transient hypotension followed by sustained hypertension, were inhibited by TAK-044 (0.1-10 mg kg-1, i.v.) in a dose-dependent manner. 5. Acute myocardial infarction induced by 1 h coronary occlusion followed by 24 h reperfusion in rats caused an infarct size of 60 +/- 2% (n = 12) of the area-at-risk by weight. 6. Intravenous injection of TAK-044 10 min before coronary occlusion reduced the infarct size in a dose-dependent manner: 32% and 54% reductions at 1 and 3 mg kg-1, respectively. 7. TAK-044 administered 10 min before or 1 h after reperfusion (1 mg kg-1, i.v.) showed similar inhibitory effects: 34% and 23% reductions, respectively. 8. We conclude that TAK-044 is an ETA/ETB receptor antagonist which shows strong inhibitory effects on the extension of myocardial infarct size after coronary artery occlusion-reperfusion in rats.

Antihypertensive and cardiovascular effects of a new potassium channel opener, TCV-295, in rats and dogs.

The antihypertensive and cardiovascular properties of a new potassium channel opener, TCV-295, were studied in rats and dogs. In conscious, spontaneously hypertensive rats (SHR), TCV-295 (0.03-1 mg/kg orally, p.o.) reduced blood pressure (BP) dose dependently with slow onset of action. The antihypertensive effects induced by TCV-295 lasted much longer than those of levcromakalim and nisoldipine, and the reflex tachycardia it evoked was less marked than that evoked by these drugs as compared at doses showing similar maximal hypotensive effects. Glibenclamide (30 mg/kg intravenously, i.v.) inhibited the TCV-295-induced BP decrease in anesthetized rats. In a 4-week chronic dosing study in SHR, TCV-295 (0.3 mg/kg/day p.o.) produced neither potentiation nor tolerance to its antihypertensive action and no rebound hypertension occurred when drug treatment was discontinued. In anesthetized normotensive dogs, TCV-295 (4.5 micrograms/kg/min i.v.) induced BP reductions accompanied by reductions in systemic vascular resistance. TCV-295 also reduced resistances of the coronary, vertebral, mesenteric, and renal vascular beds, and the most marked effect was observed in the coronary vasculature. Myocardial O2 consumption was reduced by TCV-295, possibly owing to afterload decrease. These results suggest that TCV-295 has a desirable profile for an antihypertensive agent.

A new endothelin receptor antagonist, TAK-044, shows long-lasting inhibition of both ETA- and ETB-mediated blood pressure responses in rats.

The present study describes the pharmacological profile of an endothelin (ET) receptor antagonist, TAK-044, in anesthetized rats. TAK-044 given 10 min before administration of ET-1 (0.3 nmol/kg i.v.) partially inhibited the ET-1-induced pressor response at 0.1 and 1 mg/kg i.v. and almost completely inhibited the response at a dose of 10 mg/kg. The transient depressor response induced by ET-1 was also inhibited by 1 and 10 mg/kg TAK-044. BQ-123 partially inhibited the pressor response at 0.1-10 mg/kg i.v., whereas it did not inhibit the depressor response except at a dose of 10 mg/kg. These inhibitory effects of TAK-044 were longer lasting than those of BQ-123: 3 hr for TAK-044 and 1 hr for BQ-123 at 10 mg/kg. A selective ETB agonist, sarafotoxin S6c (0.3 nmol/kg i.v.), induced both depressor and pressor responses similar to ET-1. The initial depressor response was inhibited by TAK-044 in a dose-dependent manner (0.1-10 mg/kg i.v.) and by BQ-123 at the highest dose, whereas the sustained pressor response was inhibited only by TAK-044 at a dose of 10 mg/kg. Similar differences between TAK-044 and BQ-123 were observed for sarafotoxin S6c-induced renal vasoconstriction: TAK-044 but not BQ-123 inhibited the response at a dose of 3 mg/kg i.v. We conclude that TAK-044 inhibited both ETA- and ETB-mediated blood pressure responses and that these effects were longer lasting than those of BQ-123. In addition, the ETB-mediated vasoconstriction and pressor responses were inhibited by TAK-044 and not by BQ-123.

Role of endogenous endothelin in extension of rabbit myocardial infarction.

The role of endogenous endothelin-1 (ET-1) in myocardial infarction was investigated in a rabbit ischemia-reperfusion model and in rabbit Langendorff hearts. AwETN40, a monoclonal antibody against ET-1, at 10 mg/kg i.v. inhibited hypertension and hypotension induced by ET-1 (0.3 nmol/kg i.v.): about 70-100% inhibition lasted for 24 h. In a coronary occlusion (30 min)-reperfusion (24 h) model, AwETN40 (10 mg/kg i.v.) reduced the infarct size from 60.9 +/- 4.6% (infarct region/ischemic region in weight, IgG1 kappa control; n = 5) to 37.1 +/- 5.2% (n = 5, p < 0.05). Plasma ET-1 levels were increased significantly by coronary occlusion-reperfusion and returned to control level 24 h after reperfusion. Effects of ET-1 on the coronary vessels and cardiac contractility were studied in the Langendorff heart. ET-1 increased the perfusion pressure from concentrations as low as 10 pM, whereas the developed left ventricular pressure was not altered. These results suggest that ET-1 decreases oxygen supply to the cardiac muscles by constricting coronary vessels and that this, in turn, worsens the ischemic condition of the heart to extend the infarct size.

[A pharmacokinetic study of intra-arterial chemotherapy for prophylactic treatment of liver metastasis after hepatectomy for liver cancer].

As a fundamental study of efficacy of intra-arterial administration using ADM, ERB and MMC for prophylactic treatment of liver metastasis after hepatectomy for liver cancer, the pharmacokinetics of three drugs (ADM 10mg (n = 5), ERB 20mg (n = 3) and MMC 6 mg (n = 3)) were studied in patients who underwent hepatectomy after intra-arterial injection. The hepatic extraction calculated from the areas under the plasma concentration time curve of both administrations was 40% in ADM, 60% in ERB, and 0% in MMC. From these findings, it is suggested that intra-arterial administration could reduce by half the systemic toxic side effects of ADM or ERB, but the advantage of intraarterial infusion of MMC was not obvious.

Fatal and near fatal asthma.

Despite the recent development of apparently effective asthma drugs, the number of deaths from asthma has not declined. The authors tried to establish an optimal strategy for the prevention of acute asthmatic death by analyzing the circumstances of acute fatal or near-fatal asthma. Data were collected from 51 adult patients admitted to Bokutoh Tertiary Emergency Center due to acute asthma between November 1985 and May 1990 and 38 asthmatic patients admitted to Yokohama City Hospital in 1990. Pre-admission data were obtained through interviews with the patients, their families, or doctors who had seen them. A total of 89 patients were classified into three subgroups: group 1 consisted of patients dead-on-arrival (DOA); group 2, non-DOA patients with disturbed consciousness; and group 3, patients with less severe episodes. Little background information was significantly different among groups, but symptomatic episodes in group 1 patients tended to occur more rapidly. The speed of onset of the episodes was also dependent on the asthma control status. Prehospital care of groups 1 and 2 patients was very poor despite severity of the symptoms. All patients in groups 2 and 3 were successfully treated and discharged, but five of the 26 patients in group 2 died during follow-up periods. Prognosis of patients after discharge appeared to be dependent upon asthma control status before the acute episodes. It was concluded that acute fatal or near fatal asthma could occur in apparently low-risk patients as well as high-risk ones. It was also suggested that the optimal strategy for preventing asthma deaths might be variable.

[Macrocytic anemia as a possible adverse effect of fluoropyrimidines].

One hundred and thirty-seven cases of stomach cancer given fluoropyrimidines (UFT: 66 cases, Tegafur: 58 cases, 5-FU: 13 cases) after gastrectomy as the adjuvant chemotherapy were examined as to appearance of macrocytic anemia. The mean corpuscular volume (MCV) gradually elevated in all cases but seven after administration. Macrocytic anemia, defined by the elevation over 20% compared with both pre-operative and pre-administrative values of MCV, was developed 30.3% in UFT group, 8.6% in tegafur group and 30.8% in 5-FU group. The incidence was statistically higher in UFT group (p less than 0.01) and 5-FU group (p less than 0.05) than in tegafur group. The cause was attributed to fluoropyrimidine administration because the serum folate and vitamin B12 levels remained normal and the value of MCV normalized after cessation of administration. Each total dose to induce macrocytic anemia was potentially about 70g in UFT. 100g in tegafur and 30 g in 5-FU. In conclusion, periodical hematological examination is necessary for the patients given fluoropyrimidine preparations.

[Radical operation for carcinoma of gastric cardia--lymph node dissection by laparosternophrenotomy approach].

The adequate esophago-gastric resection and lymph node dissection can be performed without the necessity of a thoracotomy, by using the laparosternophrenotomy approach. For tumors restricted to lower esophagus of 4cm in localized tumors or 3cm in invaded tumors above the EG junction, the sternotomy approach is utilized. However, if the tumor extends to more than the above criteria, the thoracoabdominal approach must be utilized. For 14 years, 85 cases with tumor of gastric cardia were performed by sternotomy approach and 76 cases were performed by thoracotomy approach. The lymph node metastatic rate in the lower thoracic cavity was 26% in total. The lymph node metastatic rate of No. 110 was 22.6%, No. 111 was 17.4% and No. 112 was 12.5%. These results show the lymph node dissection in the lower thoracic cavity is very important in tumors of gastric cardia. The five year survival rate was 41% in patients who undergone curative operation by the sternotomy approach, and 45% in patients performed by the thoracotomy approach. According to our study of the lymph fluid stream in gastric cardia tumors using carbon, the lymph node dissection around the renal vein is important. This approach has less respiratory disturbance than the thoracotomy. This procedure is one of the best approaches for carcinoma of gastric cardia according to our criteria.

[Chemo-embolization therapy of unresectable liver metastases using implantable infusion port].

Since 1987, 14 patients (10 colorectal, 3 gastric and 1 lung cancer) with unresectable liver metastases received intra-arterial infusion chemo-embolization therapy using implantable infusion port. All patients had more than one lesion in bilateral lobe (H2 and H3). Infusion catheters were placed in the proper hepatic artery through the gastroduodenal artery on laparotomy. Infusion ports were implanted in the subcutaneous tissue of the abdominal wall. Various kinds of chemotherapeutic agents such as MMC, ADR, THP-ADR, CDDP and 5-FU were injected with embolization material (DSM or Lipiodol), every 1 to 4 weeks at the outpatient clinic. Among 10 cases of H2 grade metastases, 1 CR and 3 PR (40% clinical response) were obtained. However, all 4 cases of H3 grade were judged PD. All patients except one with H2 grade metastases are still alive, but 3 out of 4 with H3 grade died within 7 to 11 months. Catheter occlusion was observed in 4 cases for 3 to 7 months. Infection around the port occurred in 1 patient. A patient with metastatic liver cancer was treated by intermittent bolus injection with MMC and DSM. Partial response was confirmed by CT and tumor markers. Histological response was demonstrated in the specimen obtained at partial hepatectomy. It is concluded that this treatment is variable to prolong the survival of patients with H2 grade metastatic liver cancer, together with maintenance of the quality of life.