Bile acid load on the DNA distribution pattern of bile ductules and cholangiocarcinoma induced by diisopropanolnitrosamine in hamsters.

This study evaluated the influence of bile acid load on the DNA distribution pattern of proliferated bile ductules and cholangiocarcinoma induced by diisopropanolnitrosamine. Ninety hamsters were separated into control, tauro- and deoxycholic acid (DCA) groups. The DNA distribution pattern of intrahepatic lesions at 15-25 weeks was measured by cytofluorometry and classified into three types: I (-A, -B), II and III, according to the degree of dispersion on the DNA histogram. Regarding proliferated bile ductule lesions, all groups showed an increase in cell populations, indicating the dispersion of nuclear DNA content from the 4C to 6C ranges over the course of 25 weeks, and two groups with bile acids, especially the DCA group, revealed significant high incidences of lesions with type I-B plus II compared with those in the control group (p < 0.05, 0.01). Changes in carcinoma types were similar to those of bile ductule lesions, and the tumors in the DCA group had a significant high frequency of type II plus III (p < 0.05). In addition, heterogeneity of the DNA distribution pattern was observed within individual lesions of not only carcinoma but also bile ductules. These results suggest that bile acid load, especially DCA, promotes an increase in nuclear DNA content or DNA polyploidization and enhances the distribution of the DNA pattern of proliferating bile ductules and carcinoma. Furthermore, a bile ductule-carcinoma sequence may be present in the development of cholangiocarcinoma.

[One-year outcome of panic disorder].

In this study we investigated the one-year outcome of panic disorder. The subjects were 169 panic disorder patients (69 males, 100 females; mean age 36.5 years), who attended the outpatient clinic of the Department of Psychiatry, Showa University Hospital, from September to December 1993. The outcome study was performed from October to December 1994. Patients who were being treated at Showa University Hospital during the outcome study were interviewed in person, and those who were not were interviewed by telephone. The one-year outcome of 100 patients (32 interviewed in person and 68 interviewed by telephone; 37 males, 63 females; mean age 39.5 years) was assessed. That of the remaining 69 patients was not assessed because they did not provide informed consent or had moved during the last year. The patients who were assessed (N = 100) were older and exhibited less severe phobic avoidance on their first visit to the clinic than those who were not assessed (N = 69). The frequency of panic attacks, and the severity of phobic avoidance and anticipatory anxiety decreased significantly between the time of the patients' first visit to the clinic and the time of the outcome study. Panic attacks, phobic avoidance and anticipatory anxiety disappeared in 27.0%, 32.9% and 13.6% and decreased in frequency or severity in 61.8%, 62.0% and 61.4% of the cases, respectively. Seventy-three patients felt that the severity of their panic disorder symptoms decreased between the time of the outcome study and the time of their first visit to the clinic, 20 felt that it had not changed and 7 felt that it had increased worse. The phobic avoidance and anticipatory anxiety at the time of the patients' first visit to the clinic were more severe, and the Global Assessment of Functioning Scale score was lower in the case of the former group of patients than in that of the latter two groups.

Pancreatic exocrine enzymes and intrapancreatic protein synthesis in acute oedematous pancreatitis.

Changes in serum and intrapancreatic enzyme content and protein synthesis in pancreas were studied in acute oedematous pancreatitis (AOP). Male Wistar rats (n = 111) were divided into 2 groups, controls with a sham operation and those with AOP. Serum amylase levels rose immediately after the procedure causing AOP and then fell gradually, while serum lipase and ribonuclease levels remained higher than control values over 48 h. (p < 0.05, 0.01). Serum deoxyribonuclease (DNase) II levels were unchanged. Intrapancreatic enzyme levels were scarcely affected by AOP. 3H-leucine uptake into pancreatic tissue of rats with AOP was decreased throughout the study (p < 0.001), but some protein synthesis continued. Intrapancreatic enzyme contents are maintained despite diffusion into the blood because the pancreas retain its ability to synthesize enzymes.

Movement of intrapancreatic calcium in dogs with experimental pancreatic lithiasis. With special reference to the process of pancreatic calculus formation.

This study was performed to clarify the movement of calcium in the pancreas of dogs with chronic pancreatitis, using scanning and transmission electron microscopes (SEM, TEM) equipped with X-ray elemental microanalyzers. Eleven adult mongrel dogs underwent incomplete ligation of the pancreatic duct. After the procedure, the levels of pancreatic enzymes in the serum did not change for 9 mo, but the endocrine function was reduced gradually. Of all dogs, 5 revealed pancreatic sclerosis, and 2 at 9 mo had calculi, 2-4 mm in size, in the small pancreatic duct. SEM examination revealed the intralobular fibrosis and irregularity of the pancreatic duct wall, and TEM examination revealed the intralobular fibrosis and irregularity of the pancreatic duct wall, and TEM examination demonstrated the amorphous or crystalloid substances and secreted granules in the acinar lumen or ductule. In elemental analysis spectra using SEM, a high calcium peak was seen in the pancreatic duct wall. In elemental analysis spectra using TEM, a high calcium peak was observed in the amorphous or crystalloid substances, and a high ratio of Ca/K was seen in these substances. Calcium was also detected in the secreted granules or microvilli. These results suggest that there is a process of calculus formation based on the congregation of the intraductular substances containing a large quantity of calcium.

Multifocal intraductal papillary adenocarcinoma of the pancreas: report of a case.

This paper describes a case of a mucin-producing tumor of the pancreas, histologically diagnosed as multifocal intraductal papillary adenocarcinoma. The patient had a markedly dilated main pancreatic duct, detected by ultrasound (US) and computed tomography (CT), and endoscopy showed a papillary tumor projecting from the patulous orifice of the enlarged papilla of Vater. Several biopsies taken from the tumor indicated a diagnosis of papillary adenocarcinoma. Total pancreatectomy was thus performed, revealing a multifocal papillary tumor growing along the main duct in the head, body, and tail of the pancreas. Microscopically, these multiple tumors were found to be mucin-producing papillary adenocarcinoma of the main and subsidiary pancreatic ducts with nodular and microfocal periductal invasion. The surgical treatment of multifocal tumors, may therefore necessitate total pancreatectomy to achieve curative resection, in some cases.

Promoting effects of bile acid load on the occurrence of cholangiocarcinoma induced by diisopropanolnitrosamine in hamsters.

This study was performed to clarify the promoting effects of primary or secondary bile acid load on the occurrence of cholangiocarcinoma, using Syrian golden hamsters. These hamsters received subcutaneously diisopropanolnitrosamine (DIPN) once weekly for 10 weeks, and simultaneously were given a standard pellet diet (control group) containing taurocholic acid (TCA group) or deoxycholic acid (DCA group). The rates of cholangiocarcinoma at 20 weeks were 23% in the control group, 60% in the TCA group and 59% in the DCA group. There were significant differences between the control and the TCA or DCA groups (p < 0.05). The rates of proliferation of bile ductules or hyperplasia of the bile duct epithelium and the bromodeoxyuridine labeling indices of bile duct epithelial cells were high in both groups treated with bile acids, compared with those in the control group. Regarding the composition of bile acids in the intraductal bile, the TCA and DCA groups revealed a decrease in primary bile acids and an increase in DCA. These results suggest that both TCA and DCA given orally promote the occurrence of DIPN-induced cholangiocarcinoma.

[Clinical effect of postoperative adjuvant chemotherapy for advanced colorectal cancer--comparisons of between tegafur (FT) and UFT].

A randomized controlled study was conducted on a FT 600 mg/day daily oral administration group and a UFT 400 mg/day daily oral administration group as an adjuvant chemotherapy after curative operation for colorectal cancer patients with injection of Mitomycin 30 mg (20 mg during operation and 10 mg on the day following), and the results were examined. FT and UFT were administered orally for one year from the 3rd week after operation. The 5-year survival rate was slightly higher in the UFT administration group. Five-year survival was 82.7% for colon cancer and 82.1% for rectal cancer in the UFT administration group, against 72.6% and 72.0 % in the FT administration group. The same trend was observed when the survival rate was studied by various factors such as the size of tumor, depth of cancer invasion of the wall, histological type, lymph node metastasis, vascular invasion and the degree of progression. There was no difference between both groups in the patterns and times of recognition of the recurrences and in the appearance rate of side effects. The results suggest that UFT 400 mg/day is equal to or better than FT 600 mg/day in therapeutic effect for colorectal cancer patients, although the UFT dose is only 2/3rd the FT dose.

[Intra-arterial infusion chemotherapy using an implantable reservoir in the treatment of hepatic metastases in colorectal cancer].

With colorectal cancer, the therapeutic outcome for multiple hepatic metastasis extending to the bilateral lobe, even when various chemotherapies are administered, is extremely poor. For multiple hepatic metastases at our clinic, from November, 1985, through February, 1991, we used an implantable reservoir to administer intra-arterial infusion chemotherapy and reviewed the results. We treated 16 patients with hepatic metastases of colorectal cancer, H2 in 3 cases and H3 in 13 cases. When we used the reduction rate of the tumor diameter as seen by CT scan as a criteria for antitumor effectiveness, 1 case was CR and 3 cases were PR, for an efficacy rate of 25.0%. Changes in the serum CEA level were related to antitumor effectiveness. Among the evaluable cases, the 1-year survival rate was 60.0%, which was significantly more favorable than the 20.0% obtained in the systemic chemotherapy group (p less than 0.05). Given the above, although there are a few problems such as the kind and dose of drugs, the use of intra-arterial infusion chemotherapy with an implantable reservoir to treat hepatic metastases of colorectal cancer permits a form of chemotherapy providing a better QOL out of hospital.

[Blood kinetics of free-platinum in CDDP hepato-arterial injection therapy].

In CDDP hepato-arterial injection therapy, platinum (Pt) concentration in hepatic and peripheral venous blood were determined in two groups with different injection rates, and the blood kinetics of Pt was examined. Seven cases of digestive cancers having liver metastases were given CDDP (100 mg) selectively into the proper hepatic artery at a constant rate (10 or 40 min). After injection, concentration of non-protein-bound Pt in hepatic and peripheral venous blood were determined. Pt concentration and AUC value were higher in hepatic venous blood at injection rate than peripheral venous blood. On the other hand, Pt concentration in hepatic venous blood in the cases 10 min-injection were higher than those received 40 min-injection, but neither Pt concentration in peripheral venous blood nor incidences of the side effects and abnormal clinical findings were influenced by the injected rates.

The effect of incomplete bile duct obstruction on diisopropanolnitrosamine-induced cholangiocarcinoma.

This study was carried out to clarify the influence of incomplete bile duct obstruction (IBDO) on the occurrence and proliferation of cholangiocarcinoma and to evaluate the effect of release of IBDO at an early stage, using 175 Syrian golden hamsters. These hamsters received 500 mg/kg body weight of diisopropanolnitrosamine (DIPN) once weekly for 10 weeks, and then were divided into 3 groups, consisting of the simple laparotomy group (SL group), the IBDO group and 2 week IBDO group, in which IBDO was released after 2 weeks. The occurrence rates of cholangiocarcinoma at 20 weeks were 42% in the SL group, 76% in the IBDO group and 30% in the 2 week IBDO group. The mean numbers of tumors per hamster in the IBDO group were significantly greater than those in other groups (p less than 0.05). Both occurrence rates and numbers of tumors in the 2 week IBDO group were similar to those in the SL group. The proliferation of bile ductules and isolation of bacteria from bile in the IBDO group had higher rates at 15, 20 weeks than those found in the other groups. These results suggest that IBDO has an influence, as promoter, on the occurrence of cholangiocarcinoma induced by DIPN, and the disappearance of its promoting effect is caused by release of the obstruction.

Influence of pancreatic neurotomy on regeneration of residual pancreas after major pancreatectomy in rats.

This study was performed to examine the influence of pancreatic neurotomy (N) on pancreatic regeneration after 90% pancreatectomy (P), excluding the parabiliary segment. One hundred and fifty male Wistar rats were divided into three groups, consisting of the PN, P, and laparotomy (L) groups. The ratios of wet wt of residual pancreas to body wt in groups with P increased after the procedures. The ratios in the P group reached their maximum at 10 d, and then decreased slightly, whereas those in the PN group rose gradually for a 60 d period. Regarding changes in the labeling indices in autoradiograms using 3H-thymidine and mitotic indices in exocrine cells, those indices in groups with P reached a peak at 3 d after the procedures, and then rapidly declined. Both indices in the PN group were lower during the first 10 d and thereafter higher than those in the P group. These results suggest that following pancreatic neurotomy, the potential for pancreatic regeneration continues over a longer period after major pancreatectomy.

Influence of incomplete bile duct obstruction on the occurrence of cholangiocarcinoma induced by diisopropanolnitrosamine in hamsters.

This study was performed to clarify the influence of incomplete bile duct obstruction (IBDO) on the occurrence of cholangiocarcinoma, using Syrian golden hamsters. These hamsters underwent simple laparotomy (SL) or IBDO at the choledochus and received diisopropanolnitrosamine (DIPN) once weekly for 20 weeks (SL-DIPN or IBDO-DIPN groups). Histological examination in the liver showed increased bile ductules, goblet cell metaplasia of the bile duct epithelium and cholangiocarcinoma in the two groups. The occurrence rates of cholangiocarcinoma at 20 weeks were 35% in the SL-DIPN group and 89% in the IBDO-DIPN group (p less than 0.01). The mean numbers of tumors per hamster in the IBDO-DIPN group were significantly higher than those in the SL-DIPN group (p less than 0.01). Regarding the composition of bile acid in the intraductal bile, both groups revealed an increase in primary bile acid, consisting of more than 80% of cholic acid. Bacteria were detected in the group with IBDO throughout the whole course. These results suggest that IBDO has an influence as promoter on the occurrence of DIPN-induced cholangiocarcinoma.

[Primary plasmacytoma of the thyroid--report of an autopsy case and review of the literature in Japan].

Primary extramedullary plasmacytoma (PEMP) of the thyroid is rare. Only nine patients with PEMP of the thyroid have been reported in Japan to date. We describe an additional autopsy case with PEMP of the thyroid and review of the literature in Japan. A 67-year-old women complaining of swelling of the anterior neck exhibited thin scalp hair, edematous face and a giant, hard, nodular goiter. Laboratory examination showed elevated levels of ESR, collagenous reaction, gammaglobulin, and a M-bow of the IgG-k type in immunoelectrophoresis. No Bence-Jones protein was found in the urine. Thyroid function test revealed a subclinically hypothyroid state, showing a T3 of 1.32 ng/ml, a T4 of 10.0 micrograms/dl, a TSH of 23.4 microU/ml and positive thyroid antibodies. The scintigram and the CT scan of the thyroid showed deviation of the trachea by the thyroid tumor and calcification within homogeneous thyroid gland. She underwent total thyroidectomy because of suspected malignancy. The histological examination of the removed thyroid weighing 117gr revealed a proliferation of plasma cells and lymphocytes and small amounts of atrophied thyroid follicles. The immunohistological examination of the removed thyroid showed the monoclonality to IgG-k chain. Plasma cells were stainable with methylgreenpyronine. Twenty-six months after thyroidectomy, she died due to progressive emaciation, anemia, hypoalbuminemia and ascites. Postmortem examination revealed widespread metastasized plasma cell tumors in the liver, intestine, spleen and mesentery with ischemic changes in heart and kidney. Based on our autopsy case and the nine cases reported in Japan, clinical and histological characteristics of PEMP of the thyroid were discussed.

The influence of cutting the pancreatic nerve plexus on exocrine function in the pancreas of rats.

This study was performed to clarify changes in protein synthesis and exocrine enzymes of the pancreas after cutting the pancreatic nerve plexus of Wistar rats. The rats were divided into two groups, consisting of a group that underwent cutting of the pancreatic nerve plexus (neurotomy group) and a group that underwent a sham operation (control group). 3H-leucine uptake in the pancreatic protein fraction of the neurotomy group at 3, 5 and 7 days after the operation was significantly lower than that of the control group (P less than 0.05-0.01), and this low uptake returned to the normal range at 14 days. Amylase, lipase and trypsin values in pancreatic tissue of the neurotomy group decreased during the period of from 1 to 7 days, and there were significant differences in the values of the respective enzymes at 5 or 7 days between the neurotomy and the control group (P less than 0.05). Thereafter, all enzyme values increased to within the normal range. Upon examination of pancreatic blood flow using a microsphere, the neurotomy group showed a significant reduction at 7 days compared with the control group (P less than 0.05), and thereafter exhibited recovery of blood flow. These results indicate that after cutting the pancreatic nerve plexus, exocrine function in the pancreas is reduced immediately but recovers within a short period of time, and that these changes in exocrine function are affected by blood flow in the pancreas.

Relationship between pancreatic enzymes and pathological changes in the pancreas in acute pancreatitis. The significance of determination of serum deoxyribonuclease.

To clarify the relationship between changes in serum pancreatic enzymes and pathological changes in pancreatic parenchyma, this study was performed by using rat models with acute pancreatitis. The models were rats with edematous and necrotizing pancreatitis. Amylase, lipase, ribonuclease (RNase), and deoxyribonuclease (DNase I, II) in the serum were determined for 48 h after the development of pancreatitis. Amylase and lipase levels rose directly in both pancreatitis groups. These enzymes in the necrotizing pancreatitis group were higher than those in the edematous pancreatitis group, but there was no significant difference. RNase levels also rose markedly, but there was no obvious difference between either of the pancreatitis groups. On the other hand, DNase levels were high in the necrotizing pancreatitis group but low in the edematous pancreatitis group, with significant differences between the two groups, especially in the DNase II levels over a 36-h period (p less than 0.05-0.01). Therefore, these results suggest that serum DNase levels reveal the necrotizing changes in pancreatic parenchyma.

[Clinical effect of postoperative adjuvant immunochemotherapy with the FT-207 suppository and PSK in colorectal cancer patients. Colorectal Cancer Chemotherapy Group in Hokuriku].

For a period of about three years from September 1980, a randomized controlled study was performed on colo-rectal cancer patients who had undergone an absolute curative operation. After operation and administration of 30 mg of Mitomycin (20 mg on the day and 10 mg on the day following the operation), all patients were randomly divided into two groups which received the treatments as follows; Group A, 750 mg x 2/day of FT-207 suppositories, was administered for one year from the 2 nd week after operation; Group B was given FT-207 3.0 g/day of PSK orally for one year. Group A included 71 patients, of whom 46 had colon cancer and 25 had rectal cancer. Group B included 53 patients, of whom 30 patients had colon cancer and 23 had rectal cancer. There was no difference between the two groups in terms of patients' background factors. In regard to the 5-year survival rates of these patients by means of the Kaplan-Meier Method, Group A and B showed 80.8% and 91.4%, respectively, but no significant difference was observed. In the colon cancer patients, 5-year survival rates were 88.6% and 93.0% in Group A and B, and in the rectal cancer patients, they were 68.0% and 87.5% in Group A and B, respectively. The survival rate of Group B was always slightly higher than that of Group B in all analyses, in which we considered such factors as degree of progression, depth of cancer invasion of the wall, lymphnode metastases and vascular invasion. There were no differences between both groups in the patterns and times of recognition of the recurrences, but the number of cases evidencing recurrences within 2 years tended to be smaller in Group B. Thus, it was suggested that PSK was effective for prolongation of the survival period in colo-rectal cancer patients after absolute curative operation.

[An intractable gastric cancer showing an extremely effective response to immunochemotherapy].

Reported herein is the case of a terminal patient with advanced gastric cancer who was shown an extremely effective response to immunochemotherapy. The patient, a 62-year-old female, was determined as having a gastric cancer, Borr. type 2, originating in the pyloric antrum. The tumor was found to be H3P3S2N2 (stage IV), and its histology revealed a mucus-producing papillary adeno-carcinoma, ss gamma, n(+), ly2, and V1. Thus the patient underwent a distal gastrectomy, and was given an operative administration of MMC, followed by postoperative immunochemotherapy with FT 207 and OK 432. Consequently, no ascites were noticed throughout the recuperative course, and repeated CT scannings of the hepatic metastatic lesions, revealed a remarkable regression. Two years after this operation, she resumed normal daily life. Further, her preoperatively elevated tumor markers have returned to normal.