[Pharmacokinetic study of the intraperitoneal administration of CPT-11 for patients with peritoneal seedings of gastric and colonic cancers].

We studied the pharmacokinetics of the intraperitoneal administration of CPT-11 for four patients with peritoneal metastasis (2 gastric cancer cases, 2 colon cancer cases). CPT-11 was administrated in a dose of 40-60 mg and the intraperitoneal and serum levels of CPT-11, SN-38 and SN-38 glucuronized (SN-38 Glu) were measured periodically. Intraperitoneal therapy with CPT-11 was effective for the control of malignant ascites. No serious side effects were observed. The levels of CPT-11, SN-38 were no different 30 min afterwards the administration of CPT-11 either intraperitoneally or intravenously. The high concentration of CPT-11 was achieved with intraperitoneal therapy and a small fraction of CPT-11 changed into SN-38 in the abdominal cavity.

[Adjuvant short-term continuous hepatoarterial infusion of 5-FU for advanced colorectal cancer using a removable hepatoarterial catheter].

We devised a removable hepatoarterial catheter which we then implanted in patients during colorectal operations, after first making sure this system worked well in an experiment with rabbits. We have applied this devise in 21 advanced colorectal cancer patients. The procedure to place the hepatoarterial catheter followed the resection of the colorectal cancer. A 16 G 30 cm TPN catheter was inserted into the gastroduodenal artery. This artery was ligated at two points with a double loop of elastic rubber threads (Elastik, Matsuda Suture, Tokyo). The catheter was fixed with Vicryl RAIDE (4-0). After the operation, 5-FU was continuously infused through the catheter for 2 weeks. We could remove the arterial catheter without any complications or bleeding after the chemotherapy was completed.

[A patient with small-cell carcinoma of the esophagus with synchronous liver metastasis surviving 48 months after surgery].

Small-cell carcinoma of the esophagus is regarded as having a poor prognosis with frequent and early systemic metastasis. Recently, several reports have described small-cell carcinoma satisfactorily treated by chemotherapy and radiation therapy combined with surgery. We herein report a patient with small-cell carcinoma of esophagus with synchronous multiple liver metastasis who survived 44 months after surgery. A 70-year-old man was found to have a polypoid lesion at the abdominal esophagus by upper gastrointestinal endoscopy. A biopsy specimen of the lower esophagus demonstrated undifferentiated carcinoma of the esophagus. Ultrasonographic investigation demonstrated solitary SOL in the liver. The patient underwent a total gastrectomy and lower esophagectomy by an abdominal approach. As ultrasonographic evaluation during laparotomy revealed multiple liver metastases, a hepatic artery infusion catheter was inserted into the proper hepatic artery. A pathological study of the resected esophagus and a biopsy specimen of the liver revealed undifferentiated cell carcinoma of the esophagus (small-cell type). During hospitalization, hepatic artery infusion therapy (CDDP 20 mg/4 h and 5-FU 750 mg/5 h) was given for 4 days starting on days 14 and 28. After chemotherapy, liver metastasis could not be detected by ultrasonographic investigation. At the outpatient clinic bi-weekly hepatic artery infusion of 5-FU (1,500 mg/body/5 h) was continued for 30 months. The patient is alive 48 months after surgery without any evidence of recurrence.

[A case of advanced gastric cancer with multiple liver metastases partially responding to combination intra-arterial chemotherapy via the hepatic artery and abdominal aorta].

A 57-year-old female diagnosed with advanced gastric cancer with multiple organ metastases was treated by various intra-arterial chemotherapies. After surgical resection of the tumor, adjuvant chemotherapy was carried out. Continuously administered 5-fluorouracil of 250 mg/day made it possible to control the growth of the liver metastases. Extrahepatic metastases were kept under control by administering 30 mg of methotrexate, 750 mg of 5-fluorouracil and 30 mg of Leucovorin per/day/week, and 60 mg/day biweekly of cisplatinum via an abdominal artery infusion port. Owing to this multiple infusion route and chemotherapy regimen, the patient lived for 18 months after her first diagnosis of gastric cancer with multiple liver metastases. Although liver metastases may respond to hepatic arterial infusion chemotherapy, extrahepatic metastases lead to poor prognosis. Given the above results, intra-abdominal aorta chemotherapy may be effective for extrahepatic metastases since this method gives high concentration of the anticancer agents at tumor sites with a low incidence of side effects.

[Pharmacokinetics of "subselective" arterial infusion chemotherapy].

Arterial infusion chemotherapy is mainly used for lymph node and peritoneal metastases. Generally, it is said that the concentration of a drug in abdominal organs is higher with arterial infusion chemotherapy than that with systemic chemotherapy. In this study, the pharmacokinetics of arterial infusion chemotherapy for a patient who had an arterial infusion port for lymph node metastasis and peritoneal metastasis, and a hepatic arterial infusion port for liver metastasis, was evaluated. Sequential arterial infusion chemotherapy with methotrexate (MTX) and 5-FU was given. One hundred mg of methotrexate (MTX) was infused over 20 minutes into the aorta, followed by 750 mg of 5-FU over 10 minutes 2 hours later. Blood samples from a peripheral vein and hepatic artery were collected at 10, 20 and 125 minutes from the beginning of the arterial infusion chemotherapy. Then the serum concentration of MTX and 5-FU was examined. The serum concentration of MTX in the hepatic artery was 1.4 to 2.3 times higher than that in peripheral venous blood. The serum concentration of 5-FU in the hepatic artery was 4.9 to 6.0 times higher than that in peripheral venous blood. The serum concentration of drug in abdominal organ was higher with arterial infusion chemotherapy than with systemic chemotherapy. It would thus seem that the effect of arterial infusion chemotherapy is higher than that of systemic chemotherapy.

[Preoperative chemotherapy for advanced colorectal carcinomas--comparison of histological effect between 5'-DFUR + leucovorin tablet and 5'-DFUR alone].

The authors analyzed the histological effect of preoperative chemotherapy for 62 advanced colorectal cancer patients using resected specimens. Thirty-one patients in the 5'-DFUR + LV group received 800 mg/day of 5'-DFUR and 30 mg/day of leucovorin for 10-14 days just before the operations. Thirty-one patients in the 5'-DFUR group received 5'-DFUR 800 mg/day during the same period. None of the patients in either group developed any side effects. The results of the histological examination showed the number of Grade 1a and 1b cases in the 5'-DFUR + LV group was 22 (66.7%) and 5 (15.2%), respectively, and in the 5'-DFUR group 21 (65.6%) and 5 (15.6%). In the 5'-DFUR + LV group, 3 lesions showed Grade 2 histological degeneration, while there were no such lesions in the 5'-DFUR group. However, our results did not demonstrate any statistical difference between the two groups (p = 0.25, U test).

Thoracoscopically managed parathyroid adenoma in the upper anterior mediastinum.

We thoracoscopically managed parathyroid adenoma of the upper anterior mediastinum in a 29-year-old man. He had a backache and was found to have bilateral ureteric stones, hypercalcemia, and extremely increased parathyroid hormone levels. 99mTc-methoxyisobutyl isonitrile scintigraphy showed an accumulation area projected onto the right thyroid lobe and the upper mediastinum. A diagnosis of primary hyperparathyroidism secondary to double adenomas was made. The patient then underwent surgical intervention. With the patient under general anesthesia with one-lung ventilation, a reddish brown adenoma of an upper mediastinum was removed thoracoscopically with three trocars, whereas the right superior parathyroid adenoma was excised by a standard open cervical procedure. Conventionally, the mediastinal parathyroid adenoma was removed by an open approach and was associated with perioperative distress to the patient. If the exact location of the mediastinal lesion is established, thoracoscopic excision of these lesions is feasible and is strongly recommended.

[Experimental study on intraperitoneal versus intravenous CPT-11 for peritoneal seeding and liver metastasis].

CPT-11 is an effective antitumor agent for gastrointestinal malignancy, but the optimum route of administration is unclear. Intraperitoneal administration of this agent was compared with intravenous administration in mouse models of peritoneal seeding and liver metastasis. The peritoneal seeding model and liver metastasis model were established by inoculation of colon 26 tumor cells into the peritoneal cavity and spleen of female BALB/c mice, respectively. CPT-11 (40 mg/kg) was injected intraperitoneally or intravenously on days 2 and 5 after inoculation of tumor cells. Intraperitoneal administration of CPT-11 was significantly more effective than intravenous administration for control of both peritoneal seeding and liver metastasis. Intraperitoneal administration of CPT-11 may be a more efficient form of adjuvant chemotherapy for prevention of both peritoneal seeding and liver metastasis in patients with gastrointestinal cancer.

[Experimental study on CPT-11 intraperitoneal chemotherapy--metabolism of CPT-11 in malignant ascites].

The metabolism of CPT-11 in malignant ascites of gastric cancer patients with peritoneal seedings was studied in advance of the intraperitoneal chemotherapy of CPT-11 in humans. Malignant ascites and blood were drawn from gastric cancer patients. CPT-11 solution (20 mg/ml; 0.2 ml) was added into 3.8 ml ascites or plasma under 37 degrees C and CPT-11, SN-38 and SN-38GLU concentrations were measured with HPLC at times of 5, 30 and 60 minutes after addition of CPT-11. The change from CPT-11 to SN-38 was minimal not only in plasma, but also in malignant ascites. SN-38 GLU concentration was below the limit of measurement. This study showed that in malignant ascites, the enzymes such as carboxyesterase that convert CPT-11 to SN-38 were not present or minimal.

[Hepatic arterial injection therapy (HAI) for metastatic liver tumor from gastric cancer].

The results and problems of hepatic artery infusion therapy (HAI) for gastric carcinoma with synchronous liver metastasis were evaluated. The response rate of HAI with CDDP and 5-FU for metastatic liver tumor was 55% (1 CR + 5 PR/11). The median survival time for responders was 16.5 months, which was statistically longer than that of non-responders at only 5.5 months. Histologically, most responder cases were with AFP producing tumors and NSE positive tumors without distant lymph node involvement. Non-responder cases developed marked distant lymph node involvement besides the liver metastasis. Most of responder patients died of lymph node recurrence or distant metastasis other than liver tumor. It may be concluded that additional therapy to HAI is needed to improve the prognosis of gastric cancer patients with multiple liver metastases.

[Experimental study on intraperitoneal and intravenous administration of anti-tumor agents for liver metastasis].

Intraperitoneal chemotherapy has been the treatment for peritoneal seedings. Most of the anti-tumor agent administered intraperitoneally is absorbed from visceral peritoneum, gets into the portal vein system and reaches the liver. Theoretically, intraperitoneal administration of anti-tumor agents must show equivalent effects on the liver metastasis to portal vein infusion. We compared the efficacy of intraperitoneal and intravenous administration of 5-FU, CDDP and CPT-11, using colon 26 mouse liver metastasis model. Intraperitoneal administration of 5-FU or CPT-11 was statistically superior to intravenous administration to diminish the liver metastatic deposits. CDDP experiment did not show a statistical difference, but the superiority intraperitoneal administration was recognized. Intraperitoneal administration of anti-tumor agents is more effective for not only peritoneal seedings but also liver metastases than intravenous administration. Intraperitoneal chemotherapy might be an effective adjuvant chemotherapy for gastrointestinal malignancies.

[Pharmaco-dynamic study of methotrexate (MTX) during intraperitoneal MTX/5-FU sequential therapy after gastric surgery].

A pharmaco dynamic study of Methotrexate (MTX) during intraperitoneal MTX/5-FU sequential therapy was carried out after gastric surgery. A comparative study of the route of MTX administration and its dose was also done. 1) Comparative study of the serum concentration of MTX between i.p. and i.v. administration revealed a similar MTX concentration except immediately after administration. 2) A comparative study of the serum concentration of MTX administered i.p. between patients with and without malignant ascites was conducted. Immediate elevation of the serum concentration of MTX was observed in patients without malignant ascites. On the other hand, the MTX concentration was slowly elevated and washed out in patients with malignant ascites. 3) The MTX concentration in the intraperitoneal fluid was compared between patient with and without malignant ascites. In patients without malignant ascites, MTX disappeared quickly from the intraperitoneal fluid. However, the MTX concentration lasted long in the malignant ascites cases. These results were similar with a low-dose MTX (30 mg/body) or moderate dose (100 mg/body). MTX/5-FU sequential i.p. therapy can thus be an effective treatment for patients after gastric surgery, though clearance of MTX was slow in cases with malignant ascites.

[Intrabiliary administration of doxorubicin for pancreaticobiliary cancer].

UNLABELLED: The effect and drug absorbtion of intrabiliary chemotherapy with Doxorubicin for pancreaticobiliary cancer with PTCD was investigated. Doxorubicin (DXR: 20 mg) was administered intrabiliary for 3 hours by PTCD catheter. Radiographic evaluation of the bile duct before and after chemotherapy and measurement of DXR concentration in the serum and bile were carried out. RESULTS: Intrabiliary administration of DXR was completed without any significant complications other than epigastric pain. Radiographic study of the bile duct of a patient with pancreatic cancer who could successfully complete DXR administration showed improvement of bile duct passage. The placement of biliary stent could be achieved. Concentration of DXR in the serum after administration was below the lowest determinable level while those in the bile maintained a considerably high concentration 4 hours after the administration. With negligible absorption from bile, intrabiliary chemotherapy with DXR was thought to be an acceptable palliative treatment for pancreaticobiliary cancer.

Microsatellite instability and loss of heterozygosity in primary and secondary proliferative lesions of the parathyroid gland.

Clonality and genetic abnormalities were evaluated to characterize proliferative lesions of the parathyroid gland. Fourteen lesions from patients with single-gland proliferation (adenomas [PA]), 6 lesions from patients with multiple-gland proliferation (primary hyperparathyroidism [PHPT]), and 47 lesions from 16 patients with secondary hyperparathyroidism (SHPT) were examined. Based on the X chromatin inactivation pattern, which was revealed by a HUMARA assay of lesions from female patients (n = 34; 24 informative cases), monoclonality was demonstrated in 6 of 10 PA (60%), 2 of 5 PHPT (40%), and 6 of 9 SHPT lesions (14 of 27 lesions, 52%). By PCR analysis using 17 microsatellite markers on eight chromosomes (chromosomes 1, 2, 3, 5, 6, 11, 13, and 17), loss of heterozygosity was sporadically observed in 4 of 14 PA, 3 of 6 PHPT, and 7 of 47 SHPT lesions, in most cases on a single locus of chromosome 11. On the other hand, microsatellite instability was observed more frequently: ie, in six PA, five PHPT, and nine SHPT lesions. The profile of microsatellite instability depended on the type of proliferation: microsatellite instability (MI) seemed to cluster in the region of chromosome 11 in PA. Microsatellite instability on TP53 was observed in 3 of 6 PHPT lesions and in 2 of 47 SHPT lesions but in no PA lesions. Microsatellite instability on Mfd47 was observed in only some cases of SHPT. Although no significant correlation was identified among histologic features, clonality, and genetic abnormalities in cases of primary proliferation, genetic abnormalities were more frequently observed in SHPT lesions that lacked fat tissues. Thus, genetic instability might be important in proliferative disorders of the parathyroid gland, either with or without uremia. However, genetic instability seems to be induced by different mechanisms in the three types of proliferation studied. In SHPT, the absence of fat tissues may indicate that the proliferation is accompanied by genetic changes.

[Experimental study on intraperitoneal administration of 5-fluorouracil for liver metastasis in comparison with intravenous administration].

We studied the effects of 5-fluorouracil intraperitoneal administration using mouse liver metastasis model. We inoculated 50 microliters Colon26 cell suspension into the spleen and resected it 15 min after cell inoculation under general anesthesia with Ketamine. Control group (n = 7) had no treatment. The intraperitoneal (i.p.) group (n = 8) and intravenous (i.v.) group (n = 7) underwent the treatment on the 2nd and 4th day after the operation. Experimental chemotherapies consisted of 1.5 ml 5-fluorouracil solution (50 mg/kg) for i.p. group and 0.2 ml 5-fluorouracil solution (50 mg/kg) for i.v. group. On the 14th day after the cell implantation, necropsies were performed. Deposits on mouse livers were counted and the mouse livers weighted. Counting of metastatic liver deposits revealed the number of deposits in the control group was 25.6 +/- 12.9, against 2.9 +/- 1.9 and 16.0 +/- 15.6, in the i.p. and i.v. group, respectively. Significant differences in the number of liver deposits were obtained between the control group and i.p. group, and between i.p. group and i.v. group (p < 0.05). The mean liver weight (mg)/mouse body weight (g) were 76.3 +/- 24.7 in the control group, 54.3 +/- 4.7 in the i.p. group and 60.0 +/- 12.7 in the i.v. group. A significant difference was observed only between the control group and the i.p. group (p < 0.05). I.p. administration of 5-fluorouracil was superior to i.v. administration for control of the liver metastasis. Moreover, the side effect by 5-fluorouracil i.p. treatment was milder than by i.v. therapy. We confirmed the effectiveness of 5-fluorouracil intraperitoneal chemotherapy for the potential liver metastasis and liver micrometastasis. Intraperitoneal chemotherapy is also useful for peritoneal seeding. We think intraperitoneal chemotherapy is a recommendable administration route for gastrointestinal malignancies.

[Hemodynamics at hepatoarterial infusion of 5-FU in a chronic renal failure patient maintained by hemodialysis].

The authors studied the hemodynamics of 5-FU hepatoarterial infusion in a colorectal cancer patient with multiple liver metastases, who had chronic renal failure maintained by hemodialysis. Under weekly high dose 5-FU hepatoarterial infusion (1,000 mg/m2, 5 hours), on a non-dialysis day, serum 5-FU concentration was 1,090 ng/ml just after the 5 h infusion, 391 ng/ml at 15 min, 217 ng/ml at 30 min, 47 ng/ml at 60 min, and < 4 ng/ml at 120 min after infusion. On a dialysis day it was 1,500 ng/ml just after infusion, 41 ng/ml at 15 min, 5 ng/ml at 30 min, and < 4 ng/ml at 60 and 120 min after infusion. A control group (n = 4), who had liver metastases from colorectal cancers and normal renal functions, showed 5-FU serum concentration of 987 +/- 384 ng/ml just after infusion, 226 +/- 117 ng/ml at 15 min, 18.5 +/- 5.8 ng/ml at 30 min, < 4 ng/ml at 60 and 120 min after infusion. The serum 5-FU concentration of the patient was maintained higher on non-dialysis days, while it decreased more rapidly on dialysis days than that of the control group. There were no clinical complications due to the weekly high dose 5-FU hepatoarterial infusion. Under the treatment of continuous 5-FU hepatoarterial infusion (500 mg/day), the serum 5-FU concentration of this patient was kept under 115 ng/ml. After hemodialysis, the concentration decreased. The serum 5-FU concentration of the control group (n = 4) was under 66 ng/ml. There were no side effects under the protocol of continuous 5-FU hepatoarterial infusion. 5-FU hepatoarterial infusion for liver metastasis was a safe treatment for a renal failure patient with hemodialysis.

[Pharmaco-dynamic influence under ascites or laparotomy on intraperitoneal sequential MTX/5-FU therapy].

We studied pharmaco-dynamic changes of intraperitoneal sequential MTX (30 mg)/5-FU (750 mg) therapy in gastric cancer patients with malignant ascites and those who had undergone a gastrectomy. The serum and ascites levels of MTX in patients with malignant ascites decreased much slower than in patients without ascites. In patients with ascites, the serum MTX concentration peaked 8 hours later and then gradually decreased. The ascites MTX level decreased as low as 1/10 2 days after the intraperitoneal administration. The serum and ascites 5-FU levels revealed a minor prolongation of 5-FU concentration in patients with ascites. Gastrectomy did not affect the pharmaco-dynamics of MTX in post-operative patients with sequential intraperitoneal administration of MTX/5-FU on 1, 8 and 15 POD.

[Telomere length in breast carcinoma of the young and aged].

In order to clarify the relationship between the telomeric length of human female breast carcinoma cells and patient age, and between telomeric length and the histological type of carcinoma, we examined 64 patients (aged 20-89 years) with breast carcinoma by histological and southern blot analysis. No difference in the telomeric length was recognizable among the three major histological types: papillotubular, solid tubular and scirrhous (7.9-8.7 kilobase pairs (kbp)). Mean telomere lengths in the groups aged under 35 (8 patients), 36-50 (10 patients), 51-70 (17 patients), 71-80 (19 patients), and over 81 years (10 patients) were 11.0, 9.9, 7.0, 7.7 and 7.6 kbp, respectively. There was no significant evidence for telomeric shortening in breast carcinoma according to patient age. Two peaks of telomeric length were observed in three carcinomas comprising a medullary carcinoma and two solid tubular carcinomas showing very prominent lymphocyte infiltration histologically.