Case report: pulmonary embolism from thrombosis in a duplicated inferior vena cava developing after an electrophysiologic procedure.

Duplicated inferior cava (IVC) is an anomaly we rarely encounter during electrophysiologic procedures. We report a case with duplicated IVC who developed thrombosis of the left IVC following an electrophysiologic procedure, which resulted in an asymptomatic pulmonary embolism. It is speculated that several catheters placed in the torturous route through the left IVC caused either endothelial damage to the vessel wall, or hemostasis in the relatively narrow portion of the vessel, resulting in thrombus formation. Since the prevalence and characteristics of thrombo-embolic complications during electrophysiologic procedures in patients with a duplicated IVC remain unknown, we believe this case should be reported.

Delay in administration of CDDP until completion of AGM-1470 treatment enhances antimetastatic and antitumor effects.

The efficacy of cis-diammine dichloroplatinum (CDDP) therapy in combination with continuous administration of angiogenesis inhibitor o-(chloroacetyl-carbamoyl) fumagillol (AGM-1470) was evaluated experimentally using a transplantable rat osteosarcoma line previously established in our laboratory. AGM-1470 (2.5 mg/kg body weight/week) was administered by Alzet osmotic pumps for 2 weeks starting from 7 days after tumor inplantation and CDDP (1.25 mg/kg) was given on days 21 and 24. The number of lung metastatic nodules was counted and the wet weights of the primary tumors were measured 5 weeks after tumor inplantation. Values with administration of CDDP 3 days after discontinuation of AGM-1470 were significantly lower than when the two agents were coadministered (P < 0.05). This animal model should facilitate optimization of the timing of combination therapy.

Telomerase activity correlates with growth of transplantable osteosarcomas in rats treated with cis-diammine dichloroplatinum or the angiogenesis inhibitor AGM-1470.

To determine the role of telomerase activity in the growth of tumors in rats undergoing chemotherapy, a comparison of the volumes of telomerase-positive transplantable osteosarcomas was made in rats treated with the antineoplastic agent cis-diammine dichloroplatinum (CDDP) or the angiogenesis inhibitor O-(chloroacetylcarbamoyl)fumagillol (AGM-1470). Male F344 rats, 8 weeks old, received transplants of macroscopic lung metastatic nodules into the subcutaneous back space and treatment was started on day 14 thereafter. CDDP was injected i.v. at doses of 0, 0.625, 1.25 and 2.5 mg/kg body weight (b.w.) and AGM-1470 was administered at total doses of 0, 2.5, 5 and 10 mg/kg b.w. over 2 weeks by osmotic pumps, also implanted into the subcutaneous back space, but remote from the transplanted tumors. On day 28, all animals were killed for measurement of transplanted tumor size and determination of telomerase activities by telomeric repeat amplification protocol (TRAP) assay. The results showed telomerase activity to be highly correlated with the treated/non-treated (T/C) tumor size ratio (r = 0.96, P < 0.0001). In a second experiment, CDDP at 2.5 mg/kg b.w. and AGM-1470 at 10 mg/kg b.w., these being the most effective doses, were given as in the first experiment, and animals were serially killed on days 14, 21, 28, 35 and 42. Tumors in rats treated with CDDP and AGM-1470 showed 18.2% and 20.5% of the control telomerase activity on days 35 and 21, respectively, when tumor growth was inhibited. However, on day 42, the activities increased to 46.5% and 92.5%, this correlating with re-growth (r = 0.73, P < 0.0001). These results suggest that decline of telomerase activity may be involved in tumor growth retardation induced by chemotherapeutic agents. This possibility clearly warrants further mechanistic studies.

Efficacy of CDDP and AGM-1470 chemotherapy against lung metastasis in rat osteosarcoma depends on the timing of combined administration.

The efficacy of combination therapy with cis-diammine-dichloroplatinum (II) (CDDP) and o-(chloroacetyl-carbamoyl) fumagillol (AGM-1470) was evaluated experimentally using a transplantable rat osteosarcoma line, previously established in our laboratory, with a high potential for metastasis. Tumor-bearing male Fischer 344 rats were administered CDDP (2.5 mg/kg) together with, or after discontinuation of, AGM-1470 treatment (10 mg/kg/body weight/week). When CDDP was administered three days after discontinuation of AGM-1470 the most pronounced antimetastatic effects were observed, although the antitumor effect was approximately the same.

Efficacy of slow-releasing anticancer drug delivery systems on transplantable osteosarcomas in rats.

New drug delivery systems for cis-diamminedichloroplatinum (CDDP) incorporated into vehicles, such as polymethylmethacrylate (PMMA), fibrin glue (F.G.), alpha-tricalciumphosphate (TCP) and ethylenevinyleacetate copolymer (Polymer) were examined using a rat osteosarcoma model. The materials containing CDDP were directly implanted into the tumors or subcutaneous tissue of rats, and the inhibitory effects on tumor growth and lung metastasis were evaluated. Data on in vitro kinetics of CDDP release revealed good results for both TCP and F.G., and the release pattern from TCP to be most appropriate for a slow-releasing drug delivery system. This was supported by the results of the implantation experiments, whereby the direct implantation of TCP containing CDDP (CDDP-TCP) into tumors, gave significantly better inhibitions of tumor growth and metastasis than either non-treatment (P < 0.01) or subcutaneous implantation (P < 0.05). In a second experiment, using different administration procedures, different inhibitory effects on tumor growth and lung metastatic potency were observed with intra-arterial and intravenous CDDP administration, as well as with CDDP-TCP implanted subcutaneously. Suppression effects of CDDP (10 mg/kg)-TCP directly implanted into tumors were equal to those of intra-arterial (2.5 mg/kg) and intravenous (5.0 mg/kg) administrations. The present results suggest CDDP-TCP implantation to be effective as a slow-release drug delivery system for inhibiting tumor growth and metastasis, and that it should be a useful adjuvant to conventional i.v. or i.a. chemotherapy.

Efficacy of the angiogenesis inhibitor O-(chloroacetyl-carbamoyl)fumagillol (AGM-1470) on osteosarcoma growth and lung metastasis in rats.

The efficacy of the anti-angiogenic agent, O-(chloroacetyl-carbamoyl)fumagillol (AGM-1470), against primary tumor growth and spontaneous lung metastasis was evaluated experimentally using a transplantable osteosarcoma line in rats previously established in our laboratory. Male Fischer 344 rats bearing the tumor with a high potential for metastasis received intermittent or continuous subcutaneous administrations of AGM-1470. Both treatment regimens resulted in significant inhibitions of spontaneous lung metastasis and primary tumor growth in a dose-dependent manner, with continuous administration of AGM-1470 exerting the most pronounced inhibitory effects on both parameters.

Total parenteral nutrition supplemented with L-alanyl-L-glutamine and gut structure and protein metabolism in septic rats.

The effects of administering total parenteral nutrition (TPN) supplemented with the dipeptide of L-alanyl-L-glutamine (Ala-Gln) on gut structure, barrier function, and protein metabolism were investigated in septic rats. Sepsis was induced by the continuous intraperitoneal administration of endotoxin via a miniosmotic pump. Twenty-three rats were divided into two groups and fed parenterally for 5 days. The Ala-Gln group (n = 11) received a conventional TPN solution supplemented with 2% Ala-Gln, whereas the control group (n = 12) received conventional TPN solution alone. One rat in each group died of endotoxemia. The groups showed similar nitrogen balance, urinary excretion of 3-methylhistidine, and plasma concentration of endotoxin in the portal vein. The groups showed similar incidence of bacterial translocation from the gut to the mesenteric lymph nodes. The intestinal mucosal weight and villous height were significantly greater in the Ala-Gln group than in the control group. Pathological derangement of the mucosal structure was more marked in the control group than in the Ala-Gln group. These results suggest that TPN supplemented with Ala-Gln preserves the gut structure without decreasing the nitrogen balance under septic conditions.

Glutamine-supplemented parenteral nutrition improves gut mucosa integrity and function in endotoxemic rats.

The effects of glutamine-supplemented parenteral nutrition on protein metabolism, small intestinal mucosal metabolism, morphology, and barrier function were studied in endotoxin-treated rats. Forty-six male Wistar rats were randomized to two groups of 23 animals each and received total parenteral nutrition solutions supplemented with either glutamine (GLN group) or glycine (GLY group) at 2% wt/vol. Endotoxemia was induced by continuous intravenous infusion of endotoxin at a dose of 2 mg/kg per day throughout the 4-day study period. The GLN group had a less-negative cumulative nitrogen balance (-14.0 +/- 132.8 mg of nitrogen in the GLN group and -86.8 +/- 161.7 mg of nitrogen in the GLY group, p < .05) and less cumulative excretion of urinary 3-methylhistidine (2910 +/- 593 nmol) than the GLY group (4447 +/- 933 nmol, p < .01). Jejunal mucosal glutaminase activity and the arterio-portal venous blood glutamine concentration differences were significantly higher in the GLN group compared with the GLY group (15.6 +/- 2.3 vs 11.1 +/- 1.9 mumol/g per minute, p < .05, and 181 +/- 52 vs 147 +/- 36 nmol/mL, p < .05, respectively). The morphology of the jejunal mucosa in the GLN group was significant for having greater mucosal weight (23.4 +/- 3.1 vs 17.6 +/- 2.5 mg/cm), villus height (445 +/- 75 vs 357 +/- 57 microns), crypt depth (197 +/- 34 vs 161 +/- 28 microns), and wall thickness (751 +/- 77 vs 648 +/- 102 microns) than the GLY group (p < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Intracavitary treatment of malignant ascitic carcinomatosis with oily anticancer agents in rats.

The anticancer effects and pharmacokinetics of intraperitoneal (ip) injection were determined for doxorubicin (DOX) dissolved in a lymphographic oily contrast medium, Lipiodol Ultrafluid (Lipiodol) (DOX/Lipiodol), using AH 130 ascitic tumor in rats. A high percentage (50%) of long-term survivors (cure) was observed with only a single ip injection of the DOX/Lipiodol on the seventh day after tumor inoculation, by which time the tumor ascites accumulated to a level similar to that seen clinically. The cure rate of this lipid formulation was much better than that for DOX dissolved in saline (DOX/saline) (17%). An immunopotentiating agent, Picibanil, given in 1 KE (clinical unit) or 5 KE doses was no better than the saline group, indicating that the above effect was not a result of immunopotentiation by Lipiodol. The severity of toxic side effects of DOX was also reduced by lipid solubilization. Pharmacokinetic study showed that DOX/saline was absorbed rapidly into the blood stream from the peritoneal cavity, whereas DOX/Lipiodol was retained in the ascites at a higher concentration for a much longer time. Thus the present results suggest that lipid formulations of anticancer agents have augmented therapeutic efficacy by intracavitary injection. The lipid formulations show increased stability in and prolonged slow release from the lipid milieu. Thus this therapeutic tactic of using oily anticancer agents appears to be promising for the control of pleural and peritoneal carcinomatoses.

[Benefits and limitation of extracorporeal circulation with autologous blood using low priming membrane oxygenator].

The high incidence of hepatitis following cardiopulmonary bypass has stimulated attempts to develop a technique of perfusion without homologous blood. Between October, 1987 and March, 1988, 36 patients underwent open heart surgery without homologous blood transfusion were investigated. Patients with infective endocarditis and urgent surgical cases were excluded from this study. Out of 36 patients using hemoconcentrator, autologous blood and the Variable Prime Cobe Membrane Lung (VPCML), 28 patients (78%) could avoid homologous blood transfusion during the operation and 24 patients (67%) received no homologous blood throughout their hospital stay. Thus, the application of lower volume extracorporeal oxygenator system, reinfusion of residual pump volume using hemoconcentrator and predonated autologous blood could achieved cardiac surgery without homologous blood transfusions in the majority of patients. Moreover, the VPCML had sufficient gas transfer in adult patients with body weight ranging from 37 kg to 70 kg. In renal function, serum creatinine levels in patients without homologous blood were within normal limits throughout 1 month after surgery. However, creatinine level was significantly elevated at the third postoperative day in the homologous blood transfusion group. Thus, these results suggest that application of VPCML and hemoconcentrator combined with predonated autologous blood is useful to achieve open heart surgery without donor blood.

Tumor targeting by arterial administration of lipids: rabbit model with VX2 carcinoma in the liver.

We previously found that a lipid contrast medium, Lipiodol, remained selectively in liver tumors for a prolonged time after injection via the hepatic artery. We now extend this technique to other lipids including linoleic acid, olive oil, tea seed oil, and medium-chain triglyceride (MCT). MCT is a semisynthetic triglyceride with a lower viscosity than that of the other lipids. Each lipid was mixed with 14C linoleic acid, and the mixture with or without anticancer agent smancs was injected via the proper hepatic artery of rabbits with VX2 carcinoma in the liver. The 14C count in the tumor tissue was always more than 100 times that of the plasma or kidney, and the radioactivity 15 min after injection of MCT was more than 2500 times greater than that of blood plasma. At 24 hr after injection, the radioactivity recovered in the tumor was 4.9-37.0% (average 19.6%) of the dose, which indicated the greatest retention in the tumor tissue; there was rapid clearance from the rest of the body primarily via the bile. Advantages of the administration of lipid-solubilized drugs are: (i) remarkable tumor-selective targeting (a decisive anticancer effect with fewer side effects); (ii) prolonged drug retention (resulting in infrequent administration); (iii) various choices of different fatty acids with various pharmacokinetic characteristics as the carriers of the anticancer agents; and (iv) arterial administration is practicable in most hospitals.

Anticancer effects of arterial administration of the anticancer agent SMANCS with lipiodol on metastatic lymph nodes.

A new method of arterially administering an oily anticancer agent was successfully established for the selective targeting of metastatic lymph nodes. A high molecular weight anticancer agent, a conjugate of copolymer (styrene maleic acid) to neocarzinostatin (SMANCS) was prepared in our laboratory and dissolved in a lymphographic oily contrast medium, Lipiodol (SMANCS/Lipiodol). SMANCS/Lipiodol was administered intraoperatively to eight patients with colorectal cancer and preoperatively to one patient with gastric cancer with lymph node metastases. In six of the patients with colorectal cancer, the drug was administered via an artery and in the other two patients the drug was injected into the wall of the colon near the primary cancer. In the patient with gastric cancer, the drug was administered via the left gastric artery. Delivery of the drug to the lymph nodes was examined roentgenologically and the anticancer effect was examined histologically. The results showed that SMANCS/Lipiodol could be delivered to the metastatic lymph node via the artery, but it could not be delivered to the metastatic lesion of the lymph node via the lymphatic route. In the patient with gastric cancer, SMANCS/Lipiodol preoperatively administered via an artery was found to remain selectively in a metastatic lymph node and an anticancer effect was histologically proved in all three of the metastatic lymph nodes.

[Prevention of hepatic metastases in rabbits by administration of an oily anticancer agent into the portal vein].

We studied one kind of prophylactic chemotherapy against hepatic metastases. The therapy was carried out with a lymphographic oily contrast medium. Lipiodol, and a high-molecular-weight anticancer agent known as SMANCS. SMANCS was dissolved in Lipiodol by sonication (SMANCS/Lipiodol, 1 mg of SMANCS in 1 ml of Lipiodol). SMANCS/Lipiodol, administered into the portal vein, remained for a long time in the portal vein and was eliminated gradually through the bile and urine. SMANCS/Lipiodol (0.4ml/kg) was injected into the mesenteric vein in rabbits, which were then inoculated with the highly malignant carcinoma VX-2. Rabbits injected with SMANCS/Lipiodol before inoculation had significantly fewer hepatic metastases than the control 12 days later (P less than 0.001). Survival was significantly longer (P less than 0.005; 36.0 +/- 7.7 days) with SMANCS/Lipiodol before inoculation than without treatment (23.5 +/- 3.0 days). Hepatic metastases might thus be prevented by portal administration of an appropriate oily anticancer agent.

Reduction of hepatic metastases in rabbits by administration of an oily anticancer agent into the portal vein.

We studied a prophylactic chemotherapy against hepatic metastases arising from the shedding of tumor cells into the portal circulation. The therapy was done with a lymphographic oily contrast medium, Lipiodol, and a high molecular weight anticancer agent named poly(styrene-maleic acid) copolymer conjugated neocarzinostatin (SMANCS), developed in our laboratory. SMANCS was dissolved in Lipiodol by sonication (SMANCS/Lipiodol, 1 mg of SMANCS in 1 ml of Lipiodol). Twelve rabbits were simply inoculated with the highly malignant carcinoma VX-2. Fifteen rabbits were given injections of SMANCS in glucose and Lipiodol into the portal vein and were subsequently inoculated with the tumor cells. Eighteen were given injections of SMANCS/Lipiodol and then the tumor cells. These rabbits were killed 12 days later. Thirteen were given injections of the tumor cells alone and were allowed to survive. Sixteen were given injections of SMANCS/Lipiodol and then with the tumor cells; they were allowed to survive. Rabbits given injections of SMANCS/Lipiodol before tumor inoculation had significantly fewer (P less than 0.001) metastases than those not treated or those given SMANCS in glucose and Lipiodol. Survival was significantly longer [P less than 0.005; 36.0 +/- 7.7 (SD) days] with SMANCS/Lipiodol before tumor inoculation than without treatment [23.5 +/- 3.0 days]. SMANCS/Lipiodol has a prolonged anticancer effect because it remains in the portal vein and allows sustained drug release from the oil (Lipiodol) to aqueous spaces. Hepatic metastases might be prevented by portal administration of the appropriate oily anticancer agent.

[CT image of the liver cancer after administration of SMANCS/lipiodol].

A new type of anticancer agent with an amphiphilic nature, poly (styrene-co-maleic acid)-conjugated neocarzinostatin [SMANCS], was dissolved in the lipid contrast medium Lipiodol [SMANCS/LPD]. This medium was injected intra-arterially and was found to be an invaluable tool for highly sensitive CT image analysis of tumors. Following administration, CT images revealed high-density areas which corresponded to the location and size of liver cancer, the smallest being 4 mm in diameter. The deposition pattern of SMANCS/LPD in liver cancers by CT was classified into 3 types. In type A, Lipiodol was distributed relatively evenly in the tumor lesion, while in type B it was accumulated predominantly around the tumor periphery, the central portion remaining low in density. A for cases exhibited a type C pattern which was a mixture of types A and B. Type A was found essentially in primary liver cancer, and types B and C in secondary liver cancer. Thus, the CT pattern was found to be useful for differential diagnosis. For a sufficient therapeutic effect, 0.08 ml of SMANCS/LPD per cm2 of the maximal CT cross-section of the tumor area was found to be necessary. As a routine protocol after SMANCS/LPD administration, CT scanning was recommended for primary liver cancer initially at one week and then once every month. Secondary liver cancer required more frequent CT follow-ups after administration, on the 3rd day, after one and two weeks, and every month, due to the relatively rapid disappearance of the stain than in primary liver cancer.

[Targeting of anticancer chemotherapy utilizing the characteristic nature of the neovasculature of solid tumors].

We have been able to achieve targeting of anticancer treatments using the differences between the neovasculature of solid tumors and the vasculature of normal tissues. The first of these differences was as follows; We discovered that when the lipid contrast medium, Lipiodol, was administered arterially, it remained selectively in the solid tumor for a long time. Using this characteristic nature of Lipiodol, we achieved targeting of anticancer chemotherapy by arterial administration of oily anticancer drugs solubilized in Lipiodol. Remarkable anticancer effects against various malignant solid tumors were observed using this targeting chemotherapy. The second of the above differences, studied by Suzuki, is responsiveness to angiotensin II, in which the blood flow in the tumor can be increased using this vasoconstrictor. With Angiotensin II, a larger volume of oily anticancer drugs could be delivered to the tumor. The third difference is the permeability of the neovasculature to drugs of high molecular weight and the duration that these drugs remain in the extracapillary space. The high-molecular-weight anticancer agent, SMANCS (m.w. 17,000) dissolved in 5% glucose solution, was administered intravenously, and its histological antitumor effects on gastric cancer and esophageal cancer were clearly observed.

Selective targeting of anti-cancer drug and simultaneous image enhancement in solid tumors by arterially administered lipid contrast medium.

Twenty-four patients with various solid tumors including metastatic liver cancer and cancer of the lung, gallbladder, and pancreas were treated with a lipophilic macromolecular drug, copoly(styrene-maleic acid) conjugated neocarzinostatin (SMANCS). The drug was dissolved in a lipid contrast medium Lipiodol and administered by catheterizing the respective feeding arteries under x-ray monitoring. The advantages of this therapy include: (1) selective deposition of Lipiodol with the anti-cancer drug in the target tumor, (2) a pronounced and long-lasting anti-cancer effect, (3) enhanced visualization of the tumor on x-ray examinations for a prolonged period which also facilitated the long-term follow-up, (4) semiquantitative evaluation of the dosage regimen by x-ray examination before further administration, (5) general applicability due to procedural simplicity, and (6) little side effect. Since the amount of Lipiodol and SMANCS used per administration for a patient (1.0-5.0 ml; 1.0-5.0 mg) was far less than the anticipated toxicity (LD50 of Lipiodol = 95 ml/60 kg, dog, intravenously; and that of SMANCS = 3.4 mg/kg, mouse, IV), no deleterious effects to such critical organs as the brain, heart, lung, liver, or kidneys were observed upon radiologic and general clinical examination.

[Arterial administration of SMANCS and other antitumor agents dissolved in lipiodol for various malignant solid tumors].

Selective deposition of lipiodol in primary and metastatic liver cancer, lung cancer, gallbladder cancer, pancreatic cancer and renal cancer was elucidated by plain X-ray film and CT. Selective delivery of anticancer agent, SMANCS was also proved by measurement of its biological activities of removed specimen. Because of these selective delivery of anticancer agent and embolization of neovasculature in the tumor, highly effective chemotherapy of unresectable cancer was established. Drug was given via celiac, the hepatic, bronchial or renal artery mostly 1-5 mg in 1-5 ml of lipiodol once every 3-8 weeks. Antitumor effects of this therapy for hepatocellular carcinoma was confirmed based on decrease in AFP levels (92% of the cases), reduction in tumor size (90% of the cases) and histology. In 76 percent of the patients with the other malignant solid tumors reduction in tumor size was recognized. Decrease in CEA level occurred in 88 percent of the cases with metastatic liver cancer and lung cancer. Major side effect was transient fever in about 50% of cases. Mitomycin C and aclarubicin dissolved in lipiodol showed remarkable antitumor effects for experimental liver cancer.

Studies on anticancer treatment with an oily anticancer drug injected into the ligated feeding hepatic artery for liver cancer.

In six adult patients with nonresectable liver cancer, as well as in mature New Zealand white rabbits with implanted VX2 carcinoma in the liver, the artery feeding the hepatic lobe with the malignant lesion was ligated, and an oily contrast medium (Lipiodol Ultra-Fluid) was injected into the hepatoproximal lumen of the ligated artery of the liver with carcinoma. The oily contrast medium was detected in all the branches of the artery injected, and thereafter was found only in tumor tissue for 7 days experimentally and for 16 months clinically. Taking advantage of this phenomenon, the therapeutic effect of the injection of an oily anticancer drug (bleomycin oil suspension) into the hepatoproximal lumen of the ligated hepatic artery was investigated in rabbits with VX2 carcinoma of the liver. The mean concentration level of bleomycin in the tumor tissue was 2.4 +/- 0.4 microgram/g 1 week after the injection of bleomycin oil suspension (1.5 mg potency/kg) in three rabbits. However, its concentration level in nontumorous tissue of the liver was undetectably low in two rabbits, but 0.6 microgram/g in the third rabbit. The group of rabbits receiving an injection of bleomycin oil suspension into the ligated artery had a significantly longer mean survival time than those of the experimental group receiving an injection of saline solution of bleomycin into the ligated artery as well as the three other groups treated (P less than 0.02, N = 5 for each group). It may be concluded that an oily anticancer drug injected into the hepatoproximal lumen of the ligated hepatic artery can intensify the anticancer effects of a ligation of the hepatic artery for liver cancer.