Percutaneous radio-frequency ablation therapy using a clustered electrode for malignant liver tumors.

GOALS: To examine the safety and effectiveness of percutaneous radio-frequency ablation therapy (PRAT) for malignant liver tumors, using a needle with cluster radio-frequency (RF) electrodes. STUDY: The subjects were 13 patients with solitary malignant liver tumors: 10 had hepatocellular carcinoma and 3 had metastatic liver tumors. One session of PRAT with cluster RF electrodes was performed until roll-off occurred two times. Dynamic computed tomography (CT) and fine needle tumor biopsy under ultrasonographic guidance were conducted to assess the therapeutic efficacy. Aspartate aminotransferase, alanine aminotransferase, lactic dehydrogenase, and total bilirubin were evaluated before and 1, 3, and 7 days after PRAT. RESULTS: There were no serious complications. Aspartate aminotransferase, alanine aminotransferase, and lactic dehydrogenase levels peaked 1 day after PRAT and decreased thereafter. No icterus occurred. Of the 13 tumors, 12 showed complete necrosis on dynamic CT; however, one of them showed histologically incomplete necrosis in the tumor biopsy. In both of the ineffective cases, the tumors were located near relatively large vessels. There was no recurrence in the liver in all cases of PRAT that were effective (observation periods: 6--14 months; mean, 10 months). CONCLUSIONS: Percutaneous radio-frequency ablation therapy using a clustered electrode is a safe and effective treatment of malignant liver tumors, if the tumor is not located near the large vessels.

Percutaneous radiofrequency ablation therapy using a clustered electrode in the animal liver.

BACKGROUND/AIMS: The aim of the present study was to examine the safety and effectiveness of percutaneous radiofrequency ablation therapy using a needle with cluster radiofrequency electrodes in an animal model. METHODOLOGY: A total of 10 radiofrequency applications were performed in the normal liver of 5 domestic pigs with real-time ultrasonography until roll-off occurred two times. Aspartate aminotransferase, alanine aminotransferase, lactic dehydrogenase, and total bilirubin were evaluated before the procedure and 1 h, 24 h, and 7 days following percutaneous radiofrequency ablation therapy. The animals were euthanized 1 or 2 weeks after percutaneous radiofrequency ablation therapy, and the livers were removed for gross and histopathologic analysis for coagulation necrosis. RESULTS: There were no complications in any of the experimental animals. Aspartate aminotransferase, alanine aminotransferase, and lactic dehydrogenase levels peaked 24 h following percutaneous radiofrequency ablation therapy, and decreased with time thereafter. Total bilirubin was not elevated in any of the animals at any time. Macroscopic examination revealed that the area of coagulated necrosis was 28 x 21 mm when using a 2.0-cm needle, and 41 x 35 mm when using a 3.5-cm needle. Coagulation necrosis did not occur near large vessels. Microscopic examination of the fixed tissue revealed that coagulation necrosis occurred in preserving lobular structure. CONCLUSIONS: Percutaneous radiofrequency ablation therapy using a clustered electrode is a safe and effective treatment for liver tumor. Incomplete coagulation necrosis, however, can occur when percutaneous radiofrequency ablation therapy is performed for tumors located near large vessels.

Treatment of solitary small hepatocellular carcinoma: consideration of hepatic functional reserve and mode of recurrence.

BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) recurs frequently after initial treatment. The subsequent prognosis varies with the mode of recurrence. Some patients die of hepatic failure even though the HCC is controlled. We consider the clinical stage (CS), using the modified Child-Pugh classification, to be an important factor influencing the prognosis of these patients. METHODOLOGY: To determine the most effective treatment for HCC, we examined 105 patients with solitary small HCC who were followed-up for more than 1 year after initial treatment. All of them were judged to be cured according to imaging or histological studies. The initial treatments were hepatic resection (n = 43), percutaneous ethanol injection therapy (PEIT, n = 33), and percutaneous microwave coagulation therapy (PMCT, n = 29). The modes of recurrence were divided into intrahepatic metastasis (IM) and multicentric occurrence (MO). RESULTS: Prognosis of MO was superior to that of IM in CS I patients, but there was no difference in prognosis between these modes in CS II. The hepatic resection group had more MO recurrences in CS I patients and more IM recurrences in CS II patients. IM developed frequently after PEIT and PMCT, regardless of the CS. Prognosis with hepatic resection was superior to that of the other treatments in CS I patients, but there was no difference in prognosis among the 3 treatment modalities in CS II patients. CONCLUSIONS: These data indicate that hepatic resection is the first choice for treating HCC in CS I patients, and that PEIT or PMCT is preferable for CS II patients.

Diagnosis of small hepatocellular carcinoma--imaging diagnosis and significance of tumor biopsy.

BACKGROUND/AIMS: To compare the effectiveness of different imaging modalities and the significance of tumor biopsy for diagnosing small hepatocellular carcinoma. METHODOLOGY: Nodules (n = 352) with diameters of 30 mm or less newly detected by periodic ultrasonography and computed tomography in 234 patients with chronic liver disease were investigated with magnetic resonance imaging and digital subtraction angiography. These findings were compared with histologic findings. Histologic diagnoses were dysplastic nodule (n = 23), well-differentiated hepatocellular carcinoma (n = 163), moderately differentiated hepatocellular carcinoma (n = 159), and poorly differentiated hepatocellular carcinoma (n = 7). We compared three groups based on-diameters of 10, 11-20, and 21-30 mm. Nodules were diagnosed as hepatocellular carcinoma if they had hypervascular staining on digital subtraction angiography, hyperintensity on magnetic resonance T2-weighted images, arterial phase enhancement on enhanced magnetic resonance imaging, or low-high-low density on enhanced computed tomography. RESULTS: Imaging alone was sufficient to diagnose hepatocellular carcinoma in 66.3% of the well-differentiated nodules and 91.6% of the moderately and poorly differentiated nodules (P < 0.001) The size of the nodule influenced the diagnosis of hepatocellular carcinoma by imaging alone in 65.5% (< or = 10 mm), 77.2% (11-20 mm), and 92.3% (21-30 mm) (< or = 10 vs. 21-30: P < 0.0001, 11-20 vs. 21-30: P < 0.0005). It was impossible to determine the degree of differentiation of the hepatocellular carcinoma by imaging alone. CONCLUSIONS: The effectiveness of imaging for the diagnosis of hepatocellular carcinoma improved with decreasing differentiation and increasing diameter of the nodules. Tumor biopsy was required to make a histological accurate diagnosis.

Dietary diosgenin attenuates subacute intestinal inflammation associated with indomethacin in rats.

We investigated the effects of dietary diosgenin (Dio), a plant-derived sapogenin, on indomethacin (Indo)-induced intestinal inflammation and alterations in bile secretion in rats. In anesthetized rats, bile secretion, intestinal inflammation, and blood chemistry were assessed 3 days after two subcutaneous injections of Indo given 24 h apart. Dio (> 80 mg.kg-1.day-1) pretreatment significantly inhibited weight and food intake decreases and intestinal inflammation. This protective effect was confirmed by examination of gross and histological findings and intestinal myeloperoxidase activity. Dio significantly increased biliary cholesterol (Chol) output and prevented the decreases in bile flow, bile acid output, and biliary alpha-muricholic acid and the increases in biliary hyodeoxycholic acid, deoxycholic acid, and hydrophobicity index of bile. Significantly more biliary Chol and phospholipids were present in macromolecules separate from bile acids and Indo in Dio-treated rats. Dio significantly increased the elimination constant of Indo and reduced plasma Indo levels at 3 and 12 h but did not influence biliary secretion of Indo for 3.5 h after injection. Although Dio dose-dependently attenuated subacute intestinal inflammation and normalized bile secretion in this model, it may also compromise the anti-inflammatory action of indo.

Evaluation of nitrofurantoin on the two stages of urinary bladder carcinogenesis in the rat.

The possibility that nitrofurantoin is a complete carcinogen or is an initiator or promoter of urinary bladder carcinogenesis was evaluated in male weanling F344 rats. No increase in tumor incidence was observed in rats fed nitrofurantoin at a level of 0.187% of the diet for 2 years compared to a control group. Also, no evidence of bladder initiating activity by nitrofurantoin was observed using sodium saccharin (5% of the diet) as a promoter, and no promoting activity was observed when nitrofurantoin was fed after initiation by N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (0.2% of the diet for 4 weeks). In a second experiment, nitrofurantoin (at a dose of 0.187% of the diet) was administered for 6 weeks to rats with a rapidly proliferating bladder epithelium following freeze ulceration, and then the rats were treated with 5% sodium saccharin in the diet for 98 weeks. In additional rats, labelling index following [3H]thymidine injection, determined after 12 weeks of feeding nitrofurantoin, was not increased above control levels in the urinary bladder, stomach, duodenum, or liver. Metabolism of nitrofurantoin by prostaglandin H synthase (PHS) was examined using solubilized ram seminal vesicle microsomes. The rate of nitrofurantoin metabolism by PHS was much less than that observed with benzidine, and the proportion of total metabolite bound to protein was also much less than that with benzidine. These results are consistent with previous reports describing the lack of effect of nitrofurantoin on urinary bladder carcinogenesis.

Initiation of urinary bladder carcinogenesis in rats by freeze ulceration with sodium saccharin promotion.

Sodium saccharin was previously shown to induce a significant incidence of transitional cell carcinoma of the bladder when administered to rats either immediately or beginning 2 weeks after ulceration of the bladder epithelium induced by freezing or cyclophosphamide injection. However, the marked regenerative hyperplasia following ulceration by either of these methods is not completely repaired until 3 to 4 weeks after ulceration. To determine whether initiation in this model was due to the ulceration and regenerative hyperplasia alone or if it was due to the administration of sodium saccharin acting on the hyperplastic epithelium, the effect of administering sodium saccharin at various times after ulceration was examined. Five-week-old F344 male rats were given sodium saccharin as 5% of the diet beginning either immediately (Group 1) or 2, 4, 6, or 18 weeks (Groups 2, 3, 4, or 5, respectively) after freezing of the bladder, and sacrificed 2 years after the start of the experiment. The incidences of rats with transitional cell carcinoma of the bladder were 11 of 36 rats (31%) in Group 1, 6 of 36 (17%) in Group 2, 12 of 40 (30%) in Group 3, 7 of 36 (19%) in Group 4, and 9 of 39 (23%) in Group 5. Sodium saccharin without prior ulceration induced a transitional cell papilloma in one rat, and freeze ulceration without subsequent sodium saccharin induced a transitional cell carcinoma in one rat. No bladder lesions were seen in the untreated control rats. Scanning electron microscopic examination of rats fed sodium saccharin after ulceration showed evidence of multifocal hyperplasia and significant surface changes either at Week 18 of the experiment (Groups 1 to 3) or 18 weeks after beginning sodium saccharin administration (Groups 4 and 5). These results indicate that freeze ulceration of the bladder induced irreversible changes in the epithelial cells related to bladder cancer initiation even though the regenerative hyperplasia is morphologically reversible, and that sodium saccharin promotes the tumorigenic expression of those freeze ulceration-induced cellular changes even after healing from the injury.

Distinction by concanavalin A agglutination between ulceration and repair of rat bladder epithelium induced by freezing or cyclophosphamide and the effect of sodium saccharin.

Agglutination of rat urinary bladder epithelial cells by concanavalin A (Con A) has been reported to be an early marker of bladder carcinogenesis. Ulceration of the bladder, induced by cyclophosphamide (CP) or freezing, followed by sodium saccharin in the diet results in the induction of bladder cancer. In the present studies, the agglutination of rat urinary bladder epithelial cells by Con A was shown to be increased during the regenerative hyperplasia following ulceration induced by i.p. CP injection, but it returned to normal levels by Day 21 when the preparative process was nearly complete. This effect correlated quantitatively with the dose of CP. However, if CP administration was followed by sodium saccharin in the diet beginning 14 days after the injection, the agglutinability of bladder cells by Con A persisted. In contrast, agglutination of bladder cells by Con A during regenerative hyperplasia following ulceration induced by freezing was not increased whether sodium saccharin was fed or not. These results indicate that Con A agglutination distinguishes between the regenerative hyperplasia induced by CP or freezing, even though either method followed by sodium saccharin in the diet results in bladder cancer in the rat.

Inhibition by aspirin of N-[4-(5-nitro-2-furyl)-2-thiazolyl] formamide-induced bladder carcinogenesis and enhancement of forestomach carcinogenesis.

N-[4-(5-Nitro-2-furyl)-2-thiazolyl]formamide (FANFT) is a potent urinary bladder carcinogen in the rat, and it can be metabolically activated in vitro by a variety of enzyme systems including aerobic cooxidation by prostaglandin H synthase. The latter enzyme is present in the rat bladder mucosa and can be inhibited by the oral administration of aspirin (ASA). To determine if ASA could inhibit the bladder carcinogenicity of FANFT, FANFT (0.2%) was co-administered in the diet with ASA (0.5%) for 12 weeks followed by 1 week of ASA only and then 56 weeks on control diet. 0.2% FANFT followed by control diet induced bladder carcinomas in 18 of 21 (87%) rats, but when ASA was co-administered, only 10 of 27 (37%) rats developed bladder carcinoma (p less than 0.001). However, forestomach tumors, not seen in rats fed only FANFT, developed in 7 rats fed FANFT plus ASA. No tumors occurred in control rats or those fed only ASA. Possible mechanisms, including the role of prostaglandin H synthase in FANFT metabolism, are discussed.

Effect of aspirin on N-[4-(5-nitro-2-furyl)-2-thiazolyl]-formamide-induced epithelial proliferation in the urinary bladder and forestomach of the rat.

The co-administration of aspirin with N-[4-(5-nitro-2-furyl)-2-thiazolyl]-formamide (FANFT) to rats resulted in a reduced incidence of FANFT-induced bladder carcinomas but a concomitant induction of forestomach tumors. An autoradiographic study was performed on male F-344 rats fed diet containing FANFT at a level of 0.2% and/or aspirin at a level of 0.5% to evaluate the effect of aspirin on the increased cell proliferation induced by FANFT in the forestomach and bladder. FANFT-induced cell proliferation in the bladder was significantly suppressed by aspirin co-administration after 4 weeks but not after 12 weeks. In the forestomach, and also in the liver, aspirin did not affect the FANFT-induced increase in labeling index. The present results are consistent with the carcinogenicity experiment suggesting that different mechanisms are involved in FANFT carcinogenesis in the bladder and forestomach, and that aspirin's effect on FANFT in the forestomach is not due to an irritant effect associated with increased cell proliferation. Also, there appears to be an adaptation by the rats to the chronic ingestion of aspirin.

Co-carcinogenicity of sodium saccharin and N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide for the urinary bladder.

The co-carcinogenic activity of sodium saccharin and N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) was evaluated in male Fischer rats by co-administering them as 5% and 0.005% of the diet, respectively, for 2 years. The effect of simultaneous administration of two urinary bladder promoting substances, sodium saccharin and L-tryptophan as 5% and 2% of the diet, respectively, was also evaluated. Five of 16 rats administered sodium saccharin plus FANFT developed bladder tumors whereas none of the rats administered FANFT, sodium saccharin, or L-tryptophan alone, sodium saccharin plus L-tryptophan, or the control diet developed bladder tumors. Possible mechanisms for the co-carcinogenic activity of sodium saccharin and FANFT are discussed.

Alterations in the rat kidney associated with sodium saccharin feeding.

Sodium saccharin has previously been demonstrated to induce hyperplasia and tumors of the urothelium of the rat urinary bladder. It was fed as 5% of the diet to male F344 rats for 2 years. In the present experiment, mild simple hyperplasia of the urinary bladder epithelium was again frequently observed, and a marked nodular and papillary hyperplasia of the urothelium of the kidney pelvis was also found in approximately half of the sodium saccharin-fed rats. This was infrequently associated with focal calcification of the renal papilla and pelvis. In contrast, rats fed sodium saccharin had a significantly reduced incidence of the interstitial nephritis frequently observed in older rats. No significant incidence was observed of lesions of tissues other than those of the urinary tract.

Neuroblastoma in situ.

Two cases of neuroblastoma in situ incidentally found in young infants at autopsy are reported. One was an 8-day-old female infant of large for dates clinically diagnosed as fetal erythroblastosis. Histologically, several foci of tumor were scattered within the medulla of the left adrenal gland. This case was thought to be multiple neuroblastoma in situ. The other was a 34-day-old male infant who was born premature and associated with patent ductus arteriosus (PDA). Grossly, a solitary small nodule was seen in the right adrenal gland. Microscopically, the lesion was located within the medulla. In both cases, the tumor was composed of lymphocyte-like small and dark cells with rosette formations. Local infiltrations were observed, but not metastasis. The review of 611 autopsy cases of neuroblastoma reported in the Annual of the Pathological Autopsy Cases in Japan, vol. 11 (1968) to vol. 20 (1977)2 revealed 7 cases of neuroblastoma in situ including one of our cases. The peculiar features of neuroblastoma were described.

Histopathological analysis of preneoplastic changes during N-butyl-N-(4-hydroxybutyl)-nitrosamine-induced urinary bladder carcinogenesis in rats.

Sequential microscopic alterations of the urinary bladder epithelium during carcinogenesis were examined in rats after oral administration of 0.01% or 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN). Simple hyperplasia appeared after 4 weeks of BBN administration. This regressed by 12 weeks after BBN discontinuation but reappeared focally in some areas after 20 weeks and persisted to the termination of the experiment. Preneoplastic papillary or nodular hyperplasia appeared earlier and more frequently in rats treated with 0.05% BBN than in those treated with 0.01%, but these lesions regressed gradually during a prolonged observation period after BBN was discontinued. These results suggest that 2 types of papillary or nodular hyperplasias exist, one reversible and the other irreversible. Tumors appeared earlier in rats treated with 0.05% BBN than in those with 0.01% BBN.

Aspirin inhibition of N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide-induced lesions of the urinary bladder correlated with inhibition of metabolism by bladder prostaglandin endoperoxide synthetase.

The effects of aspirin on N-[4-(5-nitro-2-furyl)-2-thiazolyl]-formamide (FANFT) -induced urinary bladder lesions, endogenous bladder prostaglandin E2 synthesis, and the metabolism of FANFT by bladder epithelial microsomes were examined. Rats were fed 0.5% aspirin and/or a diet containing 0.1% or 0.2% FANFT. Bladder lesions were observed with light and scanning electron microscopy, and the prostaglandin E2 content of rat bladder was measured by radioimmunoassay. Metabolism of FANFT was measured by decreased absorbance at 400 nm. Aspirin inhibited the appearance of hyperplastic lesions induced by feeding 0.1% or 0.2% FANFT for 6 or 12 weeks. Aspirin reduced bladder prostaglandin E2 content at 1, 2, 6, and 13 weeks compared to corresponding control values. Rat and rabbit microsomal metabolism of FANFT were dependent upon specific fatty acid substrate and prevented by specific inhibitors (including aspirin) of prostaglandin endoperoxide synthetase. Other inhibitor and substrate specificity studies suggest that FANFT was not metabolized by xanthine oxidase, lipoxygenase, lipid peroxidation, or mixed-function oxidases. These results suggest that the metabolism of FANFT by prostaglandin endoperoxide synthetase may be involved in the metabolic activation of FANFT necessary for the induction of bladder cancer in rats.

Effect of dose of sodium saccharin on the induction of rat urinary bladder proliferation.

The effect of sodium saccharin fed to male F344 rats at levels of 5.0, 2.5, 1.0, 0.5, and 0.1% of the diet for 10 weeks was evaluated by autoradiography and scanning electron microscopy. A dose response was evident with both techniques. The labeling index was statistically significantly elevated at all doses above 0.1%. As observed by scanning electron microscopy, the number of foci containing ropy microridges or uniform microvilli was elevated at doses of 1.0, 2.5, and 5.0% of the diet, and pleomorphic microvilli were observed at the two highest doses.

Effect of cyclophosphamide on rat urinary bladder epithelium treated wtih N-butyl-N-(4-hydroxybutyl)nitrosamine.

The effect of cyclophosphamide (CP) on the urinary bladder epithelium of rats treated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) was examined histologically to detect preneoplastic papillary or nodular hyperplasia. The urinary bladder epithelium of rats injected intraperitoneally with 40 or 80 mg/kg body weight of CP after treatment with 0.025% BBN for 2 weeks showed extensive epithelial erosion and then simple, or papillary or nodular hyperplasia, but this soon almost disappeared. In contrast, rats given BBN alone showed papillary or nodular hyperplasia later. These findings indicate that epithelial damage by CP inhibited the early neoplastic process of BBN.