A case of hepatocellular carcinoma with bone metastasis which responded to oral administration of UFT

A 61-year-old male was referred to our hospital for evaluation of right upper arm pain. He was diagnosed as having primary hepatocellular carcinoma with bone metastasis by his high titer (111,683 ng/ml) of serum alpha-fetoprotein, computed tomography and abdominal angiography, and so UFT therapy, 400 mg daily, was instituted. After 2 months of this therapy, the titer of serum alpha-fetoprotein gradually decreased. Seven months later, the titer was 3,997 ng/ml and reduction of the hepatic tumor size was shown by computed tomography and ultrasonography. Furthermore, the right upper arm pain diminished and X-ray examination revealed remarkable improvement. During chemotherapy, there was no severe side effect apart from mild anemia and the patient is presently still alive. This case suggests the efficacy of UFT for the treatment of primary hepatocellular carcinoma.     

Effects of oral administration of UFT in unresectable gastric cancer with liver metastasis

A 62-year-old male was admitted because of upper abdominal mass. Exploratory laparotomy revealed unresectable gastric cancer, liver metastases and swelling of regional lymph nodes. Histological examination showed papillotubular adenocarcinoma. After 6 months' postoperative administration of UFT at a daily dose of 600 mg, X-ray and endoscopic examination revealed remarkable improvement of the gastric cancer. Computed tomography and ultrasonography showed disappearance of the mass in the liver and a remarkable decrease in the size of paraaortic lymph nodes. The cancer marker, serum CEA also decreased from 5.2 ng/ml to 2.1 ng/ml. At present, the abdominal mass is not palpable and the patient is asymptomatic except for pigmentation and being followed up in the outpatient department. This case suggests the possibility that UFT may be effective for advanced gastric cancer with liver metastases.     

长期应用重组人血管内皮抑素联合化疗治疗骨血管内皮细胞瘤肺转移

目的　探讨长期应用重组人血管内皮抑素（恩度）联合化疗治疗骨血管内皮细胞瘤肺转移的可行性。方法　１例骨血管内皮细胞瘤肺转移患者接受恩度与化疗联合治疗,恩度１５ｍｇ静脉滴注１／日,化疗先后采用ＴＥ方案６周期（紫杉醇９０ｍｇｄ_１、ｄ_８、ｄ_１５,表阿霉素９０ｍｇｄ_１,ｑ４ｗ）和ＴＰ方案４周期（紫杉醇９０ｍｇｄ_１、ｄ_８,顺铂２０ｍｇｄ_１～ｄ_５,ｑ３ｗ）,化疗结束后疗效评价ＰＲ,继续恩度单药长期治疗（恩度１５ｍｇｄ_１～ｄ_１４,ｑ８ｗ）。按照ＲＥＣＩＳＴ标准１.０版进行疗效评价。结果　该例患者应用恩度联合紫杉类为主的治疗后获得ＰＲ,继续予恩度单药长期治疗,现已３年,取得了较长时间的疾病缓解和良好的生存质量。在长期应用恩度过程中未见药物相关不良反应,患者耐受性良好。结论　持续应用恩度联合化疗取得最佳生物疗效后单药恩度长期治疗,这一治疗策略值得临床上进一步试用观察,以积累更多的经验。     

Inhibitory effect of UFT on postoperative lung metastasis of mammary adenocarcinoma in SHR rats

It is well known that UFT has significant therapeutic effects against experimental and clinical cancers at the primary sites. In this experiment, we studied the inhibitory effect of UFT on the lung metastasis of spontaneously developed rat mammary carcinoma (SST-2) after surgical excision of the primary site. In comparison of UFT-treated (15 or 30 mg/kg/day) with 5-FU-treated (9.7 or 19.5 mg/kg/day) groups, UFT was more effective than 5-FU in the antitumor activity and the inhibitory effect of lung metastasis with/without surgical excision of the primary sites. Rats (5-10 rats per group) were inoculated s.c. with 1 x 10(6) SST-2 cells and administered with UFT orally (15, 30 or 60 mg/kg/day) starting the day after tumor inoculation for 30 days. The therapeutic effect of UFT was studied by the growth rate of primary tumor and the numbers of metastatic colonies in the lung 35 days after tumor inoculation, comparing the UFT-treated with control groups. UFT administration at the doses of 30 or 60 mg/kg/day markedly inhibited the growth of the primary tumors and the number of metastatic lung colonies decreased, compared with that of the control group. However, in the group of rats treated at the dose of 60 mg/kg/day, 60% of rats died from the side effects of UFT such as weight loss, hemorrhage etc. In all groups in which the primary tumors were surgically excised 20 days after tumor inoculation and then treated with UFT (15, 20 or 30 mg/kg/day), we observed marked prolongation of survival period and inhibition of lung metastasis as well. Furthermore, we studied the effect of combination therapy of UFT and lentinan (1 mg/kg/day i.p.) on the metastasis of SST-2 cells after surgical excision of the primary sites. It was more effective than UFT alone. Thus, it is clear that UFT is an effective anticancer drug to inhibit metastasis of tumors in the lung after surgical excision of primary tumor.     

Complete disappearance with oral UFT administration of recurrent hepatocellular carcinoma of the remnant liver and multiple lung metastasis after hepatic resection

UFT is an anti-cancer drug which combines uracil with tegafur at a mole rate of 1:4, and shows a high anti-tumor effect by raising the 5-FU level in a tumor. A 55-year-old man with hypochondriac pain was admitted to Shinshu University Hospital. The preoperative diagnosis was giant hepatocellular carcinoma (HCC) of the right hepatic anterior region, and extended anterior segmentectomy of the liver was performed. Three months later, serum alpha-fetoprotein (AFP) and PIVKA-II were elevated markedly, and computed tomography (CT) and magnetic resonance imaging (MRI) revealed a recurrence in the remnant liver and multiple lung metastasis. Chemotherapy with oral UFT (300 mg/day) administration alone was started for the unresectable HCC. Three months later, CT and MRI showed complete disappearance of the recurrent HCC and multiple lung metastasis. Also, the titers of AFP and PIVKA-II were reduced to normal levels. This case suggests that oral UFT administration is a safe and effective therapy for postoperative HCC, even with lung metastasis.     

Contributions of vascularized lymph-node metastases to hematogenous metastasis in a rat mammary carcinoma

Rats received hind-foot-web (FWI) injections of MT-100-TC mammary carcinoma cells; the resultant tumor metastasized first to the popliteal lymph nodes. Over the course of 4 weeks, in association with increases in tumor weight, the blood-flow to the popliteal nodes increased 18-fold, and their vascular densities increased 2-fold. In spite of this vascularization, cancer cells were detected in only 3 of 648 blood vessels associated with involved, ipsilateral lymph nodes compared with intravascular cells in 82 of 314 vessels associated with "primary" foot-pad lesions. The presence of tumorigenic cancer cells in the right ventricular blood of animals bearing these tumors is, therefore, considered to result from their direct entry into blood vessels from the "primary" lesions, and/or from extra-nodal invasion of vessels in tissues to which nodal tumors were adherent, as distinct from passage via lymphatico-venous communications between tumors and nodal blood-vessels. The reconstructed events occurring in the rat model, with effective restriction of regional node metastases to the nodes themselves for a time, could possibly account for the long-term survival of some patients with breast cancer and regional-node metastases, following surgery.     

Effect of UFT by oral administration using a murine hepatic metastasis model

We examined the antitumor effect of UFT, a 5-FU derivative using a hepatic metastasis model in mice. BALB/c and CDF1 mice were given orally UFT (30 mg/kg, 50 mg/kg daily or 120 mg/kg every other day) for 20 days after inoculation of colon-26 tumor cells into the portal vein. The number of metastatic nodules and the weight of the liver decreased significantly in all groups of UFT treatment. The therapeutic effect with 50 mg/kg UFT was better than those with the other doses. NK and LAK activities of spleen cells obtained from UFT-treated tumor bearing mice were not significantly different from the untreated control. IL-1 and IL-2 production of the spleen cells were also not significantly changed by the treatment with UFT. These results suggested that the oral administration of UFT represents an antitumor effect against hepatic metastasis in mice without sever suppression of the host immune system.     

The effect of the transfer of lak cells,combined with alloimmunization,on the pulmonary metastases of rat mammary carcinoma

Alloimmunization was combined with lymphokine activated killer (LAK) cells to assess its effect on mammary carcinoma in rats. The animals were injected with both irradiated allo-splenocytes and syngeneic LAK cells. Metastatic lung nodules were markedly reduced using combined therapy when compared with the transfer of LAK cells or alloimmunization alone. IL-2 activity in the serum of alloimmunized rats could be detected. This activity, maintained in vivo for one week, may be responsible for enhancing the antitumor effect of transferred LAK cells.     

Desmopressin inhibits lung and lymph node metastasis in a mouse mammary carcinoma model of surgical manipulation

BACKGROUND AND OBJECTIVES: Desmopressin (DDAVP) is a synthetic derivative of vasopressin with hemostatic and fibrinolytic properties that has been used during surgery in patients with bleeding disorders. Our aim was to investigate the effect of DDAVP on lung and lymph node metastatic cell colonization using a preclinical mouse mammary carcinoma model of subcutaneous tumor manipulation and surgical excision. METHODS: Female BALB/c mice bearing the highly aggressive F3II mammary carcinoma were subjected to repeated manipulations of primary tumors (0.5 kg/cm(2) during 2 min), followed (or not) by surgical excision. DDAVP was administered intravenously 30 min before and 24 h after each manipulation or surgery, at a dose of 2 microg/kg. At the end of the experiment, mice were sacrificed and necropsied. RESULTS: Tumor manipulation induced dissemination to the axillary nodes and increased up to 6-fold the number of metastatic lung nodules. Perioperative treatment with DDAVP dramatically reduced regional metastasis. The incidence of lymph node involvement in manipulated animals was 12% with DDAVP and 87% without treatment (P < 0.02). Histopathological analysis of axillary nodes from DDAVP-treated animals showed sinusal histiocytosis and no evidence of cancer cells. Metastatic lung nodules were also reduced about 65% in animals treated with DDAVP (P = 0.026). CONCLUSIONS: Our results suggest a potential clinical application of DDAVP in the management of breast cancer, as well as other aggressive solid tumors. DDAVP may be useful to reduce the risk of metastatic cell colonization both during and after surgical manipulation.     

Effect of combined transfer of irradiated allo-lymphocytes and LAK cells on pulmonary metastasis of mammary carcinoma (SST-2) in SHR rats

We have attempted to prevent and treat experimental pulmonary metastasis of a rat mammary carcinoma (SST-2) by adopting transfer of LAK cells and irradiated allogeneic spleen cells (as an allogeneic immune stimulator). Transfer experiments were carried out by the following schedule: SST-2 cells were inoculated intravenously on day 0, irradiated allogeneic spleen cells were transferred intravenously on day -5, 1 and 8, and LAK cells were transferred on day 2, 5 and 7. In the control groups: the average number of metastatic nodules in the lungs were 180.5, 62.0, 10.2 in the groups of allogeneic lymphocytes alone and LAK cells alone in experiment 1, and 81.2, 21.0, 3.8 in experiment 2, respectively. In the combined transfer group, the average metastatic nodules were 1.3 in experiment 1 and 0 in experiment 2, and 17 out of the total 20 rats were completely free from metastasis. Interleukine 2 (IL-2) level in the serum increased gradually and reached a peak on day 3 and thereafter, declined after the 2nd transfer of allogeneic lymphocytes. We postulate that allogeneic lymphocytes transferred are able to stimulate a release of endogenous IL-2 which supports and augments antitumor activity of LAK cells.     

High incidence of rat mammary carcinoma by oral administration of ethyl methanesulphonate.

Ethyl methanesulphonate (EMS), one of the alkylating agents, is known to be a potent mutagen. We tested EMS for its carcinogenicity in female rats by oral administration. EMS was dissolved in drinking tap water at a concentration of 10(-3) M and was given for the first 12 weeks. The subcutaneous tumors were noticed as early as 16 weeks after initiating the experiment. At the 32nd week, all the surviving rats produced tumors; the majority were multiple tumors in the neck, axillar and inguinal areas corresponding to bilateral mammary glands. Histologically, the prevailing feature of the tumors was infiltrating medullary adenocarcinoma consistent with carcinoma of mammary duct origin. Neither regional lymph node involvement nor distant metastases were shown, but intraductal spread of carcinoma was a marked finding during the 32-week period.     

Correlation of fibrinolytic activity with invasion and metastasis of R3230 AC rat mammary carcinoma cell lines

The parent R3230 AC rat mammary carcinoma cell line and the two variant cell lines, R3230 AC MET and R3230 AC LR, differ with respect to their abilities to invade bony matrices and to form lung colonies (experimental metastases). Both the R3230 AC and the R3230 AC MET, a cell line selected in vivo for enhanced metastatic capability, express high potentials for invasiveness and lung colony formation, while the Con A- and WGA-resistant R3230 AC LR cell line grows expansively at the periosseus implantation site and is unable to form lung colonies after intravenous inoculation. The abilities to invade bone and to metastasize to the lung are well correlated with the fibrinolytic activity and the production of urokinase-type plasminogen activators. The contribution of plasminogen activators to invasiveness and metastasis has been ascribed to its role in the fibrinolytic and collagenolytic (i.e., activation of latent collagenase) cascades.     

Warfarin inhibits metastasis of Mtln3 rat mammary carcinoma without affecting primary tumour growth

Coumarin anticoagulants inhibit metastasis in several animal models, but the mechanism of this effect is uncertain. In order to determine the role of cytotoxic and/or cytostatic actions of coumarins on the tumour cells, we have studied the effects of warfarin on tumour cell growth in a model in which tumour metastasis is inhibited by this drug. Clonogenic assay, growth curve analysis and thymidine labelling index revealed that warfarin had no effects on Mtln3 mammary carcinoma cell growth in vitro at concentrations below 1 mM. The growth rate of subcutaneously implanted Mtln3 tumour deposits in female F344 rats, assessed by weight and by stathmokinetic analysis of the tumour tissue, was identical in warfarin-treated and control animals. Spontaneous metastasis from such tumours to the lungs was, however, significantly reduced in warfarin-treated animals (median 0 pulmonary tumours per animal in warfarin treated, eight tumours per animal in control animals; P less than 0.05, Mann-Whitney). The mean plasma warfarin concentration in warfarin treated rats was 1.63 microM. These results suggest that warfarin treatment of the host animal can inhibit tumour metastasis without having any direct or indirect effect on the growth rate of the tumour cells.     

Rational Operation for Primary Gastric Carcinoma with Liver Metastasis

OBJECTIVE To investigate the prognosis of advanced gastric carcinoma patients with liver metastasis, and provide a foundation for rational operations. METHODS The operations and prognosis of 102 primary gastric carcinoma patients with liver metastasis were studied retrospectively. RESULTS In gastric carcinoma patients with H1 metastasis who underwent a resection operation, the 6-month, 1- and 2-year post-operative survival rates were 61%, 42% and 7%. There was a statistically significant difference in survival between resected and non-resected patients （P=0.000） in gastric carcinoma cases with H2 metastasis, resection operations resulted in 54%, 16% and 8% respective survival rates, with no significant difference compared to patients not receiving a resection （P=0.132）. Gastric carcinoma patients with H3 metastasis who received a resection operation showed 25%, 13% and 0% respective survivals with no significantly better prognosis compared to the non-resected cases （P=0.135）. There was no statistically significant difference in survival between the cases with or without peritoneal metastasis （P=0.152）. CONCLUSION A resection operation provides a better prognosis for gastric carcinoma patients with H1 metastasis independent of peritoneal metastasis, but resection has no benefit for gastric carcinoma cases with H2 or H3 metastasis. Peritoneal metastases are not the significant influencing factor for the prognosis of gastric cancer with liver metastasis.     

A case of long survival with UFT and lentinan treatment in a patient with peritoneal metastasis of gastric carcinoma

The patient was a 50-year-old female with peritoneal metastasis of Type 4 gastric cancer. She underwent a relative curative resection with total gastrectomy and peritonectomy. Postoperative chemotherapy with 5'-DFUR following 5-FU and CDDP was performed. Thirteen months after surgery, cancer recurrence was suspected due to elevated levels of the serum tumor markers carcinoembryonic antigen (8.9 ng/ml) and alpha fetoprotein (85.8 ng/ml). She was additionally treated with UFT 300 mg/day and Lentinan 2 mg/week. The serum tumor markers decreased gradually returned to normal levels. At 5 years and 8 months after surgery, she is alive without any sign of recurrence.     

原发性肝癌TACE术后与肺转移

目的探讨原发性肝癌经导管肝动脉化疗栓塞术(TACE)后发生肺转移的机制。方法回顾分析25例TACE术后患者的病历资料,发现肺转移15例;对转移患者的年龄、转移时间、生存时间、X线(胸片及CT)改变、心理因素做总结分析。结果TACE术后肺转移发生率为60.0%,且以年轻者为多见,知情者有严重的抑郁心理。结论年轻者易发生肺转移,严重的抑郁是促使其死亡的重要因素;多数死亡原因为肝肺功能衰竭。     

5-FU concentration in blood and tissue of patients with renal cell carcinoma after administration of UFT

UFT (3 capsules; 300mg FT) was administered to five of 10 patients with renal cell carcinoma, and concentrations of FT, 5-FU and uracil in the serum and tissues (normal renal tissues, renal tumor tissues and liver) were determined 5.2 hours on average, after administration. The levels were also compared with these in the five patients administered 300 mg of FT. There was no difference in FT concentration between the serum and the tissues in the group administered UFT, but the concentration of 5-FU in tumor tissues was significantly higher (25.6 times) than that in the serum. The level was also higher (3.2 times) than that in normal renal tissues. There was a positive correlation between the concentration of 5-FU in the tissues and the concentration of uracil in the tissues. Although there was no difference in the concentration of FT between serum and tissues in patients administered UFT or FT, the concentration of 5-FU in patients administered UFT was definitely higher than that in patients administered FT; the concentration of 5-FU in the tumor tissues of patients given UFT was 3.9 times higher than in those given FT. Thus, UFT induced a concentration of 5-FU in tumor tissues that was maintained at a high level, suggesting that an excellent antitumor effect on renal cell carcinoma can be expected with UFT.     

A case of advanced gastric cancer with hepatic metastasis successfully treated by combined chemotherapy with UFT and lentinan

We have experienced successful treatment of a hepatic metastasis of gastric cancer with UFT and lentinan. The patient was a 65-year-old male, who underwent distal gastrectomy for gastric cancer with hepatic and lymphatic metastases. After operation, administrations of UFT 300 mg/day and lentinan 2 mg/2 weeks were given, and the hepatic metastasis disappeared by 17 months. We performed a resection of the residual stomach and lymphatic metastasis at 52 months after operation. For over 5 years the patient has shown no evidence of a recurrence of the hepatic metastasis. This chemotherapy regimen was very effective and improved the patients quality of life.     

原发性肝癌肺转移患者行肺转移灶切除的疗效探讨

背景与目的:肺转移灶切除被认为是发生肺转移的恶性肿瘤患者的一种积极的治疗方法。本文探讨原发性肝癌(下称肝癌)肺转移患者行转移灶切除的疗效。方法:回顾性分析12例肝癌肺转移行转移灶切除患者的临床病理资料及疗效。结果:12例患者中,9例肺转移灶数目为1～2个,其中1例在首次肺转移灶切除后再次出现肺转移。3例肺转移灶数目为3个或3个以上,在首次肺转移灶切除后均再次出现肺转移。全组患者首次肝切除后中位生存时间为52个月,首次肺切除后中位生存时间为24个月。全组患者首次肝切除后1、3、5年总体生存率分别为100.0%、75.0%、47.3%,首次肺切除后1、3、5年生存率分别为83.3%、46.7%、21.0%。结论:在肝内复发肝癌病灶能够得到有效控制的前提下,肺转移灶数目为1个或2个的患者可从肺转移灶切除中获益,并有可能获得长期生存。