The purpose of this study was to determine the most effective means of treating liver metastases from gastric cancer. We retrospectively examined 43 patients with liver metastases, but without peritoneal dissemination, who had received different forms of treatment. The crude 5-year survival rates of patients who underwent gastrectomy with complete hepatectomy (curative gastrectomy), noncurative gastrectomy, and no gastrectomy were 33.3%, 3.7%, and 0%, respectively. The curative gastrectomy group showed the highest survival rate (not significant). The median survival of patients given hepatic artery infusion (HAI), systemic chemotherapy, and no chemotherapy were 353, 189, and 61 days, respectively. The patients given chemotherapy survived significantly longer than those not given chemotherapy. Three patients survived for more than 5 years without any signs of recurrence. The long-term survivors all had primary lesions without serosal invasion (T2) and no other noncurative factors. Two patients underwent curative gastrectomy and one underwent noncurative gastrectomy. All were given postoperative chemotherapy; as HAI in two cases, and as systemic chemotherapy in one case. These findings suggest that curative gastrectomy combined with HAI or systemic chemotherapy should be attempted for patients with primary tumors without serosal invasion or any other noncurative factors.

Evaluation of treatment for synchronous hepatic metastases from gastric cancer with special reference to long-term survivors.

The effectiveness of adoptive immunotherapy of cancer using LAK cells
and IL-2 depends on the accumulation of transferred effector cells at the
tumour sites. In vitro LAK cell have been demonstrated to have broad
cytotoxic activity to a wide variety of tumour cells in a non-major-histocompatibility
complex-restricted manner, and independent of the
presence of tumour specific antigens. LAK cells have now been used
effectively in a small number of human trials. The effective delivery of
these cells to the tumour site in vivo is one of the main aspects of this type
of immunotherapy that requires further investigation. Conventional
systemic infusion has shown a limited migration pattern of LAK cells. In
this study the degree of entrapment of LAK cells in organs following local
infusion has been determined. The large size and rigidity of LAK cells
may be one mechanism which restricts the distribution of these cells. In
addition, in this study the effect of mannitol, a hyperosmotic agent which
increases the space between vascular endothelial cells, on the uptake of
intraportal LAK cells into liver has been determined.
A-LAK cells are obtained by culture of N.W.P. lymphocytes with IL-2. In
this study A-LAK cells were characterised by typical morphologic
appearance, cell surface phenotype, and cytotoxic specificity. Purified A-LAK
cells were morphologically large granular lymphocytes, 67%-90% of
which showed the surface marker phenotype of NK/LGL cells (OX8). The
population contained few pan-T cells (only 4.0-6.5% of cells expressing
OX19). No B cell surface marker lg was detectable in the A-LAK cell
population. These cells showed high ability to lyse YAC-1 and P-815
cultured tumour target cells in 4h 51Cr-release cytotoxic assays. At an 
Effector:Target ratio of 40:1 A-LAK cells lysed 70% P815 and 100% YAC-1
cells.
After labelling A-LAK cells with 51Cr, the effect of intraportal infussion of
30% mannitol on the distribution of intraportally infused A-LAK cells in
liver was studied. The trafficking studies were carried out in three
groups. In Group 1, 51Cr labelled A-LAK cells were systemically infused
through the tail vein of rats as a control group. In Group 2 and Group 3,
A-LAK cells were infused into syngeneic rats through the portal vein
without or following prior portal infusion of 30% mannitol. Two hours
after LAK cell administration the rats were sacrificed and the radioactivity
in liver, lung, spleen, blood, MLN, kidney and brain were measured to
determine the distribution of A-LAK cells to these organs.
The results showed that intraportal mannitol was associated with an
increased percentage of LAK cells in the liver compared with regionally
infused LAK cells without mannitol (54% vs 24%; P<0.0005). The
administration of intraportal mannitol was also associated with increased
distribution of A-LAK cells into the brain (0.26% vs 0.08%; P<0.05) and
MLN (0.05% vs 0.02%; P<0.05). There was no significant increase in
uptake of A-LAK cells in lung (8.39% vs 6.01 %), spleen (1.00% vs 0.98%),
or kidney (1.44% vs 1.78%) following intraportal mannitol.
There was no significant increase of the A-LAK cell distribution to the
liver by regional infusion without mannitol (24% vs 16%). Systemic
injection gave greater A-LAK uptake into lungs (15.65%) than portal
injection (6.05%, P=0.05). There was no significant differences of cell
distribution in spleen, MLN, kidney and brain by these two routes of
infusion. 
These results showed that mannitol has the effect of increasing the
distribution of LAK cells into the liver. Augmentation of LAK cell
accumulation in the liver may help to enhance the tumouricidal activity of
these cells to hepatic metastases. The results of this thesis suggest area_s for
further investigation into the effect of mannitol and other agents on A-LAK
cell uptake into the liver following regional infusion.

The effect of intraportal mannitol on the short-term in vivo distribution of radiolabelled A-LAK cells in rats

Fernmetastasen solider Tumoren sind — auch bei unilokularer Manifestation — als Hinweis auf eine systemische Tumorerkrankung anzusehen und konnen mittels Operation oder Radiotherapie nur selten kurativ behandelt werden. In einzelnen Fallen, in denen die Metastasierung in nur einem Organ bzw. einer umschriebenen anatomischen Region auftritt, ist eine regionale Therapie zur erwagen. Das Konzept einer regionalen Tumorbehandlung wurde in den fruhen 50iger Jahren von Kopp et al. [1 J und Bierman et al. [2] entwickelt, die Stickstoff-Lost intraarteriell in verschiedene Tumoren infundierten. Die arterielle Leberperfusion mittels Zytostatika wurde von Watkins und Sullivan [3, 4] entwickelt, die uber einen Teflon-Katheter 5-Fluorouracil (5-FU) oder 2’-Deoxy-5-Fluorouridin (FUDR) mit Hilfe einer externen Infusionspumpe in die Arteria hepatica communis applizierten. Obwohl diese ersten Therapieversuche in zahlreichen Komplikationen resultierten, stellt die arterielle Leberinfusion (hepatic arterial infusion; HAI) aufgrund technischer Weiterentwicklungen heute fur zahlreiche Patienten eine erwagenswerte Therapieoption dar. Die regionale Therapie hepatischer Metastasen mit Standard-Chemotherapeutika ist aus mehreren Grunden durchfuhrbar: einer zweifachen Blutversorgung der Leber; einer hohen Gewebetoleranz gegenuber den meisten chemotherapeutischen Substanzen; geeigneter Pharmakokinetik der am haufigsten fur die HAI-Therapie angewendeten Zytostatika.

Regionale Therapie hepatischer Tumoren

In order to improve therapeutic efficacy for metastatic liver cancer, intermittent transarterial administration of BRM in combination with anticancer drugs was performed by use of reservoir apparatus. A total of 22 patients (12 cases of gastric cancer, 6 of colon cancer, 2 of pancreas cancer, 1 of gall bladder cancer and 1 of biliary tract carcinoid) were treated according to the following schedule: both 10 mg of ADM (or MMC) and 0.5 KE (or 1.0 KE) of OK-432 were administered on day 1 and 40 x 10(4) JRU of recombinant interleukin 2 (r-IL 2) on day 4, 7 and 11. The treatment was repeated as many times as possible. In terms of direct antitumor effect and decrease of tumor marker, the response rate was 43% (6 cases out of 14) and 75% (9 cases out of 12), respectively. As for performance status, improvement, no change and deterioration were seen in 4 cases, 8 cases and 3 cases, respectively. Even though 13 patients died, 8 of them survived more than 300 days. In the case of gastric cancer patients with liver metastasis, 50% survival time of 12 cases was 334 days, while that of 30 cases, who were administered anticancer drugs only systemically, was 144 days. In 3 cases the decrease in the size of tumors located in both liver and the other metastases also was seen. Every case developed high grade fever, but an antifebrile was effective. Otherwise severe side effects were not seen. These results indicated that intermittent arterial infusion immunochemotherapy was feasible for the treatment of metastatic liver cancer.

Therapeutic effect of transarterial infusion immunochemotherapy for metastatic liver cancer

Nineteen patients with metastatic liver tumor (9 of gastric cancer, 5 of colon cancer, 2 of pancreatic cancer, one each of mammary cancer, cholecystic cancer, carcinoid of biliary tract) and one patient with primary liver cancer were treated by endogenously induced LAK therapy consisting of transhepatic arterial infusion with ADM or MMC for induction therapy and OK-432 and rIL-2 (TGP-3) for immunotherapy. The following results were obtained. 1) Clinical response for liver tumor showed no CR but 8 cases of PR, for an overall response rate of 42.1%. 2) Reduced tumor marker value was noted in 76.5% cases, and 50% survival term became 349 days after the therapy. 3) Many CD4 and CD8 positive mononuclear cells had infiltrated around liver tumor after therapy by immuno-histochemical staining of surface marker. 4) NK activity of peripheral blood lymphocytes was markedly reduced soon after the therapy and continued for about 4-7 days, while in cases of combined subcutaneous administration with OK-432, NK activity showed only a slight decrease.

Significance of antitumor effects and immunological response on endogenously induced LAK therapy for primary or metastatic liver tumor

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Therapeutic effect of transarterial infusion immunochemotherapy for metastatic liver cancer

Significance of antitumor effects and immunological response on endogenously induced LAK therapy for primary or metastatic liver tumor