Yoichiro Hiramoto

Lymphadenectomy for cure in patients with early gastric cancer and lymph node metastasis

The anatomic distribution, size, and histologic mode of involvement of 98 metastatic lymph nodes in 49 of 370 patients were examined to determine to what extent lymphadenectomy should be performed in addition to gastrectomy in patients with early gastric cancer. Nodal involvement in the marginal sinus (30 nodes) and partial medullary sinus (37 nodes) were commonly seen, and the lymph nodes of those types were enlarged compared with 1,086 patients with no metastatic lymph nodes (control group). Lymph nodes of the wide medullary sinus (11 nodes), small nodule (3 nodes), and massive involvement types (17 nodes) did not enlarge compared with those of the other types and those of the control group. Most of the metastatic sites (76.6 percent) were in the perigastric lymph nodes along the lesser and greater curvatures, about a fifth were in the extraperigastric nodes along the left gastric, common hepatic, celiac, and splenic arteries, and the least were in the extraperigastric nodes (3.1 percent) along the hepatoduodenal ligament. Since the rate of macroscopic diagnosis during operation was so poor, regardless of the histologic modes of nodal involvement, and also in cases of metastatic lymph nodes less than 15 mm in widest diameter, for curative operation of patients with early gastric cancer, perigastric and extraperigastric lymph nodes along the main arteries near the stomach should be completely dissected, in addition to resection of the stomach.

Serum CEA levels facilitate detection of recurrences of cancer in patients after gastrectomy

In an attempt to assess the usefulness of carcinoembryonic antigen (CEA) for predicting the progression of gastric cancer, CEA productivity was evaluated according to serum CEA levels, at the time of recurrence or relapse. In cases of a recurrence, abnormal CEA levels were observed in 14 of 17 (82.4 per cent) with differentiated carcinoma and in 9 of 21 (42.9 per cent) with undifferentiated carcinoma. Preoperative abnormal CEA levels were observed in only 6 of 41 patients (14.6 per cent). A median lead time of manifestation of recurrence was 5 months. In those with relapse, 9 of 11 (81.8 per cent) patients with differentiated carcinoma and 13 of 18 (72.2 per cent) with an undifferentiated carcinoma had abnormal CEA levels. Preoperative abnormal CEA levels were observed in 24 of these 89 patients (27.0 per cent). Postoperative monitoring of CEA seems to be useful for early recognition of gastric cancer progression, irrespective of the preoperative CEA levels.

1-Hexylcarbamoyl-5-fluorouracil is more cytostatic than 5-fluorouracil against human tumors in vitro

The sensitivity of HeLa cells and 15 human tumors, including eight gastric cancers, five colorectal cancers and two lung cancers to 1-hexylcarbamoyl-5-fluorouracil (HCFU) was compared with that to 5-fluorouracil (5-FU) in vitro. HeLa cells were doubly sensitive to HCFU, as compared to 5-FU. After the HeLa cells had been treated with 5-FU or HCFU at 77 microM for 1-5 h, the intracellular levels of 5-FU and HCFU were determined, using gas chromatographic-mass spectrometric methods. The level of HCFU plus 5-FU in the HCFU-treated cells was twice as high as the level of 5-FU in the 5-FU-treated cells. The sensitivity to HCFU in 15 tumor tissues varied with the tissue; however, all tissues tested were more sensitive to HCFU than to 5-FU, assessed using the succinate dehydrogenase inhibition test. These results suggest that the hexylcarbamoyl structure facilitates the rapid uptake of HCFU through the cell membrane. HCFU may prove to be more effective for treating each individual patient with a malignant lesion.

Postoperative long-term cancer chemotherapy (PLCC) extends life-span of non-curatively resected patients with stage IV gastric cancer

Postoperative long-term cancer chemotherapy (PLCC) with a combination of Mitomycin-C, Tegafur and PSK (an immunostimulant) was applied to non-curatively resected cases with stage IV gastric cancer (invading the adjacent organs and/or with metastasis to the liver, peritoneum, and/or distant lymph nodes). This approach has a significant life-prolongation effect. The two-year survival rate was 16.8 per cent in the PLCC group, such being higher than 6.7 per cent and 1.7 per cent in MMC and no chemotherapy groups (p<0.05). 50 per cent survival periods in those with liver metastasis were 8.3 months in the PLCC group, such being longer than 5.2 and 2.8 months in MMC and no chemotherapy groups (p<0.002) respectively. Combination therapy of PLCC and intra-arterial infusion of 5-FU through the proper hepatic artery prescribed for 8 patients with liver metastasis resulted in a 3-month prolongation of 50 per cent survival periods, compared with PLCC alone (p<0.05). In those with peritoneal dissemination the rate was 10.5 months in the PLCC group, that is longer than 6.5 months in the MMC group (p<0.02). In cases of invasion to other organs plus distant lymph node metastasis, the time was 11.0 in PLCC and 7.0 months in MMC groups (p<0.05). Thus, PLCC is a palliative approach for non-curatively resected carcinoma of the stomach.

Effect of glucocorticoid deficiency after adrenalectomy on antitumor immunity

SummaryWe studied the effect of corticosterone after adrenalectomy on antitumor immunity in immunogenic tumors in mice. Antitumor immunity in the glucocorticoid deficient adrenalectomized mice (ADX mice) examined via comitant immunity and cytotoxic activity of spleen cells was compromised. Antitumor immunity was detected in ADX mice receiving sufficient supplementary doses of corticosterone. Loaded stress compromised the cytotoxic activity of the spleen cells in the ADX mice receiving adequate corticosterone, and the failure also contributed to the glucocorticoid deficiency because the activity was not affected by stress in the sham ADX mice. A matured effector cell activity was transferred to the glucocorticoid deficient ADX mice. We conclude that glucocorticoid deficiency compromises the antitumor immune response and that glucocorticoid might play an important role in the maturation of immunocompetent cells.

Bidirectional effects of splenectomy on the growth of syngeneic tumor in mice.

The effects of splenectomy on tumor growth following inoculation with a relatively large number of cells (1×107) and a smaller number of cells (5×105) of Meth I tumor were studied. When 1×107 tumor cells were inoculated, tumor growth in splenectomized mice was depressed, while tumor in sham-operated mice grew progressively. On the contrary, when 5×105 tumor cells were inoculated, the tumor take was lower in sham-operated than in splenectomized mice. The spleen cells from mice inoculated with either a large or small number of tumor cells, showed an equally potent cytotoxic activity, but no detectable suppressor cell activity. On the other hand, the activity of immunosuppressive factor was detected in sera from mice inoculated with 1×107 tumor cells, but not in those given 5×105 cells. The effect of splenectomy on tumor growth is, thus, bidirectional, depending on the dose of tumor cells inoculated.

Synergistic effect of K-18 and concomitant hyperthermia for treatment of Lewis lung carcinoma in mice.

We investigated the synergistic anti-tumor effects of K-18 (conjugate of human γ-globulin and melphalan) and concomitantly administered hyperthermia on Lewis lung carcinoma in mice. The antitumor effect of a subeffective dose of K-18 or an equivalent dose of melphalan alone was enhanced by local hyperthermia. K-18 administration demonstrated a greater potentiation for inhibition of tumor growth than that of melphalan alone. Local hyperthermia plus K-18 reduced the dose of melphalan required for tumor growth inhibition by melphalan alone. The combined application of K-18 and hyperthermia for treating cancer warrants further study.

Combination chemotherapy enhances survival of patients with unresectable gastric cancer.

Of 177 Japanese patients with a gastric cancer which could not be resected and seen at our institution during the period from 1964 to 1979, 153 were investigated with regard to the efficacy of anticancer agents, in terms of prolongation of life. The average survival time was 23 weeks in the combination chemotherapy group (57 cases), 17 weeks in the single drug chemotherapy group (42 cases) and 13 weeks in no chemotherapy group (54 cases). Three and 6 month survival rates in the overall patients were 57.1 per cent and 16.7 per cent for single drug chemotherapy group, and 37.0 per cent and 11.1 per cent for no chemotherapy group, while in the combination chemotherapy group, the rates were higher at 64.9 per cent and 29.8 per cent, respectively (combination chemotherapyvs. no chemotherapy group, p<0.05). In patients with peritoneal dissemination, hepatic metastasis and carcinomatous ascites, there was a significant difference in survival rates between those prescribed combination chemotherapy and those given no chemotherapy (p<0.05). Of 57 in the combination chemotherapy group, 6 and 9 month survival rates were 45.5 per cent and 22.7 per cent in the postoperative long-term cancer chemotherapy (PLCC) group (22 cases), such being higher than other combination chemotherapy group (35 cases), 22.9 per cent and 11.4 per cent, respectively. There was a significant difference in the survival rates between the two groups (p<0.05).