Atsunobu Murakami

Prophylactic therapy for peritoneal recurrence of gastric cancer by continuous hyperthermic peritoneal perfusion with mitomycin C

Continuous hyperthermic peritoneal perfusion (CHPP) with a solution that contains mitomycin C (CHPP‐M) has been clinically introduced as a prophylactic treatment for peritoneal recurrence of gastric cancer with serosal invasion. Two studies, each with a treated and a control group, were performed. In the historical control study the postoperative 3‐year survival rate of patients (73.7%) in the treated group (n = 38) was significantly higher than the survival rate (52.7%) of those in the control group (n = 55) (P < 0.04). In the random control study the survival rate (83%) of patients in the treated group (n = 26) was also higher than that (67.3%) of those in the control group (n = 21) in the 30 months that followed gastric surgery. However, there was no significant difference. In the historical control study with respect to the postoperative complications, anastomotic leak was observed in 8.5% of patients who were given CHPP‐M and 12.8% patients who did not have CHPP‐M. In the random control study anastomotic leak was observed in 3.1% of patients who had CHPP‐M and 7.1% of patients who did not have CHPP‐M. The incidence of adhesive ileus in patients having CHPP‐M did not increase in historical or random control groups. Postoperative prolonged intestinal paresis or chemical peritonitis were not induced by CHPP‐M. These results indicate that CHPP‐M is a simple, safe, and readily available prophylactic therapy for peritoneal recurrence that may follow gastric cancer surgery.

Carcinoembryonic Antigen in Gastric Cancer Patients

Carcinoembryonic antigen (CEA) levels were determined in 252 gastric cancer patients. In patients with resectable cancer, the preoperative CEA values and CEA positivity rates were 2.4 +/- 1.5 ng/ml and 7.7% for stage I, 24.9 +/- 72.0 ng/ml and 10.0% for stage II, 21.6 +/- 84.1 ng/ml and 17.9% for stage III, and 6.3 +/- 8.4 ng/ml and 27.1% for stage IV cancers, respectively. In patients with nonresectable cancers, the CEA value was 83.0 +/- 235.5 ng/ml, the CEA positivity rate was 47.8%. Overall, of 252 patients with primary gastric cancer, 47(18.7%) were positive for CEA. In patients with cancer recurrence, the CEA value averaged 41.8 +/- 101.8 ng/ml, the positivity rate was 63%. This rate increased as the cancer stage increased; it was highest in gastric cancer patients with liver metastasis. In 4 of 13 patients with recurrence, an elevation in CEA was observed about 4.8 months before the clinical detection of cancer recurrence. Our results suggest that in gastric cancer patients, the preoperative and periodic postoperative assay of CEA levels has predictive value in determining cancer stage, progression and recurrence.

The influence of hyperthermia in vitro on the functions of peritoneal macrophages in mice

Total-body hyperthermia (TBHT) as a treatment for cancer may lead to a reduction in the hosts immunocompetence as a result of the direct effects of heat on the immune system. Thus, we studied the influences of hyperthermiain vitro on the function of peritoneal macrophages from mice. Peritoneal macrophages from C3H/HeN mice were heatedin vitro for 3 hr at 37, 39, 40, 41 or 42°C. After exposure to heat, the phagocytic ability of the macrophages, as well as results of the nitroblue tetrazolium (NBT) reduction test and the cytotoxity test were examined. The changes in all these parameters showed almost the same pattern: a tendency for macrophage functions to be potentiated up to 40°C, and a tendency towards inhibited functioning at temperatures above 41°C. Although augmented functions of macrophages were observed after exposure to mild hyperthermia (<40°C), the possibility of TBHT (42°C)-induced inhibition of macrophage function must be further investigated in clinical trials of TBHT therapy for cancer.

Thermochemosensitivity: Augmentation by Hyperthermia of Cytotoxicity of Anticancer Drugs against Human Colorectal Cancers, Measured by the Human Tumor Clonogenic Assay

Thermochemosensitivity was examined in vitro by a human tumor clonogenic assay (HTCA) using specimens obtained surgically from 43 patients with colorectal cancer. We found that the percentages of patients whose cells showed higher sensitivity (greater than 70% inhibition of colony formation) to hyperthermia alone were 29.6 and 55.6% at 42 and 43 degrees C each for 1 h, respectively. Similarly, percentages of patients whose cells were sensitive to drugs alone were 13.8, 24.1 and 48.3%, for cis-diamminedichloroplatinum(II), 5-fluorouracil and mitomycin C, respectively. These sensitivities were augmented when hyperthermia was combined with administration of anticancer agents. Even in tumor cells that were insensitive to anticancer drugs alone or to hyperthermia alone, sensitivity was enhanced when administration of drugs was combined with hyperthermia. Our results demonstrate that HTCA of tumor cells, obtained from suitable patients, may be useful as a predictive test for application of thermotherapy and for individualization of chemotherapy.

Diagnostic accuracy of combination of assays for immunosuppressive acidic protein and carcinoembryonic antigen in detection of recurrence of gastric cancer

Two tumour markers, immunosuppressive acidic protein (IAP) and carcinoembryonic antigen (CEA), were assayed in gastric cancer patients. Levels of IAP and CEA were measured simultaneously in the preoperative and postoperative periods. The usefulness of the combined assay of these markers for detection of recurrence of cancer was investigated in terms of sensitivity, specificity and diagnostic accuracy. Sensitivity was not high (69.2%), but specificity and diagnostic accuracy were 96.7% and 86.9%, respectively. In cases with metastases in the liver, sensitivity (100.0%), specificity (100.0%) and diagnostic accuracy were high. In cases of peritoneal dissemination, these indices were low. The combination assay of IAP and CEA appears to be useful for detection of recurrence of gastric cancer, especially in patients with liver metastases.

Carbohydrate Antigen 19-9 in Tissues and Sera from Patients with Gastric Cancer

Detection of carbohydrate antigen (CA) 19-9 in tissues and sera was performed by an immunoperoxidase assay and by radioimmunoassay of samples from patients with gastric cancer. Twenty-eight of 102 (27.5%) gastrectomized patients and 13 of 21 (44.8%) patients with recurrent cancer showed abnormal and elevated levels of CA 19-9 in sera of more than 37 U/ml. Sixty-five of 102 (63.7%) patients gave positive localizations of CA 19-9 in cancerous tissues and 20 of 102 (19.6%) gave positive localizations of CA 19-9 in noncancerous gastric mucosa. Twenty-five of 28 (89.3%) patients with elevated serum CA 19-9 showed positive evidence of CA 19-9 in cancerous tissues, and 37 of 74 (50.0%) patients with normal serum levels of CA 19-9 also showed positive evidence of CA 19-9 in cancerous tissues. However, there were no clear relationships between CA 19-9 in cancerous tissues or in sera and the stage or histological type of the gastric cancer. These data indicate that CA 19-9 may be not released easily into blood circulation or that the concentration of CA 19-9 in tissues may be low, even though a large proportion of gastric cancer cells produces CA 19-9. It appears, therefore, that CA 19-9 will be restricted clinical use as a detector, monitor or tumor-associated antigen of gastric cancer.

Does preoperative radiation for thoracic esophageal cancer promote intramural lymphatic invasion

Between 1976 and 1983, 43 patients with carcinoma of the thoracic esophagus underwent esophagectomy in the Department of Surgery, Tottori University. Of these 43, 22 received a total dose of 30 to 40 Gy of Co60 (2 Gy/day) preoperatively: 21 were not given preoperative irradiation treatments. The spread of intramural lymphatic cancer invasion into the esophageal wall was compared in these two groups. The preoperatively irradiated patients manifested a significantly lower rate of lymphatic cancer invasion and the depth of invasion tended to be less than in the non-irradiated patients. However, in preoperatively irradiated subjects, the horizontal cancer spread into the extra-radiation field anal to the cancer site was greater than in the other group. In addition, a significantly higher intra-abdominal lymph node metastasis rate was found in the irradiated group than in the non-irradiated group. Our findings suggest that patients with thoracic esophageal cancer who are treated with preoperative radiotherapy must be carefully monitored for the occurrence of intramural lymphatic cancer invasion and distant lymph node metastasis.

Intra-hepato-arterial infusions of cis-diamminedichloroplatinum (II) and 5-fluorouracil clinically effective for malignant liver tumors

Four hepatocellular cancer patients and 11 metastatic liver cancer patients were treated with intra-hepato-arterial infusions of cis-diamminedichloroplatinum (II) plus 5-fluorouracil. Cis-diamminedichloroplatinum (II) (25–35 mg/m2) was given once a week, 5-fluorouracil (150–180 mg/m2) was infused daily. A partial response was obtained in 3 of 4 patients with primary cancer and in 5 of 9 evaluable metastatic cancer patients; the mean response durations were 27+ weeks in the former and 47+ weeks in the latter. However, severe bone marrow suppression occurred in 4 patients; 3 died of septicemia (2 cases) and massive intra-tracheal bleeding, respectively. This combined intra-hepato-arterial chemotherapy exerts a synergistic anticancer effect on malignant liver tumors, however, the related bone marrow suppression remains to be overcome.

Esophageal cancer associated with multiple cancerous lesions: clinicopathologic comparisons between multiple primary and intramural metastatic lesions.

SummaryDetailed histopathological examination of serial blocks and subserial sections of the entire resected esophagus in 111 patients who underwent esophagectomy for esophageal squamous cell carcinoma revealed 38 associated cancerous lesions apart from the main tumors, in 33 patients (29.7%). These associated lesions were divided into multiple primary lesions (MPLs; 27 lesions in 23 patients) and intramural metastatic lesions (IMLs; 11 lesions in 10 patients). Thirteen and fourteen MPLs were distributed on the proximal and distal sides, respectively, of the main tumor with the same mean distance of 2.6 cm. Three and 8 IMLs were located on the proximal and distal sides, respectively, with mean distances of 3.4 cm and 4.6 cm. With respect to the histological depth of cancer invasion, MPLs were all confined within the submucosal layer (superficial cancer) while IMLs varied from the submucosa to the adventitia. Histological findings indicate that MPLs may be associated with a possible increased multicentric carcinogenic potential in the non-cancerous epithelium of the esophagus of patients who have had an antecedent esophageal cancer, and that IMLs are developed by intramural lymphatic spread from the primary esophageal cancer. These results emphasize the need for careful attention to the choice of margins during the surgical resection of the esophagus.

Intra-hepato-arterial chemotherapy with CDDP and 5-FU for metastases to the liver from colorectal and gastric cancers

Thirty-five patients with metastases to the liver from colorectal (26 patients) and gastric (nine patients) cancers were treated with intra-hepato-arterial (IHA) injections of cis-diamminedichloroplatinum (II) (CDDP) plus 5-fluorouracil (5-FU). Therapeutic schedules consisted of manual bolus injections of CDDP. (25-35 mg/m2/week) and 5-FU (150-180 mg/m2/day) Regimen I, and CDDP (25-35 mg/m2/10-14 days) and 5-FU (60-70 mg/m2/day Regimen II. In patients with colorectal cancer metastatic to the liver, partial response (PR) rates in Regimens I and II were 38% and 62%, respectively. By contrast, in patients with metastases to the liver from gastric cancer, a PR was obtained in only one of nine patients (11%). IHA chemotherapy CDDP plus 5-FU, especially following Regimen II, appears to be a strongly recommendable strategy for treatment of metastatic liver tumors derived from colorectal cancer.