[Preoperative chemoradiation therapy for advanced rectal cancer].

Preoperative concurrent chemoradiation therapy with 5-fluorouracil and cisplatin was applied for advanced rectal cancer. Eligible criteria were as follows: no previous treatment, 4 more than hemicircular occupation, T3 or more invasion to adjacent organs or lymph node metastasis on CT scan, tumor fixation by digital examination. Eleven patients were enrolled with this regimen consisting of 5-FU; 500mg/day x5/w x4, CDDP; 10mg/day X 5/w x4 and radiation; 2Gy x 5/w x 4. As a toxicity, grade 2 leukopenia in 2 cases, grade 2 GI symptoms in one case and radiation dermatitis was observed in 8 cases. As a local response, there were PR in 10 cases and NC in 1 case. Surgical resection was performed on 8 patients. Histological responses in the resected specimens were grade 2, 5 cases; grade 1b, 1 case; and grade la, 2 cases. Operative radicalities were grade A, 3 cases; grade B, 3 cases; and grade C, 2 cases. Preoperative chemoradiation is one of the effective options in multimodal treatment for advanced rectal cancer.

[Local control of hepatic malignant tumors by percutaneous microwave].

We investigated the effects of percutaneous microwave coagulation under general anesthesia in the local control of hepatic malignant tumors. Coagulation at 60 W was done for normal liver of living swine using a percutaneous electrode. Wide-range coagulation at the tip of an electrode, 3 mm in diameter, was conducted. Clinically, echo-guided percutaneous microwave tumor coagulation was done for a total of 11 lesions in 5 patients with hepatocellular carcinoma and 4 with metastatic tumors in the liver under general anesthesia. Coagulation at 60 W of the liver of living swine for 1.5 and 10 min, using a percutaneous electrode, produced a maximal coagulation of 10, 20 and 30 mm, respectively. The trial electrode permitted coagulation almost at the tip of the electrode only. Percutaneous microwave coagulation of 11 lesions of the clinical cases resulted in complete coagulation in 7 lesions and incomplete coagulation in 4. The lesions showing complete coagulation were all less than 23 mm.

[Preoperative synchronized chemoradiation therapy for advanced esophageal cancer].

Synchronized chemoradiation, where 5-FU and CDDP were synchronously administered in the same schedule with radiation therapy, was applied for advanced esophageal cancer in neoadjuvant fashion. Ten patients with advanced esophageal cancer were enrolled for this regimen consisting of 5-FU; 500 mg/day x 5/w x 4, CDDP; 10 mg/day x 5/w x 4 and radiation; 2 Gy x 5/w x 4. Tumor regression was achieved in all cases. In terms of toxicity, bone marrow suppression of more than grade 3 was observed in 60% of the cases, though it was safely controlled. Radical operation was performed on 8 cases. Histological responses in the resected specimen were as following: grade 3, 3 cases; grade 2b, 4 cases; grade 2a, 1 case; and 6 node-negative cases were found. As a postoperative complication, minor leakage occurred in 62.5%, while no major complications such as pneumonia were encountered. This neoadjuvant synchronized chemoradiation improved curability of the salvage operation and permitted reduction surgery for high-risk patients.

[Preoperative chemoradiation therapy for lower rectal cancer].

To identify appropriate candidates with rectal cancer for preoperative chemoradiation therapy, the local recurrence rate and clinicopathological characteristics of 232 patients with rectal cancer undergoing curative resection in our department were investigated. The local recurrence rates were 3.8%, 10.8% and 16.5% in the Rs, Ra and Rb lesions, respectively. Regarding lower (Rb) rectal cancer, depth of lesion (> a1) and nodal metastasis consisted of high factors for local recurrence. Basing on these results, entry criteria for preoperative chemoradiation therapy were established, and concurrent chemoradiation therapy with fluorouracil and cisplatin was delivered preoperatively in 9 primary cases of locally advanced rectal cancer and 3 cases with local recurrence. A partial response was obtained in 7 of 12 cases with a response rate of 58%, size-reduction of the distant metastatic lesions was found in 2 cases, and clinical symptoms were improved in all cases. The histological responses of the 6 resected cases were Grade 2 in 2 cases and Grade 1b in 4 cases. The toxicities of this chemoradiation regimen were well tolerable. As a postoperative complication, infection of the perineal wound was most frequent. Preoperative chemoradiation therapy with the present regimen would be a useful adjuvant treatment for advanced lower rectal cancer.

[Evaluation of percutaneous microwave hepatic tumor coagulation therapy (PMTC) under general anesthesia from viewpoint of quality of life (QOL)].

We evaluated clinical benefits (QOL and local control rate) of percutaneous microwave coagulation therapy conducted with general anesthesia. Five cases with hepatic tumor (3 cases with hepatocellular carcinoma, 2 cases with metastatic hepatic tumor) were enrolled. The day following treatment all patients were virtually free of complaints with performance status ranging 0 to 1, and they were discharged from the hospital within 1 week. Four of five cases could be controlled solely with this treatment: one case showed local relapse, the tumor size of which exceeded 3 cm. PMTC may be one of the most beneficial local treatments for malignant hepatic tumor, since it shortens hospital stay with a good QOL status, and is applicable to metastatic tumor.

[Study on therapeutics adopted after occlusion of intraarterial reservoir in patients with liver tumor].

Over the last 5 years, we experienced thirty-nine patients with liver tumors undergoing implantation of an intraarterial reservoir through the gastroduodenal artery. Nine of the 39 patients had hepatocellular carcinomas, while the rest had metastatic liver tumors. In 32 patients, intraarterial chemotherapy via an implanted reservoir was discontinued either because of death in 20 patients with an average survival period of 11.7 months or because of occlusion of an intraarterial line in 12 patients with an average treatment period of 20.2 months. Regarding treatment modalities adopted for intraarterial therapy, transcatheter arterial embolization, surgical resection, microwave tumor coagulation, ethanol injection therapy, and a subselective intraarterial chemotherapy were performed in 3 patients with hepatocellular carcinomas. All of them survived more than 2 years after disuse of the reservoir. Out of 5 patients with metastatic liver tumors of colorectal cancer, one patient underwent additional surgical resection, two patients had no therapy who survived only two or three months, and two patients were still alive without additional therapies. Of four patients with metastatic liver tumors, 3 from breast cancer and one from leiomyosarcoma of stomach were treated with systemic chemotherapy or subselective intraarterial chemotherapy combined with radiation therapy. The average survival period of these 12 patients was 16.2 months, and 7 of them are still alive.

[Long-term survival in two cases of multiple liver metastasis successfully treated with intraoperative ultrasound-guided microwave tumor coagulation (MTC)].

Since April 1990, multiple metastatic liver tumors have been treated with intraoperative ultrasound-guided microwave tumor coagulation (MTC) in combination with postoperative intraarterial chemotherapy. Twenty-four patients have been enrolled in this therapeutic modality and two of five patients treated in 1990 achieved long-term survival. In case 1, a 67-year-old woman was diagnosed as bearing gastric leiomyosarcoma with multiple liver metastasis. Total gastrectomy was performed, and six hepatic lesions were treated by MTC along with implantation of an intraarterial reservoir. Postoperative intraarterial chemotherapy was administered in a selective or subselective manner. Her survival time was 4 years and 6 months. In case 2, a 47-year-old man was diagnosed as having liver metastasis from descending colon cancer 1 year and 5 months after left hemicolectomy. When he was laparotomized for the treatment of adhesive ileus, three metastatic liver tumors were treated with MTC. Afterward, he underwent hepatic resection, intraarterial and intraportal chemotherapy. He survived for 5 years and 5 months after being diagnosed with liver metastasis. MTC is one of the useful modalities for the treatment of multiple liver metastasis.

[A case of pulmonary metastasis from colon cancer successfully treated with high-dose 5'-DFUR].

We report a case, showing a complete response to high-dose 5'-DFUR, with pulmonary metastasis from colon cancer. A 52-year-old male patient underwent right hemicolectomy for ascending colon cancer in August, 1991. A recurrence of colon cancer developed in the left lower lung 16 months after surgery, and 5'-DFUR was administered at a dose of 1,600 mg/body/day. The pulmonary metastatic lesion was undetectable on chest X-ray film 9 weeks after the start of this therapy. The dose of 5'-DFUR was then reduced to 600 mg/body/day. Although this condition was maintained for 22 weeks, chest X-ray film again showed the metastatic lesion at the same site in the lung as before. The pulmonary metastasis was resected completely in April, 1994. This is suggested to be an effective therapy for pulmonary metastasis from colon cancer.

[Microwave tumor coagulation (MTC) in liver tumor: indication and percutaneous approach].

Indications for microwave tumor coagulation (MTC) and percutaneous approach in liver tumor were investigated. The study population comprised 26 patients with unresectable liver tumor (4 with hepatocellular carcinoma, 22 with metastatic liver tumor) who underwent MTC at our department after April 1990. Concomitant therapies were alcohol injection in 2 patients, hepatectomy in 12 and selective arterial chemotherapy in 20. Percutaneous MTC was performed on 2 patients with a single lesion under general anesthesia. Following tip coagulation electrode penetration under echo guidance, the lesion was thermally coagulated at 60W. To establish indications for MTC by the effect of thermal coagulation, survival periods were compared by underlying disease, number of masses coagulated, and maximum tumor size, in 23 patients who had undergone MTC at least 1 year previously. Thirteen of these 23 survived for 1 year or longer, including all 3 with hepatocellular carcinoma, 3 with breast cancer, 2 with leiomyosarcoma (gastric, small intestine), 4 of the 10 with colon cancer and 1 of the 2 with pancreatic cancer. According to evaluation of the degree of coagulation, complete coagulation was obtained in 11 of 23, all of whom had at most 6 tumor masses (of up to 3 cm in diameter) coagulated, and 9 of whom survived for 1 year or longer. Percutaneous MTC, of low invasiveness, proved useful as a tool of regional cancer therapy.

[Evaluation of colorectal hepatic metastases with combined modality therapy].

We treated synchronous hepatic metastases in colorectal cancers with combined modality therapy including hepatic resection, selective intra-arterial infusion chemotherapy, and thermocoagulation therapy using a microwave tissue coagulator and compared the value of such therapies. Synchronous hepatic metastases were noted in 563 patients with colorectal cancer who had undergone surgery in our department over the past ten years. Forty-four patients were studied. Six patients underwent hepatic resection only (group A). Another six were subjected to hepatic resection and the residual lesions were treated with selective intra-arterial infusions and thermocoagulation therapy (group B). Fourteen patients were treated with either selective or subselective intra-arterial infusions (group C). The remaining 18 patients were treated in other ways (group D). Cumulative survival, estimated by the Kaplan-Meier method, was compared. One- and three-year cumulative survival rates of patients were 100% and 74% in group A, 100% and 67% in group B, 62% and 0% in group C, and 38% and 5% in group D, respectively. H1 patients accounted for 83% in group A, 33% in group B, 7% in group C, and 22% in group D. The high rate of survival in group A was because of the greater number of H1 patients. One- and three-year survival rated among H2-H3 patients were 100% and 54% in group B, 62% and 0% in group C, and 35% and 14% in group D, respectively. Survival of H2-H3 patients was higher in group B than in group C or D.

[Liver metastases from breast cancer: survival and an attempt at cauterization and thermocoagulation therapy combined with selective intra-arterial infusion chemotherapy].

During the past thirteen years, 599 patients with primary breast cancer underwent surgery in our hospital. Nine of them died of liver metastases and the median survival time after detection of liver metastases was five months (range 1-32 months). Four are still alive with liver metastases. Based upon these results, we attempted intraoperative, ultrasound-guided cauterization and thermocoagulation for three patients to improve their prognosis and postoperatively treated them with hepatic arterial infusion chemotherapy. During surgery, a monopolar electrode was inserted with an ultrasonic guide. One round of cauterization lasted for 10 seconds at 100 W, and was repeated until the tissue around the tumor became hyperechoic. The antitumor effect of the therapy was assessed by histological examination of resected liver tissues. Tumor coagulation and necrosis were observed to be consistent with the cauterized area. On CT scanning, treated areas were shown to be of low density and homogeneous. Since this therapeutic approach acts directly on unresectable tumors and is safe, it seems to provide a useful means for intraoperative regional treatment of tumors.

[Evaluation of subselective intraarterial infusion chemotherapy in far advanced gastric and colorectal cancer].

We investigated the usefulness of subselective intraarterial infusion chemotherapy in far advanced gastric and colorectal cancer. Among gastric and colorectal cancer cases undergoing surgery at our hospital for the past ten years, patients with and without palliative resection were studied. Forty gastric cancer patients and 29 colorectal cancer patients were treated by subselective intraarterial infusion chemotherapy. In gastric cancer cases without resection, a significantly longer survival was noted in patients undergoing this therapy with over 5 g of 5-FU than those treated with conventional chemotherapy. In gastric cancer patients with palliative resection and colorectal cancer patients, survival time was longer by intraarterial infusion with over 5 g of 5-FU, but not significant. Partial response was obtained in 5 cases of gastric cancer and 3 cases of colorectal cancer, and clinical symptoms were improved in 44% of the patients. The main complications of this therapy were myelosuppression and occlusion of the catheter, but none of them were serious. For the improved quality of life of cancer patients, subselective intraarterial infusion chemotherapy is considered a safe and useful form of treatment.

[An attempt at intraoperative, ultrasound-guided microwave tissue coagulation for metastatic liver tumors].

Using a microwave tissue coagulator, we attempted intraoperative, ultrasound-guided cauterization and thermocoagulation of metastatic liver tumors. The procedure, safety and efficacy of this therapy were analyzed. During the past 2 years, this therapy was used in 10 patients with unresectable metastatic liver tumors. During surgery, monopolar electrodes were inserted with an ultrasonic guide. One round of cauterization lasted for 10 seconds at 100 W. It was repeated until the tissue around the tumor became hyperechoic. This therapy was used for 67 tumor lesions in total (2-22 lesions/patient). No complications were observed during or after this therapy, except for a case complicated by liver abscess. The anti-tumor effect of the therapy was assessed by histological examination of resected liver tissues. Tumor coagulation and necrosis were observed consistent with the cauterized area. The response to this therapy, assessed by diagnostic imaging, was CR (complete remission) in 3 cases, PR (partial remission) in 3, NC (no change) in 3 and PD (progressive disease) in 1. Thus, the efficacy (the percentage of cases showing CR or PR) was 60%. Since this therapeutic approach acts directly on tumors and is simple and safe, it seems to provide a useful means for intraoperative regional treatment of tumors.

Immunohistochemical study of p53 expression in microwave-fixed, paraffin-embedded sections of colorectal carcinoma and adenoma.

Expression of p53, a tumor-suppressor gene product, was studied immunohistochemically in microwave-fixed, paraffin-embedded sections of 84 colorectal carcinomas and 44 adenomas. Using a monoclonal antibody (PAb1801), nuclear p53 was detected successfully in 51 of 84 (60.7%) cases of carcinomas, and no stain for p53 was demonstrated in the adjacent normal mucosa. The results in the microwave-fixed, paraffin-embedded sections correlated with those in the frozen sections. The incidence of p53 expression in colorectal carcinomas was high in the cases with distant metastasis, but it was not affected by clinicopathologic features such as tumor size or depth of invasion. In colorectal adenomas, only 4 of 44 (9%) adenomas expressed p53. This expression of p53, however, was restricted to only a few glands within tubular adenomas with mild dysplasia. Thus, p53 protein was expressed preferably by malignant tumors of the colorectum. The present study demonstrated the usefulness of microwave fixation to preserve p53. The immunohistochemical detection of p53 in microwave-fixed, paraffin-embedded sections of colorectal carcinoma and adenoma can provide valuable information about the mechanism of carcinogenesis in colorectal epithelium.

Use of fibrinogen to enhance the antitumor effect of OK-432. A new approach to immunotherapy for colorectal carcinoma.

OK-432 (5 KE), an immunomodulatory agent prepared from an attenuated strain of Streptococcus pyogenes, was dissolved in 1 ml of aprotinin (1000 KIE) and mixed with 80 mg of fibrinogen containing Factor XIII. A single intratumoral injection of the mixture was performed preoperatively under endoscopy in 20 patients with colorectal carcinoma. Postoperative histopathologic examinations revealed the formation of fibrin fibers at the site of injection and marked infiltration of inflammatory cells into the tumor stroma on the day after injection; the formation of granulomas containing many giant cells after 4 to 7 days; and extensive regression of tumor tissue after 14 days. This study suggests that the high concentration of exogenous fibrinogen gelatinized enough to trap OK-432 in tumor stroma and that OK-432 induced granulomatous hypersensitivity to degenerate tumor stroma, thereby causing regression of the tumors.

Difference in Tryptophan-nicotinamide Conversion According to Dietary Nitrogen Sources; Casein, Casein Hydrolysate, and Mixtures of Amino Acids.

We investigated whether the fate of tryptophan (Trp) to nicotinamide (Nam) is changeable according to nitrogen sources or not. Male rats were fed with a nicotinic acid-free diet (Trp content was arranged at about 234mg/100g of diet) containing casein, casein hydrolysates, or mixtures of amino acids (simulating the amino acid pattern of casein) for 12 days. From the urinary excretion of Nam and its metabolites, the conversion ratio was calculated. The conversion ratio was lower in the groups fed with the casein hydrolysate diets than in the groups fed with the casein and amino acid diets. In order to find the reason, the urinary excretion of kynurenic acid, xanthurenic acid, anthranilic acid, and 3-hydroxyanthranilic acid from the upper part of the Trp-Nam conversion pathway, the contents of free Trp in whole blood, and eight kinds of enzyme activities involved in the Trp-Nam pathway were measured. From these results, it is considered that the reason why the conversion ratio was lower in the casein hydrolysate group is due to the lower concentration of free Trp in whole blood and the higher activity of aminocarboxymuconate-semialdehyde decarboxylase. As is known that this enzyme activity is induced by adrenal cortical hormone, it was suggested that the release of this hormone is stimulated by feeding the casein hydrolysate diet.

Immunohistochemical analysis of amylase isoenzymes in thyroid cancer.

The expression of amylase in various histological types of thyroid cancer was studied by an immunohistochemical technique, using a polyclonal antiamylase antiserum and two monoclonal antibodies specific for salivary and pancreatic-type amylases, respectively. Amylase was expressed in 21 of 24 (88%) thyroid cancers by polyclonal antiserum analysis. Analysis by monoclonal antibodies, however, showed that only 13 (54%) cases and three (13%) cases contained salivary-type and pancreatic-type amylases, respectively. Moreover, immunoreactivity for pancreatic-type amylase was detected only in medullary carcinoma; other histological types were positive for salivary-type amylase. These results show that thyroid cancer frequently expresses amylase, and suggest that the differences between amylase isoenzymes in thyroid cancer may correlate with those found between cellular origin of tumour.

[Intratumoral injection of OK-432 in conjunction with fibrinogen greatly enhances antitumor effect on colorectal carcinomas].

We found that antitumor effect of OK-432, a lyophylized preparation of an attenuated strain of streptococcus pyogenes, on colorectal carcinoma was greatly augmented when it was injected intratumorally in conjunction with fibrinogen. Twenty cases of colorectal cancer received intratumoral injection of 5 KE of OK-432 mixed with 80mg of fibrinogen including factor-XIII and 1ml of aprotinin at the time of endoscopic examination. Changes in the shape of the tumors were observed endoscopically within a few days after injection, and in most cases, decrease in the height of tumor margin was noted. Histopathological findings on surgically resected specimens revealed that the fine meshwork of fibrin was formed at the injected site soon after the injection, and a marked infiltration of inflammatory cells including neutrophils, plasma cells, macrophages, eosinophils and lymphocytes. Such granulomatous changes developed over 7 days after injection, and the degradation of tumors were observed. By 14 days after the injection, tumor tissues were largely replaced with granulomas, and shrinkage of tissues were observed. These findings indicated that fibrinogen including factor-XIII and aprotinin has a potential ability to augment the immunoreaction induced by biological response modifiers, and intratumoral injection of OK-432 in conjunction with fibrinogen solution was superior to intratumoral injection of OK-432 alone as the local immunotherapy of colorectal cancer.

Expression of pancreatic secretory trypsin inhibitor (PSTI) in colorectal cancer.

We examined the expression of pancreatic secretory trypsin inhibitor (PSTI) in colorectal cancer by immunohistochemical staining using an anti-PSTI antiserum, an in situ hybridisation technique utilising sulphonated PSTI cDNA probe, and a Northern blot hybridisation method, using a 32P-labelled PSTI cDNA probe. Immunohistochemically, PSTI was detected in 80 of 95 (84%) colorectal cancer cases. Analyses with in situ hybridisation as well as Northern blot hybridisation demonstrated PSTI mRNAs in immunohistochemically positive cases, showing PSTI could be produced in colorectal cancerous cells. Histologically well or moderately differentiated adenocarcinoma showed higher incidence of PSTI immunoreactivity than the other types. Furthermore, the intensity of the immunohistochemical staining for PSTI increased the more cases advanced, particularly in regard to depth of invasion and tumour size. Thus, PSTI expression is widespread in colorectal cancer, and occurs more commonly in advanced cases. Considering the suggestion that PSTI is a growth-stimulating factor as an well as inhibitor to proteolytic proteinase, the present findings may indicate that PSTI expressed in colorectal cancerous cells may play a role possibly closely associated with tumour development.

Expression of pancreatic secretory trypsin inhibitor gene in human colorectal tumor.

Expression of pancreatic secretory trypsin inhibitor (PSTI) gene was examined by Northern blotting analyses in 31 human colorectal tumors that included two benign adenomas and 26 adenocarcinomas. Among the total of 28 cases which proved to be adequate for mRNA analyses, all but one showed the expression of PSTI at various levels. In contrast, PSTI expression was not detected in two malignant lymphomas of the rectum. The level of PSTI expression was not correlated with the patient's age, sex, tumor location or size, stage of differentiation, lymph node metastasis, or progression stage. Some colorectal adenocarcinomas were also shown to express genes that can hybridize with human trypsinogen cDNA probe. It looks as though in these tumors, a protease(s) and its inhibitor are produced simultaneously as part of a cellular self-defense mechanism.