Michio Maruyama

Synergistic Effect of Methionine‐depleting Total Parenteral Nutrition with 5‐Fluorouracil on Human Gastric Cancer: A Randomized, Prospective Clinical Trial

Methionine‐depleting total parenteral nutrition (Met‐depleting TPN), infusing AO‐90 amino acid solution (lacking both L‐methionine and L‐cysteine) as a sole nitrogen source, showed synergistic effects with 5‐fluorouracil (5‐FU) in tumor‐bearing rats and in clinical trials with gastrointestinal tract cancers. In this study, the effect of Met‐depleting TPN with 5‐FU upon thymidylate synthase (TS) activity was examined, and the histological effect of this treatment on human gastric cancer was evaluated. Fourteen preoperative advanced gastric cancer patients were divided randomly into two groups. Seven cases were given Met‐depleting TPN for 7 days before surgery with continuous intravenous administration of 5‐FU (500 mg/body per day; total 4.0 g/body) (AO‐90 group). The other 7 received conventional L‐methionine‐containing TPN with 5‐FU (control group). All patients underwent gastrectomy without complications due to these treatments. Resected materials were examined for TS kinetics, and the anti‐cancer effect was also assessed histopathologically. The specimens in the AO‐90 group showed marked degeneration of cancer, while almost no effect was seen in the control group. The free TS activity of carcinoma tissue in the AO‐90 group was decreased and the TS inhibition rate was increased in comparison with the control group (P= 0.0165 and P= 0.0243, respectively). Met‐depleting TPN appears to play a role as a biomodulator of 5‐FU in human gastric cancer.

Higher frequency of point mutations in the c-K-ras 2 gene in human colorectal adenomas with severe atypia than in carcinomas

Human colorectal carcinomas may be induced from adenomas or they may occur de novo. To examine which is the main pathway, we analyzed point mutations at codon 12 in the c‐K‐ras 2 gene in 73 colorectal carcinomas, 13 metastatic tumors, 72 adenomas and 30 normal tissues. The c‐K‐ras 2 codon 12 mutation frequency was 0/30 in normal tissues, 0/17 in adenomas with mild atypia, 3/37 (8.1%) in adenomas with moderate atypia, 15/18 (83.3%) in adenomas with severe atypia, 19/73 (26.0%) in primary carcinomas and 3/13 (23.1%) in metastatic tumors. The mutation frequency in adenomas with severe atypia was much higher than that in carcinomas. These results indicate that many colorectal carcinomas may not be induced through adenomas with severe atypia.

A case of multiple carcinoid tumors of the rectum with extraglandular endocrine cell proliferation.

A case of multiple carcinoid tumors of the rectum with numerous proliferations of extraglandular endocrine cells is reported. The patient was 52‐year‐old man with five polypoid lesions in the rectum. The resected rectum contained five macroscopic carcinoid tumors, 36 microcarcinoids, and innumerous extraglandular endocrine cell proliferations. Endocrine cell microproliferations, in their early stage consisting of one to 15 micronests, were mainly located within the bundles of muscularis mucosae, having no contact with mucosal glandular structures. All of the immunohistochemically examined proliferations of extraglandular endocrine cells contained S‐100 protein‐positive dendritic cells, and some endocrine cells coexisted with submucosal ganglion cells. In contrast, there was no increase in intraglandular endocrine cells. The origin of rectal carcinoid tumor may be the extraglandular endocrine cells, a distinct compartment of mucosal endocrine cells of the rectum.

Mutations in c-K-ras 2 gene codon 12 during colorectal tumorigenesis in familial adenomatous polyposis

Colorectal carcinomas may be induced from adenomas, or they may occur de novo. To clarify the histogenesis of colorectal carcinomas, point mutations in codon 12 of the c-K-ras 2 gene in neoplasias of familial adenomatous polyposis patients were examined. Nineteen colorectal advanced carcinomas, 135 adenomatous polyps, 9 hyperplastic polyps, and 27 normal colonic mucosae were obtained from 48 patients. In 27 normal mucosae and 9 hyperplastic polyps, a mutation in the K-ras gene was not detected. Mutations were detected as follows: 0 of 24 in adenomas with mild atypia, 10 of 77 in adenomas with moderate atypia, and 24 of 34 in adenomas with severe atypia. The incidence of mutations in c-K-ras 2 codon 12 is correlated with the degree of atypia of adenomas. However, only 5 such mutations were detected in 19 advanced carcinomas, indicating that the mutation frequency in advanced carcinomas is much lower than that in adenomas with severe atypia. If a mutation of c-K-ras 2 gene is an important component in the formation of adenocarcinoma, these results did not confirm the successive development from adenomas with severe atypia to advanced carcinomas as the main route for colorectal carcinogenesis in familial adenomatous polyposis patients.

SOLITARY NEUROFIBROMA OF THE ESOPHAGUS

A rare case of solitary neurofibroma located in the esophagus is reported. A large (4.2 × 4.0 × 3.0 cm) submucosal tumor was surgically removed from the midportion of the esophagus of a 64‐year‐old woman. Light and electron microscopic examination, and immunohistochemistry of S‐100 protein in the tumor tissue confirmed neurofibroma. The patient had no evidence of von Recklinghausens neurofibromatosis. A review of literature failed to find other reports of solitary neurofibroma of the esophagus with reliable histological diagnosis. ACTA PATHOL. JPN. 35 : 527–531, 1985.

Thoracoscopically managed parathyroid adenoma in the upper anterior mediastinum.

We thoracoscopically managed parathyroid adenoma of the upper anterior mediastinum in a 29-year-old man. He had a backache and was found to have bilateral ureteric stones, hypercalcemia, and extremely increased parathyroid hormone levels. 99mTc-methoxyisobutyl isonitrile scintigraphy showed an accumulation area projected onto the right thyroid lobe and the upper mediastinum. A diagnosis of primary hyperparathyroidism secondary to double adenomas was made. The patient then underwent surgical intervention. With the patient under general anesthesia with one-lung ventilation, a reddish brown adenoma of an upper mediastinum was removed thoracoscopically with three trocars, whereas the right superior parathyroid adenoma was excised by a standard open cervical procedure. Conventionally, the mediastinal parathyroid adenoma was removed by an open approach and was associated with perioperative distress to the patient. If the exact location of the mediastinal lesion is established, thoracoscopic excision of these lesions is feasible and is strongly recommended.

Enhanced Anticancer Effect of Vincristine with Methionine Infusion after Methionine-depleting Total Parenteral Nutrition in Tumor-bearing Rats

Methionine‐depleting total parenteral nutrition (Met(−) TPN), in which an amino acid solution devoid of L‐methionine and L‐cysteine is infused, is thought to reduce tumor cell growth through acting as a partial late S‐G2 (i.e., late‐S and G2 phases) blocker. The antitumor effect of vincristine (VCR), which acts on mitotic phase cells, was examined with methionine infusion immediately after Met(−) TPN in Yoshida sarcoma (YS)‐bearing rats. Rats were given Met(−) TPN for 8 days immediately after inoculation with YS cells (days 0 to 8), which was followed by methionine‐containing (Met(+)) regular TPN for 3 days (days 9 to 11) along with intraperitoneal administration of 0.05 mg/kg/day VCR. All rats were then fed solid food and water ad libitum until they died, with 0.1 mg/kg VCR administration on days 12 and 13. As controls, a Met(−) TPN only group, Met(+) TPN groups with and without VCR, and freely fed groups with and without VCR were studied. The progression of YS was markedly suppressed by Met(−) TPN with VCR. The median survival time in days was 25 days, significantly longer (P<0.001) (generalized Wilcoxons tests) by 11 to 14 days than that of any of the other groups. In conclusion, VCR appears to have greater efficacy as an anticancer agent when administered together with methionine after Met(−) TPN.

Effect of lentinan on lymphocyte subsets of peripheral blood, lymph nodes, and tumor tissues in patients with gastric cancer.

The effect of lentinan on lymphocyte subsets of peripheral blood, lymph nodes, and tumor tissues in gastric cancer patients was investigated. A 2-mg dose of lentinan was administered to 12 patients intravenously twice, the first at 3–9 days before and the second the day before surgery. The results were then compared with a control group without lentinan administration comprising 12 patients. Regarding peripheral blood and lymph nodes without metastasis, lymphocyte subsets defined with anti-CD3, anti-CD4, anti-CD8, anti-Leu7, and anti-Leu11 were analyzed by flowcytometry. As for tumor tissues, lymphocyte subsets defined with anti-CD3, anti-CD4, anti-CD8, anti-Leu11, and anti-M3 were analyzed after immunohistochemical staining. There were no significant changes in the lymphocyte subsets of peripheral blood between the two groups. In the lymph nodes, the CD4 cell ratios increased; otherwise in regard to tumor-infiltrating lymphocytes (TILs), the number of CD4, Leu11 and LeuM3 cells showed a prominent increase. Therefore, lentinan was observed to produce different effects in accordance with the subjective organs.

Morphological changes in gastric carcinoma with progression

By combining morphological two indices, namely, (1) the degree of differentiation of glandular tubules (well or poor) and (2) the amount of intracellular mucus (rich or poor), we previously classified histological types of gastric carcinoma into four types. Using this histological classification, we studied the morphological changes of gastric carcinoma according to extra-gastric invasion in 200 autopsy and 200 resected cases. In cases in which the predominant histological type in the lamina propria was “tubular differentiation—well, mucus in cytoplasm—poor,” there was a greater incidence of co-existence with other histological types. In many of these cases, the predominant histological findings changed to “tubular differentiation—poor” in the subserosa, followed by direct invasion into neighboring extra-gastric tissues. In all cases in which the predominant histological type in the lamina propria was “tubular differentiation —poor”, the predominant histological type in the subserosa was also “tubular differentiation—poor”. To understand the mode of extension of gastric carcinoma in relation to the histological type, we must consider not only the characteristics of the predominant histological types of carcinoma but also those of coexisting types, especially in cases of “tubular differentiation—well, mucus in cytoplasm—poor”.

Feasibility of International Proposed Standardized Enteral Connector for Semi-Solid Formula Feeding

Background/Aims: The current study was undertaken to assess if the semi-solid formulas could be used with a new ENFit connector with similar force to current percutaneous endoscopic gastrostomy (PEG) tubes. Methods: Experiment 1: We measured the applied pressure (force) needed to compress the syringe containing 7 viscous semi-solid formulas with a 20 Fr PEG tube and low-profile tube through the ENFit connector or the current connector. Experiment 2: This experiment was conducted to evaluate the compression force through 2 connectors in 3 infusion velocity, 7 PEG tube types with 2 semi-solid formulas. Results: Experiment 1: The force needed to compress the syringe through the ENFit connector was higher in 3 semi-solid formulas with a 20 Fr low-profile tube; otherwise, there were no significant differences. Experiment 2: Each formula required a higher force in the ENFit connector in 6 settings out of 21. Conclusions: The ENFit connector will likely not show any remarkable change in the force to administer the semi-solid formula. However, a higher force was required under some conditions in the prototype ENFit connector. Further investigation of sensory test is needed to confirm the feasibility of the ENFit connector for using the semi-solid formulas.