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A 58-year-old woman with advanced gastric cancer underwent total gastrectomy in May 2012. The histological diagnosis was poorly differentiated adenocarcinoma, cT4a (SE), pN1, cM0; fStage IIIA. Chemotherapy by S-1 was started after surgery. Six months after the operation, two metastatic nodules were noticed on the liver. Therefore, the chemotherapy was switched to S-1 plus cisplatin (CDDP) in November 2012. TS-1 (80 mg/body) was administrated from day 1 to 21 followed by 14 days rest as one course. CDDP (70 mg/body) was infused on day 1. After 3 courses of this combination chemotherapy, remarkable diminution of the metastatic lesions on CT images was observed. Because of the adverse event of Grade 2 nausea, the patient was forced to discontinue chemotherapy. The patient underwent partial resection of the liver (Hr-0: S8, S7) at 1 year after the first operation. The resected specimens showed no sign of malignancy, although uneven fatty deposition was observed more frequently than in the surroundings, and designated as histologically complete response (CR). The patient has been alive 30 months after the second operation without any recurrent sites. Thus, combined use of peroral S-1 and CDDP should be recommended for multiple liver metastases after gastrectomy.

Purpose: Bcl-2 is a model apoptosis suppressor postulated to promote tumorigenesis. Recently, it has been reported that Bcl-2 undergoes phosphoregulation of its Ser70 to substantially alter its molecular function. Previous studies further suggest that such phospho-Bcl-2 regulation may influence tumor progression in colorectal and other cancers; however, phosphorylation status of the Ser70 of Bcl-2 (pSer70) in vivo in tumors remains obscure. To elucidate this question that may suggest the biological role, we molecularly screened a panel of human colorectal adenomas and adenocarcinomas for endogenous expression of pSer70 Bcl-2., Experimental Design: An antibody specific against pSer70 Bcl-2 was generated for thorough immunohistochemical examination of paraffin-embedded tumor specimens, allowing detection of the endogenously expressed antigen among a range of Bcl-2-positive colorectal neoplasms, including 75 tubular adenomas, 114 adenocarcinomas, and 15 cases of cancer in adenomas., Results: Loss of pSer70 Bcl-2 expression was observed in adenocarcinomas in a differentiation-dependent manner (positivities: well differentiated 63%, moderately differentiated 52%, and poorly differentiated 12%), whereas tubular adenomas maintained their expression (positivity 88%). Interestingly, an inverse correlation was found between expression of pSer70 Bcl-2 and Ki-67 antigen in those cases of cancer in adenoma (P < 0.01). It was further observed that loss of pSer70 Bcl-2 expression was associated with significantly shorter survival (P < 0.05) and correlated with clinical stages and lymph node metastasis (P < 0.05 and P < 0.05, respectively)., Conclusions: Loss of pSer70 Bcl-2 expression is closely linked to biological aggressiveness in colorectal tumors and represents a statistically significant molecular index for prognosis of patients with these tumors.

A 69-year-old woman was admitted to our hospital because of anal bleeding and fatigue. The patient was previously diagnosed as having Evans' syndrome on the basis of hematological examination and had been treated with predonisolone for 8 years. On admission, severe anemia and thrombocytopenia were noted. Colonoscopy and Barium enema studies demonstrated an irregular tumor with hemorrhagic ulceration in the rectum, which was histopathologically confirmed as an adenocarcinoma. After red blood cells and platelets were transfused, and the patient was treated with high-dose gammaglobulin, predonisolone, and camostat mesylate, the platelet count gradually increased and hemolysis was well controlled. The patient then underwent Hartmann's operation and splenectomy without any postoperative complications. Predonisolone and high-dose immunoglobulin therapy in a rectal cancer burdened patient with Evans' syndrome is considered useful in combination with surgical treatment. This is the first case report of rectal carcinoma resection in a patient with Evans' syndrome.

Extensive atrophy has been reported to occur in the thymus in a cancer-burden state but the mechanisms of this atrophy have not been fully elucidated. We investigated changes in the thymus in tumour-bearing mice inoculated with two subclones of the murine colon 26 adenocarcinoma cell line: clone 5 (non-cachectic) and clone 20 (cachectic). In clone 20 mice, body weights and thymocyte numbers decreased significantly compared with controls. Flow cytometric analysis of the thymocytes demonstrated that the frequency of single positive cells (CD4+ CD8- and CD4- CD8+) was significantly increased and that of double positive cells (CD4+ CD8+) was significantly decreased in clone 20 mice and, to a lesser extent, in clone 5 mice compared with controls. Serum levels of interleukin 6 and granulocyte-macrophage colony-stimulating factor (GM-CSF) were significantly elevated. These results suggested that thymocyte apoptosis was accelerated in the cancer-cachectic state, and increased GM-CSF might be partly responsible for thymic atrophy.

We report a successfully treated case accompanied by portal venous gas, which was associated with splenic abscess due to penetration of colon cancer. In June, 1998, a 67-year-old Japanese man was referred to our hospital because of a continuous fever over 40 degrees C and portal venous gas detected by computed tomography (CT). CT revealed low density areas in the spleen and wall thickening of the descending colon next to the spleen. Barium-enema examination demonstrated an extrinsic filling defect in the splenic flexure of the colon. Splenectomy, resection of the pancreatic tail and left hemicolectomy were performed Histopathological studies showed moderately differentiated adenocarcinoma, which made a fistula at the bottom of the ulceration to the spleen. The postoperative course was uneventful. The portal venous gas was likely to have resulted from a bacterial infection in the portal venous systems secondary to the splenic abscess.

A 42-year-old male developed pain in the right gluteal region due to local recurrence after curative resection of advanced lower rectal cancer. Radiotherapy (60 Gy) was performed, but satisfactory results were not obtained. Therefore, a reservoir was placed lowing cannulation of the internal iliac artery. The chemotherapy, in addition to intravenous administration of low dose CDDP (20 mg), included local intraarterial infusion therapy with 5-FU (1,500 mg/5 hour) once per week. After 10 courses of this chemotherapy (total dose: CDDP, 200 mg; 5-FU, 15,000 mg), the pain decreased, and the tumor size was reduced without side effects, improving the patient's QOL. At present, multidisciplinary treatments including such chemotherapy and radiotherapy is performed for local recurrence of rectal cancer, but adequate results are often not obtained. Local intraarterial infusion chemotherapy via the internal iliac artery accompanied by changes in blood flow can be safely performed on an outpatient basis, and appears to be effective for local recurrence of rectal cancer.

The changes in histidine decarboxylase (HDC) activity, histamine and tele-methylhistamine contents were examined in tissues of mice after the inoculation of Colon-26 tumor cells subcutaneously into the lower back. The HDC activity in the spleen of mice increased significantly 14 days after the inoculation of Colon-26 and the increase in HDC activity continued for up to 28 days. However, the histamine content in the spleen of tumor-bearing mice was not changed significantly during the observation period. In the following experiments, two subclones of the Colon-26 cell line, cachexia-inducing clone-20 and non cachexia-inducing clone-5, were used and the induction of HDC activity in mice was examined in four tissues, spleen, lung, liver and kidney. Both clone-20 and clone-5 induced the increase in HDC activity to the same extent in the spleen and lung, but not in the liver and kidney. As observed using the Colon-26 original cell line, the histamine contents in the four tissues of tumor-bearing mice were not different from those in the control mice. In contrast, the levels of tele-methylhistamine, one of the major catabolites of histamine, in the tumor-bearing mice increased significantly compared with the control mice in all four tissues examined. There was a correlation between the increase in tele-methylhistamine level and the increase in HDC activity in the tissues. A histological study indicated that the tissue mast cells were not increased in spleen and lung of tumor-bearing mice. These findings indicated that the increase in HDC activity in the spleen and lung occurred in parallel with the growth of inoculated tumor cells in mice and suggested that the cells other than mast cells may be involved in the increase in HDC activity. The tumor-bearing state produced histamine with a high turnover rate in the mouse tissues, especially in the spleen and lung.

To date, only around 300 cases of metastasis to the penis have been reported and the primary cancer has been generally found in genitourinary structures. However, exceptional cases in which the primary site has been situated in organs like esophagus, pancreas, stomach have been published. We report an uncommon case in which the primary tumor was located in the cecum. To our knowledge, this is the first case of penile metastasis in which the responsible tumor was located in the cecum and in which the mode of metastasis was not direct invasion. As the tumor was restricted to the colon wall without invasion to neighbouring structures, and because colon cancer follows mainly the lymph-vascular route to its dissemination, this route is the most likely mode of the spread. By magnetic resonance imaging (MRI) on penile shaft, multiple nodules were clearly visualized. Nevertheless, as in most cases, in spite of the availability of advanced and precise diagnostic methods, the information was of little value for the patient. His survival was short.

Patients with cancer cachexia often suffer from psychiatric disorders. In the present study, we investigated the changes in monoaminergic activities in the brain in tumor-bearing mice with reference to the development of cachexia. Two clones, clone-5 (noncachectic clone) and clone-20 (cachectic clone), derived from the murine Colon-26 adenocarcinoma cell line (Nippon Roche Research Center), were inoculated subcutaneously at 1 x 10(6) cells/0.2 ml into the right lower back of BALB/c mice. In clone-20 mice, body weight and locomotor activity decreased significantly 10-15 days after tumor inoculation. The levels of noradrenaline, dopamine, and 3,4-dihydroxyphenylacetic acid showed no significant change among the three groups. The noradrenaline turnover rate in clone-20 mice was increased in cerebral cortex, hypothalamus, and midbrain. The 5-hydroxytryptamine turnover rate in clone-20 mice was increased in hippocampus, cerebral cortex, midbrain, and pons-medulla oblongata. In contrast, the dopamine turnover rate in clone-20 mice was decreased markedly in hippocampus, cerebral cortex, striatum, hypothalamus, and cerebellum. There was no significant change in amine turnover between control and clone-5 mice except for dopamine in hippocampus, cerebral cortex, and striatum and 5-hydroxytryptamine in striatum. No significant change in the levels of amino acids in the brain was observed among the three groups of mice. It is concluded that some of the psychiatric disorders from which cancer cachectic patients suffer might be ascribable to changes in monoaminergic activities in the brain.

Patients with far advanced colorectal cancers received chemotherapy consisting of low-dose cyclophosphamide (LDCY) 333 mg/m2 every four weeks intravenously and by oral administration of 5'-DFUR (a masked compound of 5-Fluorouracil). Serum levels of immunosuppressive acidic protein (IAP), an acute phase protein, were measured every four weeks for a total of thirty-one LDCY trials of ten patients. LDCY chemotherapy significantly decreased the IAP levels in cancer patients with high IAP levels. These results suggested that LDCY chemotherapy could counteract host responses against tumors and could have decreased immunosuppressive responses in cancer patients.

Purpose: Mucocele of the appendix is an uncommon disorder, usually found incidentally during ultrasonography or radiographic studies. We report two cases of combined appendiceal mucocele and colonic cancer., Methods: The two cases were analyzed for the clinicopathologic characteristics such as history, presentation, laboratory data, radiologic and endoscopic studies, pathology, and p53 immunoreactivity., Results: Two patients were diagnosed with an appendiceal mucocele by ultrasound of the abdomen, together with computed tomography. Colonoscopic examination subsequently revealed synchronous colonic adenocarcinoma in both patients. Ileocecal resection following endoscopic polypectomy and a right hemicolectomy was performed for each patient. An appendiceal mucocele was histologically diagnosed as a mucinous cystadenoma. Immunohistochemical detection of abnormally high level of p53 protein was observed in colonic adenocarcinomas of both patients, whereas both appendiceal cystadenomas were negative for p53., Conclusions: To be remembered is the high frequency of concomitant gastrointestinal tumors in patients with appendiceal mucocele, especially caused by mucinous neoplasms. A total colonoscopic surveillance will afford earlier diagnosis of synchronous colonic cancers in these patients.

Three patients with colorectal cancer after irradiation for cervical cancer are described. One patient had two colorectal cancers. Three of the four cancers in these patients were located in the rectum and one in the sigmoid colon; all were within the irradiation field. Microscopic radiation proctocolitis was observed in all specimens. The interval between irradiation and the diagnosis of colorectal cancer was 20-24 years. It is important to consider patients who have undergone pelvic irradiation as being in a high risk group for the development of colorectal cancer. Close and long-term surveillance may be useful in these patients.

Cyclosporine A (CSA), an immunosuppressive agent with apparently selective effects on T lymphocytes and little myelotoxicity, was tested for its effects on hepatic metastases by inoculation of mouse colon-26 tumour cells into the portal vein in male CDF1 mice. CSA, given subcutaneously in daily doses of 10-50 mg/kg/day, for 22 days, significantly increased the incidence of hepatic nodules. This increase was positively correlated with the CSA dose. When 5-fluorouracil was injected at a dose of 15 mg/kg/day every other day after the inoculation of tumour cells a highly significant reduction in the incidence of metastases was seen (compared with the controls). This strong inhibitory effect of 5-fluorouracil on metastasis was almost completely suppressed when mice were treated with CSA concomitantly. The results suggest that CSA affects the host immune system, accelerating the production of hepatic metastases.

We measured neopterin (NPT), an indirect marker of gamma (gamma)-interferon, and the activity of thymidine phosphorylase (dThdPase) in the advancing front of colorectal carcinoma and in normal mucosa. Cancer showed a higher concentration of NPT than normal mucosa and also showed significantly higher (p < 0.0001) dThdPase activity than normal mucosa. There was a strong correlation between NPT concentration and dThdPase activity in cancerous and normal mucosa. These results suggest that endogenous gamma-interferon could activate dThdPase activity, which is essential to nucleic acid metabolism because it regulates the availability of thymidine.

Eighteen (5.0%) out of 358 patients who underwent resection of a colorectal carcinoma during the period 1978 through 1990 had synchronous colorectal carcinomas, and were 5.6 years younger on average than those with a single carcinoma. The distance between synchronous lesions was less than 10 cm in 69.6% of all the patients in the study. Among the synchronous carcinomas there was a higher incidence of ascending colon involvement, mucinous carcinoma, family history of malignant diseases, multiple malignant neoplasms associated with other organs and benign neoplastic polyps of the colorectum, and it is suggested that hereditary oncogenic factors influence these carcinomas. The synchronous lesions were detected pre-operatively in 14 of 18 patients with synchronous carcinomas, and the most common reason why synchronous lesions were missed was that the lesions on the anal side prevented the lesions on the proximal side from being examined. The prognosis in the synchronous lesion group was worse than in the solitary lesion group. Since it is difficult to predict synchronous colorectal carcinomas, careful pre-operative examination, including that of other organs, is necessary, and intra-operative colonoscopy should be carried out when pre-operative examination was insufficient.

Lateral lymph node dissection has been advocated for advanced low rectal tumours. However, its benefit is debatable because of the possibility of postoperative bladder and sexual impairment. To assess the role of lateral lymph node dissection 95 patients who underwent the procedure between 1981 and 1991 were reviewed and compared with 83 who had resection of rectal cancer without lateral node dissection. Only ten (11 per cent) of the 95 patients had lateral lymph node involvement; all had Dukes' C tumours. Lymphovascular invasion was present in 50.6 per cent of all patients and neural invasion in 27 per cent of 65 examined specimens. Local recurrence, distant metastasis and overall 5-year survival rates were 7, 9 and 76 per cent respectively in patients undergoing extended lymphadenectomy and 16, 7 and 72 per cent respectively in those who had resection alone. There were no statistically significant differences in survival between the two groups for any Dukes' stage. Recurrence, metastasis and survival were related more to venous or neural invasion and tumour spread than to node dissection. These results demonstrate that patients with Dukes' A tumours do not benefit from lateral lymph node dissection, and that local recurrence rates in those with Dukes' B and C lesions are not significantly decreased. It is concluded that extended lymphadenectomy is unlikely to provide significant benefit to patients with low rectal cancer.

Neural invasion may be one of the main causes of local recurrence, but its mechanism has not been sufficiently clarified. We previously reported that the expression of NCAM on cancer cells was correlated with neural invasion in pancreatic cancer. In this study, we examined the neural affinity of rectal cancer cells and the relationship between neural invasion and recurrence patterns of rectal cancers. A total of 64 rectal adenocarcinoma were examined. Specimens from 17 patients (27%) revealed perineural invasion. The incidence of neural invasion increased with the frequency of venous invasion and the degree of lymph node metastasis, but not significantly. The incidence of the expression of NCAM in rectal cancer cell was 45.3 percent. Neural invasion of rectal carcinoma was significantly related to the expression of NCAM (p < 0.05). NCAM immunocytolocalization was classified into the focal type, and the diffuse type. Concerning the recurrence type, 8 of 9 cases that developed local recurrence showed either presence of neural invasion or expression of NCAM. Liver metastasis was associated with absence of neural invasion or NCAM expression. The expression of NCAM may contribute to local recurrence, whereas the absence of NCAM may predict liver metastasis.

Although many agents that interfere with clotting mechanisms have been investigated for their potential to inhibit metastasis, their toxicity has prevented administration of sufficiently high doses to achieve inhibition of metastasis in clinical trials. Nafamostat mesilate (FUT-175), a synthetic serine protease inhibitor, inhibited liver metastasis in a CDF1 mice model with colon 26 adenocarcinoma cells. The apparently dose-dependent inhibitory effect was seen 21 days after all of the doses tested (0.3, 1.0, 3.0 and 10.0 mg/kg for 7 days) but the effect was only statistically significant (P less than 0.01) at the highest dose. The blood concentrations 3 min after dosing were less than 10(-6) M for all of the doses tested. At a concentration of 10(-5) M or less nafamostat mesilate was not cytotoxic towards colon 26 cells in vitro. The results indicate that it may not be difficult to achieve blood nafamostat mesilate concentrations that inhibit metastasis in mouse liver. Possible mechanisms of nafamostat mesilate are inhibition of extravasation and invasion of cancer cells, inactivation of collagenase due to inhibition of plasmin activity and inhibition of the formation of the cancer cell thrombus, and arrest in the capillaries through inhibition of thrombin activity. These preliminary results suggest that peri-operative administration of nafamostat mesilate may prevent metastasis into the liver after surgery for gastrointestinal malignancies.

Fresh surgical explants of solid tumors obtained from 50 patients were tested against six chemotherapeutic agents in the in vivo subrenal capsule assay. Control growth adequate to meet evaluable assay criteria was obtained in 36 of 50 tumors (72.0%). With activity criteria set at current drug screening levels as a change in modifidd PAPAN score in less than or equal to -2.0 for the SRC assay, 36.1% of the human tumors evaluable and 11.6% of drugs tested were sensitive, respectively. Our research reveals that gastric cancers respond to drugs about 2.5-fold higher than colorectal cancers. Comparisons were made of the drug sensitivity in terms of histologic differentiation, and it was strongly suggested that the sensitivity of the poorly differentiated type was higher than that of well or moderately differentiated type.