[A preliminary study on dihydropyrimidine dehydrogenase activity in breast cancer].

We studied dihydropyrimidine dehydrogenase (DPD) and thymidylate synthase (TS), key enzymes in regulating the pharmacokinetics and chemosensitivity to 5-FU, in 36 breast cancer patients as a control group and 18 patients as a 5-FU group, in which 5-FU was given orally for 2 weeks before surgery at a dose of 200 mg/day. Cancer tissues with adjacent normal tissue were sampled and stored until the assay. The DPD activity and TS amount were determined according to the radio-enzymatic assay and radiobinding assay, respectively. The DPD activity was significantly higher in breast cancer than in the adjacent breast tissue. This finding was observed in T1 and T2, node negative and ER positive breast cancers in the control group as well as in the 5-FU group. The DPD activity in T3 was significantly lower than in T1, and that of the adjacent breast tissue in T3 was significantly higher than in T1; therefore, the tumoral/non-tumoral ratio of DPD activity was significantly lower in T3 than T1. TS was significantly elevated in both groups, without significant differences. The clinical implication of elevated DPD activity in T1, T2, node negative or ER positive breast cancer compared to the respective normal breast tissue activity remains to be studied, because it is still unclear whether or not the tumoral DPD activity regulates the local concentration of 5-FU within the tumor. The amount of TS and DPD activity was not influenced by the oral administration of 5-FU for 2 weeks at the dose of 200 mg/day.

Ovarian carcinoma with fistula formation to the sigmoid colon and ileum: report of a case.

We describe herein an extremely rare case of clear cell type ovarian carcinoma resulting in fistula formation into the colon and intestine. The patient was a 61-year-old woman in whom a large tumor with extravasation from the sigmoid colon was found by barium enema examination. The tumor was preoperatively diagnosed as left ovarian cancer by angiography which showed the tumor feeder arising from the left ovarian and uterine arteries.

Antitumor effect of medium-chain triglyceride and its influence on the self-defense system of the body.

Medium-chain triglyceride (MCT), long-chain triglyceride (LCT), and their mixture were compared in reference to both cytotoxic effect against human tumor cells and influence on the immune system. MCT showed more potent cytotoxicity than LCT. Continuous contact with MCT also inhibited the cytotoxic effect of lymphokine-activated killer (LAK) cells much more strongly than LCT. However, there is a discrepancy between the concentration of MCT, or the mixture, that could suppress the growth of tumor cells and the concentration that inhibited the cytotoxicity of LAK cells. Moreover, no damage was observed in PBL or LAK cells or in their cytotoxicity when the cells were incubated with TG for 2 h a day. Thus, short-term contact with TG could inhibit tumor growth while immune system was maintained within normal range. Clinically fine control of the concentration of injected triglycerides, especially MCT, can be expected to provide potent antitumor effect and maintenance of normal immune system.

The expression of urokinase type plasminogen activator is a novel prognostic factor in dukes B and C colorectal cancer.

Urokinase type plasminogen activator (u-PA) secreted by cancer cells is considered to play a key role in promoting invasion and metastasis of cancer cells. This study was designed to evaluate the expression and prognostic value of u-PA in Dukes B and C colorectal cancer. u-PA expression was investigated in 57 Dukes B or C colorectal cancers using a monoclonal antibody against u-PA. u-PA expression was mainly observed on the cytoplasm of cancer cells, and was associated with relapse, especially hematogenous metastasis (p=0.025, the chi2 test). Patients with high u-PA expression had a lower rate of DFS (9/22 events) compared to those with low u-PA expression (6/35 events) (p=0.061, log-rank test). This study demonstrated that u-PA expression might be a novel prognostic factor in Dukes B and C colorectal cancer.

Thrombomodulin is a new biological and prognostic marker for breast cancer: an immunohistochemical study.

BACKGROUND: Thrombomodulin (TM) is a natural anticoagulant which inhibits thrombin. Recent studies have reported that TM is correlated with vascular diseases and a few cancers. The aim of this study was to evaluate the role and the prognostic value of TM in breast cancer. PATIENTS AND METHODS: TM expression in samples from 60 invasive breast cancer patients was examined immunohistochemically with a polyclonal antibody against TM. RESULTS: TM staining was observed mainly on both the cytoplasm and cell surface in cancer cells and on endothelial cells around or in cancer tissue. TM expression in cancer cells was not correlated with the clinicopathological features. However, low TM expression was significantly correlated with a high relapse rate (p = 0.047 by the chi 2 test and 0.05 by the Kaplan-Meier method). CONCLUSIONS: TM might play an active role in cancer invasion and metastasis, and serve as a new prognostic factor in invasive breast cancer.

Role of endogenous somatostatin in postprandial hypersecretion of neurotensin in patients after gastrectomy.

OBJECTIVE: The purpose of this report is to elucidate the mechanism of the hypersecretion of neurotensin (NT) after gastrectomy. SUMMARY BACKGROUND DATA: NT secretion induced by fat ingestion is increased after pancreatoduodenectomy or distal gastrectomy. The hypersecretion of NT in the patients undergoing resection of the upper gastrointestinal tract is suppressed by an exogenous somatostatin (SST) analog. METHODS: We observed simultaneously the secretion of NT and SST in the same patients before and after gastrectomy (n = 7). We also observed the secretion of these hormones induced by intraduodenal (ID) fat infusion in the normal volunteers (n = 6). RESULTS: The response of plasma NT to fat ingestion was significantly increased after gastrectomy compared with that before gastrectomy. The response of plasma SST after gastrectomy was significantly suppressed. The response of plasma NT and SST after ID fat infusion in the normal volunteers was similar to the gastrectomized state. CONCLUSION: Diminution of SST secretion, probably caused by the lack of SST cells in the distal part of the stomach, may play a role in augmenting NT secretion after gastrectomy.

Urokinase type plasminogen activator receptor is a novel prognostic factor in breast cancer.

BACKGROUND: There have been many reports that the u-PA system plays an important role in cancer invasion and metastasis. The binding of u-PA to its specific cell-surface receptor, u-PAR, is necessary for the activation of u-PA system. The aim of this study is to evaluate the role and the prognostic value of u-PAR in cancer invasion and metastasis. PATIENTS AND METHODS: u-PAR expression in 104 breast cancers was investigated immunohistochemically using a monoclonal antibody against u-PAR. RESULTS: u-PAR expression was mainly observed both on cancer cells and stromal cells. Patients with high u-PAR expression in cancer cells or stromal cells had a high relapse rate compared with patients with low u-PAR expression by the Kaplan-Meier method (p = 0.035 and 0.011, respectively). In uni- and multivariate analysis, u-PAR expression in stromal cells was significantly correlated with relapse (p = 0.017 and 0.043, respectively). CONCLUSIONS: This study has shown that not only cancer cells but also stromal cells have an important roles in breast cancer invasion and metastasis, and that u-PAR expression in cancer cells and stromal cells might be a novel prognostic factor in breast cancer.

A prospective study on the prognostic significance of urokinase-type plasminogen activator levels in breast cancer tissue.

Urokinase-type plasminogen activator (u-PA), which cleaves plasminogen to yield plasmin, is a serine protease of fibrinolysis and is presumed to play a key role in extracellular proteolysis and facilitate the migration of cancer cells. This study was conducted prospectively to evaluate the prognostic significance of u-PA antigen level in breast cancer tissues. u-PA concentrations in the cytosol of 226 breast cancer tissues were determined prospectively by enzyme-linked immunosorbent assay using cytosol fractions prepared for steroid hormone assay. The median follow-up period of the patients was 60 months. Various prognostic factors were evaluated by univariate analysis or multivariate analysis using the Cox proportional-hazards method. Patients with primary breast cancer containing high levels of u-PA had a significantly shorter disease-free survival than patients with low levels of u-PA antigens. In multivariate analysis, a high level of u-PA was an independent risk factor for disease-free survival, being independent of age, axillary node status, and estrogen receptor status. Among the major prognostic factors, a high u-PA antigen level, lymph node involvement, and a positive estrogen receptor status were the most important for predicting relapse-free survival (P = 0.044, P < 0.0001, P = 0.0039). This first prospective study confirmed the prognostic significance of the u-PA antigen level in association with other major prognostic factors. The results of our present study suggest that u-PA in breast cancer tissue might be involved in breast cancer invasion and metastasis.

Simultaneous observation of endocrine and exocrine functions of the pancreas responding to somatostatin in man.

Six patients who underwent segmental autotransplantation of the caudal pancreas (SAT) following total pancreatectomy for pancreatic cancer were investigated. The graft was transplanted to the left groin, and pancreatic juice was diverted outside through a polyethylene tube indwelled into the main pancreatic duct. In these SAT patients, the responses of insulin (IRIS) in terms of plasma levels and pancreatic secretion to subcutaneous injections of somatostatin octreotide (Sandostatin: SMS201-995) were simultaneously observed. Four doses (0.039, 0.156, 0.625 and 2.5 micrograms/kg) of SMS201-995 were given on separate days. As a control, saline was injected subcutaneously. Standard liquid test meal was given 1 h after the subcutaneous injection. The basal plasma IRI were significantly decreased with doses greater than 0.156 microgram/kg. The postprandial responses of IRI was also significantly suppressed with the same doses. On the other hand, the basal pancreatic exocrine secretion was significantly suppressed with doses greater than 0.625 microgram/kg. The postprandial pancreatic exocrine secretion was also significantly suppressed with doses greater than 0.625 microgram/kg. Those suppressions were dose-dependent. The postprandial CCK secretion was also significantly suppressed in dose-dependent manner with SMS201-995. The CCK suppression was significantly correlated with the suppression of pancreatic exocrine secretion. This clinical study under the setting of SAT demonstrated not only the direct inhibitory effect of somatostatin on both the islet and acinar cells but also, probably, the indirect inhibitory effect on the acinal cells via suppression of CCK release in humans.

Immunohistochemical Detection of P-glycoprotein in Breast Cancer and Its Significance as a Prognostic Factor.

Overexpression of P-glycoprotein (Pgp) in tumors is one of the major mechanisms which mediates the multidrug resistance (MDR) phenotype. To evaluate the prognostic significance of Pgp in breast cancer, Pgp expression was examined in paraffin-embedded tissue sections of 94 breast cancer specimens by immunohistochemistry. Tissue specimens were obtained by mastectomy without preoperative chemotherapy. UIC2 monoclonal antibody which recognizes an extracellular epitope of human Pgp was employed. Of the 94 breast cancer specimens, 35(37.2%)were positive for Pgp expression. Pgp expression had no correlation with menopausal or hormone receptor status, axillary Iymph node involvement or tumor size. However, a significant correlation was observed between Pgp expression and disease relapse (p=0.0322). Pgp-positive patients showed a significantly shorter disease-free survival period than Pgp-negative patients by the Kaplan-Meier method (p=0.0433). These results suggest that immunohistochemical detection of Pgp in breast cancer tissue may have prognostic value after radical operation.

Stimulation of pancreatic growth. Distal small bowel resection mediated by increased levels of cholecystokinin.

SUMMARY BACKGROUND DATA: Distal, but not proximal, resection of the small bowel induces growth of rat pancreas, but the mechanism of this phenomenon is poorly clarified. The release of cholecystokinin (CCK), a trophic hormone for the pancreas, is regulated by a negative-feedback control of bile salts. The ileum is a major site for reabsorption of bile salts. Thus, unsuppressed release of CCK due to deleted reabsorption of bile salts after distal small bowel resection may be a cause of pancreatic growth. In this study, the authors have examined whether pancreatic growth after distal small bowel resection was mediated by endogenous CCK and have determined whether the mechanism of this pancreatic growth required biosynthesis of polyamine. METHODS: Male Fischer 344 rats underwent 70% distal small bowel resection or transection of the ileum. Beginning 48 hours after surgery, CR1409 (a CCK-receptor antagonist) or saline was injected subcutaneously every 8 hours. All animals were pair-fed and killed 14 days after surgery. The pancreas from each rat was excised, weighed, and assayed for DNA, RNA, protein, and polyamine content. RESULTS: Distal small bowel resection increased pancreatic weight, DNA, RNA, and protein, as well as polyamine levels; all of these increases were significantly suppressed by CR1409. Postprandial release of CCK into the circulation was significantly increased after distal small bowel resection. CONCLUSIONS: Pancreatic growth after distal small bowel resection was associated with the stimulation of polyamine biosynthesis; growth appeared to be mediated by endogenous CCK.

Possible involvement of calpain in the growth of estrogen receptor positive breast cancer cells.

Calpain (Ca2(+)-activated neutral protease, EC 3.4.22.17) has been reported to hydrolyze the estrogen receptor (ER). However, there has been no report available regarding the role of calpain in the growth of breast cancer cells. To investigate the role of calpain in the growth of various breast cancer cell lines, we employed a synthetic peptide, calpeptin, which is a cell permeable specific inhibitor of calpain. Calpeptin inhibited the cell growth of ER positive breast cancer cells, such as MCF-7, T-47D, and ZR-75-1 in a dose dependent manner in the presence of E2. However, the growth of ER negative breast cancer cells, MDA-MB-231, was not inhibited by calpeptin. It is suggested that calpain plays an important role in the growth of ER positive breast cancer cells.

Secretion of gastric inhibitory polypeptide in patients with bile duct obstruction.

BACKGROUND: The direct contribution of bile to gastric inhibitory polypeptide (GIP) release and the role of bile in regulating GIP secretion in response to fat ingestion are still obscure. The present study was aimed to clarify the influence of bile on GIP release. METHODS: Seven patients with obstruction of the common bile duct and nine volunteers participated in the study. Fifty milliliters of Lipomul was ingested, and GIP was measured serially for 180 min. After intraduodenal instillation of pooled autologous bile for 2 days, the same study was carried out. RESULTS: The fat-stimulated GIP response was significantly lower in the patients than in the controls. The basal GIP level did not change on bile instillation, but the GIP response to fat ingestion was significantly increased on bile instillation compared with that in the absence of bile. CONCLUSIONS: Intraluminal bile alone does not stimulate the secretion of GIP, but it promotes GIP secretion in response to fat ingestion.

Role of bile and trypsin in the release of cholecystokinin in humans.

The influences of (a) intraluminal bile deficiency due to common bile duct obstruction and (b) intraduodenal administration of pooled own bile and bovine trypsin on the plasma cholecystokinin (CCK) response to oral fat (Lipomul) ingestion were investigated in seven patients with periampullary tumors and 10 healthy volunteers. Basal and fat-stimulated plasma CCK levels in the patients were significantly higher than in the normal controls. Intraduodenal administration of pooled own bile at a rate of 100 ml/h significantly suppressed both basal and fat-stimulated CCK secretion. Simultaneous administration of pooled own bile (100 ml/hr) and bovine trypsin (600 mg/hr) caused further significant suppression of fat-stimulated CCK secretion compared with that under bile infusion alone. These results indicate that both intraluminal bile and trypsin exert a negative feedback effect on the release of CCK in humans.

Serial changes in plasma levels of pancreatic elastase 1 after pancreatic surgeries.

The alterations of the plasma level of elastase 1 (Ela) were investigated in 15 patients undergoing total pancreatectomy (TP), 18 patients undergoing pancreatoduodenectomy (PD), 8 patients undergoing distal pancreatectomy (DP) and 10 patients undergoing gastrectomy for gastric cancer (GR). The Ela level decreased rapidly below the normal level after TP. The plasma half-life of Ela was 4.6 +/- 1.2 h (Mean +/- SEM). The Ela levels after PD were abnormally elevated until the 7th postoperative day. The Ela levels after DP and GR were elevated gradually until the 7th postoperative day. From 1 to 6 months after PD, DP and GR, the Ela levels were normal. An additional release of Ela from the remaining pancreas following direct surgical interventions to the pancreas resulted in the elevated of the plasma level of Ela in the early postoperative period. The plasma level of Ela was normalized within 2 weeks after pancreatic surgery.

Simultaneous surgery for coronary artery disease and gastric cancer.

Of 26 patients who underwent both coronary artery bypass grafting and abdominal surgery at our institution between 1977 and 1992, nine had severe coronary artery disease associated with UICC stage I gastric cancer. They were treated by coronary artery bypass grafting followed by a curative operation for gastric cancer; the initial four patients underwent two-staged surgery (group A), and the most recent five patients underwent simultaneous surgery (group B). The cardiac surgery was performed first in all patients, and in group A the interval between the two procedures was 2 to 7 weeks. There were no significant differences between the two groups in terms of preoperative characteristics: sex, age, preoperative complications, NYHA class, prior myocardial infarction, ejection fraction, cardiac index, number of vessels diseased, or number of grafts. There were no significant differences between the two groups in terms of blood loss during the gastric operation (A: 649 +/- 194 ml; B: 842 +/- 326 ml) or the operating time (A: 371 +/- 106 minutes; B: 343 +/- 46 minutes). Two group A patients had postoperative complications (one had arrhythmia, and one died of sepsis caused by sutural insufficiency). On the other hand, four group B patients had complications (three cases of transient hyperbilirubinemia and one case of postoperative bleeding; none died). The postoperative hospital stay after gastrectomy was not prolonged in group B compared with group A (A: 41.7 +/- 22.7 days; B: 46.0 +/- 25.0 days). In conclusion, simultaneous procedure of coronary artery bypass grafting and gastric surgery can be performed safely, although careful management is indispensable.

[Therapeutic strategy for anaplastic carcinoma and malignant lymphoma of the thyroid].

Therapeutic strategies for anaplastic carcinoma and malignant lymphoma of the thyroid are reviewed. Because of the rarity of both diseases among thyroid malignancies, the generally accepted treatment policy has not been established, although the importance of radiation therapy and chemotherapy has been well recognized for the treatment of both diseases. Hyperfractionated radiation therapy combined with suitable systemic chemotherapy will counter anaplastic thyroid carcinoma and prolong survival. Most patients with thyroid malignant lymphoma have better prognoses than anaplastic carcinoma patients. But delayed diagnosis and inadequate treatment still results in a poor prognosis, in spite of the more treatable characteristics of thyroid malignant lymphoma than anaplastic thyroid carcinoma. At present, early detection of the tumor and selection of a suitable therapy is necessary for the improvement of prognosis, and further clinical studies are required to establish effective regimens for multidisciplinary treatment.

The development of a small bowel volvulus in the early postoperative period following a distal gastrectomy: report of a case.

A 51-year-old Japanese man who underwent a standard distal gastrectomy for cancer of the stomach developed abdominal pain when oral intake was commenced on the 6th postoperative day after an uneventful postoperative course. Complete obstruction of the jejunum led to a sudden deterioration in his general condition and a laparotomy was performed, revealing counterclockwise rotation of the mesenterium. The necrotic portion of the small intestine was removed, while 10 cm of the upper jejunum and 100 cm of the terminal ileum were preserved. His second postoperative course was uneventful apart from the development of "intestinal hurry," which is now under medical control 9 months after his second laparotomy.

Gastric inhibitory polypeptide secretion after gastrectomy in patients with diabetes mellitus.

Gastric inhibitory polypeptide (GIP) secretion after distal gastrectomy was compared between patients with diabetes mellitus (DM-group) and patients with normal glucose tolerance (N-group). GIP secretion in the DM-group was significantly greater in the early postcibal response period, but less in the late postcibal response period after gastrectomy, the total secretion of GIP being less after gastrectomy than before in this group. In the N-group, both the early and total postcibal responses of GIP were greater after gastrectomy than before. Moreover, the early and total postcibal secretions of GIP after gastrectomy were less in the DM-group than in the N-group. These findings suggest that GIP secretion in diabetics becomes insufficient after gastrectomy.