Continuous infusion of 5-fluorouracil with versus without low-dose, consecutive administration of cisplatin in advanced colorectal cancer. A prospective randomized phase II study.

Recently, the treatment of advanced gastric cancer by continuous infusion of 5-fluorouracil (5-FU) with low-dose cisplatin (CDDP) has improved efficacy without severe toxicities. The possible effectiveness of 5-FU+low-dose CDDP for colorectal cancer (CRC) is intriguing. One hundred fifty-five patients with far-advanced CRC including at least one measurable lesion were enrolled in a prospective randomized clinical trial funded by the Japanese Foundation for Multidisciplinary Treatment of Cancer. These patients were assigned to the two arms to assess the value of low-dose CDDP when added to a continuous intravenous infusion of 5-FU at a dose of 300 mg/m(2)/24 hrs in a one-week cycle consisting of 5 days of treatment and 2 days of rest for at least 12 weeks. CD-DP was given intravenously at a dose of 3 mg/m(2) on days 1-5 and days 8-12, and then at a dose of 7 mg/m(2) twice a week. Three patients were excluded from the trial. The response rate in the 5-FU+low-dose CDDP arm (n=75) was significantly higher than that in the 5-FU arm (n=77) (25.3% vs. 11.7%; P = 0.037). There was no significant difference in the median overall survival time between the 5-FU+low-dose CDDP arm and the 5-FU arm (479 and 491 days, respectively). Grades 3/4 toxicities occurred infrequently in both arms. The quality of life was almost the same between the arms. Low-dose CDDP improved the response rate while keeping toxicities within clinically acceptable limits. However, this combined treatment did not confer a survival advantage over treatment with continuous infusion of 5-FU alone for patients with far-advanced CRC; that might be attributable to the short CDDP administration setting of 12 weeks.

Abdominal wound dehiscence in patients receiving long-term steroid treatment.

Steroids inhibit primary wound healing and delay the formation of granulation tissue, but it has been controversial whether long-term steroid treatment by itself increases the risk of abdominal wound dehiscence. The aim of this study was to determine whether the pre-operative dose and post-operative total dose of steroids influence abdominal wound dehiscence. Of 28 patients who had surgery while receiving long-term steroid treatment, seven had abdominal wound dehiscence and 21 did not have dehiscence. The two groups differed significantly in the post-operative dose of steroids (404.3 +/- 147.1 and 135.6 +/- 118.7 mg, respectively) and the duration of wound healing (57.3 +/- 18.0 and 12.4 +/- 3.8 days), but no other differences were found. Abdominal wound dehiscence may be influenced by the post-operative rather than the pre-operative steroid dose.

Methylenetetrahydrofolate reductase C677T is not associated with expression of pyrimidine metabolic enzyme genes in colorectal cancer.

Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism may influence the chemosensitivity of colorectal cancers to fluorouracil (5-FU) by increasing intracellular 5,10-methylenetetrahydrofolate. The effect of this polymorphism on the expression of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyl transferase (OPRT) and thymidine phosphorylase (TP) in colorectal cancer was investigated. The MTHFR C677T polymorphism was analysed and TS, DPD, OPRT and TP mRNA expression was measured in tumour and adjacent normal mucosal tissue. In all patients, the genotypes of the tumour and normal tissues were identical. No differences were found in the expression of TS, DPD or TP mRNA by genotype in either tumour or normal tissue. Although the OPRT mRNA level in tumour tissue was not associated with the genotype, normal mucosa with the TT genotype showed a significantly higher OPRT mRNA level than mucosa with other genotypes. The MTHFR C667T polymorphism is not associated with intratumoural expression of TS, DPD, OPRT or TP.

Greater development of 1,2-dimethylhydrazine-induced colon cancer in a rat model of type 2 diabetes mellitus.

Several clinical cohort and case-control studies have suggested a link between diabetes and colon cancer. Otsuka Long-Evans Tokushima Fat (OLETF) rats spontaneously develop type 2 diabetes mellitus and Long-Evans Tokushima Otsuka (LETO) rats are non-diabetic. The relationship between type 2 diabetes mellitus and colon cancer was examined in these rats. The carcinogen 1,2-dimethylhydrazine was administered subcutaneously once weekly for 10 weeks, and the animals were killed and necropsied in week 29. All OLETF rats and 80% of the LETO rats developed cancer. The number of colon cancers per rat was significantly greater in the diabetic than in the non-diabetic rats. Although the tumours tended to be larger in diabetic rats, the difference was not statistically significant. No significant differences were observed in the depth of invasion or histological type of cancer in the two groups. Type 2 diabetes mellitus may enhance the generation and growth of colon cancer.

Genomic copy-number aberrations related to lymph-node metastasis of colon cancer.

Lymph-node metastasis is an important indicator in the diagnosis of colon cancer. In order to determine the genes involved in metastasis, genomic copy-number aberrations in the primary tumours and lymph-node metastases were analysed in 12 patients using comparative genomic hybridization. This method detects genomic copy-number changes at the chromosomal level and the identification of the regions of aberration on any chromosome. Copy-number gains at 6p12 and losses at 8p12 were observed in a greater number of the primary tumours than in the metastases. These aberrations appear to be involved in lymph-node metastasis of colon cancer, and may allow measurement of the risk of lymph-node metastasis from a given colon cancer.

Analysis of the relationship between sex and chromosomal aberrations in colorectal cancer by comparative genomic hybridization.

Colorectal cancer is thought to be more common in men than in women. The chromosomal locations of DNA gains and losses in surgical specimens of colorectal tumours were detected by comparative genomic hybridization and were compared by gender. Five chromosomal regions, 7p, 8p, 8q, Xp and Xq, contained multiple gains that were significantly more common in males than in females, and within these regions, the differences were significant for Xp21, Xp11.3, Xp11.4 and Xq26. Regions 1p, 3q, 11q, 12p, 12q and 15q contained multiple sites of gain that were significantly more common in females than in males. Tumours from male and female patients showed significantly more losses at 11p and 15q, and at 4q and Xq, respectively. The fact that gains in X-chromosomal regions were detected with a significantly higher frequency in tumours from male patients suggests that the difference between the genders might be explained by X-chromosomal inactivation.

Combined effects of cholecystectomy and lithocholic acid on pancreatic carcinogenesis of N-nitrosobis(2-hydroxypropyl)amine in Syrian golden hamsters.

The effects of cholecystectomy and/or lithocholic acid (LCA) on the composition of biliary bile acid and on pancreatic carcinogenesis by N-nitrosobis(2-hydroxypropyl)amine (BHP) were examined in male Syrian golden hamsters. Cholecystectomy was performed 1 wk before BHP initiation. BHP (250 mg/kg of body weight) was injected s.c. once a wk for 5 wk. A diet containing 0.5% LCA was begun 1 wk after the final BHP injection. All hamsters were sacrificed 36 wk after cholecystectomy, and the pancreas was examined histologically. Only the LCA treatment but no other treatment influenced the bile acid composition, i.e., the increase in LCA and decrease in cholic acid. The incidence of pancreatic carcinoma was 23 of 30 (76.7%) in hamsters receiving cholecystectomy plus BHP followed by LCA diet. The tumor incidence was five of 18 (27.8%) with BHP followed by basal diet, ten of 18 (55.6%) with cholecystectomy plus BHP followed by basal diet, and six of 18 (33.3%) with BHP followed by LCA diet, respectively. The total number of pancreatic carcinomas in hamsters receiving cholecystectomy and BHP followed by LCA diet also increased significantly. These results indicate that combined treatments of cholecystectomy and dietary LCA enhanced BHP-inducing pancreatic carcinogenesis in hamsters.

Colonic carcinoma resembling submucosal tumor: report of a case and review of the literature.

Submucosal tumor-like colorectal carcinoma, most of whose surface is covered with normal mucosa, is very rare. We report a case of colonic carcinoma resembling submucosal tumor. A 54-yr-old man visited our institution for an evaluation of a positive fecal occult blood test. Colonoscopic examination revealed a small, mainly red polypoid lesion with a central deep ulceration and many white spots in the sigmoid colon. Indigocarmine staining demonstrated that the white spots were faint shallow depressions. Magnifying colonoscopic examination showed that the lesion surface, except for the ulceration and the depressions, was covered with normal mucosa. Although the tumor was small, we strongly suspected its malignancy due to a deep ulceration. As we could not excise it endoscopically, we performed sigmoidectomy. The lesion was 12 mm in size. Histologic examination revealed that the lesion was a moderately differentiated adenocarcinoma that was mainly covered with normal mucosa, that carcinoma was exposed only at the ulceration and the depressions on the surface, and that it had expanded to the muscularis propria. Together with considerations from the literature, this type of colorectal carcinoma is supposed to be invasive and surgical resection should be considered, no matter how small it may be.

Feasibility of measuring 5-fluorouracil catabolic potential by oral loading.

The efficacy of 5-fluorouracil (5-FU) treatment and the incidence of adverse events differ among patients and depend to some extent on individual variations in drug catabolism. This feasibility study aimed to determine the optimum conditions for a 5-FU oral load test, which would allow the simple evaluation of individual differences in 5-FU catabolism. Patients with colon cancer were given oral 5-FU (200 mg/day) for 3 days (n = 36) or a single 100 mg dose (n = 14). Serum concentrations of uracil, dihydrouracil, 5-FU and 5-fluoro-5,6-dihydrouracil were measured before and after 5-FU administration. The results suggested that a decline in 5-FU metabolism was associated with continuous administration and increasing age. We conclude that a continuous load of 5-FU is necessary in order to predict the efficacy and side-effects of the drug. The 3-day regimen, with its ease of administration, merits further study to assess its possible clinical application.

Common duct carcinoma and obstruction in female hamsters treated with N-nitrosobis(2-oxopropyl)amine and/or cholecystectomy.

Detailed histologic observations were performed on the head of the pancreas of hamsters treated with 10 mg/kg body weight N-nitrosobis(2-oxopropyl)amine (BOP) once a week for 6 weeks with or without cholecystectomy. Cholecystectomy was performed 5 weeks before starting BOP initiation. The incidence of head cancers was 100% and cholecystectomy did not affect pancreatic carcinogenesis by BOP. Common bile duct dilatation was produced by advanced pancreatic head carcinomas and microadenocarcinomas in common duct. Micro-adenocarcinomas were not macroscopically detected since the tumors were located in the lumen of common duct.

Metastatic gastrinoma to the liver 20 years after primary resection.

Gastrinoma is a rare endocrine tumor that is frequently associated with liver metastasis. The liver metastasis is usually seen simultaneously or soon after a primary operation. A 47-year-old woman who had had a total gastrectomy 20 years earlier developed liver metastasis. An interval of this length between surgery and metastasis is extremely rare. The total gastrectomy prevented the patient from developing the usual symptoms of hypergastrinemia that would have enabled early diagnosis of the metastasis. Laboratory examinations on admission revealed a high serum gastrin concentration (1500 pg/ml). Computed tomography showed an irregularly enhanced mass lesion with an uneven, low-density central area in the right anterior inferior segment of the liver. An extended right hepatectomy was performed. Intraoperative ultrasonography showed no abnormalities in the remnant pancreas. Examination of the cut surface of the specimen revealed a yellow, firm, elastic tumor, 55 mm in diameter. The interior of the tumor appeared necrotic. Histopathologically, the tumor was composed of cells with hyperchromatic, dysplastic nuclei arranged in a trabecular pattern with nest formation. Gastrin staining was positive. A histologic diagnosis of metastatic gastrinoma was made. The patient's gastrin concentration returned to normal and she was well at 2-year follow-up.

Comparison of stent placement and colostomy as palliative treatment for inoperable malignant colorectal obstruction.

BACKGROUND: Stent placement is a useful palliative treatment for inoperable acute malignant colorectal obstruction. However, data comparing stent placement with colostomy are scarce. METHODS: We compared the clinical outcome of 18 patients who had stent placement and 17 patients who underwent only colostomy. RESULTS: The postoperative hospital stay was 22.3 days for stent placement compared with 47.4 days for colostomy (p = 0.016). The duration to readmission was 129.2 days for stent placement and 188.4 days for colostomy. The estimated duration of primary stent patency was 106 days. Mean survival period was 134 days in patients with stent placement and 191 days in patients with colostomy. CONCLUSION: Postoperative hospital stay was shorter in patients with stent placement but duration to readmission and survival were longer in patients with colostomy. However, stent placement increases the option of palliative treatment and is an effective treatment contributing to improving quality of life.

Reduced low-density-lipoprotein cholesterol causing low serum cholesterol levels in gastrointestinal cancer: a case control study.

Several epidemiological studies suggested an inverse relation between serum cholesterol level and cancer mortality. We analyzed the relation between gastrointestinal cancers and serum cholesterol levels. A total of 631 patients were recruited as cancer-bearing cases, comprising 181 esophageal cancers, 251 gastric cancers and 199 colorectal cancers. A case-control analysis was conducted on the serum TC, HDL-C, LDL-C and TG levels. TC and LDL-C were significantly lower in cancer-bearers by approximately 15 mg/dl. Furthermore, analyses by cancer site also showed significantly lower TC and LDL-C levels in cancer-bearers than in controls for all three sites. In this analysis, early stage cancer-bearers showed a significant decrease in TC levels by approximately 11 mg/dl compared with controls, and also a similar decrease in LDL-C levels. These results suggest that low TC levels are not related to cancer stage. Furthermore, findings of no significant differences in HDL-C and TG between cancer-bearing cases and controls in addition to a specific decrease in LDL-C in cancer-bearers suggest that hypocholesterolemia observed in these cases stems from low LDL-C. However, cancer-bearers and controls showed a similar distribution of TC and LDL-C levels. We should be aware that latent cancer bearers may be present among subjects with hypocholesterolemia.

A case of inflammatory breast cancer following augmentation mammoplasty with silicone gel implants.

A 54-year-old-woman who underwent augmentation mammoplasty with silicone gel implants 30 years previously, visited our hospital with complaints of bloody nipple discharge, redness and itching of her right breast. Cancer of the right breast was diagnosed by dynamic magnetic resonance imaging (MRI) examination with Gadolinium (Gd)-DTPA enhancement. Radical mastectomy was subsequently performed. The histopathological findings demonstrated scirrhous and inflammatory breast cancer with invasion of dermal lymphatics.

ELISA determination of serum hyocholic acid concentrations in humans and their possible clinical significance.

BACKGROUND/AIMS: Hyocholic acid (HCA), a bile acid isolated from pigs, has a different structure from the predominant bile acids from humans. METHODOLOGY: We prepared an antiserum to HCA in rabbits and developed an enzyme-linked immunosorbent assay (ELISA), which we used to measure serum HCA in healthy subjects and patients with a variety of gastrointestinal and non-gastrointestinal diseases. RESULTS: Patients with hepatic cirrhosis had a mean HCA concentration that was 120-fold greater than that in healthy subjects. Markedly elevated HCA levels were also present in patients with primary hepatoma or pancreatic cancer but not in patients with cancer of the breast, bile duct, duodenum, or stomach. CONCLUSIONS: If these results are confirmed by further study, HCA measurement may prove clinically useful.

Influence of endotoxemia on hepatic energy metabolism in rats with obstructive jaundice.

BACKGROUND/AIMS: A secondary insult in patients with obstructive jaundice can lead to multiple system organ failure. We evaluated the influence of endotoxin on hepatic energy metabolism and hepatic tissue blood flow in obstructive jaundiced rats. MATERIAL AND METHODS: Male Sprague-Dawley rats were divided into a control group, an endotoxin administration group, an obstructive jaundice group, and an obstructive jaundice with endotoxin administration group. To evaluate hepatic energy metabolism, we have measured arterial blood ketone body ratio, and arterial blood total ketone body concentration. Hepatic tissue blood flow was determined by laser Doppler velocimetry. RESULTS: In the endotoxin administration group, no change was observed in hepatic energy metabolism. However, the obstructive jaundice group was associated with decreased hepatic tissue blood flow shortly after the outset of jaundice, while no change was observed in hepatic energy metabolism until 3 weeks later. In the obstructive jaundice with endotoxin administration, a significant decrease in hepatic tissue blood flow and an increase in hepatic energy metabolism were measured. CONCLUSION: Endotoxin administration alone had no influence on hepatic energy metabolism, while endotoxin administration in the presence of obstructive jaundice results in a rapid decrease in hepatic energy metabolism. This occurred as a result of the secondary insult of endotoxin in the setting of decreased hepatic tissue blood flow caused by obstructive jaundice.

Impaired hepatic function in segmental biliary obstruction demonstrated with a receptor-binding radiotracer.

A patient with cholangiocarcinoma underwent left-sided cholangiojejunostomy, and hepatic functional imaging with a receptor-binding radiotracer and SPECT was performed to evaluate the distribution of functional reserve. It revealed decreased accumulation in the regions with residual dilatation of the intrahepatic bile ducts, indicating several kinds of focal damage in hepatic function caused by segmental biliary obstruction. The radioligand may be useful in assessing regional hepatic function, and the high spatial resolution provided by SPECT appears to play an important role for this purpose.

Factor analysis of multigated cardiac blood pool scintigram for the measurement of left ventricular ejection fraction.

Left ventricular ejection fraction (EF) was measured by factor analysis (FA) of multigated cardiac blood pool scintigram in 38 consecutive patients, and compared with that measured by the variable ROI method (EFVROI) with automated left ventricular contour detection. FA was automatically performed without operator intervention with a success rate of 100%. The correlation of EF with EFVROI was significant in the group of 22 patients with normal wall motion (r = 0.65, p less than 0.001), and the entire group of patients (r = 0.70, p less than 0.001), but not significant (p = 0.19) in the group of 16 patients with abnormal wall motion. In conclusion, left ventricular ejection fraction can be estimated by factor analysis of MUGA in patients with normal wall motion.

Measurement of cerebral blood flow with two-dimensional cine phase-contrast mR imaging: evaluation of normal subjects and patients with vertigo.

PURPOSE: The purpose of this study was to determine whether or not the vertebral flow of patients with vertigo and normal brain magnetic resonance (MR) images was decreased in comparison with normal controls. MATERIALS AND METHODS: Cerebral blood flow (CBF) was quantitatively measured by a two-dimensional phase contrast cine MR imaging technique in 24 normal controls (mean age, 38.6 years; range, 12-70) and 23 patients (mean age, 53.7 years; range, 19-76) with a 1.5 Tesla MR imaging unit. RESULTS: Inter- and intraobserver variation in blood flow measurements was small (r = 0.970, standard error of the estimate [SEE] = 2.9 ml, n = 80; r = 0.963, SEE = 4.6 ml, n = 40, respectively). In the normal group, mean summed vertebral flow (171 ml/min, SD = 40.6) was significantly less than mean summed carotid flow (523 ml/min, SD = 111). Right vertebral flow (80.2 ml/min, SD = 30.5) was less than left vertebral flow (91.2 ml/min, SD = 38.2), but the difference was not statistically significant (p < 0.05). In the 23 patients, although the summed vertebral flows of two patients (63.3, 88.8 ml/min) were significantly less than that of the normal group, mean summed vertebral flow (165 ml/min, SD = 59.1) showed no significant difference from that of the normal group (p < 0.05). CONCLUSIONS: In this study, the majority of patients had normal CBF. This method is clinically useful for estimating CBF.

Quantitation of cerebral blood volume by 99mTc-DTPA-HSA SPECT.

The characteristics of technetium-99m diethylenetriaminepentaacetic acid human serum albumin (99mTc-DTPA-HSA) as an agent for quantitation of cerebral blood volume (CBV) were examined. The radioactivity after decay correction as a percentage of the activity at 10 minutes was 84.3 +/- 1.3% at 120 minutes after the injection of 99mTc-DTPA-HSA. Radioactivity was found exclusively in plasma, with little in blood cells. The blood retention of 99mTc-DTPA-HSA is sufficient, and its use in the quantitation of CBV omits the need for centrifugation of the blood sample. CBV quantified using the tracer and a SPECT system with a single-head rotating gamma camera was 4.09 +/- 0.60 ml/100 g brain, similar to values reported previously. Two serial SPECT scans provided similar images, and the CBV values determined by the two scans were closely correlated (p < 0.001). The high reproducibility suggests that the method may be used to monitor the cerebrovascular response to drugs. It was concluded that 99mTc-DTPA-HSA has useful properties for quantitative CBV measurement and that quantitation of CBV by 99mTc-DTPA-HSA SPECT is feasible using a system with a single-head rotating gamma camera.