Comparison of 5-fluorouracil pharmacokinetics in whole blood, plasma, and red blood cells in patients with colorectal cancer

STUDY OBJECTIVE: To compare 5-fluorouracil (5-FU) pharmacokinetics in whole blood, plasma, and red blood cells in patients with colorectal cancer. DESIGN: Prospective, unblinded observational study in consecutive patients. SETTING: Large regional teaching hospital. PATIENTS: Five patients with colorectal cancer. INTERVENTIONS: Patients received folinic acid 200 mg/m2 intravenously over 2 hours, followed by 5-FU 600 mg/m2 intravenous bolus over 30 minutes, then 5-FU 600 mg/m2 intravenous infusion over 22 hours, administered on days 1 and 2. This 48-hour cycle was repeated every 14 days. MEASUREMENTS AND MAIN RESULTS: Concentrations of 5-FU in whole blood, plasma, and red blood cells were determined by high-performance liquid chromatography. ADAPT II was used for pharmacokinetic computations. The optimum model was determined for each matrix by calculating Akaike's information criteria values. Concentrations of 5-FU in whole blood were 106-115% of simultaneous plasma concentrations (median 112%), and packed red blood cell levels were 5-17% of plasma concentrations (median 11%). The drug's concentration-time profile was similar in the three matrices. The drug is reported to be unstable in whole blood, and red blood cell 5-FU concentrations were near the limit of detection (10 ng/ml), supporting plasma as the preferred matrix for therapeutic drug monitoring studies. Six pharmacokinetic models were fitted to the 5-FU individual data sets to determine the best curve fit. The optimal model for whole blood and plasma data sets was one compartment with both linear and nonlinear elimination models; a one-compartment model with nonlinear elimination provided the best curve fit for 5-FU in red blood cells. A two-compartment model with nonlinear elimination gave a similar degree of curve fit for plasma 5-FU as the one-compartment model with both linear and nonlinear elimination. CONCLUSIONS: These pharmacokinetic results provide the basis for further investigation into the ability to correlate 5-FU systemic exposure with clinical drug activity.     

Omega-3 polyunsaturated fatty acid levels in the diet and in red blood cell membranes of depressed patients

The objective of this study was to clarify the possible angiogenesis-promoting factors from human trophoblasts in early stage gestation. The existence of angiogenic growth factors such as basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) in the condition medium from human villous trophoblasts was determined. Biological activity of angiogenic growth factors released by trophoblasts was examined using vascular endothelial cell lines. The condition medium from trophoblasts enhanced the growth of endothelial cells. Although cultured trophoblasts exhibited immunoreactive products for both bFGF and VEGF in the cytoplasm, only bFGF was detected in the condition medium by ELISA. The growth-enhancing activity of the condition medium was eliminated completely by the addition of anti-bFGF antibody but not with anti-VEGF antibody. Thus, trophoblastic cells seem to play an important role in extensive angiogenesis occurring in early gestation, mainly by releasing bFGF but not VEGF.     

Liver metastasis rare in colorectal cancer patients with fatty liver

BACKGROUND/AIMS: As no reports in terms of the relationship between fatty liver and liver metastasis of colorectal cancer clinicopathological analysis of colorectal cancer patients with fatty were found a liver was carried out. PATIENTS AND METHODS: Among 839 patients with single colorectal carcinoma who underwent operations at our department between 1985 and 1994, 121 patients were designated as fatty liver using ultrasonography (FL group). The remaining 718 non-fatty liver patients with colorectal cancer (NFL group) were compared to the FL group regarding clinicopathological aspects. RESULTS: (1) There were only two patients who had liver metastasis in the FL group (1.7%), while the NFL group included 115 patients with liver metastasis (16.0%) (p < 0.01). (2) The five-year survival rate of the FL group was 95.7%, which was significantly higher than that in the NFL group (9.8%) (p < 0.001). (3) In the multivariate analysis, the fatty liver was identified as an independent prognostic factor. CONCLUSIONS: The FL group had a much better prognosis compared to the NFL group. Especially, liver metastasis was extremely rare in the FL group. We believe that these results will lead to the clarification of the liver metastasis mechanism.     

Changes in plasma and colonic mucosa fatty acid profiles in rats with ulcerative colitis induced by trinitrobenzene sulfonic acid

Polyunsaturated fatty acids have a key role in the pathogenesis of inflammatory bowel disease since some of the arachidonic acid-derived eicosanoids have been found to be increased in inflamed intestinal mucosa in the acute phase of human disease. The aim of this study was to prospectively assess plasma and colon mucosa fatty acid patterns in rats with experimental ulcerative colitis. Twenty rats were treated with trinitrobenzene sulfonic acid and 20 with NaCl; two groups were killed after one week and two after two weeks to evaluate colon damage. Plasma was obtained by aortic puncture and colonic mucosa was scraped off and the fatty acid pattern was determined by gas-liquid chromatography. Total, saturated, and monounsaturated plasma fatty acids were significantly higher in both periods of ulcerative colitis as compared to controls. Plasma n-6 fatty acids were increased after treatment, but no significant changes were observed concerning to n-3 fatty acids. With regard to colon mucosa, saturated and monounsaturated fatty acids did not change because of the disease; however, n-6 fatty acids decreased in the first week and increased in the second week and n-3 fatty acids were increased. Changes on the fatty acid distribution in plasma did not parallel to those of colonic mucosa except for 22:6(n-3). We have also found that experimental ulcerative colitis induced by trinitrobenzene sulfonic acid reproduces many of the features related to changes in plasma and colon mucosa fatty acids observed in the human disease.     

A clinical and economic evaluation of red blood cell transfusions in patients receiving cancer chemotherapy

A clinical and economic evaluation of red blood cell (RBC) utilization in cancer patients during chemotherapy is described. Using a randomized sampling process, 100 patients who had received chemotherapy with or without cisplatin were selected (50 in each group). Multiple logistic regression was then used to identify risks factors for transfusion requirements. Twenty-five percent of patients in the cisplatin and 12% in the noncisplatin group received at least one blood transfusion during chemotherapy (p = .09). Depressed hemoglobin levels and cisplatin dosage were identified as risk factors for transfusion requirements. Combining all transfused patients revealed an overall cost of Can $599 (95% CI: $513-$683) per transfusion. The results of the current study indicated that anemia is a common complication of cancer chemotherapy that can be costly to manage.     

X-ray and neutron scattering density profiles of the intact human red blood cell membrane

Hemoglobin-free human red blood cell membranes have been prepared with glutaraldehyde to maintain an intact structure on partial dehydration. Treatment of resealed ghosts with poly(L-lysine) produced an essentially constant structural unit and permitted correlation of electron microscopy results with x-ray and neutron diffraction profiles. These profiles provide detailed information, for the intact membrane, on the location and relative distribution of lipids and proteins.     

Changes in plasma endothelin-1 and lipid peroxidate levels and amount of superoxidate dismutase in red blood cell in patients with pregnancy-induced hypertension

OBJECTIVE: To evaluate the role of endothelin (ET-1) and lipid peroxide (LPO) in the pathogenesis of pregnancy-induced hypertension (PIH). METHODS: The plasma concentrations of ET-1, LPO and the amount of superoxide dismutase (SOD) in red blood cell were measured by radioimmunoassay, thiobarbituric acid fluorimetric determination and catechol self-oxidation determination respectively in total 95 women (normal non-pregnant women 15, Late pregnant women 20 and patients with PIH 60). RESULTS: (1) The levels of ET-1, LPO and SOD in normal late pregnant women were significantly higher than those in non-pregnant women (P < 0.01), but the LPO/SOD ratio was not significantly different between the two groups. (2) The levels of plasma ET-1 and LPO/SOD ratio in cases with PIH were markedly higher than those in normal late pregnant women, and it increased with the severity of the disease and returned to the levels of normal late pregnant women within 3-7 days after delivery. (3) There was a positive correlation between ET-1 and LPO/SOD ratio in PIH. CONCLUSIONS: The imbalance of oxidation and antioxidation and endothelial cell injury may play an important role in the pathogenesis of PIH.     

Detection of mutant K-ras DNA in plasma or serum of patients with colorectal cancer

Increased understanding of the molecular basis of colorectal cancer and recognition that extracellular DNA circulates in the plasma and serum of cancer patients enables new approaches to detection and monitoring. We used a polymerase chain reaction (PCR) assay to demonstrate mutant K-ras DNA in the plasma or serum of patients with colorectal cancer. Plasma or serum was fractionated from the blood of 31 patients with metastatic or unresected colorectal cancer and from 28 normal volunteers. DNA was extracted using either a sodium chloride or a gelatin precipitation method and then amplified in a two-stage PCR assay using selective restriction enzyme digestion to enrich for mutant K-ras DNA. Mutant K-ras DNA was detected in the plasma or serum of 12 (39%) patients, all confirmed by sequencing, but was not detected in any of the normal volunteers. K-ras mutations were detected in plasma or serum regardless of sex, primary tumour location, principal site of metastasis or proximity of chemotherapy and surgery to blood sampling. Tumour specimens available for 19 of the patients were additionally assayed for ras mutations and compared with blood specimens. Our results indicate mutant K-ras DNA is readily detectable by PCR in the plasma or serum of patients with advanced colorectal cancer. Thus, plasma- or serum-based nucleic acid amplification assays may provide a valuable method of monitoring and potentially detecting colorectal cancer.     

Anemia in patients with colorectal cancer

Although anemia is one of the signs of colorectal cancer, the relationships between histological findings and hematological findings other than hemoglobin level have not been adequately investigated. We investigated the relationship between hematological findings, serum iron, and histological findings in 358 patients (207 men and 157 women) with colorectal cancer. Their mean (+/-SD) ages were 64.3 +/- 12.4 and 63.8 +/- 13.3 years. A hemoglobin level of less than 10 g/dl was the criterion for anemia, and 20.8% of the men and 25.8% of the women met this criterion. Univariate analysis showed that carcinoma of the cecum, ascending colon, and transverse colon; large-size carcinoma, invasion beyond the proper muscle layer; positive lymph node metastasis: and clinical stage (Dukes' B, C, and D) were factors associated with high incidence of anemia. Histological type did not affect the hematological findings. Multivariate analysis showed that age, tumor site, and tumor size were significant factors related to anemia. Depth of invasion, the presence or absence of lymph node metastasis, and Dukes' classification were not significant factors. In the presence of these factors, mean corpuscular volume and mean corpuscular hemoglobin concentration values were low, and red blood cells were microcytic and hypochromic. The incidence of a low serum iron level was about twice the frequency of a hemoglobin level of less than 10 g/dl. The results of the multivariate analysis showed that none of the factors were significantly related to iron deficiency.     

Phase II trial of intravenous endotoxin in patients with colorectal and non-small cell lung cancer

We report the immunological and clinical results of a phase II trial with intravenously administered highly purified endotoxin (Salmonella abortus equi) in patients with advanced cancer. 15 patients with non-small cell lung cancer and 27 with colorectal cancer were entered into the study. 37 evaluable patients received at least four injections of endotoxin (4 ng/kg body weight) and 1600 mg ibuprofen orally in 2-week intervals. Transient renal (WHO grade 0-1) and hepatic (WHO grade 0-4) toxicities occurred in several patients. Constitutional side-effects such as fever, chills and hypotension could not be prevented completely by pretreatment with ibuprofen. 3 patients in the colorectal cancer group demonstrated objective responses (1 complete remission (CR), 2 partial remission (PR)). The complete remission has been maintained for more than 3 years, while the partial remissions were stable for 7 and 8 months, respectively. Only marginal antitumour effects were seen in the lung cancer group. Tolerance of the macrophage system to the stimulatory effect of endotoxin, as measured by human necrosis factor alpha (TNF-alpha) release into serum, built up after the first administration and remained at a steady-state level after each subsequent injection. In constrast, rising CD4:CD8 ratio and release of tumour necrosis factor beta (TNF-beta) indicated the continuing activation of the lymphocyte system by repetitive injections of endotoxin.     

Hemodynamics in nailfold capillaries of patients with systemic scleroderma: synchronous measurements of capillary blood pressure and red blood cell velocity

There is increasing evidence that endothelial damage occurs at a very early stage during the course of systemic scleroderma. Endothelial damage is accompanied by impaired microvascular function, which has clearly failed in patients with systemic scleroderma, as evidenced by necrosis of the fingertips in severe cases. We investigated two important determinants of microvascular function, namely capillary blood pressure and capillary red blood cell velocity, simultaneously in the same capillary. In patients with systemic scleroderma and in healthy volunteers matched for age and sex, capillary blood pressure was measured by direct cannulation and capillary red blood cell velocity by video microscopy. Capillary blood pressure and capillary red blood cell velocity were significantly lower in patients (14.27 +/- 4.34 mmHg, 230 +/- 310 microm per s) than in healthy controls (19.06 +/- 3.69 mmHg, p < 0.008, and 910 +/- 240 microm per s, p < 0.003) at an ambient temperature of 22 degrees C, whereas no significant difference in skin temperature was observed (23.7 +/- 0.9 degrees C vs 24.7 +/- 1.9 degrees C) and no occlusion of finger arteries was detected. Capillary blood pressure in enlarged capillaries did not differ from that in normal-shaped capillaries in the patients (correlation of diameter and capillary blood pressure, R2 = 0.04), which was also the case with capillary red blood cell velocity (R2 = 0.13). Capillary pulse pressure amplitude and capillary red blood cell velocity showed a strong correlation (R2 = 0.81), suggesting that the pressure gradient across the capillary loop, which is the driving force for capillary red blood cell velocity, was mainly dependent on precapillary resistance. These observations reflect the inadequate microvascular function in systemic scleroderma, which may be due mainly to a pathophysiologic functional increase in precapillary resistance, even at comfortable ambient temperatures.     

Aberrant crypt foci in patients with colorectal cancer

Aberrant crypt foci (ACF) are clusters of abnormally large colonic crypts identified on the mucosal surface of the human colon. They are thought to be preneoplastic lesions. The aim of the present study was to compare density (number of ACF per square cm of mucosal surface), crypt multiplicity (number of crypts per ACF) and histology of ACF in colonic resections of colorectal cancer patients resident in two Italian provinces with a twofold difference in colorectal cancer incidence rates. Thirty-two and 26 colonic resections were collected after operation in Ragusa (Southern Italy) and Modena (Northern Italy), respectively, and fixed in 10% formalin. Mucosal layers were observed under a light microscope at 25x after staining with methylene blue. Density of ACF was significantly higher in Modena (median 0.101 ACF cm(-2)) than in Ragusa (0.049, P = 0.001), whereas there was no difference in crypt multiplicity. ACF were classified into three groups according to histological features: ACF with mild alterations (hypertrophic ACF, 73%), ACF with hyperplasia (hyperplastic ACF, 17%) and ACF with dysplasia (microadenomas, 10%). The proportions of ACF in the three groups were similar in the two provinces. Density of ACF was higher and crypt multiplicity lower proceeding from proximal to distal large bowel. Microadenomas were observed only in the colon, whereas hyperplastic ACF were more frequent in the rectum. In conclusion, density of ACF correlates with colorectal cancer rates in two Italian provinces, and shows a positive gradient from proximal to distal large bowel. Histology of ACF suggests that they may be precursors of both hyperplastic and adenomatous polyps. These data provide further evidence of the role of ACF in human colorectal carcinogenesis.     

Phospholipid fatty acid profiles in selected members of soil microbial communities

Fatty acids derived from phospholipids and lipopolysaccharides were investigated from 33 taxonomically different organisms (bacteria, fungi and plant cells) known a priori to inhabit soil (except E. coli). The extended extraction procedure used, liberated non-ester-linked fatty acids in addition to ester-linked fatty acids, hydroxy substituted fatty acids in three different fractions. The amount of non-ester-linked fatty acids was as high as 70% of the total phospholipid fatty acids in some fungi and varied considerably in different organisms. The cis vaccenic acid constituted about 50% of phospholipid fatty acids in selected bacteria belonging to the alpha subclass of Proteobacteria. These fatty acids were not found in other selected organisms. A large amounts of branched chain fatty acids were found in various organisms. If the branching are localised on positions other than iso and anteiso they were strong indicators for gram positive bacteria. The cyclopropyl fatty acids are mainly localized in gram negative bacteria. The beta hydroxy fatty acid of the outer membrane are widespread among bacterial taxa and fungi. These fatty acids are not recommended to use as "signature" fatty acids for gram negative bacteria.     

Outcome of large-bowel perforation in patients with colorectal cancer

PURPOSE: Perforation of the colon is seldom associated with malignant disease. Operative mortality varies widely in published studies and little is known about patterns of failure and long-term outcome. An observational study was undertaken to assess the outcome of colorectal cancer complicated by perforation. METHOD: We reviewed a series of 83 consecutive patients treated during a 14-year period at one institution. RESULTS: Fifty-four (65 percent) patients had perforation of the tumor itself, and 29 (35 percent) had diastatic perforation proximal to an obstructing tumor. Twenty-six (31.5 percent) patients had metastatic disease at laparotomy. Primary resection of the diseased segment was performed in 47 (87 percent) patients with perforation of the tumor itself and in 21 (72.4 percent) patients with diastatic perforation proximal to an obstructing tumor. However, only 57 patients (39 (72.2 percent) with perforation of the tumor itself; 18 (62 percent) with diastatic perforation proximal to an obstructing tumor; P = not significant) were potentially cured. Operative mortality was 16.7 and 48.3 percent, respectively (P < 0.01) and correlated significantly with Hinchey's stage (P < 0.001) and advanced disease (P = 0.023). At a mean follow-up of 43 (median 31) months, 21 (46 percent) of the 46 potentially cured survivors were alive. The local recurrence rate was 22.9 percent in patients with perforation of the tumor itself and 18.2 percent in patients with diastatic perforation proximal to an obstructing tumor (P = not significant). Peritoneal seeding occurred in 17 and 0 percent (P = not significant); the mean disease-free interval was 33.9 and 49.9 months (P = not significant); and five-year cumulative disease-related survival probability was 0.51 and 0.90 (P = 0.049), respectively. CONCLUSIONS: Diastatic perforation proximal to an obstructing tumor is associated with higher operative mortality and better cancer-related survival than a tumor perforating through the bowel wall. Early diagnosis in diastatic perforation and aggressive management of sepsis associated with radical surgical resection is recommended.