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Biomedical subjects

C Seynaeve

Publications and source records attributed to C Seynaeve.

At least 37 records · Page 2Linked to original sources
PubMed2003

Altered clearance of unbound paclitaxel in elderly patients with metastatic breast cancer.

The pharmacokinetic behaviour of anticancer drugs may be altered with aging due to (for example) differences in body composition and decreased hepatic and renal function. To address this issue for paclitaxel, we studied the pharmacokinetics of the drug in eight elderly women (>or=70 years) with metastatic breast cancer (median age (range), 77 years (70-84 years)) and a control group of 15 patients aged <70 years (median age (range), 54 years (22-69 years)). Paclitaxel was administered as a 1-h intravenous (i.v.) infusion at a dose of 80 (elderly) or 100 mg/m(2) (<70 years), and serial blood samples were obtained at baseline, and up to 24 h after the end of infusion. Paclitaxel concentration-time profiles were fitted to a linear three-compartment model without any demonstration of saturable behaviour. The clearance of unbound paclitaxel was 124+/-35.0 (elderly) versus 247+/-55.4 l/h/m(2) (<70 years) (P=0.002), and was inversely related to the patient's age (R(2)=0.857; P<0.00001). Total plasma clearance of the formulation vehicle Cremophor EL (CrEL) was 150+/-60.7 (elderly) versus 115+/-39.2 ml/h/m(2) (<70 years) (P=0.04). These data indicate an approximately 50% change in total body clearance of unbound paclitaxel and a concomitant significant increase in systemic exposure with age, most likely as a result of altered CrEL disposition. The clinical relevance of these observations with respect to toxicity profiles and antitumour efficacy requires further evaluation.

Adult↗
PubMed2003

Microsatellite instability in a pleomorphic rhabdomyosarcoma in a patient with hereditary non-polyposis colorectal cancer.

AIMS: To describe the rare occurrence of a pleomorphic sarcoma with microsatellite instability in a patient with hereditary non-polyposis colorectal cancer (HNPCC). METHODS AND RESULTS: A soft tissue tumour was removed from the upper leg of a patient who had previously been shown to harbour a germ-line MSH-2 mutation. The tumour was analysed with immunohistochemistry and molecular methods. The morphology and immunohistochemical findings were in keeping with a pleomorphic rhabdomyosarcoma. Microsatellite instability was documented in the tumour with molecular methods and in addition loss of MSH-2 expression in the tumour cells was confirmed by immunohistochemistry. CONCLUSIONS: Although sarcomas do not form part of the HNPCC diagnostic criteria, they may occur in this mismatch repair syndrome and, moreover, may well be caused by the underlying genetic defect.

Adult↗
PubMed2003

Psychological distress and breast self-examination frequency in women at increased risk for hereditary or familial breast cancer.

BACKGROUND: The Magnetic Resonance Imaging Screening study evaluates the efficacy and psychological impact of a surveillance program for women at increased risk for hereditary or familial breast cancer in the Netherlands. Surveillance consists of biannual physical examination, annual mammography, annual MRI and monthly breast self-examination (BSE). OBJECTIVE: To examine the association between psychological distress and reported BSE frequency. METHODS: Two months prior to surveillance demographics, BSE frequency, general distress (Hospital Anxiety and Depression Scale and the somatic scale of the Symptom Checklist-90) and breast cancer-specific distress (Impact of Event Scale) were assessed in 316 women (mean age 40.5 years, range 21-63 years). RESULTS: The majority (57%) reported performing monthly BSE. Ten percent reported never performing BSE, 20% less frequently than once a month and 13% at least once a week. Women below the age of 40 who examined their breasts more frequently than recommended (i.e. at least once a week) were shown to be significantly more distressed than the other women in the sample (p = 0.03). These women represented 15% of all the women below the age of 40 years in our study sample. CONCLUSION: Higher breast cancer-specific distress scores were observed among younger women who examined their breasts at least once a week. It is important for physicians to be aware of this hypervigilant behaviour, especially since it is correlated with breast cancer-specific distress.

Adult↗
PubMed2002

Clinical experience of prophylactic mastectomy followed by immediate breast reconstruction in women at hereditary risk of breast cancer (HB(O)C) or a proven BRCA1 and BRCA2 germ-line mutation.

AIM: Women with a proven BRCA1 or BRCA2 germ-line mutation or with a 50% risk of carrying the mutation, have an increased risk of breast cancer. Regular surveillance, chemoprevention or prophylactic mastectomy (PM) are options to detect breast cancer at an early stage or to reduce the risk. We describe the management of women who have opted for PM, the postoperative complications of PM, especially in combination with immediate breast reconstruction (IBR), and the oncological follow-up. METHODS: The medical records of all women who underwent a PM from December 1993 to December 1999 have been reviewed with respect to management, patient characteristics, complications and oncological follow-up. RESULTS: During the study period 112 women with a median age of 38.8 years opted for a PM: 76 were germline mutation carriers. After PM, 79 women without breast or ovarian cancer in their medical history, were free of disease after 2.5 years (median). Before PM, 29 women had been treated for breast cancer, 3.9 years (median) previously; 5 of these women had developed metastatic disease by the last consultation. Before PM, 2 patients had been treated for DCIS and 2 patients for ovarian cancer. Four DCIS were found; none of these women had evidence of disease 4.0 years (median) after PM. In 59 women laparoscopic prophylactic bilateral oophorectomy (PBO) was performed; 36 simultaneously with PM and 23 separately. A total of 103 women (92%) opted for IBR. After PM, the complication rate for IBR was 21%: 11% within 6 weeks and 10% at long-term follow-up (median 3.5) after PM, including the removal of 10 prostheses. CONCLUSIONS: Women with an increased risk of breast cancer due to a genetic predisposition should be adequately informed about the different treatment options in the setting of a multidisciplinary approach. PM can simultaneously be combined with PBO and IBR. IBR can facilitate the decision to undergo a PM. PM followed by IBR has an acceptable complication rate.

Adult↗
PubMed2001

Breast cancer after prophylactic bilateral mastectomy in women with a BRCA1 or BRCA2 mutation.

BACKGROUND: Women with a BRCA1 or BRCA2 mutation have a high risk of breast cancer and may choose to undergo prophylactic bilateral total mastectomy. We investigated the efficacy of this procedure in such women. METHODS: We conducted a prospective study of 139 women with a pathogenic BRCA1 or BRCA2 mutation who were enrolled in a breast-cancer surveillance program at the Rotterdam Family Cancer Clinic. At the time of enrollment, none of the women had a history of breast cancer. Seventy-six of these women eventually underwent prophylactic mastectomy, and the other 63 remained under regular surveillance. The effect of mastectomy on the incidence of breast cancer was analyzed by the Cox proportional-hazards method in which mastectomy was modeled as a time-dependent covariate. RESULTS: No cases of breast cancer were observed after prophylactic mastectomy after a mean (+/-SE) follow-up of 2.9+/-1.4 years, whereas eight breast cancers developed in women under regular surveillance after a mean follow-up of 3.0+/-1.5 years (P=0.003; hazard ratio, 0; 95 percent confidence interval, 0 to 0.36). The actuarial mean five-year incidence of breast cancer among all women in the surveillance group was 17+/-7 percent. On the basis of an exponential model, the yearly incidence of breast cancer in this group was 2.5 percent. The observed number of breast cancers in the surveillance group was consistent with the expected number (ratio of observed to expected cases, 1.2; 95 percent confidence interval, 0.4 to 3.7; P=0.80). CONCLUSIONS: In women with a BRCA1 or BRCA2 mutation, prophylactic bilateral total mastectomy reduces the incidence of breast cancer at three years of follow-up.

Adult↗
PubMed2001

Effectiveness of breast cancer surveillance in BRCA1/2 gene mutation carriers and women with high familial risk.

PURPOSE: Women with a high breast cancer risk due to a familial predisposition may choose between preventive surgery and regular surveillance. The effectiveness of surveillance in high-risk women and especially BRCA1/2 mutation carriers is unknown. We present first results from a single large family cancer clinic. PATIENTS AND METHODS: Women with breast cancer risk over 15% were examined by physical examination every 6 months and mammography every year. Detection rates and screening parameters were calculated for the total group and separately for different age and genetic risk groups. RESULTS: At least one examination was performed in 1,198 women: 449 moderate and 621 high-risk women and 128 BRCA1/2 mutation carriers. Within a median follow-up of 3 years, 35 breast cancers were detected (four ductal carcinoma-in-situ; 31 invasive tumors); the average detection rate was 9.7 per 1,000. Detection rates (95% confidence interval) for moderate and high-risk women and BRCA1/2 carriers were 3.3 (1.1 to 8.6), 8.4 (5.4 to 13.2), and 33 (17 to 63) per 1,000 person-years, respectively. The ratio of observed cases versus breast cancers expected in an average-risk population of comparable age was 2.7, 7.0 and 23.7 respectively. Overall, node negativity was 65%; 34% of primary tumors were less than 10 mm; sensitivity was 74%. Results with respect to tumor stage and sensitivity were less favorable in BRCA1/2 carriers and in women under the age of 40. CONCLUSION: It is possible to identify young women at high risk for breast cancer. The number of cancers detected was significantly greater than expected in an age-matched average-risk population and related to the risk category. Overall, screening parameters were comparable to population screening data, with less favorable results in the youngest age group (< 40) and BRCA1/2 carriers.

Adult↗
PubMed2001

Large regional differences in the frequency of distinct BRCA1/BRCA2 mutations in 517 Dutch breast and/or ovarian cancer families.

In 517 Dutch families at a family cancer clinic, we screened for BRCA1/2 alterations using the Protein Truncation Test (PTT) covering approximately 60% of the coding sequences of both genes and direct testing for a number of previously identified Dutch recurrent mutations. In 119 (23%) of the 517 families, we detected a mutation in BRCA1 (n=98; 19%) or BRCA2 (n=21; 4%). BRCA1/2 mutations were found in 72 (52%) of 138 families with breast and ovarian cancer (HBOC), in 43 (13%) of the 339 families with breast cancer only (HBC), in 4 (36%) of 11 families with ovarian cancer only (HOC), and in nine of 29 families with one single young case (<40 years) of breast cancer. Between the different subgroups of families (subdivided by the number of patients, cancer phenotype and age of onset) the proportion of BRCA1/2 mutations detected, varied between 6 and 82%. Eight different mutations, each encountered in at least six distinct families, represented as much as 61% (73/119 families) of all mutations found. The original birthplaces of the ancestors of carriers of these eight recurrent mutations were traced. To estimate the relative contribution of two important regional recurrent mutations (BRCA1 founder mutation IVS12-1643del3835 and BRCA2 founder mutation 5579insA) to the overall occurrence of breast cancer, we performed a population-based study in two specific small regions. The two region-specific BRCA1 and BRCA2 founder mutations were detected in 2.8% (3/106) and 3.2% (3/93) of the unselected breast tumours, respectively. Of tumours diagnosed before the age of 50 years, 6.9% (3/43) and 6.6% (2/30) carried the region-specific founder mutation. Thus, large regional differences exist in the prevalence of certain specific BRCA1/BRCA2 founder mutations, even in very small areas concerning populations of approximately 200000 inhabitants.

Adult↗
PubMed2001

Phase II study of weekly gemcitabine in patients with metastatic breast cancer relapsing or failing both an anthracycline and a taxane.

A phase II study was performed to investigate the efficacy and tolerability of gemcitabine as third-line chemotherapy for patients with metastatic breast cancer, previously treated with both an anthracycline- and taxane-containing regimen. Twenty-three patients were treated with gemcitabine 1200 mg/m2 in a 30-min infusion on day 1, 8 and 15 of a 28 day cycle. Seventy-four percent of the patients had visceral metastases. No complete or partial responses were observed. Six patients (26%) had stable disease with a median duration of 4.0 months. The median time to progression was 1.9 months and the median survival time was 7.8 months. Neutropenia grade 3 and 4 was observed in four patients (18%). Non-hematological toxicity grade 3 included nausea and vomiting in 14%, skin toxicity in 9% and elevation of transaminases in 23% of the patients. Gemcitabine is ineffective as third-line single agent therapy in patients failing anthracycline and taxane treatment for metastatic breast cancer.

Adult↗
PubMed2001

A comparative atomic force microscopy study on living skin fibroblasts and liver endothelial cells.

Atomic force microscopy (AFM) has been used to image a wide variety of cells and has proven to be successful in cellular imaging, by comparing results obtained by AFM with SEM or TEM. The aim of the present study was to investigate further the conditions for AFM imaging of living cells and compare the results with those obtained by SEM. We chose to image skin fibroblast and liver sinusoidal endothelial cells of two different sources, because these cells have been well described and characterized in earlier studies. AFM imaging of living cells mainly reveals submembranous structures, which could not be observed by SEM. This concerns the visualization of the overall cytoskeletal architecture and organelles, without the necessity of any preparative steps. The AFM study of living cells allows a time lapse study of dynamic changes of the actin cytoskeleton under the influence of the cytoskeleton-disturbing drug cytochalasin B in cells that can be followed individually during the process. However, softer samples, such as the fenestrated parts of living rat liver sinusoidal endothelial cells in culture could not be visualized. Apparently, these cell parts are disrupted due to tip-sample interaction in contact mode. To avoid the lateral forces and smearing artefacts of contact mode AFM, non-contact imaging was applied, resulting in images of higher quality. Still, endothelial fenestrae could not be visualized. In contrast, contact imaging of immortomouse liver sinusoidal endothelial cells, which are devoid of fenestrae, could easily be performed and revealed a detailed filamentous cytoskeleton.

Animals↗
PubMed2000

Prognostic significance of germline BRCA2 mutations in hereditary breast cancer patients.

PURPOSE: Breast cancer in BRCA2 gene mutation carriers differs from BRCA1-associated breast cancer or so-called sporadic breast cancer in clinical features and behavior. These differences may be of importance for the prevention, screening, and ultimately treatment of breast cancer in women with such germline mutations. METHODS: We reviewed the few studies that have reported on survival in patients with BRCA2-associated breast cancer. In this article we discuss why family history is no substitute for hereditary breast cancer with regard to studying survival and possible reasons why studies using family history yield contradictory results, why BRCA2-associated breast cancer should be considered a unique entity, and what methodological problems may exist, especially with regard to family-based studies. RESULTS: Five studies have reported on survival in BRCA2-associated breast cancer. Two studies showed a statistically significant worse survival for BRCA2 patients, but the patients from one of these studies were later claimed to have a trend toward better prognosis when controls were matched for age and year of diagnosis. The other study found that the unfavorable prognosis of BRCA2 patients was, to a great extent, due to a worse stage of the disease at time of diagnosis. The remaining three studies showed no significant effect of germline BRCA2 mutations on survival. The numbers of BRCA2 patients investigated in these studies were 42, 20, 23, 28, and 54 patients. Five-year overall survival in these patients varied from 65% to 74%. CONCLUSION: No definite conclusion can be made with regard to the prognosis of BRCA2-associated breast cancer, but large differences in comparison with sporadic breast cancer are not likely to exist. Breast cancer caused by BRCA2 mutations is also a distinct entity with its own features when compared with BRCA1-associated breast cancer. In contrast with BRCA1-associated breast cancer, BRCA2 tumors tend to be more often steroid receptor-positive.

BRCA2 Protein↗
PubMed2000

Presymptomatic DNA testing and prophylactic surgery in families with a BRCA1 or BRCA2 mutation.

BACKGROUND: Germline mutations in the BRCA1 and BRCA2 genes highly predispose to breast and ovarian cancer. In families with BRCA1 or BRCA2 mutations, identification of mutation carriers is clinically relevant in view of the options for surveillance and prevention. METHODS: We assessed presymptomatic DNA testing and prophylactic surgery in 53 consecutive families presenting to the Rotterdam Family Cancer Clinic with a known BRCA1 or BRCA2 mutation. We identified predictors for DNA testing and prophylactic surgery with univariate and multivariate analysis. FINDINGS: 682 unaffected individuals with a 50% risk (275 women and 271 men) or with a 25% risk (136 women) for carrying a mutation were identified and offered a DNA test. Presymptomatic DNA testing was requested by 48% (198 of 411) of women and 22% (59 of 271) of men (odds ratio for difference between sexes 3.21 [95% CI 2.27-4.51]; p<0.001). In women, DNA testing was significantly more frequent at young age, in the presence of children, and at high pre-test genetic risk for a mutation. Of the unaffected women with an identified mutation who were eligible for prophylactic surgery, 51% (35 of 68) opted for bilateral mastectomy and 64% (29 of 45) for oophorectomy. Parenthood was a predictor for prophylactic mastectomy but not for prophylactic oophorectomy. Age was significantly associated with prophylactic oophorectomy, but not with prophylactic mastectomy, although there was a tendency towards mastectomy at younger ages. INTERPRETATION: In a clinical setting, we show a high demand for BRCA1 and BRCA2 testing by unaffected women at risk, and of prophylactic surgery by unaffected women with the mutation. Young women with children especially opt for DNA testing and prophylactic mastectomy.

Adult↗
PubMed2000

Combined treatment with buserelin and tamoxifen in premenopausal metastatic breast cancer: a randomized study.

BACKGROUND: Surgical or medical castration and antiestrogenic treatment with tamoxifen are common endocrine treatments for premenopausal women with breast cancer. However, tamoxifen therapy induces high levels of plasma estradiol, with unknown long-term effects. In this study, we investigated the effect of combining estrogen suppression with the luteinizing hormone-releasing hormone agonist buserelin and estradiol receptor blockade with tamoxifen to determine whether the high estradiol levels induced by tamoxifen could be reduced and whether the antitumor effects would be better. METHODS: In a three-arm, randomized, prospective trial, from 1988 through 1995, a total of 161 premenopausal patients with advanced breast cancer were randomly assigned to treatment with buserelin, tamoxifen, or both. Patients with steroid receptor-negative tumors or with tumors of unknown receptor status who had a disease-free interval of less than 2 years were excluded. The median follow-up was 7.3 years, during which 76% of the patients died, all of breast cancer. Patient and tumor characteristics were well balanced among treatment groups. All P values are from two-sided tests. RESULTS: Combined treatment with buserelin and tamoxifen was superior to treatment with buserelin or tamoxifen alone by objective response rate (48%, 34%, and 28% of patients who could be evaluated, respectively; P =.11 [chi(2) test]), median progression-free survival (9.7 months, 6.3 months, and 5.6 months; P =.03), and overall survival (3.7 years, 2.5 years, and 2.9 years; P =.01). Actuarial 5-year survival percentages were 34.2% (95% confidence interval [CI] = 20.4%-48.0%), 14.9% (95% CI = 3.9%-25.9%), and 18.4% (95% CI = 7.0%-29.8%), respectively. No differences in antitumor effects were observed between single-agent treatment groups. During combined treatment or treatment with buserelin alone, plasma estradiol levels were suppressed equally; in contrast, during treatment with tamoxifen alone, plasma estradiol levels increased threefold to fourfold over pretreatment levels. CONCLUSION: Combined treatment with buserelin and tamoxifen was more effective and resulted in longer overall survival than treatment with either drug alone.

Adult↗
PubMed2000

Contralateral breast cancer risk is influenced by the age at onset in BRCA1-associated breast cancer.

BRCA1/2 mutation carriers diagnosed with breast cancer have a strongly elevated life-time risk of developing a contralateral tumour. We studied the contralateral breast cancer risk in 164 patients from 83 families with a proven BRCA1 mutation in relation to the age at diagnosis of the first primary breast cancer. In the actuarial outcomes after 10 years' follow-up, 40% of the 124 BRCA1-patients diagnosed with breast cancer < 50 years had developed contralateral breast cancer, vs 12% of the 40 patients > 50 years at first diagnosis (Plogrank = 0.02). These data suggest that age at diagnosis of the first tumour should be taken into account when prophylactic mastectomy in BRCA1-patients is considered.

Adult↗
PubMed2000

Phase II study of miltefosine 6% solution as topical treatment of skin metastases in breast cancer patients.

Topical treatment of skin metastases with a cytotoxic agent is attractive for its easy self-administration and absence of major systemic interference. Miltefosine exerts its cytotoxicity by acting on cell membrane phospholipids and can be administered topically. Twenty breast cancer patients with progression of skin metastases were treated with a 6% solution of miltefosine, which was topically administered once daily during the first week and twice daily thereafter. Sixteen out of 20 patients also had metastatic disease at other sites. Concomitant systemic treatment when ongoing for at least 2 months prior to study entry was permitted, and consisted of chemotherapy and hormonal therapy in seven and nine patients, respectively. Prior palliative cytotoxic and hormonal therapy had been administered to 11 and 19 patients, respectively. No grade 3 and 4 toxicity occurred. Miltefosine therapy was discontinued in two patients due to nausea and in one patient due to skin toxicity. Grade 1 and 2 adverse skin reactions, and nausea and vomiting were seen in 11 and two patients, respectively. In 18 patients evaluable for response, four partial responses were noted (response rate 22%), while seven patients had stable disease. Three partial responses were observed in patients in whom the skin lesions were smaller than 1.5 cm2. Median duration of response was 2.5 months and median time to progression for all patients was 1.9 months. In this study topically applied miltefosine for metastatic skin lesions of breast cancer showed modest activity in a relatively heavily pretreated patient population, without serious systemic toxicity.

Administration, Topical↗
PubMed2000

Randomized phase II study of docetaxel versus doxorubicin in first- and second-line chemotherapy for locally advanced or metastatic soft tissue sarcomas in adults: a study of the european organization for research and treatment of cancer soft tissue and bone sarcoma group.

PURPOSE: To assess antitumor response and time to progression (TTP) with docetaxel compared with doxorubicin in first-line treatment of advanced and/or metastatic soft tissue sarcoma. PATIENTS AND METHODS: Patients with measurable soft tissue sarcoma lesions and adequate bone marrow, liver, and renal function were entered onto the study. They were randomized to either docetaxel 100 mg/m(2) given as a 1-hour intravenous infusion every 3 weeks or doxorubicin 75 mg/m(2) given as a bolus injection every 3 weeks. A maximum of seven cycles of treatment were scheduled. The study was designed as a randomized phase III study evaluating TTP by log-rank model. There was a clause for premature closure of the trial if fewer than five responses were observed among the first 25 assessable patients in the docetaxel treatment arm. RESULTS: Eighty-six patients were entered onto the study; 85 were assessable for toxicity and 83 for response. The rate of severe granulocytopenia was not significantly different between the two arms. Nausea (P =.001), vomiting (P <.001), and stomatitis (P =.005) were more common with doxorubicin therapy, whereas neurotoxicity was more frequent with docetaxel treatment. The response rate to doxorubicin therapy was 30% (95% confidence interval, 17% to 46%), whereas no responses to docetaxel therapy were seen (P <.001). In view of this, the trial was closed prematurely and the phase III study part was not conducted. CONCLUSION: Docetaxel is inactive in soft tissue sarcomas and cannot be recommended for further use in treatment of this disease.

Adult↗
PubMed1999

Pit cells (Hepatic natural killer cells) of the rat induce apoptosis in colon carcinoma cells by the perforin/granzyme pathway.

The high mortality of colon cancer is to a large extent caused by the frequent occurrence of liver metastasis. This is remarkable, because the liver harbors two distinct cell populations that can eliminate invading cancer cells, namely hepatic natural killer (NK) cells and Kupffer cells. These hepatic NK cells, known as pit cells, are the most cytotoxic cells of the naturally occurring NK cells. However, the mechanism by which pit cells eliminate tumor cells is largely unknown. Because we recently found an indication that apoptosis is involved, we tried to assess the role of this mode of cell death using an in vitro system with isolated pure pit cells (>90%) and CC531s cells, a rat colon carcinoma (CC) cell line. Pit cells induced apoptosis in CC531s cells as shown by quantitative DNA fragmentation, agarose gel electrophoresis, and different modes of microscopy. When extracellular Ca2+ was chelated by ethylene glycol-bis(beta-aminoethyl ether)-N,N,-tetraacetic acid (EGTA) during coincubation or when the pit cells were preincubated with the granzyme inhibitor 3,4-dichloroisocoumarin (DCI), the induction of apoptosis was abolished. These results show that pit cells use the Ca2+-dependent perforin/granzyme pathway to induce apoptosis in the CC531s cells, and not the alternative Ca2+-independent Fas pathway. To further exclude the possibility of the involvement of the Fas pathway, we treated CC531s cells with recombinant Fas ligand. This treatment did not result in the induction of apoptosis, indicating that CC531s cells are resistant to Fas-mediated apoptosis. We conclude therefore that pit cells induce apoptosis in CC cells in vitro by the perforin/granzyme pathway.

Animals↗
PubMed1999

The 21-aminosteroid U74389G enhances hepatic blood flow and preserves sinusoidal endothelial cell function and structure in endotoxin-shocked dogs.

BACKGROUND: 21-Aminosteroids are potent anti-inflammatory and antioxidant drugs that provide remarkable endothelial protection in different models of tissue ischemia-reperfusion and inflammation. The effects of 21-aminosteroids in sepsis, a highly inflammatory condition leading to panendothelial activation and injury, are largely uninvestigated. We therefore explored the effects of the 21-aminosteroid U74386G on hepatic blood flow, endothelial cell function, and sinusoidal structure in a canine model of fluid-resuscitated, hyperdynamic endotoxic shock. MATERIALS AND METHODS: Following invasive hemodynamic monitoring and placement of ultrasonic flow probes around the common hepatic artery and the portal vein, 12 anesthetized dogs received 2 mg/kg iv of Escherichia coli endotoxin, followed by generous saline infusion, before randomization into two groups. One group (N = 6) received U74389G as an iv bolus of 80 microg/kg, followed by a continuous infusion of 10 microg/kg. min. The other group (N = 6) received an equivalent volume of vehicle. Hyaluronic acid was measured in plasma for in vivo evaluation of endothelial cell function. Liver biopsies were taken after 4 h of endotoxic shock and prepared for light and electron microscopic examination. RESULTS: Compared with the vehicle-treated controls, U74389G maintained a higher blood flow in the hepatic artery and in the portal vein, without markedly influencing the systemic hemodynamic response. The endotoxin-induced increase in plasma hyaluronic acid levels was significantly attenuated following U74389G treatment (70 +/- 14 vs 188 +/- 24 ng/mL after 3 h of endotoxic shock; P < 0.05). Morphological studies showed that the U74389G-treated group had less sinusoidal endothelial cell damage together with a dramatic reduction of neutrophil infiltration into the liver tissue. CONCLUSION: U74389G can preserve the functional and structural integrity of endothelial cells in the hepatic sinusoid during hyperdynamic endotoxic shock. This endothelial-protective effect was associated with a better maintained hepatic blood flow and a significant attenuation of inflammatory liver injury.

Animals↗