Real-World Metastatic Renal Cell Carcinoma Treatment Patterns and Clinical Outcomes in The Netherlands.

The number of treatment options for patients with metastatic renal cell carcinoma (mRCC) has significantly grown in the last 15 years. Although randomized controlled trials are fundamental in investigating mRCC treatment efficacy, their external validity can be limited. Therefore, the efficacy of the different treatment options should also be evaluated in clinical practice. We performed a chart review of electronic health records using text mining software to study the current treatment patterns and outcomes. mRCC patients from two large hospitals in the Netherlands, starting treatment between January 2015 and May 2020, were included. Data were collected from electronic health records using a validated text mining tool. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Statistical analyses were performed using the Kaplan-Meier method. Most frequent first-line treatments were pazopanib (n = 70), sunitinib (n = 34), and nivolumab with ipilimumab (n = 28). The overall median PFS values for first-line treatment were 15.7 months (95% confidence interval [95%CI], 8.8-20.7), 16.3 months (95%CI, 9.3-not estimable [NE]) for pazopanib, and 6.9 months (95% CI, 4.4-NE) for sunitinib. The overall median OS values were 33.4 months (95%CI, 28.1-50.9 months), 39.3 months (95%CI, 29.5-NE) for pazopanib, and 28.1 months (95%CI, 7.0-NE) for sunitinib. For nivolumab with ipilimumab, median PFS and median OS were not reached. Of the patients who finished first- and second-line treatments, 64 and 62% received follow-up treatments, respectively. With most patients starting on pazopanib and sunitinib, these real-world treatment outcomes were most likely better than in pivotal trials, which may be due to extensive follow-up treatments.

Effectiveness and toxicity of lenvatinib in refractory thyroid cancer: Dutch real-life data.

OBJECTIVE: The SELECT trial showed progression-free survival (PFS) benefit for lenvatinib for advanced radioiodine-refractory differentiated thyroid cancer (RAI-refractory or RR-DTC) patients, on which current clinical practice is based. We assessed whether the effectiveness and toxicity of lenvatinib in real-life clinical practice in the Netherlands were comparable to the pivotal SELECT trial. METHODS: From three Dutch centres Electronic Health Records (EHRs) of patients treated in the lenvatinib compassionate use program or as standard of care were reviewed and checked for SELECT eligibility criteria. Baseline characteristics, safety, and efficacy measures were compared and PFS and overall survival (OS) were calculated. Furthermore, PFS was compared to estimates of PFS reported in other studies. RESULTS: A total of 39 DTC patients with a median age of 62 years were analysed. Of these, 27 patients (69%) did not fulfil the SELECT eligibility criteria. The most common grade ≥3 toxicities were hypertension (n = 11, 28%), diarrhoea (n = 7, 18%), vomiting (n = 4, 10%), and gallbladder disease (n = 3, 8%). Median PFS and median OS were 9.7 (95% confidence interval (CI): 4.0-15.5) and 18.3 (95% CI: 4.9-31.7) months, respectively, response rate was 38% (95% CI: 23-54%). PFS in the Dutch real-life situation was comparable to previous real-life studies, but inferior to PFS as shown in the SELECT trial (P = 0.04). CONCLUSIONS: PFS in our non-trial population was significantly shorter than in the SELECT trial population. In the interpretation of results, differences in the real-life population and the SELECT study population regarding patient characteristics should be taken into account.

Population pharmacokinetics of treosulfan in paediatric patients undergoing hematopoietic stem cell transplantation.

AIMS: Treosulfan is an alkylating agent increasingly used prior to haematopoietic stem cell transplantation. The aim of this study was to develop a population pharmacokinetic (PK) model of treosulfan in paediatric haematopoietic stem cell transplantation recipients and to explore the effect of potential covariates on treosulfan PK. Also, a limited sampling model (LSM) will be developed to accurately predict treosulfan exposure suitable for a therapeutic drug monitoring setting. METHODS: In this multicentre study, 91 patients, receiving a total dose of 30, 36 or 42 g/m2 treosulfan, administered over 3 consecutive days, were enrolled. A population PK model was developed and demographic factors, as well as laboratory parameters, were included as potential covariates. In addition, a LSM was developed using data from 28 patients. RESULTS: A 2-compartment model with first order elimination best described the data. Bodyweight with allometric scaling and maturation function were identified as significant predictors of treosulfan clearance. Treosulfan clearance reaches 90% of adult values at 4 postnatal years. A model-based dosing table is presented to target an exposure of 1650 mg*h/L (population median) for different weight and age groups. Samples taken at 1.5, 4 and 7 hours after start of infusion resulted in the best limited sampling strategy. CONCLUSIONS: This study provides a treosulfan population PK model in children and captures the developmental changes in clearance. A 3-point LSM allows for accurate and precise estimation of treosulfan exposure.

Personalized busulfan and treosulfan conditioning for pediatric stem cell transplantation: the role of pharmacogenetics and pharmacokinetics.

Busulfan- and treosulfan-based conditionings are the cornerstone of pediatric allogeneic hematopoietic stem cell transplantation (HSCT). Although both drugs are alkylating agents, their mechanisms of action, pharmacokinetics (PK) and toxicity profiles are different. Experience with busulfan in pediatric HSCT is broad and the knowledge on the pharmacodynamics (PD), PK and, to a lesser extent, pharmacogenetics (PG) has resulted in a more effective therapy. Treosulfan has only recently been introduced in pediatric HSCT and is considered a promising new therapy because of its beneficial toxicity profile. However, knowledge of the PK and PG of treosulfan is limited. In this review, we describe the pharmacology of both agents and discuss factors causing variability in PK in relation to therapeutic outcome in HSCT.

Effect of genetic polymorphisms in genes encoding GST isoenzymes on BU pharmacokinetics in adult patients undergoing hematopoietic SCT.

BU is used in conditioning regimens before hemopoietic SCT. High BU exposure is associated with toxicity, whereas low BU exposure leads to higher rates of therapy failure. The pharmacokinetics of BU show large interpatient variability, hypothesized to be caused by variability in BU metabolism. In this report, the effect of genetic polymorphisms in three gluthatione S-transferase genes involved in BU metabolism (hGSTA1), GSTM1 (deletion-mutation) and GSTP1 (313A/G) on the pharmacokinetics of BU in Caucasian adult patients was investigated. In all, 66 adult patients received BU as part of their conditioning regimen. After the first infusion, two serum samples were collected and measured using a HPLC assay. A one-compartment population model was used to estimate individual pharmacokinetic parameters. The genetic variants of the three glutathione S-transferase (GST) genes were determined by pyrosequencing and PCR. A reduction of 14% in BU clearance was seen for the GSTA1*B allele and an increase in BU exposure was found. No relationship was found between polymorphisms in GSTM1 and GSTP1 and BU pharmacokinetics. This study shows that an increasing number of copies of GSTA1*B allele results in a significant decrease of BU clearance.

Results of streamlined regional ambulance transport and subsequent treatment of acute abdominal aortic aneurysms.

OBJECTIVE: To describe the triage of patients operated for non-ruptured and ruptured abdominal aortic aneurysms (AAAs) before the endovascular era. DESIGN: Retrospective single-centre cohort study. METHODS: All patients treated for an acute AAA between 1998 and 2001 and admitted to our hospital were evaluated in the emergency department for urgent AAA surgery. All time intervals, from the telephone call from the patient to the ambulance department, to the arrival of the patient in the operating theatre, were analysed. Intraoperative, hospital and 1-year survival were determined. RESULTS: 160 patients with an acute AAA were transported to our hospital. Mean (SD) age was 71 (8) years, and 138 (86%) were men. 34 (21%) of these patients had symptomatic, non-ruptured AAA (sAAA) and 126 patients had ruptured AAA (rAAA). All patients with sAAA and 98% of patients with rAAA were operated upon. For the patients with rAAA, median time from telephone call to arrival at the hospital was 43 min (interquartile range 33-53 min) and median time from arrival at the hospital to arrival at the operating room was 25 min (interquartile range 11-50 min). Intraoperative mortality was 0% for sAAA and 11% for rAAA (p = 0.042), and hospital mortality was 12% and 33%, respectively (p = 0.014). CONCLUSIONS: A multidisciplinary unified strategy resulted in a rapid throughput of patients with acute AAA. Rapid transport, diagnosis and surgery resulted in favourable hospital mortality. Despite the fact that nearly all the patients were operated upon, survival was favourable compared with published data.

Intravenous busulfan in children prior to stem cell transplantation: study of pharmacokinetics in association with early clinical outcome and toxicity.

We studied the pharmacokinetics of intravenous busulfan (Bu) in children in order to further optimize intravenous Bu dosing in relation to toxicity and survival. A total of 31 children undergoing Bu-based conditioning for allogeneic SCT were enrolled in a study. The starting dose was 1.0 mg/kg (age < 4 years) and 0.8 mg/kg (age > or =4 years), four doses per day during 4 days. Dose adjustment was allowed up to a maximum dose of 1.0 mg/kg per dose if the target area under the serum concentration-time curve (AUC) was not reached. Pharmacokinetic studies were performed after the first dose. Donor engraftment was established in 28 out of 31 patients. The average AUC after the first dose was the same in children < 4 years as in children > or =4 years. Mean clearance was higher in children < 4 years than in children > or =4 years. In 35% of all patients, total AUC was within the target AUC. The other children's AUCs were below the target range. No relationships were found between systemic exposure to Bu and toxicity or clinical outcome. We concluded that, in accordance with previous data, within the observed AUCs no clear relationship was observed between Bu AUC and outcome with respect to toxicity, engraftment and relapse.

Randomized, placebo-controlled trial of the anti-tumor necrosis factor antibody fragment afelimomab in hyperinflammatory response during severe sepsis: The RAMSES Study.

OBJECTIVE: This study investigated whether treatment with the anti-tumor necrosis factor-alpha monoclonal antibody afelimomab would improve survival in septic patients with serum interleukin (IL)-6 concentrations of >1000 pg/mL. DESIGN: Multicenter, double-blind, randomized, placebo-controlled study. SETTING: Eighty-four intensive care units in academic medical centers in Europe and Israel. PATIENTS: A total of 944 septic patients were screened and stratified by the results of a rapid qualitative immunostrip test for serum IL-6 concentrations. Patients with a positive test kit result indicating IL-6 concentrations of >1000 pg/mL were randomized to receive either afelimomab (n = 224) or placebo (n = 222). Patients with a negative IL-6 test (n = 498) were not randomized and were followed up for 28 days. INTERVENTIONS: Treatment consisted of 15-min infusions of 1 mg/kg afelimomab or matching placebo every 8 hrs for 3 days. Standard surgical and intensive care therapy was otherwise delivered. MEASUREMENTS AND MAIN RESULTS: The study was terminated prematurely after an interim analysis estimated that the primary efficacy end points would not be met. The 28-day mortality rate in the nonrandomized patients (39.6%, 197 of 498) was significantly lower (p <.001) than that found in the randomized patients (55.8%, 249 of 446). The mortality rates in the IL-6 test kit positive patients randomized to afelimomab and placebo were similar, 54.0% (121 of 224) vs. 57.7% (128 of 222), respectively. Treatment with afelimomab was not associated with any particular adverse events. CONCLUSIONS: The IL-6 immunostrip test identified two distinct sepsis populations with significantly different mortality rates. A small (3.7%) absolute reduction in mortality rate was found in the afelimomab-treated patients. The treatment difference did not reach statistical significance.

Retransplantation of the liver in children.

BACKGROUND: Because of the poor outcome of hepatic retransplantation, it is still debated whether this procedure should be performed in an era of donor organ scarcity. The aim of this study was to analyze outcome of hepatic retransplantation in children, to identify risk factors influencing this outcome, and to assess morbidity and causes of death. METHODS: A series of 97 children after a single transplantation and 34 children with one retransplantation was analyzed. RESULTS: The 1-, 3-, and 5-year survival of children with a retransplantation was 70, 63, and 52%, respectively, compared with 85, 82, and 78%, respectively, for children after a single transplantation (P=0.009). Survival of children with a retransplantation within 1 month after primary transplantation was worse (P=0.007) and survival of children with a late retransplantation was comparable (P=0.66) with single transplantation. In early retransplantations, the Child-Pugh score was higher, donors were older and weighed more, and more technical variant liver grafts were used compared with single transplantations. Biliary atresia and a high Child-Pugh score were associated with decreased patient survival after retransplantation. Sepsis was the most important complication and cause of death after retransplantation. CONCLUSIONS: Retransplantation is a significant event after pediatric liver transplantation. Outcome after hepatic retransplantation in children is inferior compared with single transplantation. This difference is explained by low survival after early retransplantation and can be explained by the poor clinical condition of the children at time of retransplantation, especially in children with biliary atresia, and by the predominant use of technical variant liver grafts in retransplantations.

Prognostic factors for long-term actual patient survival after orthotopic liver transplantation in children.

BACKGROUND: Orthotopic liver transplantation has become the treatment of choice for children with end-stage liver disease. Although results have improved the last decades, still a considerable number of children die after transplantation. The aim of this study was to analyze long-term actual survival and to identify prognostic factors for such survival rates. METHODS: A consecutive series of 66 children receiving transplants who had or could have had a follow-up of at least 5 years was retrospectively analyzed. Actual survival and prognostic factors in relation to patient, donor, and operation related variables were assessed after multivariate analysis. RESULTS: Actual 1-, 3-, and 5-year patient survival was 86%, 79%, and 73%, respectively. A high Child-Pugh (C-P) score or C-P class C, high donor age, high blood loss index, and retransplantation were predictive factors for actual patient survival. A high blood loss index was correlated with biliary atresia, low recipient age and weight, and with previous upper abdominal operations. The duration of stay of the donor at the intensive care unit (ICU) was a predictive factor for retransplantation. CONCLUSIONS: Children with diseases eligible for liver transplantation should be seen early in the course of their disease in a transplantation center. All possible measures should be taken during the transplantation procedure to keep the blood loss at a minimum. Children with biliary atresia deserve special attention in this respect. The choice of donors has implications for survival.

Endotoxins and cytokines during liver transplantation: changes in plasma levels and effects on clinical outcome.

Endotoxins, tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), and IL-6 are believed to have a key role in liver transplantation. The origin and course of these factors is not completely known. In this prospective study of 40 patients, we sought more understanding of the relations between these factors and their effects on clinical outcome by sampling at different sites. Endotoxemia was only present in 20% of the patients. In 75% of these patients, it was present during the anhepatic phase and quickly resolved after reperfusion. Endotoxemia was not related to a clinical adverse event. TNF-alpha was released from the graft after reperfusion, and initial levels after reperfusion were related to predonation levels in the donor. Only levels of TNF-alpha in the recipient before transplantation were found to be predictive of postoperative complications. We conclude that monitoring endotoxins and these cytokines is of very limited value in predicting outcome.

Procalcitonin behaves as a fast responding acute phase protein in vivo and in vitro.

OBJECTIVES: Procalcitonin (PCT) is a 13 kD protein of which plasma concentrations are strongly increased in inflammatory states. PCT concentrations are claimed to have a more powerful discriminatory value for bacterial infection than the acute phase proteins serum amyloid A (SAA) or C-reactive protein (CRP). The source of production and its mechanism of induction are unknown. We investigated the inducibility of PCT both in vivo and in vitro and compared the behavior of PCT with those of SAA and CRP. DESIGN: A prospective descriptive patient sample study and a controlled liver tissue culture study. SETTING: A university hospital. PATIENTS: Cancer patients who were treated with human tumor necrosis factor-alpha (rhTNF-alpha; 5 patients) or interleukin-6 (rhIL-6; 7 patients). MEASUREMENTS AND MAIN RESULTS: Serial serum samples were collected for analysis of concentrations of PCT, SAA, and CRP. In the TNF-alpha group, frequent sampling was performed on the first day to allow analysis of initial responses. In a human liver slice model, the release of PCT, SAA, and CRP was measured on induction with rhTNF-alpha and rhIL-6 for 24 hrs. We found that PCT displayed acute phase reactant behavior in vivo after administration of both rhTNF-alpha and rhIL-6. After rhTNF-alpha-administration, PCT reached half-maximal concentrations within 8 hrs, 12 hrs earlier than either SAA or CRP did. PCT, SAA, and CRP were produced in detectable quantities by liver tissue in vitro. PCT production by liver slices was enhanced after stimulation with rhTNF-alpha or rhIL-6; SAA and CRP concentrations were elevated after stimulation with rhTNF-alpha. CONCLUSIONS: We found that PCT and acute phase proteins such as CRP are induced by similar pathways. The liver appears to be a major source of PCT production. Thus, PCT may be considered an acute phase protein. The different kinetics of PCT, rather than a fundamentally different afferent pathway, may explain its putative diagnostic potential to discriminate bacterial infection from other causes of inflammation.

Blunted rise in platelet count in critically ill patients is associated with worse outcome.

OBJECTIVE: To test the hypothesis that a low rate of change of platelet counts (PCs) after admission to the intensive care unit (ICU) is associated with mortality. Low PCs are known to be associated with disease severity in critically ill patients, but the relevance of time-dependent changes of PCs has not been investigated. DESIGN: Retrospective study. SETTING: A 12-bed surgical ICU of a university hospital. PATIENTS: All adult patients admitted to the ICU for at least 4 days during a 7-yr period. INTERVENTIONS: At admission, Acute Physiology and Chronic Health Evaluation scores were calculated. PCs and leukocyte counts were analyzed from admission to day 10. The daily rise of the PCs (deltaPC/deltat from day 2 to day 10 was calculated. Rates for 30-day mortality as well as hospital mortality were determined. MEASUREMENTS AND MAIN RESULTS: A total of 1,415 admissions were studied. Median PCs (interquartile range) initially decreased and subsequently increased, with a higher PC in 1,203 survivors than in 212 nonsurvivors from day 2 onward (302 [range,181-438] x 10(3)/mm3/day vs. 129 [range, 62-228] x 10(3)/mm3 at day 10; p < 0.001). After stratification of patients per type of surgery, within each group PC was also higher in survivors. Mean deltaPC/deltat was more than five times higher in survivors compared with nonsurvivors: 30 +/- 46 x 10(3)/mm3/day vs. 6 +/- 28 x 10(3)/mm3/day (p < 0.001). The area under the receiving operating characteristic curve of deltaPC/deltat for 30-day survival was 0.743 compared with 0.728 for the Acute Physiology and Chronic Health Evaluation. Leukocyte counts showed marginal differences between nonsurvivors and survivors. CONCLUSION: A blunted or absent rise in PCs in critically ill patients is associated with increased mortality. deltaPC/deltat is a readily available and simple parameter to improve assessment of critically ill patients.

Gastric mucosal pH is associated with initial graft function but is not a predictor of major morbidity after liver transplantation.

Gastric mucosal pH reflects splanchnic perfusion. Monitoring gastric mucosal pH might be useful in predicting outcome after liver transplantation. Forty patients were included in the study. Gastric mucosal pH and gastric mucosal pH corrected for systemic pH were compared with regard to initial liver function and morbidity. Eighty percent of the patients had at least one episode with a gastric mucosal pH of <7.32, and 84% of these had a concomitant arterial pH of <7.32. No differences in morbidity were found between patients with a gastric mucosal pH of <7.32 and those with a gastric mucosal pH of >7.32. If gastric mucosal pH was corrected for arterial pH, only 49% of the patients had an episode during transplantation with a corrected gastric mucosal pH of <7.32. Comparing these patients with the group that did not have such an episode, we found that flow in the venovenous bypass system was significantly lower (2.9 v 3.4 L/min; P < .02) in the first group. Also alanine aminotransferase and aspartate aminotransferase levels were higher, antithrombin III levels and lidocaine clearance rates were lower, and prothrombin times were longer in the group with corrected gastric mucosal pH of <7.32. No differences with regard to major morbidity and mortality were noted. Gastric mucosal pH during liver transplantation should be corrected for arterial pH. Patients with a corrected gastric mucosal pH of <7.32 are more likely to develop initial liver function tests disturbances, but morbidity is not different from patients with gastric mucosal pH of >7.32.

Effects of hyperthermic isolated limb perfusion with tumor necrosis factor-alpha and melphalan on pulmonary function assessments.

High doses of tumor necrosis factor-alpha (TNF) seem to be effective in the treatment of solid tumors in the extremities. By applying current intensive care technology, systemic administration of high doses of TNF levels might be feasible for the treatment of cancer in other localizations. To establish the early and late effects of high systemic TNF levels on the lungs, we determined lung function parameters in 12 patients before and after hyperthermic isolated limb perfusion (HILP) with TNF and melphalan. Because of leakage during perfusion, mean maximum systemic TNF levels of 60.0 ng/ml (range, 0.3-356 ng/ml) were obtained. Significant alterations in the vital capacity (VC), the capillary blood volume (Vc), the diffusing capacity of the alveolocapillary membrane (Dm), and the transfer capacity of the lungs for carbon monoxide per unit alveolar volume (KCO) were observed 1 week after HILP. Eight weeks after HILP, they returned to pretreatment value. Alterations in lung functions were not related to the maximum systemic TNF level. In conclusion, disturbances in pulmonary functions are observed in patients after HILP with TNF and melphalan. These disturbances, which are probably partly caused by high systemic TNF levels, are reversible and would not preclude administration of systemic TNF in high doses.

Surgical treatment of giant haemangioma of the liver.

BACKGROUND: The treatment of giant symptomatic haemangioma of the liver is still controversial. This retrospective study reviewed the results of surgical treatment. METHODS: Twenty-eight patients with symptomatic giant haemangioma of the liver were treated by liver resection (n = 24) or liver transplantation (n = 4). The median diameter of the haemangiomas was 11 (range 5-20) cm. RESULTS: Complications occurred in five of the 24 patients treated by partial liver resection, although all survived and remain alive and well more than 2 years after surgery. In six patients there was residual haemangioma in the liver remnant which did not enlarge during the 2-year follow-up. In four patients the haemangioma was considered irresectable and liver transplantation was performed. One died after a 'two-stage' liver transplantation; the remaining three patients are alive and well, 1, 4 and 9 years after transplantation. CONCLUSION: Liver resection is the treatment of choice for giant haemangioma of the liver where possible. In selected cases liver transplantation is indicated.

Renal function in cancer patients treated with hyperthermic isolated limb perfusion with recombinant tumor necrosis factor-alpha and melphalan.

Hyperthermic isolated limb perfusion (HILP) with recombinant tumor necrosis factor-alpha (r-TNF alpha) and melphalan has been shown to result in a sepsis-like syndrome due to leakage of r-TNF alpha from the perfusion system to the systemic circulation. We have studied renal function parameters in 11 cancer patients, who underwent 12 perfusions. Three patients, perfused with melphalan only, served as controls. All patients treated with r-TNF alpha developed a sepsis syndrome and needed volume replacement and inotropes to remain normotensive; controls had an uneventful postoperative course. Creatinine clearance decreased transiently on the day of perfusion in both groups (mean preperfusion clearance 118 ml/min, mean post-perfusion clearance 68 ml/min, p < 0.02, n = 15). Follow-up measurements of renal plasma flow and glomerular filtration rate in 9 r-TNF alpha-treated patients did not suggest permanent damage. One patient became hypotensive and developed transient multiple organ dysfunction with renal failure needing hemofiltration. In r-TNF alpha-treated patients, but not in controls, a transient increase in clearance of beta2-microglobulin (0.05 vs. 8 ml/min, p < 0.001) and urinary excretion of phosphate (12 vs. 48 mmol/l, p < 0.05) was seen, compatible with proximal tubular dysfunction. These data suggest that HILP with melphalan decreases glomerular function, whether or not r-TNF alpha is added to the perfusion circuit. Extension of the treatment regimen with r-TNF alpha may result in additional proximal tubular dysfunction. If hypotension can be avoided, this deterioration in renal function seems to be transient, with full recovery within weeks.

Augmented procoagulant activity in cancer patients, treated with recombinant interferon-gamma in addition to recombinant tumor necrosis factor-alpha and melphalan.

Several investigators have reported that interferon-gamma (IFN gamma) can alter tumor necrosis factor alpha induced effects in vitro. We assessed in vivo effects of recombinant interferon-gamma (rIFN gamma) on recombinant tumor necrosis factor-alpha (rTNF alpha) induced activation of systemic blood coagulation in a non-randomized study in 20 consecutive cancer patients. Eight patients were treated with rIFN gamma prior to and during hyperthermic isolated limb perfusion with rTNF alpha and melphalan (IFN gamma group). They were compared with twelve patients who did not additionally receive rIFN gamma (non-IFN gamma group). Before start of perfusion, higher levels of TNF alpha, F1+2 and TAT levels were found in the IFN gamma group. Fibrinogen and ATIII levels tended to be lower in this group. High TNF alpha levels, due to leakage during perfusion, were associated with activation of coagulation in all patients, that became obvious after the end of perfusion, when heparin treatment had been antagonized. Activation, measured by increased F1+2 and TAT levels, was significantly stronger in the IFN gamma group. Monocytic TF remained low, possibly due to shedding of TF positive vesicles and/or sequestration of TF positive activated monocytes against the vessel wall. In both groups F1+2 and TAT levels declined 24 h after the perfusion, whereas monocytic TF increased to levels that were higher in the IFN gamma group. In conclusion, our data confirm a strong activation of coagulation induced by rTNF alpha in cancer patients. They suggest that rIFN gamma may lead to a slight activation of coagulation and augments TNF alpha induced procoagulant activity. These effects may be due to rIFN gamma induced sustained monocytic TF activity.

Changes in portal hemodynamics and acute rejection in the first 2 weeks after orthotopic liver transplantation. A prospective Doppler ultrasound study.

RATIONALE AND OBJECTIVES: To analyze changes in Doppler ultrasound variables of the portal vein in relation to liver biopsy findings, the authors performed a prospective study of 316 Doppler ultrasound examinations in the first 2 weeks after orthotopic liver transplantation on 23 patients. METHODS: Recordings were obtained daily from the portal vein (diameter, maximum velocity, and flow). Correlations were explored between the Doppler ultrasound findings and histologic data. The chi-square test was used to analyze differences in Doppler ultrasound variables in patients with and without acute rejection. RESULTS: In our series of 23 patients, acute rejection was diagnosed by liver biopsy in nine of them (39%). Changes in portal vein diameter, maximum velocity, and flow did not correlate consistently with liver biopsy findings, due to a multifactorial origin. Changes in portal hemodynamics were observed in patients with hepatic artery thrombosis, portal vein stenosis, acute rejection, and sepsis. CONCLUSIONS: Although routine screening using Doppler ultrasound proved to be useful for the determination of rapid changes in portal hemodynamics within a short time, serial Doppler ultrasound examinations were not helpful in predicting acute rejection.

Lack of specific renal haemodynamic effects of different doses of dopamine after infrarenal aortic surgery.

Dopamine is administered frequently in the operating theatre and intensive care unit patients undergoing mechanical ventilation with the aim of specifically enhancing renal blood flow. In an uncontrolled, open study, we administered sequentially different doses of dopamine (0, 2, 4, 8 and 0 microgram kg-1 min-1) during a 1-h period each. Systemic haemodynamic and renal haemodynamic variables were measured simultaneously using a pulmonary artery catheter and radiopharmaceuticals, respectively. We studied seven haemodynamically stable patients (mean age 66 yr), with a serum creatinine concentration < 160 mumol litre-1, after elective infrarenal abdominal aortic reconstruction. All patients received extradural analgesia with bupivacaine and sufentanil, and none had a previous history of heart failure. Dopamine induced a dose-dependent increase in cardiac index which returned to baseline after cessation of the dopamine infusion. Glomerular filtration rate (GFR) increased with all doses of dopamine, whereas renal blood flow (RBF) increased significantly only with the 2- and 4-microgram kg-1 min-1 doses. However, the ratio RBF/cardiac output remained unchanged with the 2- and 4-microgram kg-1 min-1 doses, but decreased with 8 micrograms kg-1 min-1 from 14 (1.5)% to 10 (1.3)%. We conclude that dopamine increased RBF and GFR as a result of an increase in cardiac output.