Acute pancreatitis: a comparison of intervention rates precipitated by early vs guideline CT scan timing.

AIM: To assess whether computed tomography (CT) examination earlier in acute pancreatitis (AP) precipitates any surgical or radiological intervention. MATERIALS AND METHODS: A single-centre retrospective cohort study comparing intervention rates in AP precipitated by early (<6 day of admission, n=100) and UK guideline (≥6 day of admission, n=103) CT examinations. RESULTS: No intervention was precipitated by performing CT before the sixth day of admission in AP. A statistically significant larger number of interventions were precipitated when CT was performed on the sixth day or later (p<0.05). Of note, this study was conducted using day of admission, rather than day of symptom onset. Six patients underwent repeat CT examination in the same admission after an early CT examination. CONCLUSION: Performing CT before the sixth day of admission does not lead to earlier intervention. Such early examinations waste resources and may offer false reassurance to clinicians.

MR-Eye: High-Resolution Microscopy Coil MRI for the Assessment of the Orbit and Periorbital Structures, Part 2: Clinical Applications.

In the first part of this 2-part series, we described how to implement microscopy coil MR imaging of the orbits. Beyond being a useful anatomic educational tool, microscopy coil MR imaging has valuable applications in clinical practice. By depicting deep tissue tumor extension, which cannot be evaluated clinically, ophthalmic surgeons can minimize the surgical field, preserve normal anatomy when possible, and maximize the accuracy of resection margins. Here we demonstrate common and uncommon pathologies that may be encountered in orbital microscopy coil MR imaging practice and discuss the imaging appearance, the underlying pathologic processes, and the clinical relevance of the microscopy coil MR imaging findings.

MR-Eye: High-Resolution Microscopy Coil MRI for the Assessment of the Orbit and Periorbital Structures, Part 1: Technique and Anatomy.

Microscopy coil MR imaging of the orbits has been described previously as a technique for anatomic depiction. In the first part of this 2-part series, the improvement in spatial resolution that the technique offers compared with conventional MR imaging of the orbits is demonstrated. We provide a guide to implementing the technique, sharing pearls and pitfalls gleaned from our own practice to make implementation of microscopy coil MR imaging at your own center easy. As a quick reference guide to the small-scale structures encountered when reading the studies, a short anatomy section is included, which doubles as a showcase for the high-quality imaging that can be obtained. In the second part, our experience of microscopy coil MR imaging in day-to-day clinical practice takes it far beyond being a useful anatomic educational tool. Through a series of interesting cases, we highlight the added benefit of microscopy coil MR imaging compared with standard orbital MR imaging.

The protein kinase C inhibitor CGP41251 suppresses cytokine release and extracellular signal-regulated kinase 2 expression in cancer patients.

Components of cell signaling pathways provide important targets for anticancer drugs. Protein kinase C (PKC) is a serine/threonine-specific kinase that regulates cell growth and differentiation. It is also implicated in tumor promotion. The staurosporine analogue CGP41251 is a PKC inhibitor, and it is currently in a Phase I clinical trial for treatment of advanced cancer. However, it is difficult to define its biological activity. We have used two approaches to measure the in vivo biological response to CGP41251: (a) sequential whole blood samples were taken from 27 patients before and during treatment and incubated with mitogen (PHA), and cytokine [tumor necrosis factor (TNF)-alpha and interleukin (IL)-6] release was measured ex vivo; and (b) peripheral blood lymphocytes were isolated from seven of these patients, and the levels of extracellular signal-regulated kinase 2 were measured by Western blotting. Response to PHA was significantly lowered during treatment (P < 0.001 for TNF-alpha production; P < 0.03 for IL-6). This was most evident at 7 and 28 days after the start of treatment in patients receiving higher doses (150-300 mg/day; P = 0.002 and P = 0.02, respectively, for TNF-alpha and P = 0.001 and P = 0.003, respectively, for IL-6 release). Whole blood cytokine production returned to pretreatment levels after drug administration ceased. The levels of extracellular signal-regulated kinase 2 were reduced by 50-97% during treatment in all seven patients tested. These results show for the first time that a PKC inhibitor can block in vivo signaling pathways in cancer patients. The assays we describe complement toxicity studies in selecting relevant doses for Phase II trial of novel agents, particularly when biological activity occurs at doses below those that cause obvious side effects.

Soluble Tie2 and Flt1 extracellular domains in serum of patients with renal cancer and response to antiangiogenic therapy.

Antiangiogenesis drugs can be difficult to evaluate because they produce disease stabilization rather than tumor regression. Markers of endothelial mass in tumors may be of value to monitor therapy and evaluate such drugs. Soluble domains of the endothelial receptor tyrosine kinases, sTie2 (angiopoietin receptor) and sFlt1 (vascular endothelial growth factor receptor-1) were analyzed by sandwich ELISA in serum samples from 43 patients with advanced renal cancer before and 1 month after antiangiogenic therapy with razoxane. Pretreatment sFlt1 levels were 0.77 ng/ml +/- 0.48 (SD) and sTie2 74.3 ng/ml +/- 15 (SD). Pretreatment sFlt1 levels above the median were associated with a lesser chance of stable disease (P = 0.04) and poorer survival (P = 0.01). Fall of sTie2 on treatment was associated with stable disease (P = 0.05) and improved survival (P = 0.04). The soluble receptors measured weeks before response were assessed and correlated with response and survival, showing they may be useful to monitor and develop antiangiogenic therapy.

A phase II study of razoxane, an antiangiogenic topoisomerase II inhibitor, in renal cell cancer with assessment of potential surrogate markers of angiogenesis.

Renal cell carcinoma (RCC) is an angiogenic tumor resistant to standard cytotoxic chemotherapeutic agents. Although often responsive to immunomodulatory agents including interleukin 2 and IFN-alpha, the overall results in randomized Phase III studies are disappointing with only modest improvements in overall survival. This Phase II study evaluated the efficacy and tolerability of razoxane, an antiangiogenic topoisomerase II inhibitor, in 40 patients (32 men, 8 women; age: range, 31-76 years; median, 58 years) with inoperable RCC. Twenty patients received razoxane 125 mg p.o., twice a day for 5 days each week for 8 weeks (one cycle). This was repeated in patients with stable disease (StD), but was discontinued after 16 weeks if there was no evidence of an objective response. Because minimal toxicity was seen, subsequent patients (n = 20) were treated until progressive disease (PD) was documented. Of 38 evaluable patients, 11 (29%) had StD for a minimum of 4 months, and the remainder had PD. Median overall survival was 7.3 months. Duration of survival was significantly better in patients with StD compared with those with PD (P = 0.003). The effect of treatment on six potential surrogate serum/plasma (vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), urokinase plasminogen activator soluble receptor (uPAsr), E-selectin, vascular cell adhesion molecule-1 (VCAM-1) and von Willebrand's factor (vWF) and two urinary (VEGF and bFGF) markers of angiogenesis was evaluated before and after 1 cycle of treatment. Pretreatment serum VEGF and E-selectin levels above the median value were associated with a poor prognosis. Serum VCAM-1 levels and urinary VEGF levels rose significantly after one cycle in patients with PD but not in those with StD. Serum VEGF, bFGF, VCAM-1 and vWF, plasma uPAsr and urinary bFGF levels were significantly higher in PD patients compared with StD patients before and/or after 1 cycle of treatment. In conclusion, razoxane is an antiangiogenic agent that has minimal toxicity and that requires further evaluation in combination with other active agents in the treatment of RCC. Surrogate serum and urinary markers of angiogenesis may have a role to play in predicting disease response and overall survival in RCC.

Epirubicin in patients with liver dysfunction: development and evaluation of a novel dose modification scheme.

This study aimed to develop an epirubicin dose modification scheme in women with breast cancer and liver dysfunction. We first identified target areas under the concentration-time curve (AUCs) of 2400 and 1600 ng/ml.h from pharmacokinetic studies in 15 women with normal liver tests. In a second group of 16 women with abnormal liver biochemistry, the relationship between raised asparate aminotransferase (AST) and epirubicin clearance was: dose=AUC (97.5-34.2xlog AST). Adaptive dosing was evaluated prospectively in a third group of 41 women with serum AST > or =2xnormal+/-raised bilirubin. The median AUCs were 2444 and 1608 ng/ml.h, close to the high and low target AUCs, respectively. Variability in AUC was lower with adaptive dosing than in a fourth group given an unadjusted dose of epirubicin (coefficient of variation=25.8, 30.0 and 46.5%, respectively; P=0.06). Epirubicin dosing based on AST is safe and may reduce pharmacokinetic variability.

Patient acceptability and practical implications of pharmacokinetic studies in patients with advanced cancer.

We have studied the practical implications and acceptability to patients of pharmacokinetic studies in 34 women receiving anthracyclines for advanced breast cancer. The following parameters were recorded: age, ECOG performance status, psychological state (Rotterdam Symptom Checklist), cytotoxic drug and dose, number of venepunctures for treatment and sampling, and time when the sampling cannula was removed. Immediately after finishing pharmacokinetic sampling, patients completed a questionnaire which revealed that (i) all patients understood sampling was for research, (ii) 35% of patients experienced problems with sampling, (iii) benefits from participation were perceived by 56% of patients. Of 20 patients later questioned after completion of their treatment course, 40% recalled difficulties with blood sampling. Factors identifying in advance those patients who tolerate pharmacokinetic studies poorly were not identified but the number of venepunctures should be minimised. Patients may also perceive benefits from 'non-therapeutic' research.

Phase II studies of BBR3464, a novel tri-nuclear platinum complex, in patients with gastric or gastro-oesophageal adenocarcinoma.

BBR3464, a novel tri-nuclear platinum complex, forms long-range DNA adducts and is highly potent when compared with cisplatin in vitro. Preclinical studies demonstrated activity in cisplatin-resistant tumours and tumours with mutated p53 status. Phase I & II clinical studies gave preliminary indications of activity in melanoma, pancreatic, lung and ovarian cancers. The aim of this study was to determine the efficacy and confirm the toxicity of BBR3464 when given either as first- or second-line treatment for advanced disease in patients with gastric and gastro-oesphageal adenocarcinoma. Two multicentre, open label, Gehan design studies were conducted; one study used BBR3464 as first-line and the other as second-line treatment for metastatic or locally advanced disease. Nineteen first-line and 26 second-line patients were enrolled receiving a total of 74 and 53 infusions, respectively. Initially, seven patients in the second-line study received BBR3464 using the planned schedule of 1.1 mg/m2 every 4 weeks; however, 5 of these patients experienced dose-limiting grade 3 or 4 febrile neutropenia; subsequent patients in both studies were treated using the modified schedule of 0.9 mg/m2, every 21 days. In 1 of 17 evaluable, previously untreated patients, regression of multiple skin lesions was noted with stabilisation of lung metastases and maxillary sinus mass, lasting 155 days. In the first-line study, the median time to progression was 85 days [95% Confidence Interval (CI): 42, 127] (2.8 months) and in the second-line study, the median time to progression was 71 days [95% CI: 42, 109] and 38 days [95% CI: 32, 73] in the 1.1 and 0.9 mg/m2 dose level groups, respectively. Toxicity data were available for 45 patients. Neutropenia was the main toxicity seen (G3: 40%, G4: 40%). Febrile neutropenia was observed in six patients (15%) treated with 0.9 mg/m2 compared with five patients (71%) treated with 1.1 mg/m2 BBR3464. Other drug-related toxicities (G3/4) included: anaemia, thrombocytopenia, nausea, vomiting, diarrhoea, mucositis and fatigue. Diarrhoea and nausea/ vomiting were adequately controlled by the use of loperamide and antiemetics, respectively. Recruitment to the second-line study was closed early due to the poor response rate (1/17 evaluable, 6%; 95% CI: 1%, 27%) and short time to progression noted in the first-line study. Further studies with BBR3464 in this tumour type are not recommended.

Epirubicin in hepatocellular carcinoma: pharmacokinetics and clinical activity.

The pharmacokinetics and clinical activity of epirubicin were investigated in 16 patients with hepatocellular carcinoma (HCC) who received epirubicin at 75 mg/m2; the drug was given intravenously to 7 patients and via the hepatic artery to 9 patients (7 of whom also underwent embolisation). Lignocaine (1 mg/kg) was also given intravenously to 15 patients, and the metabolite monoethylglycinexylidide (MEGX) was measured as an indicator of liver function. Epirubicin clearance correlated with serum aspartate aminotransferase (AST), albumin and bilirubin values in patients treated intravenously or intraarterially. Although the route of administration did not affect the median total plasma clearance of epirubicin, early- and intermediate-phase clearance was higher following intraarterial administration. MEGX levels correlated with serum bilirubin levels but there was no correlation with albumin or AST values or epirubicin clearance. The rate of response to epirubicin was 3/13 (23%; 95% confidence interval, 8%-50%). Intravenous epirubicin was tolerated well, but intraarterial treatment was associated with significant morbidity. These data confirm that although current recommended dose adjustments are based primarily on serum bilirubin levels, altered epirubicin pharmacokinetics correlate more strongly with AST and albumin values than with serum bilirubin concentrations. However, at this dose and schedule, epirubicin has only modest activity against HCC.

Comparative pharmacokinetics of doxorubicin given by three different schedules with equal dose intensity in patients with breast cancer.

The pharmacokinetics of doxorubicin given according to three different schedules with a similar dose-time intensity have been studied and compared in 16 women with metastatic breast cancer. Six patients were treated with doxorubicin 75 mg/m2 by i.v. bolus repeated every 3 weeks; 5 patients received doxorubicin by 4-day continuous infusion every 3 weeks (4 at 75 mg/m2 and 1 at 60 mg/m2); 5 patients received 25 mg/m2 by i.v. bolus given weekly. Timed blood samples were collected and plasma levels of doxorubicin and its metabolite doxorubicinol were measured by high-performance liquid chromatography with fluorescence detection. Peak plasma concentrations were measured, and areas under the concentration-time curves calculated. Peak plasma levels of doxorubicin were significantly lower with the 4-day infusion than with either of the bolus injections. The 4-day infusion, however, gave significantly greater total exposure to doxorubicin and doxorubicinol, as indicated by area under the concentration-time curve, than weekly or 3-weekly bolus treatment. A single bolus injection of doxorubicin 25 mg/m2 yielded a total exposure to doxorubicin approximately half that achieved with a 75 mg/m2 bolus injection. Over a 3-week period, therefore, total exposure to doxorubicin would be greater with the weekly low-dose schedule than with the 3-weekly administration. We conclude that drug scheduling has significant effects on doxorubicin pharmacokinetics.

Gender affects doxorubicin pharmacokinetics in patients with normal liver biochemistry.

We studied the variability in doxorubicin pharmacokinetics in 27 patients, all of whom had normal liver biochemistry tests. Blood samples were collected after the first cycle of single-agent doxorubicin given as an i.v. bolus and plasma levels were measured by high-performance liquid chromatography (HPLC). The relationship of doxorubicin clearance (dose/AUC) with biochemical tests (AST, bilirubin, alkaline phosphatase, albumin, creatinine) and physical characteristics (age, gender, height, weight, tumour type) was investigated. The 6 men had a significantly higher doxorubicin clearance than did the 21 women (median values, 59 and 27 lh-1 m-2, respectively; P = 0.002). Doxorubicin clearance was significantly lower in patients with breast cancer than in those with other tumours (median values, 26 and 53 lh-1 m-2, respectively; P = 0.0008). The other biochemical and physical parameters did not correlate with doxorubicin clearance. However, in multivariate analysis, gender was the only factor predicting doxorubicin clearance (r2 = 40%). The ratio of the AUCs for doxorubicinol and doxorubicin (R) was higher in the men than in the women (median values, 0.62 and 0.36, respectively; P = 0.03). We conclude that gender may be an important determinant of doxorubicin clearance in patients with normal liver biochemistry.

Doxorubicin pharmacokinetics: the effect of abnormal liver biochemistry tests.

We studied variability in doxorubicin pharmacokinetics in 24 patients with abnormal liver biochemistry tests. Blood samples were collected after the first cycle of single-agent doxorubicin given as an i.v. bolus and plasma levels were measured by high-performance liquid chromatography. The relationship between doxorubicin clearance (dose/AUC) and liver biochemistry tests (AST, bilirubin, albumin, alkaline phosphatase and indocyanine green clearance) was investigated. Patients with a raised bilirubin level had reduced doxorubicin clearance, but there was no clear relationship between the extent of this elevation and the reduction in doxorubicin clearance. Doxorubicin clearance was lower in patients with an isolated increase in AST than in those with normal liver biochemistry, but this difference was not statistically significant. Nevertheless, there was a significant correlation between reduced doxorubicin clearance and both raised serum AST levels and low indocyanine green clearance. These pharmacokinetic data suggest that current dose reductions based solely on the extent to which bilirubin is elevated may not be optimal.

Phosphorus-31 metabolism of human breast--an in vivo magnetic resonance spectroscopic study at 1.5 Tesla.

We have studied the metabolism of compounds containing 31P in normal breast using magnetic resonance spectroscopy (MRS). Spectra were acquired from non-lactating pre-menopausal breast (n = 14 women), lactating breast (n = 8) and post-menopausal breast (n = 8). The standard acquisition protocol used a 5.5 cm surface coil with the volunteer prone to minimize chest wall signal contamination. In pre-menopausal non-lactating women the phosphocreatine (PCr) peak area, expressed relative to the sum of all 31P peak areas, was negatively correlated with breast size (r = -0.56, p = 0.02) suggesting that much of the PCr signal originated from the chest wall. The phosphodiester (PDE) relative peak area was positively correlated with breast size (r = 0.71; p = 0.002). Spectra could be acquired at all phases of the menstrual cycle. In sequential examinations of five women not taking the oral contraceptive pill (OCP), phosphomonoester (PME) relative peak area was significantly lower on Week 2 than other weeks of the cycle (p = 0.03). Among pre-menopausal women no clear difference was apparent between the spectra from women taking the OCP and those not taking the OCP. Lactating breast had significantly higher PME relative peak area than non-lactating pre-menopausal breast (p = 0.02), probably reflecting the higher proportion of epithelial tissue in lactation; the lower PCr relative peak area in lactating breast (p = 0.05) is probably due to the greater size of the breast during lactation. Spectra were acquired from post-menopausal women but with a relatively low signal-to-noise ratio. The only significant difference between 31P relative peak areas of breast spectra acquired from pre- and post-menopausal women was that less PCr was detected in the post-menopausal volunteers (p = 0.03), probably as a result of differences in breast size.

What is the effect of adjusting epirubicin doses for body surface area?

Doses of cytotoxic drugs are routinely adjusted according to body surface area. We have evaluated this practice in 32 women with advanced breast cancer treated with single-agent epirubicin 12.5-120 mg m(-2). Epirubicin and its metabolites were measured by high-performance liquid chromatography (HPLC). Unadjusted plasma clearance was calculated from dose in mg, and adjusted clearance from dose in mg m(-2). Unadjusted clearance did not correlate with surface area, height, weight, per cent ideal body weight or body mass index. There was no difference in the coefficient of variation (CV) of adjusted and unadjusted clearance (39.4% and 37.7% respectively). The AUC that would have resulted from giving an unadjusted dose was calculated. This predicted AUC was accurate, unbiased and had the same CV as the actual AUC. Similarly, in 11 patients an analysis of actual and predicted neutropenia confirmed that unadjusted dosing would have had no significant effect on the pattern of myelosuppression. Normalization of epirubicin dosage according to surface area appears not to reduce either pharmacokinetic or pharmacodynamic variability.

Anthracycline doses in patients with liver dysfunction: do UK oncologists follow current recommendations?

The question of whether UK oncologists follow current anthracycline dose modifications when treating patients with liver dysfunction was addressed through a questionnaire. Oncologists were asked the dose of doxorubicin or epirubicin they would prescribe for a woman with breast cancer and liver metastases who had one of four different patterns of abnormal liver chemistry. In each case, the median dose of anthracycline that would have been prescribed was close to that currently recommended. There was, however, wide variation in the dose that oncologists said they would prescribe, some avoiding an anthracycline altogether, whereas others would give full-dose treatment. Medical oncologists would prescribe a significantly lower dose of anthracycline than clinical oncologists for a patient with the most severely disturbed liver tests. Overall, medical oncologists were also significantly more likely to prescribe epirubicin. These results show the need for new, widely accepted anthracycline dose modifications for patients with liver dysfunction.

Measurement of epidoxorubicin and its metabolites by high-performance liquid chromatography using an advanced automated sample processor.

A sensitive and rapid method for measuring epidoxorubicin and its six metabolites by high-performance liquid chromatography using an advanced automated sample processor is described. Plasma samples (1 ml) were extracted using C2 cassettes, and reversed-phase chromatography was performed with an Apex II ODS column. The isocratic mobile phase of acetonitrile-0.019 M NaH2PO4 (pH 4.0) had a flow-rate of 1 ml/min and the fluorescence detector an excitation wavelength of 480 nm with an emission at 580 nm. Linear calibration curves were obtained which were reproducible both within-day and day-to-day (coefficients of variation less than 10%). The extraction efficacy of epidoxorubicin was 88% and ranged from 51 to 88% for the metabolites. This method has been successfully applied to measure the plasma levels of these compounds in patients receiving epidoxorubicin over a wide dose range (12-120 mg/m2) and in patients with disturbed liver biochemistry.