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W D Ensminger

Publications and source records attributed to W D Ensminger.

At least 73 records · Page 4Linked to original sources
PubMed1987

Analysis of bromodeoxyuridine incorporation into DNA: comparison of gas chromatographic/mass spectrometric, CsCl gradient sedimentation, and specific radioactivity methods.

A sensitive new method for the quantitation of 5-bromodeoxyuridine (BrdUrd) incorporated into DNA by GC/MS analysis of enzymatically released Thy and bromouracil (BrUra) is presented. The hydrolysis procedure was characterized and found to give uniform results when sample size was 1-10 micrograms DNA and incubation time for DNA digestion was between 40 min and 16 h. Samples of DNA containing 3H-labeled BrdUrd were analyzed in parallel by the GC/MS technique and by specific radioactivity and buoyant density measurements, in order to compare the three methods. The GC/MS procedure gave values for percentage replacement of Thy by BrUra which were higher than those obtained by specific activity and lower than those obtained by buoyant density. This GC/MS method can detect 1% replacement in a 1-microgram DNA sample, equivalent to approximately 10(5) cells or 0.1 mg tissue, and will permit sensitive and quantitative analysis of the presence of this chemotherapeutic agent/radiosensitizer in cellular DNA from biopsy samples of normal or tumor tissue.

Animals↗
PubMed1987

Local thrombolytic therapy for hepatic artery thrombosis following chemotherapy infusion catheter placement.

Nine patients with hepatic artery thrombosis subsequent to catheter placement (four surgical and five percutaneous) for hepatic arterial infusion chemotherapy were treated with local thrombolytic therapy. The thromboses were located in the common hepatic, proper hepatic and hepatic arteries. Thrombolytic therapy was instituted within seven days of catheter placement, at a rate of 5,000 to 20,000 units/hour (streptokinase) or 5,000 to 15,000 units/hour (urokinase) for 15 to 64 hours. All patients had repeat angiography and 99mTc-MAA hepatic artery perfusion scintigraphy after the infusion. In eight of the patients, thrombolytic therapy resulted in dissolution of the thrombus and recanalization of the hepatic artery. In three of these patients, rethrombosis occurred within a few days, and was attributed to underlying arterial abnormalities. The other five had documented continued hepatic arterial patency allowing completion of the chemotherapy course. The patient who did not respond to the lytic therapy had developed extensive collateral flow through the gastroduodenal artery to the liver.

Adult↗
PubMed1987

Hypervascular hepatic metastases: CT evaluation.

Recent reports have indicated that non-contrast material-enhanced scans are of less value than urographic contrast material-enhanced studies in the computed tomographic (CT) evaluation of hepatic metastases. The authors retrospectively reviewed the CT scans of 28 patients with hypervascular liver metastases to determine whether these metastases were more likely to become isodense with the liver after contrast material enhancement, thus necessitating the performance of non-contrast-enhanced scanning. Non-contrast-enhanced and contrast-enhanced incremental dynamic scanning was performed in patients with proved liver metastases from carcinoid tumors (13 patients), islet cell neoplasms (ten patients), pheochromocytomas (four patients), or renal cell carcinoma (one patient). Eleven of the 28 patients (39%) had metastases with non-contrast liver-to-lesion attenuation differences greater than 15 HU. These metastases subsequently became isodense or nearly isodense on contrast-enhanced scans. The authors conclude that non-contrast-enhanced CT scanning should be performed in patients with suspected liver metastases from tumors that are usually hypervascular.

Adenoma, Islet Cell↗
PubMed1987

MR imaging of hepatic focal nodular hyperplasia: characterization and distinction from primary malignant hepatic tumors.

Spin-echo MR imaging at 0.35 T was used to image hepatic focal nodular hyperplasia (FNH) and to attempt to distinguish it from primary malignant hepatic tumors. There were six FNH and 10 malignant tumors including seven hepatocellular carcinomas, two cholangiocarcinomas, and one hepatoblastoma. Our results show that FNH has a fairly consistent appearance, dissimilar from that of malignant primary hepatic tumors. Four of six FNH lesions were isointense (except for a central scar in three) and indistinguishable from normal hepatic parenchyma on all pulse sequences, whereas two of six were homogeneous but slightly hyperintense on T2-weighted sequences. Furthermore, a central hyperintense scar was seen in three of six lesions on T2-weighted sequences. In contrast, each of the malignant primary hepatic tumors was hyperintense on T2-weighted sequences and seven of 10 were hypointense on T1-weighted sequences; in nine of 10, heterogeneous areas of intensity were noted. In two fibrolamellar hepatocellular carcinomas a central scar was seen that was hypointense on all pulse sequences. By using quantitative data, the best characterization was obtained by using lesion/normal-liver intensity ratios from a T2-weighted sequence; all FNH had a ratio less than 1.33, while in nine of 10 primary malignant tumors it was greater than 1.41. We conclude that focal nodular hyperplasia may have a consistent appearance on spin-echo MR imaging and probably can be distinguished from primary malignant lesions in most instances.

Adenoma, Bile Duct↗
PubMed1987

Visualization of tumor vascularity in a rabbit VX2 carcinoma by Doppler flow mapping.

Using an ultrasonic dynamic flow imager that displays both soft tissues and color-coded flow in the same two-dimensional slice, we were able to display neovascularity in a rabbit VX2 carcinoma. Intravenous infusion of epinephrine altered the flow dynamics in two arteries, one within the tumor and one at the periphery. Further, we were also able to visualize areas of multidirectional flow presumably due to complex arterial patterns and arteriovenous shunts. It is concluded that the color-coded Doppler instrument may overcome some of the methodological problems associated with tumor diagnosis via flow characteristics in the human breast. The literature indicates that the vascular response to the vasoactive drugs or thermal stress may increase differentiation of malignant breast lesions. This experiment suggests that Doppler images and measurements may be made efficiently with color-coded Doppler images, particularly with the addition of more quantitative features to the imager.

Animals↗
PubMed1986

Determination of plasma trimetrexate levels using gas chromatography-mass spectrometry with selected-ion monitoring.

Trimetrexate is a potent inhibitor of dihydrofolate reductase and has demonstrated significant antitumor activity against murine and human cell lines both in vitro and against several murine transplanted tumors. The importance of antifolate concentration and exposure time in determining toxic and therapeutic effects necessitates an assay of suitable sensitivity, accuracy and specificity for investigation of trimetrexate pharmacokinetics. This paper describes a gas chromatographic-mass spectrometric (GC-MS) procedure using selected-ion monitoring (SIM) for the determination of plasma trimetrexate levels. Using the C18 Bond-Elut extraction columns, the drug and internal standard are removed from plasma, derivatized to their bis(trimethylsilyl) derivatives and analysed by GC-SIM-MS. The reproducibility of the daily standard curves had coefficients of variation ranging from 4.9 to 11.4%. The precision of the assay yielded a coefficient of variation ranging from 5.6 to 10.1%, and the concentration means for the seeded control samples were found to be within -3.7 to +0.7% of the theoretical values for trimetrexate. No interfering peaks have been observed in application of the procedure on patient samples. The minimum detectable level under the conditions described was 0.005-0.014 microM trimetrexate.

Folic Acid Antagonists↗
PubMed1986

Simultaneous determination of thymine and 5-bromouracil in DNA hydrolysates using gas chromatography-mass spectrometry with selected-ion monitoring.

The gas chromatographic-mass spectrometric method using selected-ion monitoring (GC-MS-SIM) described here quantitatively determines the amount of DNA thymine replacement by 5-bromouracil (BU) after exposure to 5-bromo-2'-deoxyuridine (BUDR) in as few as 10(5) cells. DNA is extracted, enzymatically hydrolyzed, the nucleic acid bases (with added internal standards, 5-iodouracil and 5-chlorouracil) are extracted into ethyl acetate, concentrated and derivatized with bis(trimethylsilyl)trifluoroacetamide. Thymine and BU are then quantitated by GC-MS-SIM. Response is linear to thymine over the range of 100-2000 ng per sample and BU of 1.3-52 ng per sample with a coefficient of variation of less than 10% and an accuracy for seeded samples within 8% of theoretical value. With V79 cells in culture, exposure to increasing BUDR concentrations (0.03-1.0 microM) results in increasing thymine substitution by BU over a range of 1-28%. Other important applications of this technique are mentioned.

Bromodeoxyuridine↗
PubMed1986

Evaluation of focal hepatic masses: a comparative study of MRI and CT.

We evaluated suspected hepatic lesions in 30 patients using both nongated spin-echo magnetic resonance imaging (MRI) on a 0.35 T superconducting magnet and contrast-enhanced dynamic incremental computed tomography (CT). In the 27 patients with focal lesions, both modalities detected abnormalities in 26 patients. Liver lesions were equally well demonstrated using MRI and CT in 15 patients, better demonstrated by CT in 11 patients, and better demonstrated by MRI in 1 patient. Small lesions (less than 2 cm) were much better demonstrated using CT than MRI; this was significant when knowledge of the precise extent of disease was necessary for planning surgical therapy or for evaluating response to chemotherapy. Five patients had significant extrahepatic disease detected by CT; MRI identified extrahepatic abnormalities in only 2 of these 5 patients. We conclude that at the current time CT is more useful than nongated spin-echo MRI in the evaluation of suspected hepatic masses.

Humans↗
PubMed1986

A dog model using an implanted system for protracted hepatic arterial chemotherapy.

A model for hepatic arterial chemotherapy studies using large dogs and an implantable infusion pump has been developed. Using this technique near complete perfusion (greater than 90%) of the liver can be achieved in vivo as determined by hepatic arterial perfusion scintigraphy with technitium 99m macroaggregated albumin. The system is reliable and has been in use for a total of 1353 days (mean of 104 days, range 52-239) in 13 dogs. Pump implantation causes no apparent acute liver damage based on pre- and post-operative alkaline phosphatase and serum glutamic-pyruvic transaminase determinations and does not affect the general mobility or behavior of the animals. Careful placement of the catheter and attention to the physicochemical properties of the solutions loaded are factors contributing to the success of the model. The model permits comprehensive preclinical pharmacokinetic and toxicologic studies of new or preexistent chemotherapeutic agents in the same device that will be used for later administration in human subjects. By providing the means to examine and develop new treatment modalities, it enables the design of even more potent cytotoxic therapy directed into the tumor vascular bed.

Animals↗
PubMed1986

Phase II study of hepatic arterial degradable starch microspheres and mitomycin.

Twenty four patients with incurable primary or metastatic liver cancer were treated with hepatic arterial Mitomycin C admixed with degradable starch microspheres (DSM). Six objective responses (25% PR) were obtained in this heavily pretreated population with advanced disease. The median response duration was 3.5 months. Hematologic toxicity was minimal as would be expected from the reduced systemic exposure generated by the increased regional drug deposition. An apparent chemical hepatic arteritis developed in five patients after multiple courses, however, its relationship to prior hepatic arterial infusion therapies, Mitomycin, starch microspheres, and repeated dosing of the drug-microsphere mixture remains unclear. The responses seen in this study are encouraging given the heavily pretreated population in which they were obtained. Studies delineating the relative contribution of DSM to both the response and the toxicities of hepatic arterial Mitomycin and other appropriate antineoplastic agents in the treatment of single tumor types are needed.

Adult↗
PubMed1986

Effects of intraventricular methotrexate on cerebrospinal fluid monoamine metabolites in rhesus monkeys.

Previous work suggested that methotrexate (MTX) may cause encephalopathy by inhibiting biosynthetic pathways for dopamine and serotonin in the brain. We examined this issue by measuring the neurotransmitter metabolites homovanillic acid and 5-hydroxyindoleacetic acid in the lumbar CSF of rhesus monkeys receiving continuous intracerebroventricular infusions of MTX or dichloromethotrexate. Infusion of the lowest dose (0.05 mg/day) produced a large (300%) rise in homovanillic acid levels and a modest elevation in 5-hydroxy-indoleacetic acid. During higher dose infusion, which was associated with clinical encephalopathy, the biogenic amine metabolites fell from their previous elevated levels. In one encephalopathic monkey, an injection of 1 mg of leucovorin produced a marked elevation in CSF monoamine metabolites within 1 hour and rapid clinical recovery. In contrast, leucovorin produced no change in monoamine metabolites in control animals. The data suggest that MTX may block egress of monoamine metabolites from CSF at the lower doses and suppress neurotransmitter turnover at toxic doses which cause encephalopathy. Serial measurements of CSF monoamine metabolites deserve further investigation as biochemical markers for toxic effects of MTX on neuronal metabolism in the CNS.

Animals↗
PubMed1986

Phase I-II evaluation of intra-arterial diaziquone for recurrent malignant astrocytomas.

Diaziquone (AZQ) is a lypophilic alkylating agent that crosses the blood-brain barrier and has shown broad activity in animal tumor models. Five of 12 patients with malignant astrocytoma treated with iv AZQ had clinical and/or radiographic improvement (Schold, Neurology 34:615, 1984). Intra-arterial administration of AZQ to patients with brain tumors should produce higher peak levels of drug in the tumor and should reduce systemic toxicity. Twenty-one patients with astrocytoma (grade II, four; grade III, 11; and grade IV, six), in all of whom irradiation and intra-arterial carmustine chemotherapy failed, received intra-arterial AZQ as a single dose every 28 days. Two of 20 evaluable patients experienced partial responses of 5 and 8+ months, respectively. Four patients had disease stabilization of 3, 4, 5, and 8 months' duration, respectively, and one of these patients had tumor shrinkage (partial response) after seven courses of AZQ. The initial dose in the first three patients was 10 mg/m2, and doses in subsequent groups of three patients were begun at increases of 5 mg/m2. The within-group dose escalation was 5 mg/m2 per course if there was no hematologic toxicity. Dose-limiting toxicity was myelosuppression, which occurred at doses greater than 15 mg/m2. The maximum tolerated dose was 25 mg/m2. Intra-arterial AZQ appears to be of marginal effectiveness in patients refractory to carmustine and offers no advantage over iv AZQ in efficacy or toxicity.

Adult↗
PubMed1986

Steady-state nonlinear pharmacokinetics of 5-fluorouracil during hepatic arterial and intravenous infusions in cancer patients.

Hepatic arterial catheters were placed for therapy in 8 patients with primary or metastatic liver cancer. Temporary hepatic venous catheters allowed direct sampling of blood for hepatic venous drug concentrations. Patients were administered from three to six infusions at rates of 10, 30, 90, 135, 180, 210, and 270 mg/kg/day (0.053 to 1.43 microM/kg/min), given over 2 h, of 5-fluorouracil (FUra). In Method 1, FUra was infused i.v., and FUra was measured in plasma from hepatic arterial and hepatic venous blood. In Method 2, FUra was given i.v. at one time and infused into hepatic arterial blood at another time, and FUra was measured in plasma from peripheral blood at the same site in both cases. Steady-state FUra plasma concentrations were measured by a sensitive and specific high-performance liquid chromatography method. Data were computer fitted to the equations appropriate for a physiological two-compartment flow model with Michaelis-Menten elimination from the peripheral compartment and blood flow rate, Q, between the central and peripheral compartment. Methods 1 and 2 gave mean Vmax and Km values which did not differ significantly; the overall mean Vmax was 2.02 microM/kg/min, and the overall mean Km was 10.9 microM. For Method 1 the mean Q1 value was 0.0803 liters/(kg X min) or 5.26 liters/min, which is the same as cardiac output, but for Method 2 the mean Q2 value was higher, namely 0.189 liters/(kg X min) or 13.0 liters/min. Steady-state systemic and intrinsic clearances and extraction ratios decreased progressively as the dose rate increased. Intra- and inter-subject variation of both Vmax and Km were of the same order of magnitude. As a result, dose rate escalation should be conservative for dose rates above 135 mg/kg/day. The results support hepatic arterial infusion as a means of improving the therapeutic index of FUra in the treatment of cancer of the liver.

Adult↗
PubMed1985

Atlas of hepatic arterial perfusion scintigraphy.

Tc-99m MAA intra-arterial perfusion studies are necessary to determine blood flow distribution for hepatic arterial chemotherapy. In this mini-atlas, examples selected from over 900 cases to illustrate important points to aid in a better understanding and interpretation of these studies with particular emphasis on diagnostic and therapeutic interventions are presented.

Humans↗
PubMed1985

Hepatic falciform artery: anatomy, angiographic appearance, and clinical significance.

Three patients developed supraumbilical skin rashes during hepatic artery infusion chemotherapy by a surgically placed perfusion catheter and drug-infusion pump. In one patient, hepatic arterial scintigraphy with technetium-99m macroaggregated serum albumin showed increased uptake corresponding to the rash, and a hepatic arteriogram showed a dilated falciform branch of the left hepatic artery. Surgical ligation of the falciform artery permitted further treatment without recurrent rash. Based on a review of 100 celiac arteriograms, the incidence of the falciform artery on angiographic studies is approximately 2%. The angiographic appearance of this artery is presented, and its potential clinical significance in hepatic artery perfusion chemotherapy is discussed.

Abdominal Muscles↗