PubMed Health⌕ Search

Biomedical subjects

W D Ensminger

Publications and source records attributed to W D Ensminger.

At least 91 records · Page 5Linked to original sources
PubMed1985

The utility of SPECT for 99mTc-MAA hepatic arterial perfusion scintigraphy.

The utility of single-photon emission computed tomography (SPECT) for hepatic arterial perfusion scintigraphy was evaluated in 86 patients (91 studies). Previous reports have shown planar studies to be valuable for the clinical management of patients receiving intraarterial chemotherapy and more reliable than angiography in determining blood flow distribution. However, overlying areas of intra- and extrahepatic perfusion can sometimes make interpretation of these two-dimensional images difficult. Since SPECT has the potential to depict the three-dimensional distribution of perfusion, separate out overlying activity, and improve contrast resolution, SPECT Tc-MAA perfusion studies were compared to planar studies. Planar and SPECT studies both demonstrated the extent of hepatic and tumor perfusion, although occasionally SPECT added additional information. SPECT was most useful in confirming or excluding extrahepatic perfusion that was suspected but not definite on planar studies. Extrahepatic abdominal perfusion was found to be present in 11 (12%) of 91 studies. All patients with confirmed extrahepatic perfusion who received intraarterial chemotherapy had symptoms of drug toxicity compared to only a 23% incidence in those without evidence of extrahepatic perfusion (p less than 0.001). This report demonstrates that SPECT can improve the qualitative interpretation of hepatic arterial perfusion studies.

Adult↗
PubMed1985

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

Intraarterial administration of 40-microns degradable starch microspheres (DSM) in a drug solution can temporarily retard flow of the drug-blood column through the arteriolar-capillary bed and lead to increased local drug deposition. Premonitory to Phase II-III efficacy studies applying this concept to regional therapy, it was necessary to determine the DSM dose to use. Patients with hepatic cancers were treated with varying doses of DSM with mitomycin C coadministered into the hepatic artery to define a dose of DSM which produces acceptable toxicity with maximal hepatic drug deposition as determined by a reduction in systemic mitomycin C exposure. Comparison of six patients receiving 6 ml of DSM (6 X 10(6) particles/ml) with ten patients receiving 15 ml showed a lower incidence and decreased severity of acute toxicity in terms of nausea/vomiting (16% versus 50%) and right upper quadrant hepatic pain (none versus 40%) with 6 ml of DSM. Reduction in systemic mitomycin C exposure evaluated by decrements in the area under the concentration curve in peripheral blood with time due to DSM was similar in both groups. Another seven patients were treated with escalating doses of DSM concurrently with 5 mg of mitomycin C. Although all seven patients tolerated 6 ml of DSM, higher doses (9 ml, 12 ml, 15 ml) led to incremental patient drop-out due to severe, acute right upper quadrant pain with only two patients able to receive 15 ml of DSM. In these patients, 6 ml of DSM appeared nearly equivalent to higher doses in terms of systemic exposure to mitomycin C. Eleven additional patients were evaluated for tolerance to repeated 6-ml dosing of DSM. Four patients had epigastric pain correlating with flow to the stomach demonstrated by nuclide angiography. The seven patients with no pain and no flow to stomach were treated with good tolerance for three-plus courses. Thus, 6 ml of DSM appear to be appropriate for Phase II-III studies.

Adult↗
PubMed1984

A totally implanted injection port system for blood sampling and chemotherapy administration.

We evaluated a totally implanted system consisting of a subcutaneous injection port connected to a silicone elastomer central venous catheter for vascular access, including blood drawing, in 35 patients with cancer. All patients lacked peripheral venous access sites and were undergoing aggressive chemotherapy programs. The cumulative duration of successful access exceeded 2,900 days (for individual patients: range, five to 203 days; median, 61 days). In no instance were infusions or injections unsuccessful. Blood-sampling attempts were successful 90% of the time. The system did not require flushing between uses, being filled with heparinized saline after each entry. There were no instances of irreversible catheter occlusion or shear and no system-related infections. Thus, this device appears to have advantages over other central venous catheters in terms of patient acceptance and lack of maintenance between uses.

Adolescent↗
PubMed1984

Constant intraperitoneal 5-fluorouracil infusion through a totally implanted system.

Five-day continuous intraperitoneal (ip) infusions of 5-fluorouracil (FU) were injected into five patients as part of a phase I clinical pharmacology study. They received 20 courses through a totally implanted catheter/injection port system. Six courses are evaluable for kinetic parameters and all courses are evaluable for toxicity. In each course a 2 to 3 log FU concentration differential in favor of the peritoneal cavity was achieved and maintained. Steady-state venous plasma FU concentrations averaged 0.34 microM, whereas steady-state ip FU concentrations averaged 697 microM. Mean total body clearance (TBC) in these patients was 18.4 l/min and mean permeability-area (PA) product for diffusion from the peritoneum was 13.7 ml/min. Mean TBC of 20 l/min with ip FU infusion was observed in one patient who also received a 24-hr IV FU infusion for comparison. The TBC during the later infusion was 5.9 l/min. In this patient, calculations indicate 75% extraction of drug during the passage from the peritoneum to the systemic circulation, presumably representing in large part hepatic extraction of FU taken into the portal venous circulation. Ip constant infusion and bolus kinetics were compared in one patient. TBC for the ip bolus was 14.3 l/min, which was approximately half of the TBC of 29.5 l/min determined during the 5-day constant ip infusion. Thus constant ip infusion of FU (l gm/day) can provide an improved regional advantage over bolus ip FU because of an increased TBC. Toxicity was acceptable in all courses. Dose limiting toxicity was regional, namely moderate chemical peritonitis seen in two of the five patients on repeated courses. There was no myelosuppression, alopecia, nausea, or vomiting.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1984

Hepatic arterial perfusion scintigraphy with Tc-99m-MAA. Use of a totally implanted drug delivery system.

Tc-99m-MAA hepatic arterial perfusion scintigraphy ( HAPS ) using a totally implanted drug delivery system was employed for hepatic arterial chemotherapy in 147 patients (335 studies). Complete perfusion of the involved liver was seen in 88% of patients initially [more so in those with normal hepatic vascular anatomy (93%) than those with vascular variants (79%)] and remained good on follow-up. In 67 consecutive patients (95 studies), arteriovenous shunting to the lung ranged from 0.4 to 32% (mean, 6.2% +/- 4.1 S.D.). Uptake at the tip of the catheter was increased in 20% of patients, but good perfusion was usually maintained. A significant decrease in hepatic and/or extrahepatic perfusion associated with a "hot spot" at the tip of the catheter indicated hepatic arterial thrombosis. Extrahepatic perfusion was seen in 14% of cases, usually in the distribution of the stomach, small bowel, and spleen. Significant symptoms of drug toxicity were seen in 70% of patients with extrahepatic perfusion, compared to 19% of those without it.

Adult↗
PubMed1984

BCNU solubility and toxicity in the treatment of malignant astrocytomas.

Administration of BCNU into the carotid artery as treatment for malignant astrocytomas has produced retinal and brain toxicity. It is unclear whether the BCNU diluent, ethanol, is the cause of the toxicity, but the elimination of the ethanol is an attractive possibility. Clinically, decreasing the ethanol from 2.0 ml/100 mg BCNU to 0.75 ml/100 mg BCNU resulted in a marked decrease in eye toxicity. To simulate this clinical situation, three 500-mg solutions of BCNU, ethanol, and saline were prepared, decreasing the ethanol concentration from 3.0 ml to 2.0 ml to 0.75 ml/100 mg BCNU. The amount of BCNU recovered in vitro after simulated clinical administration of the three solutions decreased from 84.9% to 38.3% as the diluent decreased. Therefore, drug delivery at a fixed BCNU dose will decrease with the amount of ethanol diluent used. The clinical decrease in eye toxicity must be partly attributed to a decrease in the amount of BCNU delivered to the retina. Simulated administration of a solution of 500 mg BCNU/150 ml of 5% dextrose in water (D5W) gave 83.7% BCNU recovery. The D5W gives solubility comparable to that provided by 3.0 ml ethanol to each 100 mg BCNU, and its use eliminates ethanol as a potential retinal and brain toxin.

Astrocytoma↗
PubMed1984

Intra-arterial BCNU chemotherapy for treatment of malignant gliomas of the central nervous system.

Because of the rapid systemic clearance of BCNU (1,3-bis-(2-chloroethyl)-1-nitrosourea), intra-arterial administration should provide a substantial advantage over intravenous administration for the treatment of malignant gliomas. Thirty-six patients were treated with BCNU every 6 to 8 weeks, either by transfemoral catheterization of the internal carotid or vertebral artery or through a fully implantable intracarotid drug delivery system, beginning with a dose of 200 mg/sq m body surface area. Twelve patients with Grade III or IV astrocytomas were treated after partial resection of the tumor without prior radiation therapy. After two to seven cycles of chemotherapy, nine patients showed a decrease in tumor size and surrounding edema on contrast-enhanced computerized tomography scans. In the nine responders, median duration of chemotherapy response from the time of operation was 25 weeks (range 12 to more than 91 weeks). The median duration of survival in the 12 patients was 54 weeks (range 21 to more than 156 weeks), with an 18-month survival rate of 42%. Twenty-four patients with recurrent Grade I to IV astrocytomas, whose resection and irradiation therapy had failed, received two to eight courses of intra-arterial BCNU therapy. Seventeen of these had a response or were stable for a median of 20 weeks (range 6 to more than 66 weeks). The catheterization procedure is safe, with no immediate complication in 111 infusions of BCNU. A delayed complication in nine patients has been unilateral loss of vision secondary to a retinal vasculitis. The frequency of visual loss decreased after the concentration of the ethanol diluent was lowered.

Adult↗
PubMed1984

Definition of hepatic tumor microcirculation by single photon emission computerized tomography (SPECT).

Single photon emission computerized tomography coupled with Tc-99m MAA hepatic-arterial perfusion scintigraphy has been used to examine the density of the functional microcirculation of hepatic tumors relative to normal liver in 24 patients. In both colorectal and carcinoid tumors we have demonstrated an average three-fold greater arteriolar-capillary density in areas of tumor proliferation. The depth of the evoked tumor hypervascularity was found to extend about 4 cm. Tumors greater than 8-9 cm in diameter were uniformly found to have a central hypovascular core. These observations are of importance in the design of selective strategies utilizing therapeutic microspheres directed against the hypervascular proliferating regions of human tumors.

Adult↗
PubMed1984

Regional cancer chemotherapy.

Regional cancer chemotherapy is a means of exploiting dose-response effects by delivering more drug to regionally confined tumors. Regional chemotherapy can be divided into two major categories, third-space (cerebrospinal, peritoneal, pleural, and pericardial fluid) and intra-arterial treatments. Interest in regional chemotherapy has risen recently for a variety of reasons, including evidence for significantly higher response rates compared to systemic therapies. The applicable pharmacokinetic principles for drug selection have been defined and indicate that regional drug exposure advantage is directly proportional to total-body drug clearance and is inversely proportional to rate of egress from a third-space or to regional blood flow. Reliable drug delivery to the entire region in question is important. The recently introduced totally implanted devices (pumps and ports) make regional therapy more reliable, safe, and convenient. In addition, nuclear medicine scanning techniques have proven useful in assessing drug distribution with regional delivery. Regional therapy may control regional tumor, but extraregional failure may ensue. However, when regional therapy is regionally selective in its toxic effects, systemic therapy may be combined in full doses. Future efforts will need to focus on the development of more potent regional therapies, alone and in combination with systemic therapies, as well as on the validation of such treatments through controlled clinical trials.

Antineoplastic Agents↗
PubMed1983

Intensive sequential chemotherapy with bleomycin, Oncovin, mitomycin C, and methotrexate followed by adriamycin, cisplatin, and cyclosphosphamide in squamous cell cancer of the head and neck.

Twenty-six patients with advanced squamous cell cancer of the head and neck were treated with bleomycin, Oncovin, mitomycin C, and methotrexate (BOMM) for ten weeks. Partial and nonresponders then received adriamycin, cisplatin, and cyclophosphamide (APC) in a planned sequential program. The response rate to BOMM was 65% (19% complete remission, CR). The overall response rate to APC was 20%. Only three of eight nonresponders to BOMM could receive APC and non responded. Six of seven partial responders received APC and only one responded. One complete responder to BOMM received APC at relapse and attained a partial response. The major side effects of BOMM were mucositis and myelosuppression. Patients receiving methotrexate 60-72 hours following the bleomycin infusion had less myelosuppression than patients who were treated 36-42 hours after bleomycin. The toxicities with APC included nausea, vomiting, and myelosuppression. Including a prior series, a total of 45 patients have been treated with BOMM with a 71% response rate (69% in previously irradiated patients). Twenty-eight percent of previously treated patients achieved complete remission, and two of these patients are disease free at 31 and 37 months. Methotrexate dose-rate alteration to low dose twice weekly followed by a single dose of oral leucovorin did not improve the complete or partial response rate when compared to weekly methotrexate administration. The complete remission rate and response duration were also not improved by the planned sequential use of this cisplatin-containing regimen.

Adult↗
PubMed1983

Regional chemotherapy of neoplastic diseases.

Recent developments have made regional chemotherapy a more rational endeavour. The important pharmacokinetic principles have been defined. The increase in regional exposure achieved is a direct function of a drug's total body clearance and is an inverse function of the permeability-area product (defining ease of egress) for third spaces or of the regional arterial blood flow for intraarterial infusion. Agents having appropriate properties are available. For new agents with appropriate pharmacokinetic parameters, regional chemotherapy may provide a means to examine the dose response against measurable tumors in the regions in question. The observation that most tumors are hypervascular may be crucial to the development of selective treatments using microspheres to deliver therapy in direct proportion to the density of the microvasculature. Regionally infused vasoconstrictors (epinephrine, angiotensin) may allow shunting of flow away from normal tissue toward tumor without potentially serious systemic cardiovascular effects. Investigations and applications of regional chemotherapy have been fostered immensely by the reliably and convenience of the Infusaid implantable pump and by implantable injection ports. The problem of systemic failure with regional approaches still remains but is approachable using pharmacologically rational programs aimed at delivering maximal systemic chemotherapy along with regional treatment. In hepatic arterial therapy, in particular, a randomized prospective study is being considered to examine the impact of such combined treatment versus regional therapy alone and versus systemic chemotherapy alone for metastatic colorectal cancer to liver. Thus, the future for regional chemotherapy appears exciting. There are many opportunities to apply therapeutic principles rationally with the potential of significant benefit to many patients.

Animals↗
PubMed1983

Improved regional selectivity of hepatic arterial mitomycin by starch microspheres.

Biodegradable starch microspheres, 40 microns in diameter, were administered through hepatic arterial catheters in 16 subjects with primary and metastatic liver tumors. These microspheres temporarily obstruct blood flow at the precapillary arteriole (microcirculation) level. Our study was undertaken to determine whether such occlusion would enhance hepatic deposition of, and thereby decrease systemic exposure to, simultaneously administered hepatic arterial mitomycin C (mito). When mito (10 mg/m2 over 1 min) was given with 90 X 10(6) microspheres (10 subjects), there was a 17% to 70% reduction in systemic mito exposure. When mito (10 mg/m2 over 1 min) was given with 36 X 10(6) microspheres (six subjects), there was a 15% to 60% reduction in systemic exposure, which may correlate with dose-dependent shunting (8% to 29%) through the liver to the lung (and hence to the systemic circulation), attributed to the starch microspheres. No life-threatening myelosuppression was noted; hepatic toxicity consisted of transient pain and elevation of liver enzymes.

Adult↗
PubMed1983

Hepatic arterial streptozocin: a clinical pharmacologic study in patients with liver tumors.

Hepatic arterial infusions of streptozocin (STZ) were compared with peripheral venous infusions administered for 3 h at a dose rate of 0.5 or 1.0 g/m2 . h in five patients with liver-predominant neoplastic disease. Peripheral venous plasma STZ levels were measured during and for 3 h after completion of all infusions. Steady-state was achieved at 2 h and the elimination half-life was 35-40 min, the total body clearance was 400 ml/min, and the volume of distribution of STZ was 20-22 liters in these patients. Comparison of steady-state drug levels demonstrated minimal hepatic extraction (mean 5%). Assuming a hepatic arterial blood flow of 100-200 ml/min with a total body clearance of 400 ml/min, hepatic arterial administration of STZ can be expected to result in a three- to sixfold greater exposure of tumor in the liver compared with the intravenous route. Toxicity was minimal and two patients had evidence of response.

Adult↗
PubMed1983

Quantitative hepatic arterial perfusion scintigraphy and starch microspheres in cancer chemotherapy.

Hepatic arterial infusion chemotherapy results in a higher concentration of drug delivered to the tumor with less systemic exposure than is possible with intravenous therapy. However, extrahepatic blood flow and/or shunting to the lung can impose a limitation. This study describes a quantitative method for calculating the extrahepatic component and monitoring its changes due to a new adjunctive therapy, degradable starch microspheres (DSM). DSM temporarily occlude the hepatic arterial circulation, thereby increasing the uptake of therapeutic drugs. Twenty patients with metastatic liver cancer underwent hepatic arterial perfusion scintigraphy (HAPS) using Tc-99m MAA to determine blood-flow distribution and to quantitate extrahepatic uptake. The percent shunt index (PSI) was determined at baseline and after each incremental dose of DSM. The baseline PSI ranged from 6-26% (mean 12.3 +/- 5.8 s.d.) and changed progressively after each injection of DSM/Tc-MAA suspension. The patterns of change in shunting are described. Quantitative HAPS provides a means of measuring the extrahepatic component, warns of potential side effects, and helps guide chemotherapeutic decisions.

Adult↗