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Biomedical subjects

J W Gyves

Publications and source records attributed to J W Gyves.

At least 19 recordsLinked to original sources
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

CT evaluation of extrahepatic disease in patients with metastatic colorectal carcinoma receiving hepatic arterial chemotherapy.

Computed tomography (CT) of the abdomen and pelvis in 88 patients with hepatic metastases from colorectal carcinoma undergoing hepatic arterial chemotherapy has been reviewed. Extrahepatic disease was present as determined by CT examination in 83 (94%). Tissue proof was available for 23 sites in 19 patients, with the most common sites being retroperitoneal lymph nodes (5), lung (3), abdominal wall (3), and peritoneum or mesentery (3). Clinical proof was obtained for 78 sites in 51 patients, the most common being lung (20), retroperitoneal lymph nodes (19), and porta hepatis lymph nodes (12). CT detection of extrahepatic disease is useful, since its presence has prognostic and therapeutic implications.

Antineoplastic Agents↗
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

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 cavernous hemangioma: magnetic resonance imaging. Work in progress.

Using a 0.35-T superconducting magnet and spin echo imaging, we prospectively evaluated 11 patients who had proved hepatic cavernous hemangioma. Magnetic resonance (MR) identified more lesions than either contrast-enhanced CT, or ultrasonography. The MR appearance was consistent; hemangiomas were homogeneous and generally isointense at short TR and TE intervals but were hyperintense at long TR intervals and greatly hyperintense at long TR and long TE intervals. However, the MR appearance of hemangioma was not specific; 2/14 other focal hepatic masses had similar features. The calculated relaxation times (T1, T2) were not useful in lesion characterization, although the intensity ratio of hemangioma to normal liver at the TR = 2.0 sec TE = 56 msec pulse sequence was useful in diagnosis since hemangiomas always had a ratio greater than 1.4.

Adult↗
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↗
PubMed1985

Gastroduodenal ulcerations in patients receiving selective hepatic artery infusion chemotherapy.

Ninety-three patients with liver metastases underwent selective hepatic arterial infusion of chemotherapeutic agents through a surgically implanted hepatic artery catheter and pump. Fourteen patients who developed upper gastrointestinal symptoms at some time during the course of treatment were found to have gastroduodenal disease endoscopically. The severity of symptoms did not necessarily correlate with severity of endoscopic findings. There was no temporal relation between 5-fluoro-2'-deoxuridine infusion and symptoms; however, with mitomycin C, symptoms worsened in five of eight patients within 2 wk of the initial injection. Patients who received mitomycin C had more severe endoscopic findings and two of the 14 patients required partial or total gastrectomy. When biodegradable starch microspheres were coadministered with mitomycin C this was not associated with a higher incidence of gastroduodenal disease. The early experience with therapy using this system has been associated with a significant incidence of upper gastrointestinal symptoms. The presence of gastrointestinal symptoms in such patients should alert one to potentially serious disease.

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

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

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↗