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Biomedical subjects

R D Williams

Publications and source records attributed to R D Williams.

At least 127 records · Page 7Linked to original sources
PubMed1987

Recombinant alfa interferon in renal cell carcinoma: a randomized trial of two routes of administration.

Ninety-seven patients with recurrent or metastatic renal cell carcinoma were randomized to receive recombinant interferon (IFN) alfa-2b (Intron A; Schering-Plough, Kenilworth, NJ) by either the subcutaneous (SC) or intravenous (IV) route. The SC dosage was 2 X 10(6) IU/m2 three times weekly, and the IV dose 30 X 10(6) IU/m2 for five consecutive days every 3 weeks. Dose escalation to a maximum of 10 X 10(6) IU/m2 SC and 50 X 10(6) IU/m2 IV was allowed for patients with minimal or absent toxicity. Five of 51 of the SC-treated patients (10%) and three of 46 of the IV-treated patients (7%) had a partial response (PR) or complete response (CR). Patients with prior nephrectomy, no prior treatment, and lack of bone metastases were most likely to respond, and a retrospective analysis of this subgroup revealed a 23% response rate. Achievement of response took from 3 weeks to 11 months, while response duration lasted from 3 to 31+ months. All responders had prior nephrectomy; six of eight had no prior chemotherapy or hormonal therapy; five had lung metastases, and none had bone metastases. Regardless of route, almost all patients developed a flu-like syndrome; however, grade 3 or greater toxicity was much more common for IV-treated patients. This trial demonstrates modest, but definite antitumor activity for recombinant interferon in advanced renal cell carcinoma. SC administration with lower dose and toxicity is as effective as treatment administered IV.

Adult↗
PubMed1987

Inhibition of serine palmitoyltransferase activity in rabbit aorta by L-cycloserine.

Serine palmitoyltransferase (EC 2.3.1.50) initiates the biosynthesis of sphingolipids. Its activity is induced in the aortas of rabbits fed a Purina lab chow supplemented with 2% cholesterol (Williams, R. D., D. S. Sgoutas, and G. S. Zaatari. 1986. J. Lipid Res. 27: 763-770). Induction occurs during atherogenesis in parallel with increased arterial sphingomyelin concentrations. In this study, L-cycloserine was shown to be a potent inhibitor of serine palmitoyltransferase in aortas from New Zealand White rabbits. Activity was reduced in vitro by 50% using 5 microM L-cycloserine with 50 micrograms of microsomal protein. To assess in vivo inhibition, L-cycloserine was administered by intraperitoneal injection to rabbits maintained on either a standard Purina laboratory chow or one supplemented with 2% cholesterol. Serine palmitoyltransferase activity was inhibited by 76% in the aortas of rabbits on the standard chow 4 hr after a single 25 mg/kg body weight dose and 52% after a 10 mg/kg dose. Activity was reduced by 36% in animals on the standard chow and by 37% in the cholesterol-fed group after 1 week of daily doses. These experiments demonstrate that L-cycloserine inhibits serine palmitoyltransferase in aorta, and thus may be used to reduce sphingomyelin concentrations during experimental atherogenesis.

Acyltransferases↗
PubMed1987

Vasospastic exercise-associated unilateral leg ischemia: evaluation with thallium-201.

Thallium 201 (Tl-201) as a marker of regional tissue perfusion is described as a diagnostic aid in a case of exercise-induced vasospastic disease affecting the lower leg of a physically active young adult male who had no evidence of atherosclerotic disease. The success and failure of various therapeutic attempts made in behalf of this patient have been monitored by repeated Tl-201 administrations. Exercise-associated ischemia in tissues other than the myocardium can be investigated with Tl-201.

Adult↗
PubMed1986

Chronic renal failure: a significant risk factor in the development of acquired renal cysts and renal cell carcinoma. Case reports and review of the literature.

Three male patients with end-stage renal disease on chronic hemodialysis presented with gross hematuria and were subsequently found to have acquired renal cyst disease and progressive bilateral renal cell carcinoma. There are now more than 84 similar cases in the literature, but the precise roles that renal failure and hemodialysis play in the development of renal cysts and renal neoplasms remain unclear. The high incidence of acquired renal cyst disease (45%) and the development of renal tumors (9%, with a 5% to 7% metastatic rate) in patients with end-stage renal failure clearly underscores the need for more intense radiologic monitoring.

Adult↗
PubMed1986

Preoperative assessment of retroperitoneal pathology by magnetic resonance imaging. Primary leiomyosarcoma of inferior vena cava.

A woman with a retroperitoneal mass was found to have a leiomyosarcoma arising in the wall of the inferior vena cava. The extensive preoperative radiologic findings were compared with those of magnetic resonance imaging. The latter allowed a more precise preoperative diagnosis and determination of tumor origin and extent than any of the other diagnostic techniques.

Aged↗
PubMed1986

Assessment of renal preservation by phosphorus-31 magnetic resonance spectroscopy: in vivo normothermic blood perfusion.

To evaluate the usefulness of the monophosphate/inorganic phosphate ratio (MP/Pi) in assessing renal viability in a renal transplantation setting, we monitored intracellular phosphorous metabolites of 33 canine kidneys by phosphorus-31 magnetic resonance spectroscopy (MRS) after various amounts of ischemia. Renal viability (adequate perfusion and function) was directly assessed by the presence of intraoperative urine production in each kidney. Twelve normal, well-perfused kidneys (Group 1) exhibited high control MP/Pi ratios, with a mean of 0.87 +/- 0.12. Six in situ kidneys (Group 2), subjected to 45 minutes' warm ischemia followed by reperfusion, had a mean MP/Pi ratio of 0.50 +/- 0.12 after warm ischemia, which increased by a mean of 0.50 +/- 0.11 (to 1.0 +/- 0.07) after two to four hours of reperfusion. Fifteen kidneys (Group 3) were removed, cold-flushed and transplanted after 24 hours of hypothermic storage. In eight (Group 3A), reperfusion was excellent; in seven (Group 3B), reperfusion was inadequate secondary to hypotension in two, hemorrhage in two, and renal vein thrombosis in three. Group 3A kidneys had a mean MP/Pi ratio after cold-storage ischemia of 0.54 +/- 0.08. After successful transplantation and two to four hours of reperfusion, this increased by a mean of 0.23 +/- 0.12 to 0.77 +/- 0.15. Group 3B kidneys all showed a continuous decline of MP/Pi, with a mean loss of 0.26 +/- 0.09 from baseline values (mean 0.56 +/- 0.08) to nonviable levels of 0.28 +/- 0.12 within four hours of transplantation. We conclude that MP/Pi ratios enable assessment of renal viability and ischemic damage and can predict the efficacy of renal preservation maneuvers in the dog kidney. These preliminary data support the theory that MRS can be applied to the noninvasive assessment of viability in ex vivo, cold-stored cadaveric human kidneys awaiting renal transplantation.

Animals↗
PubMed1986

Assessment of renal viability by phosphorus-31 magnetic resonance spectroscopy.

To assess the applicability of phosphorus-31 magnetic resonance spectroscopy (31P-MRS) in the analysis of renal transplant viability and preservation techniques with respect to pre-transplant ischemia, we studied two rat groups. Twenty-five rat kidneys were subjected to various time increments of warm ischemia (Group A), and 31P-MRS was performed on each kidney at time intervals of up to 72 hours during simple hypothermic storage. We correlated findings of 31P-MRS with simultaneous findings of electron microscopic (EM) ultrastructural viability parameters (in Group A) and subsequent survival and renal function in 30 rats (Group B) subjected to similar amounts of variable ischemia. Intracellular phosphorus metabolite levels were nondestructively monitored by 31P-MRS via spectral peaks of NAD, sugar monophosphates (SP), and inorganic phosphate (Pi). We concluded: SP/Pi and NAD/Pi ratios decay in a time-dependent manner for both warm and cold ischemia, although this process is much slower during cold storage; EM viability parameters correlate with the development of acute tubular necrosis (irreversible damage) versus nonviability (gross cell death) on a qualitative basis only; and 31P-MRS enables a quantitative assessment of renal viability and ischemic renal damage and can predict the degree of acute tubular necrosis and post-ischemic renal function. 31P-MRS is potentially a noninvasive, nondestructive method of assessing viability during simple hypothermic storage of the rat kidney. Preliminary evidence shows that this MRS method can be applied to human kidney viability studies for clinical renal transplantation and urologic research concerning renal preservation.

Animals↗
PubMed1986

Diagnostic tests for impotence: a comparison of papaverine injection with the penile-brachial index and nocturnal penile tumescence monitoring.

The diagnostic usefulness of nocturnal penile tumescence monitoring, penile-brachial index and intracorporeal injection of papaverine (60 mg. in 20 ml. normal saline) was compared in 43 impotent men. Intracorporeal pressure was measured with a pressure transducer. Based on turgidity, and the time of onset and duration of erection, we classified the impotence as psychogenic/neurogenic (normal vascular competence), mild or severe arteriogenic, or venogenic. The intracorporeal injection of papaverine was useful as a functional diagnostic test for impotence. The penile-brachial index, an indirect measurement of the flaccid penis, did not correlate well with the results of the papaverine test. A poor response to papaverine injection documents organic impotence and, under these circumstances, nocturnal penile tumescence monitoring is not necessary. We conclude that the intracorporeal injection of papaverine currently is the best screening technique for the differential diagnosis of vasculogenic impotence.

Adult↗
PubMed1986

Pathogenesis of hypercalcemia in nude mice bearing a human renal carcinoma.

When grown as sc tumors in the nude (nu/nu) mouse, cells of the established human renal carcinoma cell line 786-0 produce hypercalcemia; this has an apparent humoral basis because it is reversed by resection of the primary tumor. We have investigated the pathogenesis of hypercalcemia in this model. Tumor-bearing mice were hypercalcemic (13.4 +/- 0.9 vs. 9.52 +/- 0.13 mg/dl in control mice) and hypophosphatemic (10.0 +/- 0.8 vs. 13.8 +/- 1.5 mg/dl in control mice; all values are mean +/- SEM). The serum concentration of 1,25-dihydroxyvitamin D was increased in tumor-bearing animals (70.0 +/- 9.3 vs. 43.8 +/- 4.8 pg/ml in control animals). Urinary excretion of cAMP was similar in control (33.7 +/- 1.4 nmol/mg creatinine) and tumor-bearing mice (38.2 +/- 4.7 nmol/mg creatinine). However, in the latter, the acute response of urinary cAMP to PTH was blunted. Although intestinal calcium transport in everted duodenal sacs in vitro was increased in tumor-bearing mice, hypercalcemia was unaffected by feeding the animals for 8 days a diet containing less than 0.02% calcium. Hence, absorption of dietary calcium did not play a significant role in maintenance of hypercalcemia. In hypercalcemic animals, the calcium content of the humerus was decreased (2.95 +/- 0.08 vs. 3.29 +/- 0.13 mg in controls; P less than 0.05). Quantitative histomorphometric analysis of the distal femoral metaphysis disclosed a significant reduction in trabecular bone volume in tumor-bearing mice (12.0 +/- 1.1% vs. 16.1 +/- 1.1% in controls; P less than 0.02). A strong trend for increased osteoclast surface and number was observed, suggesting that bone resorption was increased. Osteoblast surface and number were also somewhat increased, as was the rate of mineral apposition (2.55 +/- 0.14 vs. 1.91 +/- 0.04 micron/day in controls; P less than 0.01). Thus, the decrease in trabecular bone volume was associated with high turnover of bone, with an apparent net increase in bone resorption. We conclude that hypercalcemia in the nude mouse bearing human renal carcinoma cells is associated with increased bone resorption, high bone turnover, hypophosphatemia, and increased serum levels of 1,25-dihydroxyvitamin D.

Adenocarcinoma↗
PubMed1986

Photodynamic therapy of bladder carcinoma.

Photodynamic therapy for bladder cancer is an intriguing modality with theoretical potential for successful treatment of visible tumor and areas of carcinoma in situ and dysplasia throughout the bladder mucosa. There remain many unanswered determinations about photodynamic therapy, including the most effective photosensitizer, the dose of laser that should be used, and the optimum timing for laser therapy following the injection of photosensitizer. Nonetheless, clinical studies thus far have shown photodynamic therapy to have efficacy in eradicating superficial noninvasive tumors. Treatment of diffuse carcinoma in situ at present appears the most impressive. Prospective studies designed to examine photodynamic therapy in a standardized protocol in comparison with other conventional methods for treatment and prophylaxis of noninvasive bladder cancer are most needed and are currently in progress. In the future, development of alternate photosensitizers or methods of direct intravesical uptake of DHE, perhaps limiting cutaneous phototoxicity, are expected.

Fluorescence↗
PubMed1986

Enzymology of long-chain base synthesis by aorta: induction of serine palmitoyltransferase activity in rabbit aorta during atherogenesis.

Serine palmitoyltransferase [EC 2.3.1.50] initiates the biosynthesis of sphingolipids by catalyzing the condensation of a fatty acyl-CoA with serine to yield the committed intermediate 3-ketosphinganine or one of its homologues. The presence of serine palmitoyltransferase in aorta was established under optimal assay conditions using microsomes from New Zealand White rabbits. Its activity was dependent on microsomal protein, L-serine, pyridoxal 5'-phosphate, and palmitoyl-CoA. Although several different saturated and unsaturated fatty acyl-CoA thioesters were utilized as substrates, maximal activity was with palmitoyl-CoA, suggesting that this enzyme contributes to the predominance of 18-carbon long-chain bases in sphingolipids from aorta. Rabbits, fed a Purina lab chow supplemented with 2% cholesterol, were used to study serine palmitoyltransferase activity in aorta during experimental atherogenesis. An increase in activity from intimal-medial preparations was detectable prior to prominent lipid accumulation or cellular proliferation. Activity continued to elevate over the 12-week duration of feeding concurrent with the increase in serum cholesterol and in proportion to the development of plaques resulting in a 3.7-fold increase in activity (20.7 +/- 2.6 pmol per min per mg microsomal protein +/- SE in the cholesterol-fed group versus 5.6 +/- 1.9 in the pair-fed controls also matched for age and sex; P less than 0.005). Thus, the accumulation of sphingomyelin that occurs in aorta during experimental atherogenesis may be related to increased long-chain base synthesis by serine palmitoyltransferase.

Acyltransferases↗
PubMed1985

A randomized study of doxorubicin versus doxorubicin plus cisplatin in endocrine-unresponsive metastatic prostatic carcinoma.

Thirty-seven patients with hormonally refractory prostatic carcinoma entered a randomized trial comparing doxorubicin and doxorubicin plus cisplatin. All patients had failed prior hormonal treatment. Mean Karnofsky performance status (76% doxorubicin versus 75% combination), percent of patients with prior palliative irradiation (40% doxorubicin versus 35% combination), and hemoglobin levels of less than or equal to 12 g/dl (30% doxorubicin versus 24% combination) were roughly equivalent in the two treatment groups. More patients treated with doxorubicin than the combination treatment had an elevated acid phosphatase level at study entry (90% versus 65%). Measurable bidimensional tumors were present in 13 patients in 16 sites in the doxorubicin arm and in 10 patients in 11 sites in the combination arm. Partial responses were seen in 1 of 13 patients in the doxorubicin arm and 2 (20%) of 10 patients in the combination arm. Improvement in Karnofsky performance status of 20% or greater was rarely observed with either treatment (7% doxorubicin versus 8% combination). Acid phosphatase levels normalized or improved by 50% in 39% of patients who received doxorubicin and 27% of patients who received the combination. The overall response rate by National Prostatic Cancer Project Criteria was 53% for doxorubicin and 59% for doxorubicin plus cisplatin. Myelotoxicity and gastrointestinal toxicity were severe, particularly in the combination arm, and required discontinuation of treatment in some patients who responded to treatment. Moderate renal dysfunction (creatinine value 2.0-3.0 mg/dl) occurred only in the combination arm at an incidence of 23%. Time to progression and survival were similar for the two treatment groups. In this small group of 37 patients, the combination of cisplatin and doxorubicin showed no improvement over doxorubicin alone in response, response duration, or survival, and was difficult to administer in this patient population.

Adenocarcinoma↗
PubMed1985

Enhanced MRI of tumors utilizing a new nitroxyl spin label contrast agent.

Nitroxyl spin labels have been shown to be effective in vivo contrast agents for magnetic resonance imaging (MRI) of the central nervous system, myocardium, and urinary tract. A new pyrrolidine nitroxyl contrast agent (PCA) with better resistance to in vivo metabolic inactivation than previously tested agents was studied for its potential to enhance subcutaneous neoplasms in an animal model. Twenty-two contrast enhancement trials were performed on a total of 15 animals 4-6 weeks after implantation with human renal adenocarcinoma. Spin echo imaging was performed using a .35 T animal imager before and after intravenous administration of PCA in doses ranging from 0.5 to 3mM/kg. The intensity of tumor tissue in the images increased an average of 35% in animals receiving a dose of 3 mM/kg. The average enhancement with smaller doses was proportionately less. Tumor intensity reached a maximum within 15 min of injection. The average intensity difference between tumor and adjacent skeletal muscle more than doubled following administration of 3 mM/kg of PCA. Well-perfused tumor tissue was more intensely enhanced than adjacent poorly perfused and necrotic tissue.

Animals↗
PubMed1985

Improved continuous flow transurethral prostatectomy.

We compared 2 continuous flow resectoscopes for transurethral resection of the prostate--a new intrinsic bladder pressure-controlled drainage system and the suction drainage system. In 31 patients undergoing transurethral prostatic resection who were assigned randomly to a pressure-controlled (17) or suction drainage (14) resectoscope group the required irrigant volume and operative blood loss (milliliter per gram resected tissue) were appreciably less with pressure-controlled drainage, while the resection rate (gram per minute) was significantly greater. Irrigant absorption, as evidenced by weight gain and changes in hematocrit, serum osmolality and serum sodium, was minimal in either group, with no significant difference between the 2 methods. In addition, there was no significant difference in intraoperative intravesical pressure between the 2 groups. The suction drainage system led to pump drainage failure in certain rotational positions, resulting in diminished visibility and increased resection time. The pressure-controlled drainage system required no suction devices or adjustments, thus, allowing constant improved visibility and uninterrupted resection. These results suggest that the efficiency and ease of transurethral prostatic resection are superior with the pressure-controlled continuous flow drainage system than with the suction drainage system.

Drainage↗
PubMed1985

Incidental carcinoma of the prostate: significance of staging transurethral resection.

We compared the results of staging by a second circumferential transurethral resection and/or transperineal needle biopsy in 42 patients with stage A prostatic adenocarcinoma on initial transurethral resection (defined as tumor of low grade, Gleason sum 2 to 4, and low volume, less than 5 per cent of the specimen or less than 3 foci). Transurethral resection only was done in 16 patients, transperineal needle biopsy only in 2 and both procedures in 24. In the 24 patients who underwent both procedures residual carcinoma was identified by transurethral resection in 6 and confirmed by transperineal needle biopsy in only 1. Thirty-two patients (76 per cent) had no residual carcinoma. Of the 10 patients (24 per cent) with residual carcinoma 5 underwent radical prostatectomy with pelvic lymphadenectomy, 1 had interstitial irradiation with pelvic lymphadenectomy and 1 had pelvic lymphadenectomy only. No lymphatic metastases were detected; persistent carcinoma confined to the prostate was noted in all 5 patients who had undergone radical prostatectomy and 3 of these tumors were upstaged because of higher grade and/or volume. We conclude that residual carcinoma cannot be assessed accurately with transperineal needle biopsy, whereas transurethral resection staging enabled us to define a substantial number of our patients (24 per cent) with persistent disease. Importantly, upstaging by either low volume/high grade or high volume carcinoma was identified in 3 patients at the time of radical prostatectomy. However, the true stage and prognosis of those patients with persistent low volume and low grade prostatic carcinoma remain to be determined.

Adenocarcinoma↗
PubMed1985

Magnetic resonance imaging in the diagnosis and staging of renal and perirenal neoplasms.

Thirty-one adult patients underwent magnetic resonance (MR) imaging after CT scans had demonstrated findings consistent with renal cell carcinoma. MR images were interpreted prospectively and independently of the CT findings. Because the CT scanning was performed at multiple institutions by many examiners, this study was not a direct comparison of CT versus MR. The preoperative diagnoses and staging of the neoplasms, as judged by MR, were compared with those obtained at laparotomy (n = 28), autopsy (n = 1), or biopsy (n = 2). Correct preoperative diagnoses were rendered in 31 patients (100%) on the basis of MR findings. The anatomic staging of 27 renal cell carcinomas was correctly performed by MR in 26 patients (86%). When compared with results of previous studies of the value of CT in the diagnosis and staging of renal neoplasms, MR appears to have several advantages in determination of the origin of the mass; the evaluation of vascular patency; the detection of perihilar lymph node metastases; and the evaluation of direct tumor invasion of adjacent organs. MR is sensitive in determining the extent of tumor thrombus and in evaluating invasion of the inferior vena caval wall. MR should assume an important role in the diagnosis and staging of renal neoplasms.

Adult↗
PubMed1985

Human transforming growth factor-alpha stimulates bone resorption in vitro.

Tumor-derived transforming growth factors (TGF) have been proposed as possible mediators of hypercalcemia in malignancy. We have studied the action of recombinant human TGF-alpha in cultured bone cells and in bone explant cultures. In clonal UMR-106 rat osteosarcoma cells, TGF-alpha and epidermal growth factor (EGF) were equipotent in binding to the EGF receptor. TGF-alpha and EGF both stimulated resorption of neonatal mouse calvaria, and maximal responses were obtained with 10 ng/ml of TGF-alpha after 72 h in culture. The effects of both TGF-alpha and EGF in calvaria, but not those of parathyroid hormone, were inhibited by 5 X 10(-7) M indomethacin. Fetal rat limb bone cultures were less sensitive to TGF-alpha than neonatal mouse calvaria, with a concentration of 30 ng/ml being required to stimulate resorption in this system. The bone-resorbing activity of TGF-alpha in fetal rat bones was inhibited by 10 ng/ml calcitonin but not by 5 X 10(-7) M indomethacin. EGF at concentrations up to 300 ng/ml did not stimulate resorption of the limb bones at time periods up to 66 h. The results indicate that human TGF-alpha is a potent bone-resorbing agent, and support the concept that this growth factor exhibits some effects distinct from those of EGF. TGF-alpha could play an etiologic role in the hypercalcemia of malignancy.

Animals↗