Search PubMed⌕ Search

Biomedical subjects

W H Miller

Publications and source records attributed to W H Miller.

At least 91 records · Page 5Linked to original sources
PubMed1995

Some implications of managed care for physician assistants.

The American health industry is now focusing on managed care, capitated payment, and the formation of regional networks. As a result, additional cost constraints in the delivery of our nation's health services should be expected. Such proposals are also anticipated to have a major impact on PAs: (a) there will be an increased demand for qualified PAs to provide primary care services; (b) PAs will be better positioned for advancement than other health professionals despite industry-wide cost-containment efforts; and (c) most PAs can expect to practice in less "user-friendly" environments, irrespective of the implementation of the procompetitive concept of managed care or more regulatory global budgetary targets.

Cost Control↗
PubMed1995

Pilot study of all-trans retinoic acid as post-remission therapy in patients with acute promyelocytic leukemia.

Chemotherapy may decrease relapses of acute promyelocytic leukemia (APL) following induction with all-trans retinoic acid (ATRA), however the optimal timing of these two modalities remains to be determined. We treated eight patients with morphologic evidence of APL with intensive induction chemotherapy followed by ATRA (45 mg/m2/d for 10 weeks). All eight patients achieved a complete remission following chemotherapy. After a median follow-up of 29.0 months, seven patients remain in complete remission; one patient relapsed at 26.9 months. RT-PCR analysis for the PML/RAR alpha rearrangement was performed to monitor patients for evidence of minimal residual disease. Both of the patients with persistence of this rearrangement after induction chemotherapy converted to negative following ATRA. Toxicity of ATRA given in the post-remission setting was mild and consisted of headache, dry skin, and elevations of triglycerides and transaminases. No patient developed evidence of the retinoic acid syndrome. The administration of ATRA after intensive induction chemotherapy is associated with durable remissions and minimal toxicity in patients with APL. Disappearance of the PML/RAR alpha rearrangement after ATRA suggests that ATRA is effective against minimal residual disease.

Adult↗
PubMed1995

Sequential targeted therapy for relapsed acute promyelocytic leukemia with all-trans retinoic acid and anti-CD33 monoclonal antibody M195.

Acute promyelocytic leukemia (APL) provides a model to examine the sequential use of selective oncogene product-targeted and lineage-targeted agents. All-trans retinoic acid (RA) has been shown to produce brief remissions by a novel differentiating mechanism in most patients with APL. M195, a mouse monoclonal antibody (moAb) reactive with the cell-surface antigen CD33, can target myeloid leukemia cells in patients and reduce large leukemic burdens when labeled with 131I. We studied whether 131I-M195 could safely reduce minimal residual disease and prolong remission and survival durations in patients with relapsed APL after they had attained remission with all-trans RA. Seven patients with relapsed APL in second remission were treated with either 70 (n = 2) or 50 (n = 5) mCi/m2 of 131I-M195. As a measure of minimal residual disease, we serially monitored PML/RAR-alpha mRNA by a reverse transcription polymerase chain reaction (RT-PCR) assay. There was no immediate toxicity. Late toxicity was limited to myelosuppression, but no episodes of febrile neutropenia were seen. Six patients had detectable PML/RAR-alpha mRNA after all-trans RA therapy; two had single negative RT-PCR determinations following 131I-M195. Median disease-free survival of the seven patients was 8 months (range 3-14.5). Four patients with median follow-up of 24 months remain alive, and median overall survival exceeds 21+ months (range 5.5-33+). This regimen based on targeted therapy compares favorably to other approaches for the treatment of relapsed APL, including that used in the immediately preceding trial in which patients were induced into remission and maintained with all-trans RA, as well as other chemotherapy-based regimens. These data support further study of moAb-based therapy for minimal residual disease in acute leukemia.

Adult↗
PubMed1994

Sensitive nested reverse transcription polymerase chain reaction detection of circulating prostatic tumor cells: comparison of prostate-specific membrane antigen and prostate-specific antigen-based assays.

A highly sensitive nested reverse transcriptase-PCR assay, with primers derived from the prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSM) cDNA sequences, has been used to detect occult hematogenous micrometastatic prostate cells. In 77 patients with prostate cancer, PSM and PSA primers detected circulating prostate cells in 48 (62.3%) and 7 (9.1%) patients, respectively. In treated stage D disease patients, PSM primers detected cells in 16 of 24 patients (66.7%), while PSA primers detected cells in 6 of 24 (25%). In post-radical prostectomy patients with negative serum PSA values, PSM primers detected metastases in 21 of 31 patients (67.7%), whereas PSA primers detected cells in only 1 of 33 (3.0%), indicating that micrometastatic spread may be a relatively early event in prostate cancer. The analysis of 40 individuals without known prostate cancer provides evidence that this assay is highly specific and suggests that PSM expression may predict the development of cancer in patients without clinically apparent prostate cancer. Using PSM primers, we detected micrometastases in 4 of 40 controls, 2 of whom had known benign prostatic hyperplasia and were later found to have previously undetected prostate cancer. The clinical significance of detection of hematogenous micrometastic prostate cells using PSM primers and potential applications of this molecular assay, as well as the assay for PSA, merit further study.

Antigens, Neoplasm↗
PubMed1994

A ribozyme which discriminates in vitro between PML/RAR alpha, the t(15;17)-associated fusion RNA of acute promyelocytic leukemia, and PML and RAR alpha, the transcripts from the nonrearranged alleles.

Acute promyelocytic leukemia (FAB M3) is distinguished by the presence of the t(15;17) and clinical response to all-trans retinoic acid (RA) treatment. Acute promyelocytic leukemia is associated with a chromosomal translocation which results in the fusion of genes encoding a putative transcription factor (PML) and the retinoic acid receptor alpha (RAR alpha). It is suggested that the PML/RAR alpha fusion protein functions as an inhibitor of myeloid differentiation. The potential use of ribozymes as therapeutic agents has been investigated in the present study. Hammerhead ribozymes, which by hybridizing to both PML and RAR alpha sequences discriminate between the fusion transcript and the normal transcripts from the nonrearranged alleles, were designed and synthesized. Two hammerhead cleavage sites were targeted: site 1, an AUU located 4 nucleotides 3' to the fusion junction; and site 2, a UUC located 26 nucleotides 3' to the junction. Both sites are located in the RAR alpha portion of the fusion transcript. Using a full-length PML/RAR alpha RNA or an RNA corresponding to 788 nucleotides of the PML/RAR alpha mRNA and a full-length RAR alpha RNA or an RNA corresponding to 960 nucleotides of the RAR alpha mRNA as model substrates, the catalytic behavior of several ribozymes was studied. A modified hammerhead directed against site 2 displayed the highest degree of selectivity for PML/RAR alpha. It is hypothesized that ribozyme-mediated inactivation of PML/RAR alpha provides a new approach to study the role of PML/RAR alpha in the deregulated growth and RA response of acute promyelocytic leukemia.

Base Sequence↗
PubMed1994

9-Cis retinoic acid inhibits growth of breast cancer cells and down-regulates estrogen receptor RNA and protein.

All-trans retinoic acid (tRA) inhibits growth of estrogen receptor-positive (ER+) breast cancer cells in vitro, and a variety of retinoids inhibit development of breast cancer in animal models. 9-cis retinoic acid (9-cis RA) is a naturally occurring high affinity ligand for the retinoid X receptors, as well as the retinoic acid receptors (RARs). Whether 9-cis RA has a different spectrum of biological activity from tRA, which only binds RARs with high affinity, is largely unknown. We studied the effects of 9-cis RA on growth and gene expression in ER+ and ER- human breast cancer cells. 9-cis RA inhibited the growth in monolayer culture of several ER+, but not ER-, cell lines in a dose-dependent manner. Growth inhibition and morphological changes by 9-cis RA were similar to those of tRA, suggesting that the ability to bind both RAR and retinoid X receptors did not significantly augment growth inhibition or confer sensitivity to tRA-resistant lines. MCF-7 cells exposed to 9-cis RA showed a dose-dependent accumulation in G1. Northern analyses showed that RAR-alpha and RAR-beta were not significantly regulated, while RAR-gamma was up-regulated and retinoid X receptor alpha was down-regulated by 9-cis RA. Since interactions between tRA and ER-dependent transcription have recently been reported, we investigated whether these retinoids regulate expression of ER itself or estrogen-responsive genes. Both 9-cis RA and tRA induce down-regulation of ER mRNA and protein in MCF-7 cells. 9-cis RA down-regulates expression of the estrogen-responsive genes PR and pS2 in MCF-7 cells as reported previously for tRA. In several ER-positive subclones, we found that the degree of ER expression and regulation, but not always estrogen-sensitivity, correlates with the growth-inhibitory effects of 9-cis RA. Further, in an ER-, retinoid-unresponsive breast cancer cell line, induced ER expression confers responsiveness to retinoid growth inhibition. These data, combined with reports of additive growth inhibition of tRA and tamoxifen in vitro, suggest that 9-cis RA might augment the ability of tamoxifen to inhibit growth of ER+ breast cancer cells in vivo.

Breast Neoplasms↗
PubMed1994

Early mortality and the retinoic acid syndrome in acute promyelocytic leukemia: impact of leukocytosis, low-dose chemotherapy, PMN/RAR-alpha isoform, and CD13 expression in patients treated with all-trans retinoic acid.

All-trans retinoic acid (RA) has proven a major advance in the treatment of acute promyelocytic leukemia (APL). However, the proper management of patients who present with or develop leukocytosis during remission induction with all-trans RA is not established, nor is there a clear relation between leukocytosis and the development of the retinoic acid syndrome. We reviewed the course of our patients who underwent induction with all-trans RA to identify potential factors that might predict for the development of this syndrome and to identify which patients, if any, might specifically benefit from additional treatment with cytotoxic chemotherapy. Seventy-eight courses of all-trans RA therapy were administered to patients with a molecular diagnosis of APL. Initial and peak leukocyte counts, their rate of rise, leukocyte count criteria developed in Europe, and cell surface marker expression were all analyzed relative to subsequent development of both the RA syndrome as well as all causes of early mortality. The outcome of patients who received specific treatment for retinoid-induced leukocytosis was also examined. No factor was found to consistently predict for the development of the RA syndrome. Although the occurrence of the syndrome was positively associated with the peak value of the peripheral blood leukocyte count (P = .001), neither the initial leukocyte count nor the rate of rise in leukocyte counts on days preceding onset of the syndrome were sufficiently well-correlated to be clinically useful (P = .21). The leukocyte count criteria developed in Europe had a sensitivity of 62%, a specificity of 69%, and a positive predictive value that ranged from only 44% to 72%. However, we unexpectedly found that basal expression of CD13 (aminopeptidase N), a cell surface enzyme previously linked to tumor cell invasion and an inferior outcome in patients with acute myeloid leukemia, was highly associated with both development of the syndrome (P < .05) as well as an elevated leukocyte count (P = .006). Neither low-dose chemotherapy nor leukapheresis prevented development of the syndrome nor ameliorated its effects. In fact, 9 of 11 patients who received these interventions sustained fatal or near-fatal events, most of which were due to hemorrhage. However, early treatment with a short-course of high-dose corticosteroids halted progression of the syndrome in most cases. Finally, we found that expression of the type "A" isoform of PML/RAR-alpha (also known as bcr3 or "short") was associated with a significantly shorter duration of relapse-free and overall survival (P = .005).(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenal Cortex Hormones↗
PubMed1994

All-trans retinoic acid for acute promyelocytic leukemia. Results of the New York Study.

OBJECTIVE: To evaluate the safety and efficacy of all-trans retinoic acid to induce complete remission and to examine its effects on duration of remission and survival in patients with acute promyelocytic leukemia. DESIGN: Phase II evaluation and comparison with historical control patients. SETTING: Tertiary care cancer referral center. PATIENTS: Consecutive patients with morphologic diagnoses of acute promyelocytic leukemia were treated during a 2-year period with all-trans retinoic acid (daily oral dose, 45 mg/m2). Newly diagnosed patients discontinued the drug approximately 30 days after they achieved complete remission, at which time they received three courses of combination chemotherapy. Patients treated with previous cytotoxic chemotherapy who then relapsed were continued on all-trans retinoic acid as "maintenance" therapy until they relapsed again. RESULTS: 56 patients entered the study: 34 were newly diagnosed and 22 had relapsed from previous treatment. Fifty-one patients subsequently were found to have the PML/RAR-alpha gene rearrangement indicative of acute promyelocytic leukemia, and 44 of these patients achieved complete remission (86%; 95% Cl, 76% to 96%). A distinctive respiratory distress syndrome developed in 13 patients (23%) during treatment, and 5 patients (9%; Cl, 3% to 20%) died of this complication. The 5 patients who lacked PML/RAR-alpha rearrangements were withdrawn and given chemotherapy. The 13 patients given all-trans retinoic acid alone as maintenance therapy (10 of whom had relapsed from a chemotherapy-induced remission) had a median duration of remission of only 3.5 months (range, 1 to 23 months). Only 3 of 19 patients who relapsed from a remission induced by all-trans retinoic acid could be brought into remission again using this drug. The median survival time of all newly diagnosed patients has not been reached, but it now exceeds 31 months (range, 0.4 to 36+ months). No decrease in the early mortality rate was observed compared with a historical control group composed of 80 consecutive, newly diagnosed patients treated only with chemotherapy at this center; however, overall survival was superior. CONCLUSIONS: All-trans retinoic acid is an effective agent to induce remission in patients with a molecular diagnosis of acute promyelocytic leukemia, but remissions are short and resistance develops rapidly. Although the incidence of early death was not reduced, the use of all-trans retinoic acid to induce remission, followed by cytotoxic chemotherapy for "consolidation," was associated with longer survival times when compared with historical controls treated only with chemotherapy. Additional studies to prevent or mitigate consequences of the "retinoic acid syndrome" and to identify specific patients who might benefit from earlier intervention with chemotherapy are needed to maximize the advantages of this approach.

Adolescent↗
PubMed1994

A novel macromolecular structure is a target of the promyelocyte-retinoic acid receptor oncoprotein.

Acute promyelocytic leukemia (APL) is associated with a t(15;17) translocation that creates the promyelocyte-retinoic acid receptor alpha (PML-RAR alpha) fusion gene. Immunohistochemistry demonstrates that PML is a part of a novel macromolecular organelle (including at least three other nuclear proteins) referred to as PML oncogenic domains (PODs). In APL cells, the POD is disrupted into a microparticulate pattern as a consequence of the expression of the PML-RAR oncoprotein. RA treatment of APL cells triggers a reorganization of PML to generate normal-appearing PODs. We propose that PML-RAR is a dominant negative oncoprotein that exerts its putative leukomogenic effect by inhibiting assembly of the POD. According to this proposal, not only is the POD a novel structure, but it can be ascribed an imputed function such that its disruption leads to altered myeloid maturation; this may represent a novel oncogenic target.

Cell Nucleus↗
PubMed1994

Design of a potent and orally active nonpeptide platelet fibrinogen receptor (GPIIb/IIIa) antagonist.

The direct design of the potent nonpeptide platelet fibrinogen receptor (GPIIb/IIIa) antagonist, 8-[[[4- (aminoiminomethyl)phenyl]amino]carbonyl]-2,3,4,5-tetrahydro-3-oxo- 4- (2-phenylethyl)-1H-1,4-benzodiazepine-2-acetic acid, (3) (SB 207448), based on the structure and conformation of the potent and highly constrained cyclic peptide antagonist SK&F 107260 (2), has been reported [Ku et al., J. Am. Chem. Soc. 1993, 115, 8861]. While 3 displayed in vivo activity in the conscious dog following intravenous administration, it was not active following intraduodenal administration; activity was measured with an ex vivo platelet aggregation assay. The secondary amide in 3 was N-methylated in the expectation of increased absorption and bioavailability. The resulting tertiary amide, 4 (SB 208651), also showed high binding affinity for human GPIIb/IIIa and potent antiaggregatory activity in human platelet-rich plasma. Most importantly, 4 was active in vivo following intravenous and intraduodenal administration. Comparison of the iv and id inhibition curves suggests an apparent bioavailability of approximately 10%. Thus, 4 represents the first orally active compound in this series of potent, nonpeptide fibrinogen receptor antagonists.

Administration, Oral↗
PubMed1994

All-trans-retinoic acid and hexamethylene bisacetamide (HMBA) regulate TGF-alpha and Hst-1/kFGF expression in differentiation sensitive but not in resistant human teratocarcinomas.

The multipotent human teratocarcinoma (TC) cell NTera-2 clone D1 (abbreviated NT2/D1) differentiates into a neuronal lineage after retinoic acid (RA) treatment and a distinct phenotype after hexamethylene bisacetamide (HMBA) treatment. We previously reported that RA treatment of NT2/D1 cells reduces cellular cloning efficiency and nude mouse tumorigenicity. This accompanied a loss of mRNA expression of transforming growth factor-alpha (TGF-alpha) and the fibroblast growth factor kFGF, also known as hst-1 (abbreviated hst-1/kFGF). This study extends prior work by reporting that the distinct phenotype induced by HMBA also decreases cloning efficiency, tumorigenicity, and TGF-alpha and hst-1/kFGF mRNA expression in NT2/D1 cells. These RNA findings were confirmed by measurements of growth factor protein in the conditioned media of inducer-treated and untreated NT2/D1 cells. In two established human TC lines refractory to the actions of RA, N2102ep and Tera-1, RA fails to decrease expression of either growth factor despite induction of its nuclear receptor, RAR-beta. However, HMBA induces morphologic maturation and down-regulation of these growth factors in N2102ep cells. This indicates that the loss of TGF-alpha and hst-1/kFGF expression serves as a new marker of differentiation in human TCs. To explore the effects of these growth factors on growth and differentiation of NT2/D1 cells, TGF-alpha or hst-1/kFGF protein was added following inducer treatment or no treatment. Neither growth factor blocked immunophenotypic differentiation, but both promoted the growth of uninduced NT2/D1 cells in cloning assays.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetamides↗
PubMed1994

Simple system upgrades for outmoded health physics instrumentation.

Older radiation detection equipment used in Health Physics operations suffers from unreliable and outdated electronics, even when the radiation detectors, shielding, and mechanical components are still serviceable. Upgrading these systems through relatively simple interfaces to modern personal computers can provide a cost-effective solution to extend the life of these systems and provide state-of-the-art options for computer control and automation. This paper outlines the basic needs and requirements for this type of upgrade and describes three projects at University of Missouri--Columbia that have used this approach.

Costs and Cost Analysis↗
PubMed1994

Intracellular metabolism of (-)- and (+)-cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine in HepG2 derivative 2.2.15 (subclone P5A) cells.

The (-) and (+) enantiomers of the nucleoside analog cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine (2',3'-dideoxy-5-fluoro-3'-thiacytidine; FTC) have been shown to inhibit hepatitis B virus replication in vitro in HepG2 derivative 2.2.15 (subclone P5A) cells. (-)-FTC and (+)-FTC were anabolized to 5'-monophosphate, 5'-diphosphate, and 5'-triphosphate in this cell line. (-)-FTC was more efficiently phosphorylated to the 5'-triphosphate than (+)-FTC, and levels of 3.6 and 0.2 pmol/10(6) cells, respectively, were detected after incubation with 1 microM compound for 24 h. A time course study showed that nucleotides were formed rapidly in a dose-dependent manner and reached a steady-state intracellular concentration by 3 to 6 h. The intracellular half-life of (-)-FTC 5'-triphosphate was 2.4 h. Both (-)- and (+)-FTC were converted to diphosphocholine derivatives, analogous to CDP-choline, but only (+)-FTC was converted to the diphosphoethanolamine derivative, analogous to CDP-ethanolamine. (-)-FTC was not detectably deaminated at either the nucleoside or nucleotide level. (+)-FTC was partially deaminated by these cells. The transport of (-)-and (+)-FTC was examined in HepG2 cells. (+)-FTC enters these cells by way of the nitrobenzylthioinosine-susceptible, equilibrative nucleoside transporter. In contrast, the influx of (-)-FTC was only partially susceptible to inhibitors of nucleoside transport, indicating that (-)-FTC may have multiple transport mechanisms. These metabolic results are consistent with the conclusion that (-)-FTC 5'-triphosphate mediates the anti-hepatitis B virus activity of (-)-FTC.

Antiviral Agents↗
PubMed1994

Treatment of acute promyelocytic leukemia with all-trans retinoic acid: an update of the New York experience.

In an ongoing study, we treated 79 patients with a molecular diagnosis of acute promyelocytic leukemia (APL) using all-trans retinoic acid (RA) for remission induction. Newly diagnosed patients received cytotoxic chemotherapy for consolidation, and previously treated patients received extended all-trans RA therapy, or a radionuclide-conjugated monoclonal antibody as post-remission treatment. Unlike studies in Europe, full-dose chemotherapy was not given during induction for patients who developed leukocytosis. Overall, 43 of 49 newly diagnosed patients (88%) and 25 of 30 previously treated patients (83%) achieved complete remission. We did not encounter de novo resistance to all-trans RA in any patient who was positive for PML/RAR-alpha rearrangements by reverse transcription polymerase chain reaction analysis. Ten patients died during induction from intracranial or pulmonary hemorrhage (six patients) or the 'retinoic acid syndrome' (four patients). The use of leukapheresis or low-dose chemotherapy (hydroxyurea or cytosine arabinoside) for drug-induced leukocytosis did not decrease early mortality. Compared to historical controls, early mortality was not affected by treatment with all-trans RA; however, both relapse-free and overall survival were significantly increased. Maintenance therapy with all-trans RA was associated with short remission duration, and relapses while taking the drug were universally associated with resistance to further retinoid treatment. We conclude that the use of all-trans RA for remission induction, with or without full-dose chemotherapy, has significantly increased the survival of patients with APL. While early mortality has not yet been reduced, the avoidance of full-dose chemotherapy during induction has significantly reduced early morbidity. The major outstanding clinical issue is the development of strategies that maximize safety in high-risk patients for whom intracranial hemorrhage remains the major cause of death.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1994

Clemastine fumarate as an antipruritic agent in pruritic cats: results of an open clinical trial.

Clemastine fumarate was administered to 10 presumed or proven atopic cats to determine its efficacy in controlling their pruritus. Initially, each cat received 0.34 mg orally every twelve hours for 14 days. When none responded satisfactorily, the dosage was increased to 0.68 mg/cat every twelve hours. At that dosage, the pruritus in five cats (50%) was eliminated. Diarrhea was seen in one cat. Under the conditions of the study, clemastine was a useful antipruritic agent for the cat.

Administration, Oral↗
PubMed1994

Efficacy of tylosin tablets for the treatment of pyoderma due to Staphylococcus intermedius infection in dogs.

Tylosin tablets (20 mg/kg, q12h) were administered orally to 21 dogs with superficial or deep staphylococcal pyodermas. Response to therapy was excellent in 90.5% of the dogs, and in vitro susceptibility testing correlated perfectly with therapeutic response. Duration of therapy varied from 17 to 91 days, with an average of 33 days. Relapses occurred in 28.6% of the dogs within a three-month period. No side effects were reported. Under the conditions of the study, tylosin was an effective and safe antibiotic for the treatment of staphylococcal pyoderma in dogs.

Administration, Oral↗
PubMed1994

Failure of terfenadine as an antipruritic agent in atopic dogs: results of a double-blinded, placebo-controlled study.

Terfenadine (5 mg/kg body weight, q12h) and placebo (0.5 grain/dog q12h) were both administered orally as individual agents to 18 dogs with atopy in a double-blinded study. No dog improved. Hyperactivity, polyphagia, lethargy, anorexia, increased pruritus, or ocular discharge were seen in three dogs treated with terfenadine. Under the conditions of the study, terfenadine was not a useful antipruritic agent for the atopic dog.

Administration, Oral↗