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J W Smith

Publications and source records attributed to J W Smith.

At least 145 records · Page 8Linked to original sources
PubMed1996

Phase II trial of interleukin 1 alpha and indomethacin in treatment of metastatic melanoma.

BACKGROUND: The rising incidence of malignant melanoma and the lack of curative therapies for metastatic disease represent a therapeutic challenge. New agents effective in treating this disease are needed. PURPOSE: Because of the additive antitumor effects of interleukin 1 alpha (IL-1 alpha) and indomethacin in vivo, we conducted a phase II trial of this combination in patients with melanoma. We used the recommended dose determined from our phase I trial to ascertain the antitumor activity of the combination. METHODS: From August 1, 1990, through July 28, 1992, 49 patients entered the study. They were stratified into two groups based on the presence of visceral (n = 14) and nonvisceral (n = 35) metastases. The patients received 7 days of both IL-1 alpha (O.1 micrograms/kg per day by intravenous bolus) infusion) and indomethacin (50 mg orally every 8 hours). At least two cycles of therapy, repeated at 21-day intervals, were planned. Additional treatment was given to those patients who had stable or responding lesions. A chi-squared test for homogeneity of proportions was used to compare groups on several measures. All P values resulted from two-sided tests. RESULTS: Fever, chills, and hypotension were among the most common side effects. None of the 14 patients with visceral metastases responded to the treatment. Of the 35 patients with non-visceral metastases, three showed a partial response for 6 months each and one showed a complete response for more than 34 months; the response rate was 11% (95% confidence interval [CI] = 5%-26%). All responding patients required phenylephrine for treatment of IL-1 alpha-induced hypotension, whereas six (19%) of 31 of the nonresponding patients with nonvisceral metastases required phenylephrine (P = .0008). The response rate in women was higher; three of 10 women (30%; 95% CI = 11%-60%) responded, whereas one of 25 men (4%; 95% CI = 0%-20%) responded (P = .029). All three women were positive for human leukocyte antigen (HLA) B7 expression (P = .011). CONCLUSIONS: The combination of IL-1 alpha and indomethacin has minimal antitumor activity in melanoma patients. All responses were confined to patients with nonvisceral metastases. IL-1 alpha-induced hypotension, gender, and HLA B7 expression were positively associated with response. IMPLICATIONS: Administration of higher doses of IL-1 alpha alone has been shown to produce hypotension in a large proportion of patients but can be given safely with phenylephrine support. Because of the association of hypotension with antitumor activity, treatment with higher IL-1 alpha doses alone may be a strategy for attaining better response rates.

Adult↗
PubMed1996

Divalent cations regulate the organization of integrins alpha v beta 3 and alpha v beta 5 on the cell surface.

Extracellular divalent cations are important regulators of integrin ligand binding activity. In this study we evaluated how divalent cations affect the organization of integrins into focal adhesion sites. Integrins alpha v beta 3 and alpha v beta 5 were compared because they share a high degree of structural homology and because both integrins mediate cell adhesion to vitronectin. On MG-63 osteosarcoma cells, we found that both the extent and pattern of integrin organization was regulated by the type of extracellular divalent ion. Integrin alpha v beta 3 organized in focal contacts when Mn2+ or Mg2+ was present, but not in Ca2+. In contrast, alpha v beta 5 organized in focal contacts only when Ca2+ or Mg2+ was present. Integrin alpha v beta 5 clustered in a centrally located punctate field on the ventral surface of the cell in the presence of Mn2+. These observations reveal a previously unappreciated role for divalent ions in regulating the organization of integrins into focal adhesion sites.

Antigens, CD↗
PubMed1996

Interleukin 1 trials in cancer patients: a review of the toxicity, antitumor and hematopoietic effects.

Clinical trials of interleukin 1 alpha (IL-1 alpha) and IL-1 beta have been completed that assess the toxicities of these cytokines as well as their hematopoietic and antitumor effects. Both forms of IL-1 recognize the same cell surface receptors and have similar toxicities and similar biological activities. Toxicities including fever, flu-like symptoms and dose-limiting hypotension can be severe yet manageable, and IL-1 can be given safely to human cancer patients. Most toxicities and biological effects appear to be dose-related. IL-1 alone has little antitumor activity against melanoma, renal cell carcinomas or other malignancies. The hematopoietic effects, including megakaryocytopoietic effects, are modest and are probably not worth the toxicity necessary to achieve them. However, IL-1 seems to endow certain progenitor cells with responsiveness to other hematopoietic cytokines including colony-stimulating factors and IL-3. One potential application of IL-1 is to help expand bone marrow ex vivo following stem cell harvest, which could allow further chemotherapy dose escalations in chemotherapy-sensitive tumors.

Antineoplastic Agents↗
PubMed1996

Frequency of human immunodeficiency virus (HIV) infection among contemporary anti-HIV-1 and anti-HIV-1/2 supplemental test-indeterminate blood donors. The Retrovirus Epidemiology Donor Study.

BACKGROUND: Follow-up studies from the mid-1980s showed that 1 to 5 percent of blood donors testing reactive in anti-human immunodeficiency virus type 1 (HIV-1) enzyme immunoassay (EIA) and testing indeterminate in Western blot were infected with HIV-1 and were in the process of seroconverting. The present study was conducted to establish the rate of HIV infection among contemporary anti-HIV-1/HIV type 2 (HIV-2) EIA-reactive, Western blot-indeterminate donors. STUDY DESIGN AND METHODS: Donations (n = 607) with indeterminate HIV supplemental test results were identified by screening 3,021,342 donations given from November 1990 through August 1993 at five participating blood centers. Consenting donors were enrolled and samples taken 4 to 8 weeks after donation. Follow-up sera were tested by EIA and Western blot for anti-HIV-1 seroconversion and by type-specific peptide assays for antibodies to HIV-2 and HIV-1 subtype O. Peripheral blood mononuclear cells and/or plasma from the follow-up samples were tested for HIV-1 DNA and/or RNA by polymerase chain reaction. The rate of HIV-1 infection among Western blot-indeterminate donors was also estimated by multiplying the incidence rate of HIV-1 seroconversion in this donor population by the estimated duration of the EIA-reactive and Western blot-indeterminate window during seroconversion (8.5 days). RESULTS: Supplemental test-indeterminate donors (n = 355) enrolled a median of 38 days after donation; 265 (75%) of these donors were identified as indeterminate after an anti-HIV-1/2 EIA-reactive donation. Enrolled and non-enrolled donors had similar distributions of demographic characteristics and band patterns. Follow-up samples from all 355 donors tested negative for HIV-1 in polymerase chain reaction. Follow-up sera tested Western blot-negative in 54 cases (15%) and Western blot-indeterminate in 299 (84%). Two follow-up sera (0.6%) were interpreted, according to manufacturer's package insert criteria, as Western blot positive with p24 and gp41 bands and/or gp120/160 bands; however, paired testing of index and follow-up sera from these two cases showed identical Western blot and EIA reactivity, and polymerase chain reaction was negative for HIV RNA and DNA, which ruled out HIV infection. The absence of HIV infection in 355 Western blot-indeterminate donors was consistent with our incidence-based model analysis, which yielded an estimate of one HIV-1 infection for every 215 Western blot-indeterminate donations (95% CI, 1/39-1/8333). CONCLUSION: Contemporary blood donors classified as indeterminate in supplemental HIV testing are infrequently infected with HIV. Donors whose follow-up samples test negative in anti-HIV-1/2 EIAs and negative or persistently indeterminate in Western blots should be considered eligible for reinstatement.

Adult↗
PubMed1996

Maternal recognition of pregnancy in swine. I. Minimal requirement for exogenous estradiol-17 beta to induce either short or long pseudopregnancy in cycling gilts.

Five experiments were conducted to determine the minimal requirement for estradiol-17 beta (E2) injections to induce either short pseudopregnancy (SPP) or long pseudopregnancy (LPP) in cycling gilts. In experiments 1 through 5, E2 was injected i.m. on combinations of days between 11 and 25 days postestrus. Exogenous E2 on Days 12 and 13 or on Days 12 through 19 was optimal for induction of SPP or LPP, respectively. The duration of E2-induced diestrus was clearly demarcated between SPP (n = 73, duration 23-35 days) and LPP (n = 23, duration > 50 days). A sixth experiment was conducted to determine the minimum dose of intrauterine E2 required to induce SPP, and these gilts received intrauterine infusions of 0, 4, 40, or 400 micrograms E2 per 24 h on Days 12 and 13 postestrus. Pseudopregnancy was induced in 0 of 12, 1 of 4, 1 of 11, and 4 of 7 gilts in the treatment groups, respectively. These data suggest that uterine exposure alone is not sufficient to induce SPP. The present results indicate that the optimal signal for inducing LPP in unmated cycling gilts, and perhaps also for maternal recognition of pregnancy in mated gilts, may occur in two phases with continuous exposure to E2 being required from Day 12 to Days 17-19.

Animals↗
PubMed1996

Endocrine effects of IL-1 alpha and beta administered in a phase I trial to patients with advanced cancer.

Previous primate and rodent studies suggested that interleukin-1 alpha (IL-1 alpha) caused changes in the secretion of pituitary, adrenal, thyroid, and gonadal hormones, as well as acute-phase reactants. Plasma samples were obtained after IL-1 alpha and beta treatment in cancer patients to document the changes in endocrine function suggested by the animal models. Successive groups of patients were treated at IL-1 alpha doses of 0.01, 0.03, 0.1, 0.3, and 1.0 microgram/kg, given daily as a 15-min intravenous bolus. IL-1 beta was given at 0.1 microgram/kg by the same route and time course. After the first dose of IL-1, statistically significant elevations of a.m. and p.m. cortisol, growth hormone (GH), and prolactin (PRL) occurred. Thyroid-stimulating hormone (TSH) and C-reactive protein (CRP) were elevated by the sixth treatment day. Testosterone decreased significantly in male patients. Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were more variable but decreased in most patients. The changes in cortisol, GH, PRL, TSH, CRP, FSH, LH, and testosterone resolved after treatment and did not result in clinically apparent endocrinopathies. Bolus doses of IL-1 alpha and beta cause significant changes in many endocrine laboratory parameters and influence the in vivo activities of multiple homeostatic endocrine functions in human beings.

Acute-Phase Proteins↗
PubMed1996

Influence of interleukin-2 regimens on circulating populations of lymphocytes after adoptive transfer of anti-CD3-stimulated T cells: results from a phase I trial in cancer patients.

The adoptive transfer of anti-CD3-stimulated T killer (T-AK) cells was tested with different bolus and infusional interleukin-2 (IL-2) regimens, and anti-CD3 stimulation procedures to determine immunologic and antitumor effects in patients with a variety of advanced cancers. Indium-111 labeling was used to observe traffic patterns of the infused T-AK. Autologous peripheral blood mononuclear cells were obtained by leukapheresis. Cyclophosphamide (300 mg/m2) was given to most patients immediately after leukapheresis. The harvested cells were activated ex vivo with anti-CD3 overnight or for 4 days, at which time cells were reinfused and an IL-2 regimen was begun. Treatment was repeated 28 days later. This treatment regimen induced significant increases in leukocytes, lymphocytes, and eosinophils in patients in most treatment cohorts. Circulating lymphocytes were predominantly CD3+ T cells with preferential expansion of the CD8+ subset. Patients receiving cells stimulated in vitro for 4 days had significant T-cell lymphocytosis with either infusional or bolus plus infusional IL-2 regimens. T-cell viability was decreased in culture after a second 4-day stimulation with anti-CD3 at day 28; this decrease could be prevented by adding IL-2 to the culture media. Cells stimulated overnight required both bolus and infusional IL-2 to show an atypical lymphocytosis in vivo. Overnight-stimulated T-AK did not show decreases in in vitro viability at the day 28 restimulation. Indium-III-labeled cells trafficked to the liver, spleen, and bone marrow. No increase in uptake was observed in tumor deposits. There were 2 patients with partial responses, 5 with minor responses, 19 with stable disease, and 88 with progressive disease. The length of in vitro anti-CD3 stimulation, and the dose and timing of IL-2 administration in vivo results in different circulating leukocyte populations after adoptive T-AK infusion. Generally, the CD8+ T-cell subset was preferentially expanded by this treatment approach. Repeated ex vivo stimulation with anti-CD3 may cause cell death.

Adolescent↗
PubMed1996

A phase I randomized study of subcutaneous adjuvant IL-2 in combination with an autologous tumor vaccine in patients with advanced renal cell carcinoma.

We performed a prospective, randomized study to determine whether subcutaneous administration of interleukin-2 (IL-2) in combination with an autologous renal cell vaccine is feasible and can potentiate antitumor immunity. Seventeen patients with metastatic renal cell carcinoma underwent surgical resection with preparation of an autologous tumor cell vaccine. Patients were vaccinated intradermally twice at weakly intervals with 10(7) irradiated tumor cells plus bacillus Calmette-Guérin, and once with 10(7) tumor cells alone. Patients were randomized to one of three groups: no adjuvant IL-2, low-dose IL-2 (1.2 x 10(6) IU/m2), or high-dose IL-2 (1.2 x 10(7) IU/m2). IL-2 was administered subcutaneously on the day of vaccination and the subsequent 4 days. Immune response was monitored by delayed-type hypersensitivity (DTH) response to tumor cells as compared with normal autologous renal cells. Sixteen of 17 patients received vaccine therapy. Four patients developed cellular immunity specific for autologous tumor cells as measured by DTH responses; two had received no IL-2 and two had received high-dose IL-2. There were two partial responses (PR) noted, both in patients who received high-dose IL-2. One responding patient was DTH(+) and one was negative. A third patient who was DTH(+) after vaccination with no IL-2 had a dramatic PR after receiving IL-2 subcutaneously in a subsequent protocol. Prospective testing of response to recall antigens indicated that only 5 of 12 tested patients were positive, including both clinical responders. These data suggest that subcutaneously administered adjuvant IL-2 does not dramatically augment the immunologic response to autologous renal cell vaccines as determined by the development of tumor-specific DTH response.

Adjuvants, Immunologic↗
PubMed1996

Chronic expanding hematoma within a periprosthetic breast capsule.

Three cases of chronic expanding hematoma occurring within the capsule surrounding breast implants are described. All developed at least 4 years after the last operation. No identifiable etiology could be demonstrated. Although this pathologic entity has been widely reported in other anatomic locations, a periprosthetic chronic expanding hematoma of the breast has not been described previously.

Aged↗
PubMed1996

Semisynthetic echinocandins affect cell wall deposition of Pneumocystis carinii in vitro and in vivo.

Cyclic lipodepsipeptide compounds of the echinocandin class exhibit broad-spectrum antifungal activity and have been shown to be effective in the treatment of Pneumocystis carinii pneumonia in laboratory animal models. Previous studies have led investigators to propose that these compounds, active against fungal cell walls, are selectively active against the cyst forms of P. carinii. We demonstrate that a semisynthetic, water-soluble echinocandin analog, LY307853, is effective in reducing the number of all life cycle forms of P. carinii and is more effective in mice immunosuppressed with monoclonal antibody to L3T4+ cells than in mice immunosuppressed with dexamethasone. Treatment of P. carinii isolates with LY307853 in a short-term in vitro culture model resulted in cytoarchitectural alterations suggesting that this echinocandin may interfere with the export of surface glycoprotein and the formation of the tubular elements normally found on the surfaces of trophic forms. The cytoarchitectural changes in trophic forms treated in vitro with LY307853 were also observed in trophic forms in the lung tissue of rats treated with a closely related echinocandin analog, LY303366.

Anidulafungin↗
PubMed1996

Development of type-specific PCR for typing Pneumocystis carinii f. sp. hominis based on nucleotide sequence variations of internal transcribed spacer region of rRNA genes.

The nucleotide sequence variations in the internal transcribed spacer region 1 (ITS1) and region 2 (ITS2) of rRNA genes were found to be useful for typing Pneumocystis carinii isolates that infect humans. Two types of ITS1 (A and B) and three types of ITS2 (a, b, and c) sequences have been found, and P. carinii isolates are classified based on sequence types of ITS1 and ITS2 as Ax or Bx (where x may be a, b, or c). Type determination has been achieved by sequencing the ITS regions or by reacting the ITS regions amplified by PCR with type-specific oligonucleotide (TSO) probes. However, TSO typing alone does not work on a specimen from an individual who is infected by more than one strain of P. carinii where different ITS1 types are present in the same specimen. In this study, type-specific PCR assays were developed to supplement TSO typing. Type-specific PCR primers were made so that they differ at their 3' ends by the two nucleotides which distinguish type A from type B of ITS1 plus an additional "A" residue at the extreme 3' ends of the primers. These two primers were paired separately with a general primer which anneals to a region downstream from ITS2 to specifically amplify Ax or Bx. The amplified products were then reacted separately with ITS2-specific probes 2-a, 2-b, and 2-c to identify their types.

Base Sequence↗
PubMed1996

Phase I study of subcutaneously administered interleukin-2 in combination with interferon alfa-2a in patients with advanced cancer.

PURPOSE: Although high-dose interleukin-2 (IL-2) can produce durable remissions in a subset of responding patients with renal cell carcinoma (RCC), this occurs in the setting of significant toxicity. The purpose of this study is to define the maximum-tolerated dosage (MTD) of IL-2 and interferon alfa-2a (IFN alpha-2a) that can be administered chronically on an outpatient basis. PATIENTS AND METHODS: Fifty-three patients with advanced cancer of variable histology with good prognostic features were treated in six cohorts. Patients in cohorts one through five received IL-2 (1.5 or 3.0 x 10(6) million units (mU)/m2) Monday through Friday and IFN alpha-2a (1.5 or 3 x 10(6) mU/m2) daily for a 4-week cycle. In cohort six, IFN alpha-2a was given three times a week. Immunologic monitoring, including serum levels of soluble IL-2 receptor (sIL-2R) and neopterin, flow cytometry, and natural killer cell (NK) activity, were measured. Patients were evaluated for toxicity, response, and survival. RESULTS: Almost all patients developed grade I/II toxicities commonly associated with cytokine therapy. Symptoms were most severe with the first treatment of each week. Dose-limiting toxicities included grade III fatigue, hypotension, and creatinine elevations. The MTD was 1.5 mU/m2 daily x 5 given subcutaneously repeated weekly for IL-2 and 1.5 mU/m2 daily subcutaneously (dose level 3) for IFN. Six of 25 assessable patients with RCC (24%) achieved a partial response (PR), including four of eight patients who were previously untreated. There were no objective responses in patients with other tumors, including 12 melanoma patients. CONCLUSION: IL-2 and IFN alpha-2a can be given with tolerable toxicities on an outpatient basis and shows significant activity in patients with metastatic RCC.

Adult↗
PubMed1996

Varus malalignment of the talar neck. Its effect on the position of the foot and on subtalar motion.

We performed an in vitro study on twelve specimens of the foot and ankle from cadavera to determine whether varus malalignment of the talar neck alters the position of the foot and subtalar motion. An osteotomy of the talar neck was performed, and the specimens were studied with and without removal of a medially based wedge of bone. Removal of the wedge produced an average varus malalignment of the talar neck of 17.1 +/- 2.4 degrees (range, 12.5 to 21.0 degrees). In the coronal plane, the average arc of motion of the subtalar joint decreased from 17.2 +/- 3.3 degrees before the osteotomy to 11.7 +/- 2.9 degrees after the osteotomy and removal of the wedge. In the transverse plane, it decreased from 17.5 +/- 2.9 degrees to 11.9 +/- 2.4 degrees. In the sagittal plane, it decreased from 8.9 +/- 2.4 degrees to 6.8 +/- 2.3 degrees. The decrease in subtalar motion was characterized by an inability to evert the foot; inversion was not limited, however. The malalignment produced an average of 4.8 +/- 1.2 degrees of varus deformity and 8.7 +/- 2.3 degrees of internal rotation of the hindfoot and an average of 5.5 +/- 2.0 degrees of varus deformity and 11.5 +/- 2.4 degrees of adduction of the forefoot. A linear correlation analysis was used to compare the change in subtalar motion and the position of the foot with the degree of varus malalignment at the talar neck. The correlation coefficient was 0.90 (p < 0.01) for subtalar motion, 0.76 (p < 0.01) for internal rotation of the calcaneus, and 0.81 (p < 0.01) for adduction of the forefoot. This indicated a direct correlation between the degree of varus malalignment at the talar neck and the change in the position of the foot and in subtalar motion.

Ankle Joint↗
PubMed1996

The type III connecting segment of fibronectin contains an aspartic acid residue that regulates the rate of binding to integrin alpha 4 beta 1.

The type III connecting segment (IIICS) within fibronectin is the major binding site for the integrin alpha 4 beta 1. Most integrin ligands have an essential acidic residue within their integrin binding site, in IIICS this residue is hypothesized to be the aspartic acid at position 21. Alanine scanning mutagenesis was used to determine the amino acid residues within the intact IIICS domain required for interaction with alpha 4 beta 1. IIICS was cloned and expressed as a fusion protein with glutathione S-transferase. This recombinant form of IIICS supports the adhesion of CHO cells that express human alpha 4 beta 1 in a cation dependent manner. Alanine scanning mutagenesis of the EILDVP sequence in recombinant IIICS demonstrated that only two of these residues are critical for adhesion of alpha 4 beta 1 expressing cells. Mutations of leucine at position 20 and aspartic acid at position 21 to alanine significantly reduced cell adhesion. Conservative mutations of aspartic acid at position 21 to asparagine or glutamic acid also reduced the ability of the recombinant protein to support cell adhesion, although not to the same extent as the corresponding alanine replacement. Most importantly, we show that although the mutation of asp 21 impairs cell adhesion, an examination of cell adhesion as a function of time demonstrated that asp 21 is not necessary for cell adhesion through alpha 4 beta 1. In comparison to wild type IIICS, the asp 21 to ala mutant supported minimal adhesion at early time points (10-30 min.), but was equivalent to wild type IIICS in supporting adhesion over one hour.

Amino Acids↗
PubMed1996

Dealing with brittleness in the design of expert systems for immunohematology.

In recent years, there has been increased discussion about the potential of expert systems to support medical decision-making tasks, including applications in clinical laboratory settings. This study provides data regarding the cognitive errors that technologists make on an important problem-solving task: the identification of antibodies in a patient's blood. It explores alternative designs for expert systems developed to reduce such errors. It also evaluates the effects of these alternative designs on the ability of the users to effectively stay "in the loop," applying their own expertise and judgment while using the computer as a tool to assist with their analyses. A pilot study was conducted involving 32 certified medical technologists, which compared two alternative roles for the computer: (1) use of the computer to automatically complete subtasks upon request, and (2) use of the computer as a monitoring device to critique technologists as they completed the analyses themselves. The system design that automatically completed subtasks for the technologist induced a 29 percent increase in errors relative to the design that critiqued technologists as they completed the analyses themselves.

Journal Article↗