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Biomedical subjects

J A Roth

Publications and source records attributed to J A Roth.

At least 325 records · Page 18Linked to original sources
PubMed1991

Low-dose continuous infusion cisplatin combined with external beam irradiation for advanced colorectal adenocarcinoma and unresectable non-small cell lung carcinoma.

In a dose escalation study, CIS-diamminedichloroplatinum II (cisplatin) was combined with a standard dose of external beam irradiation in 15 patients with localized non-small cell lung cancer (NSCLC) and 16 patients with fixed or recurrent localized adenocarcinoma of the rectum. Cisplatin was given 5 days a week during irradiation using an outpatient portable infusion pump system, at doses of 3.2 mg/m2/24 hr in 15 patients, 4.0 mg/m2/24 hr in 13 patients, and 5.0 mg/m2 24 hr in 3 patients. Twelve of 15 patients with NSCLC received 66 Gy in 33 fractions in 6 1/2 weeks; one received 46 Gy followed by a surgical resection; for the other two patients treatment was discontinued after 50 Gy and 64 Gy, respectively, because they developed distant metastases. The 16 patients with rectal carcinoma received a preoperative dose to the pelvis of 45 Gy in 25 fractions in 5 weeks. Of 12 patients who underwent laparotomy, 10 had a surgical resection, 2 with close or positive surgical margins. Four patients who had resections received an intraoperative electron boost. Of the two patients who did not undergo resection at laparotomy, one received an intraoperative electron boost, the other a boost with interstitial iridium-192. Among the four patients with rectal adenocarcinoma who were not candidates for surgery because of advanced local disease, two had further external beam therapy up to 59.4 Gy, and two had no further therapy. Major toxicity was site-specific, with esophagitis predominating in the patients with NSCLC, diarrhea in the patients with rectal carcinoma, and nausea experienced by both. Cisplatin dose and toxicity seemed to be related. The maximum tolerated dose for low-dose continuous infusion cisplatin given 5 days/week in these patients was 3.2 mg/m2/24 hr combined with 66 Gy in patients with NSCLC and 4.0 mg/m2/24 hr combined with 45 Gy in patients with rectal carcinoma.

Adenocarcinoma↗
PubMed1991

Radiation therapy following resection of non-small cell bronchogenic carcinoma.

Between 1970 and 1982, 102 patients received postoperative radiotherapy after attempted curative resection of bronchogenic carcinoma at The University of Texas M. D. Anderson Cancer Center. Surviving patients had a minimum follow-up of 3 years. Eight patients had pathological Stage I disease, 29 Stage II, and 65 Stage III. The 5-year actuarial survivals for patients with stages I, II, and III disease were 83%, 55%, and 38%, respectively (p = .04). Corresponding values for patients with N0, N1, and N2 disease were 74%, 56%, and 28% (p = .01). No significant differences in survival were seen based on T stage or tumor histology. Nine patients had gross residual disease following surgery, and 19 had microscopic residual disease. The 5-year actuarial survival was 78% for 12 patients without nodal disease who had known gross (4 patients) or microscopic (8 patients) residual tumor following attempted curative resection. The pathologic status of the hilar and mediastinal lymph nodes was the most significant factor affecting the frequency of metastatic relapse, with 19% of patients with N0, 33% of those with N1, and 69% of those with N2 disease developing distant disease. The low overall rate of recurrence intrathoracically (16%) confirms that postoperative radiotherapy is effective in preventing local relapse even in patients with proven nodal involvement. The impact of adjuvant radiation therapy on survival cannot be determined from these data, and further data are needed, preferably from well designed prospective studies.

Adenocarcinoma↗
PubMed1991

Benefits of implantable defibrillators are overestimated by sudden death rates and better represented by the total arrhythmic death rate.

Benefits of the implantable defibrillator on survival were studied in 56 consecutive patients (concomitant coronary bypass or arrythmia surgery in 15) during an 8 year period between 1982 and 1990. During a follow-up period of 29 +/- 25 months, six patients had a sudden death and eight patients had a nonsudden cardiac death. Nonsudden cardiac deaths included three surgical deaths (death within 30 days after the surgery; two in patients without and one in a patient with concomitant cardiac surgery), one arrhythmia-related nonsudden death (death within 24 h after an arrhythmic event despite initial termination of the arrhythmia by the implantable defibrillators) and four nonarrhythmic cardiac deaths. The actuarial survival rate free of events at 1, 2 and 3 years was 96%, 96% and 92%, respectively, for sudden death, 91%, 91% and 87% for sudden death and surgical mortality and 89%, 89% and 85% for total arrhythmic death (sudden death, surgical mortality and arrhythmia-related nonsudden death). Thus, in patients treated with an implantable defibrillator, 1) the rate of sudden death is low (8% at 3 years); 2) 50% of nonsudden cardiac deaths are causally related to arrhythmia (surgical mortality or arrhythmia-related nonsudden death); 3) the total arrhythmic death rate is substantially higher than the sudden death rate; and 4) benefits of an implantable defibrillator are overestimated by reported sudden death and nonsudden cardiac death rates. The benefits may be better represented by the total arrhythmic death and nonarrhythmic cardiac death rates.

Actuarial Analysis↗
PubMed1991

Resectability of small-cell lung cancer following induction chemotherapy in patients with limited disease (stage II-IIIb).

A prospective study of multimodality therapy was conducted incorporating adjuvant resection in patients who presented with limited small-cell lung cancer (SCLC). This preliminary report addresses the resectability rate after induction chemotherapy. Twenty-five patients (1 with Stage II, 12 with Stage IIIa, and 12 with Stage IIIb disease) completed the induction regimen of 3 cycles of intravenous cyclophosphamide 750 mg/m2 on day 1, vincristine 2 mg on day 3, cisplatin 20 mg/m2 on days 1-3, and etoposide 100 mg/m2 on days 1-3, (every 3-4 weeks). Patients with complete response or partial response, 10 (40%) and 14 (56%) patients, respectively, were considered for surgical resection. Six were ineligible for surgery because of medical or surgical contraindications, and four refused surgery. Of the 14 patients taken to surgery, 10 had resectable disease (40% of the original group of 25). Three pneumonectomies, two bi-lobectomies, two lobectomies, and two wedge resections were performed. In the remaining patient multiple biopsies revealed no residual disease and resection was not performed. Surgery-related complications included one death, one bronchopleural fistula, and one episode of pneumonia. Induction chemotherapy was generally well tolerated. These preliminary data demonstrate that a significant percentage of patients with SCLC, Stages II-IIIb, can feasibly be resected after response to brief induction chemotherapy.

Adult↗
PubMed1991

Phenotype and cytolytic activity of mouse tumor-bearer splenocytes and tumor-infiltrating lymphocytes from K-1735 melanoma metastases following anti-CD3, interleukin-2, and tumor necrosis factor-alpha combination immunotherapy.

We studied the phenotype and antitumor cytolytic activity of splenocytes from mice with K-1735 pulmonary metastases and tumor-infiltrating lymphocytes (TILs) from these metastases following treatment with anti-CD3, IL-2, and TNF combination immunotherapy. Mice were injected with 5 x 10(4) tumor cells and received a single 5 micrograms i.p. dose of anti-CD3 on day 3, followed by either IL-2 alone or fourfold less IL-2 with TNF (25,000 U/day) given at 3-day intervals. A single dose of anti-CD3 followed by low-dose IL-2 and TNF caused the greatest reduction in metastases compared to anti-CD3 alone, higher doses of IL-2 alone, or IL-2 + TNF. Reduction in metastases (greater than 80%) using the three agents was equal to or exceeded that achieved by ninefold higher concentrations of IL-2 alone. Treatment with anti-CD3 + IL-2 and TNF significantly prolonged survival, and resulted in 60% of mice achieving long-term survival greater than 120 days. This was superior to single agents or other combinations with the three agents causing a synergistic rather than additive effect. The anti-CD3-activated splenocytes were a heterogeneous population of T cells, with an increased number of CD8+ cells compared to splenocytes from mice treated with high doses of IL-2 alone. Analysis of TILs showed a greater proportion of CD8+ cells in anti-CD3-treated mice compared to IL-2 alone, but a lower proportion of CD4+ cells. Lymphokine-activated killer (LAK) and natural killer (NK) activities of both splenocytes and TILs in vitro increased following anti-CD3/IL-2 + TNF treatment, and were consistently greater than that generated with four times more IL-2 alone. TNF appeared to potentiate cytolytic activity rather than affect phenotypic changes. These results indicate that the sequential use of anti-CD3, IL-2, and TNF for LAK induction and maintenance potentiates antitumor activity, and suggests novel strategies for combination immunotherapy.

Animals↗
PubMed1991

Increase in beta-1,4-galactosyltransferase activity during PC12 cell differentiation induced by forskolin and 2-chloroadenosine.

Galactosyltransferase (GALTase) activity was measured in differentiating PC12 cells induced by either forskolin or 2-chloroadenosine. The specific activity of GALTase in whole cells and isolated Golgi membranes increased as early as 3 h after initiating treatment with 2-chloroadenosine, and maximal activity was reached at approximately 12 h. In two mutant PC12 cell lines deficient in protein kinase A, both forskolin and 2-chloroadenosine failed to increase GALTase activity. The adenosine A2 receptor antagonist, xanthine amine congener, prevented 2-chloroadenosine stimulation of GALTase, demonstrating that this adenosine derivative was mediating its effect via the A2 receptor. These data suggest that GALTase activity during PC12 cell differentiation is regulated by cyclic AMP (cAMP)- and protein kinase A-dependent processes. In support of the role of cAMP in regulating GALTase activity were studies with murine PC carcinoma cells demonstrating that the greatest stimulation of GALTase activity occurred with cells treated with both retinoic acid and dibutyryl cAMP.

2-Chloroadenosine↗
PubMed1991

Ventricular tachycardia/fibrillation: therapeutic alternatives.

It is now clear that no single therapy is appropriate for a consecutive series of patients with ventricular tachycardia or ventricular fibrillation (VT/VF). Drug responders by electrophysiological studies, patients who are not inducible following surgery, and patients treated with an implantable cardioverter defibrillator (ICD) all can have similarly low sudden death rates and virtually identical long-term mortality. However, many patients fail to respond to drugs, and surgical risks are excessive in others, and always higher than for an ICD implant. Nevertheless, overall survival in each of these groups (and probably for patients treated with antitachycardia pacers and ablation) is about 60% at 60 months. Major challenges now are: (1) choosing therapy to maximize risk-benefit ratio; and (2) treatment of the pump failure and progressive disease that now accounts for most cardiac mortality.

Anti-Arrhythmia Agents↗
PubMed1991

Direct current shock ablation: quantitative assessment of proarrhythmic effects.

Catheter ablation using direct current (DC) shock has proved invaluable in the management of a variety of tachycardias. However, sporadic reports of fatal arrhythmias following ablation have raised the question of the proarrhythmic potential of DC shock ablation. The present study was undertaken in 45 patients to assess prospectively any proarrhythmia related to DC shock ablation, using matched pre- and postablation Holter monitors and programmed electrical stimulation (PES). Nineteen of these patients had Holter monitors for three successive postablation days to observe trends. There was unmatched data in 11 additional patients. All 56 patients provided prospective follow-up for clinical events. There was no immediate sustained VT/VF at the time of the ablation. Four patients had sustained VT in the first 72 hours after ablation; three episodes were similar to the preablation clinical arrhythmias; one patient had torsades de pointes interrupting bradycardia. Twelve patients met Holter, PES, or clinical criteria for proarrhythmia; none were treated on the basis of these findings. On Holter monitoring, there were significant increases in VPCs/hour and couplets/hour in patients undergoing atrial or atrioventricular junctional ablations; and an increase in couplets after accessory pathway ablations. Increases in these categories were not significant for VT patients; nor were increases in episodes of VT/hour or atrial arrhythmias significant in any group. Patients were followed for 44 +/- 33 months, with an actuarial survival of 95% at 1 year, 88% at 3 years, and 85% at 4 years. There were six deaths during follow-up. Two patients had sudden death: one at 2 months had early evidence of proarrhythmia; the other at 32 months may have represented later myocardia deterioration. One patient died of heart failure at 77 months; and there were three noncardiac deaths. DC shock ablation in humans is much less proarrhythmic than in dogs. The low incidence of clinical proarrhythmic events during prolonged follow-up after discharge resulted in low sensitivity, specificity, and positive predictive values for Holter and PES, although the negative predictive values of these tests were greater than 90%. Only one of 12 patients who met criteria for proarrhythmia in the days immediately following ablation had subsequent clinical events consistent with proarrhythmia. These results may be useful as standards for comparison with results of radiofrequency or other ablation modalities.

Arrhythmias, Cardiac↗
PubMed1991

Recombinant porcine somatotropin: an immunotoxicology study.

The present study was designed to determine the effect of recombinant porcine somatotropin (rpST; 5, 15, or 25 mg.pig-1.d-1 for 57 d) on a variety of immune function variables. We observed no significant effect of rpST treatment on the gross pathology of the pigs, histopathology of the immune system organs, total and differential white blood cell counts, lymphocyte blastogenic response to mitogens, or the neutrophil functions of chemotaxis, ingestion, reduction of cytochrome C, iodination, and antibody-dependent cell-mediated cytotoxicity. Those variables that were significantly affected by rpST treatment include a decreased hemoglobin and packed red blood cell volume (at some time points for all three rpST dosages), a decrease in plasma protein level at the 25-mg dose, a small increase in neutrophil random migration (at all three rpST dosages), and a decrease in IgG antibody response to tetanus toxoid at 15 d after immunization (but not at d 8, 22, or 29). Additionally, rpST treatment was associated with a decreased rate of BW gain (at 15-mg dose), increased liver and kidney weights (at all three dosage levels), and an increased incidence of renal tubular cytoplasmic vacuolation of minor severity. There were no observed differences in the overall health of the pigs due to rpST treatment, based on clinical observations as well as determination of antibody titer to, and isolation of, common swine pathogens. Therefore, there was no evidence that the observed influence of rpST treatment on immune function would be clinically relevant.

Animals↗
PubMed1991

Effects of alpha-ketoisocaproate on adrenocorticotropin-induced suppression of lymphocyte function in sheep.

Previous studies of the amino acid analogue, alpha-ketoisocaproate (KIC), indicate that it can stimulate lymphocyte blastogenesis and antibody responses of sheep. To determine whether KIC could overcome the effects of adrenocorticotropic hormone (ACTH)-induced lymphocyte suppression, 24 lambs were fed a control diet, a diet supplemented with 0.05% KIC, or a diet supplemented with 0.05% of the parent amino acid leucine. Immune status was monitored by determining lymphocyte blastogenic responsiveness to phytohemagglutinin-P (PHA), concanavalin A (conA), and pokeweed mitogen (PWM) and percentages of T-cell subsets in the blood, using monoclonal antibodies and a flow cytometer. Serum cortisol, insulin, and glucagon concentrations also were determined. After 60 days of consuming the respective diet, lambs were administered either saline solution or ACTH (100 IU) twice daily for 3 consecutive days. Administration of ACTH increased serum cortisol and insulin concentrations; however, no effects were seen for serum glucagon concentration. Compared with saline administration, ACTH administration significantly (P less than 0.05) suppressed mitogen-stimulated lymphocyte blastogenesis by approximately 50%, regardless of the mitogen used, and significantly (P less than 0.01) decreased the percentage of circulating T lymphocytes and decreased (P less than 0.01) the ratio of T4 to T8 cells. Lambs fed KIC had greater PHA- and conA-stimulated blastogenic responses and significantly (P less than 0.05) increased ratio of T4 to T8 cells in the blood, compared with lambs fed the leucine-supplemented diet or the control diet and given corresponding injections. These data indicate that ACTH decreased in vitro lymphocyte blastogenesis and altered the subset ratios of blood lymphocytes in sheep. These changes were partially prevented by feeding KIC.

Adrenocorticotropic Hormone↗
PubMed1991

Histologic observations and P-glycoprotein expression in gastric and esophageal adenocarcinomas treated with preoperative chemotherapy.

To describe histologic changes associated with chemotherapy response, we reviewed biopsy and resection specimens from 52 patients with locally advanced esophageal or gastric adenocarcinoma who were treated with preoperative chemotherapy, followed by resection. P-Glycoprotein expression in the adenocarcinomas was also determined with the use of antibody C219. Significant changes in morphologic appearance of the tumor between prechemotherapy and postchemotherapy samples was noted in 17 tumors (32.7%). The most frequent changes observed in these 17 tumors were a decrease in tumor cellularity and an increase in dense fibrosis in comparison with the prechemotherapy specimen. In signet-ring cell carcinomas, the intracytoplasmic mucin vacuoles were often smaller after chemotherapy, making tumor cells more difficult to identify. Another finding observed in tumors that showed histologic alteration after chemotherapy was the formation of large mucin pools that contained lymphocytes and macrophages. The remaining 35 tumors showed similar histologic features in prechemotherapy and postchemotherapy specimens. P-Glycoprotein was identified in 15 (29.4%) of 51 specimens after chemotherapy. P-Glycoprotein content of the residual tumors did not correlate with stage, degree of differentiation, or clinically determined chemotherapy response. We concluded that chemotherapy-induced changes in morphology were frequent in patients with upper gastrointestinal tract adenocarcinomas treated with preoperative chemotherapy. These changes should be recognized as they may cause difficulties in both gross and histologic evaluation of the extent of tumor in postchemotherapy resection specimens. The response of adenocarcinomas to this chemotherapy protocol does not appear to be linked to P-glycoprotein expression.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1991

Photodynamic therapy of oncogene-transformed cells.

Photodynamic therapy with dihematoporphyrin ether sensitizes malignant cells to damage by 630 nm light. The in vitro, in vivo photodynamic therapy sensitivity of a cell line transformed by the Kirsten ras oncogene (45342) was studied to establish a new photodynamic therapy model. With the colony formation assay, neither light alone nor dihematoporphyrin ether alone affected 45342 survival. Energy-dependent photodynamic therapy effects were seen in vitro in dihematoporphyrin ether-incubated and light-exposed cells (90% cytotoxicity = 950 joules/m2; 99% cytotoxicity = 1575 joules/m2; p2 less than 0.05). Subcutaneous allografts of 45342 were established in nu/nu mice, and ideal route (intravenous or intraperitoneal) of dihematoporphyrin ether delivery, dihematoporphyrin ether tissue kinetics, and in vivo photodynamic therapy effects were examined. Intravenous administration not only gave higher levels of the sensitizer in various tissues, but also was associated with less variation than the intraperitoneal route. Selective dihematoporphyrin ether retention was documented in the tumors at 24 hours after injection compared with other tissues, and photodynamic therapy with 0.3 W/cm2 to a total dose of 150 joules/cm2 led to progressive coagulative tumor necrosis and tumor regression. These studies confirm that transformed, malignant cells are sensitive to photodynamic therapy, and this model may prove in future studies to increase efficacy to photodynamic therapy (i.e., with dihematoporphyrin ether delivery by monoclonal antibodies).

Animals↗
PubMed1991

Defective function of leukocytes from cattle persistently infected with bovine viral diarrhea virus, and the influence of recombinant cytokines.

Cattle persistently infected with bovine viral diarrhea (BVD) virus have decreased neutrophil and lymphocyte functions. We reevaluated these functions and further characterized the inhibition of persistent BVD virus infection in neutrophils, using sensitive kinetic assays. In addition, the influence of in vitro incubation of neutrophils with recombinant bovine interferon gamma (rBoIFN gamma) and in vitro incubation of lymphocytes with recombinant bovine interleukin-2 was evaluated. Significant (P less than 0.05) decrease in random migration under agarose, Staphylococcus aureus ingestion, cytochrome-C reduction, iodination, antibody-independent cell-mediated cytotoxicity, oxidant production, and cytoplasmic calcium flux were observed in neutrophils from cattle persistently infected with BVD virus, compared with noninfected control cattle. Incubation of neutrophils from noninfected controls with rBoIFN gamma significantly (P less than 0.05) decreased random migration under agarose, cytochrome-C reduction, and cytoplasmic calcium flux. Neutrophils from cattle persistently infected with BVD virus also had decreased random migration under agarose after incubation with rBoIFN gamma; in addition, antibody-independent cell-mediated cytotoxicity, elastase release, and cytoplasmic calcium flux were significantly enhanced. The rBoIFN gamma induced significantly (P less than 0.05) different effects on chemotaxis, cytochrome-C reduction, iodination, and cytoplasmic calcium flux of neutrophils from infected and control cattle. The rBoIFN gamma was more effective at improving the function of neutrophils from cattle persistently infected with BVD virus, compared with neutrophils from controls. Lymphocytes from infected cattle had decreased blastogenesis in response to phytohemagglutinin, concanavalin A, and pokeweed mitogen.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Oncogene activation in esophageal cancer.

We used molecular biology techniques to study the genetic events associated with the development of human esophageal cancer. Point mutations of the p53 tumor suppressor gene were detected in one of 10 squamous cell and one of 14 adenocarcinomas of the esophagus, a frequency that implicates this gene in tumorigenesis. However, the finding of p53 mutations in Barrett's epithelium adjacent to adenocarcinomas may have clinical implications for p53 as a premalignant marker for esophageal cancer.

Adenocarcinoma↗
PubMed1990

Characterization of a tyrosylprotein sulfotransferase in human liver.

Sulfation of tyrosyl residue(s) has been found to be a post-translational modification that precedes the secretion of many biologically active proteins or peptides. In the present paper, we report on the characterization of human liver tyrosylprotein sulfotransferase (TPST), the enzyme responsible for sulfation of tyrosine in proteins. Using poly Glu,Ala,Tyr (6:3:1; EAY) as the model substrate, human liver TPST was recovered in the microsomal fraction after differential centrifugation. This enzyme displayed a pH optimum of 6.4 and was stimulated approximately 2.5-fold in the presence of 0.5% non-ionic detergents, such as Lubrol-PX and Triton X-100. The divalent cation Mn2+ was required for enzymatic activity and produced maximal activation at 30 mM, whereas other divalent cations, including Mg2+ and Co2+, failed to enhance sulfoconjugation at this concentration. Using the optimized assay condition, the apparent Km for EAY was found to be approximately 1.5 microM, with significant substrate inhibition at EAY concentrations above 2 microM. The 16 amino acid peptide of the C-terminus of C4 possessed an apparent Km of approximately 2.1 microM. Using EAY as a substrate, TPST activity was measured in liver samples from ten organ donors to detect the variability of this enzyme among human subjects. The activity in the male group (1.065 +/- 0.074 pmol/min/mg) was significantly (P less than 0.005) higher than that of the female group (0.662 +/- 0.158 pmol/min/mg), suggesting that TPST activity may be regulated, in part, by sex hormones.

Cations, Divalent↗