Esophageal cancer: does preoperative chemotherapy make a difference?
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Antineoplastic Combined Chemotherapy Protocols↗
Biomedical subjects
J A Roth
Publications and source records attributed to J A Roth.
Membrane-bound catechol-O-methyltransferase: a reevaluation of its role in the O-methylation of the catecholamine neurotransmitters.
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Animals↗
A patient with primary biliary cirrhosis and multiple sclerosis.
A 48-year-old woman with primary biliary cirrhosis (PBC) and multiple sclerosis (MS) is reported. She presented with a visual deficit in 1975. In the course of a diagnostic evaluation, she was found to have PBC. In 1986, the diagnosis of MS was made. The patient's liver function deteriorated and liver transplantation was performed in May 1988. This is the third known case of this association.
Adult↗
Prognostic significance of computed tomography in resected N2 lung cancer.
We reviewed 124 patients from 1982 to 1988 who had a resected primary non-small cell lung cancer metastatic to mediastinal (N2) lymph nodes and a preoperative assessment of the mediastinum with computed tomography of the chest. Sixty-three patients studied had computed tomographic evidence of mediastinal lymph node enlargement. In these patients the survival at 5 years was only 6.6%, compared with the 5-year survival of 13.5% in 61 patients in whom the mediastinum was normal. Plain chest roentgenography with evidence of mediastinal adenopathy did not predict a poorer outcome. In addition, patients with tumors located in the left upper lobe were found to have an improved survival. These patients had a 5-year survival of 20.8%. Tumor histology, central location of the tumor, extranodal extension, and type of resection did not result in a significant survival difference.
Adult↗
Long-term survival after resection of pulmonary metastases from carcinoma of the breast.
Resection of isolated pulmonary metastases may yield improved survival in select patients. Between 1981 and 1991, 44 women (median age, 55 years) with a history of breast cancer underwent 47 thoracotomies with no operative deaths and only three minor postoperative complications (3/47, 6.4%). Confirmation of the metastatic origin of the lung lesion was made by direct histological comparison with the primary. Three patients had benign nodules and were excluded, and 4 patients had less than complete resection at thoracotomy. The median survival after thoracotomy of the remaining 37 patients with completely resected metastases was 47 +/- 5.5 months, and their actuarial 5-year survival was 49.5%. Patients with a disease-free interval of longer than 12 months had a longer survival (median survival, 82 +/- 6 months; 5-year survival, 57%) than patients with a disease-free interval of 12 months or less (median survival, 15 +/- 3.6 months; 5-year survival, 0%) (p = 0.004). Patients with estrogen receptor-positive status (n = 14) tended to have longer survival after resection than patients with estrogen receptor-negative status (n = 15) (median survival, 81 +/- 9 months versus 23 +/- 6 months, respectively; p = 0.098). Other clinical variables analyzed did not predict survival after thoracotomy. We conclude that resection of pulmonary metastases in patients with breast cancer can be done safely and may result in long-term survival for a substantial number of patients. Patients with a disease-free interval of longer than 12 months have an excellent prognosis after complete resection.
Adult↗
Alteration of neutrophil function in BCG-treated and non-treated swine after exposure to Salmonella typhimurium.
Salmonella typhimurium infection in swine causes an enterocolitis followed by a persistent carrier state, but little is known about the mechanisms that allow this organism to colonize and persist in host tissues. Neutrophils provide a first line of defense against invading pathogens such as Salmonella typhimurium. The purpose of this study was to evaluate porcine neutrophil function after in vivo exposure to Salmonella and to determine if the immunomodulator, bacillus Calmette Guerin (BCG), exerts any effect on neutrophil function or on the colonization and persistence of S. typhimurium in the pig. Compared to negative controls, neutrophils from pigs exposed to S. typhimurium exhibited significantly decreased iodination, cytochrome-C reduction, antibody-dependent cell-mediated cytotoxicity, random migration, and chemotaxis (P less than or equal to 0.05). Neutrophil bactericidal activity against S. typhimurium was significantly enhanced. Most of the significant differences were noted in the first two days after exposure to Salmonella. Often the functional alterations were biphasic, peaking again 7-10 days after exposure. BCG alone significantly depressed random migration and cytochrome-C reduction in unstimulated neutrophils. The clinical course, colonization pattern, and persistence of Salmonella were similar between pigs receiving BCG and untreated pigs. These data suggest that S. typhimurium infection causes a depression in oxidative metabolism and motility, yet an increase in overall bactericidal activity against S. typhimurium in circulating porcine neutrophils. It also appears that BCG treatment, as reported here, does not enhance resistance of pigs to S. typhimurium colonization or reduce the number of persistent organisms in the porcine ileum.
Animals↗
A comparison of virulent and avirulent strains of Salmonella choleraesuis and their ability to invade Vero cell monolayers.
The mechanisms of invasion used by virulent and avirulent Salmonella choleraesuis were compared using a Vero cell invasion assay. Mouse virulent S. choleraesuis strain 38 and avirulent strain 9 were examined for their ability to invade and survive in Vero cells. The assay was performed by S. choleraesuis infection of the Vero cell monolayer alone and in the presence of various treatments applied to the Vero cell monolayers. Intracellular S. choleraesuis colony forming units were then counted to characterize the mechanism of bacterial uptake. Invasion was not affected by colchicine, but was significantly inhibited in the presence of cytochalasins B and D, chloroquine, and dansylcadaverine. Inhibition by the above substances suggested the importance of microfilaments and of receptor recycling in receptor mediated endocytosis. Both bacterial strains had decreased invasion in the presence of mannose and after enzymic treatment with trypsin. Mannose exposure caused a significant 48% decrease in the uptake of virulent S. choleraesuis 38 and a 28% decrease in avirulent S. choleraesuis 9. Inhibition of endosome acidification did not affect the virulent strain 38 as much as it affected avirulent strain 9. Results from these experiments suggested that Vero cell invasion by S. choleraesuis was due to host uptake by receptor mediated endocytosis, and was mediated in part by mannose-sensitive adhesins. Outer membrane proteins were extracted from the virulent and avirulent strain and compared using SDS-PAGE following surface protein labeling with 125I. Virulent S. choleraesuis 38 had a unique 35 kD protein. The outer membrane proteins of both strains were then examined by radio-immunoprecipitation and western blot using guinea pig polyclonal antisera and the 35 kD protein was again found to be unique to the virulent strain 38. Antisera against the 35 kD protein significantly inhibited invasion of Vero cells by S. choleraesuis strain 38.
Actin Cytoskeleton↗
Prolonged chemotherapy for localised squamous carcinoma of the oesophagus.
We evaluated the feasibility of six courses of chemotherapy in 34 consecutive patients with localised squamous cell carcinoma of the oesophagus. All 32 evaluable patients first received at least two courses of chemotherapy. There were 18 patients with resectable carcinomas who underwent surgery and 14 patients with unresectable carcinomas who received definitive chemoradiotherapy. After two courses of 5-fluorouracil and cisplatin 21 (66%) of 32 patients had either a complete or major response. A median of five courses (range, 1-6 courses) was administered. 17 out of 18 (94%) patients with resectable carcinoma had a 'curative' resection (negative proximal, distal, and radial margins by histopathology in an en-block resection specimen) and 2 patients had a complete pathological response. The median survival duration of all patients was 28 months (range, 2-46+ months). The median survival duration of 14 patients with unresectable carcinoma was 23 months (range, 8-36+ months), and the median survival duration of 18 patients with resectable carcinoma has not been reached at a median follow-up of 24+ months (range, 10+ to 46+ months). No deaths occurred because of chemotherapy or chemoradiation therapy. Our data suggest that prolonged chemotherapy is feasible in patients with locoregional squamous carcinoma of the oesophagus. An ongoing controlled trial will determine the contribution of chemotherapy to patients' survival.
Antineoplastic Combined Chemotherapy Protocols↗
Autocrine growth stimulation by transforming growth factor-alpha in human non-small cell lung cancer.
We studied the biological response to and production of transforming growth factor-alpha (TGF-alpha) by the non-small cell lung carcinoma (NSCLC) clonal cell lines H226b, H322a, H460a, H596b. Each of these cell lines expressed epidermal growth factor receptor (EGFR) as determined by [125I]EGF competitive binding and Scatchard analysis and by phosphorylation. The receptors were functionally active as determined in immune complex kinase assays. H322a, H226b, H460a, and H596b cells showed stimulated [3H]thymidine (Thd) uptake in response to TGF-alpha. Exogenously added TGF-alpha increased colony formation in soft agar for three of the cell lines in media containing serum. All cell lines expressed TGF-alpha detected by immunohistochemistry and TGF-alpha mRNA, although to differing degrees. Cell lysates and spent media competed for EGFR binding with EGF, thus demonstrating production of TGF-alpha-like activity. The anti-TGF-alpha monoclonal antibody AB-3 inhibited the uptake of [3H]Thd by proliferating H322a and H226b cells but not H460a and H596b cells. No inhibition occurred with MOPC21 antibody and inhibition was completely reversed by addition of TGF-alpha to the culture. Suramin inhibited cell proliferation and [3H]Thd uptake by all cell lines. Inhibition of H460a and H596b cells was reversed with exogenous TGF-alpha but not PDGF. Our data suggests that TGF-alpha is a mediator of autocrine growth stimulation for NSCLC cells, and that for some NSCLC cells cytoplasmic binding of receptor and ligand is the primary mechanism for autocrine growth stimulation.
Animals↗
IL-1 synergy with IL-2 in the generation of lymphokine activated killer cells is mediated by TNF-alpha and beta (lymphotoxin).
Interleukin 1 is a pleuripotent cytokine shown to synergize with IL-2 in the generation of lymphokine-activated killer (LAK) cells, when cultured with human peripheral blood mononuclear cells (PBMC) or peripheral blood lymphocytes (PBL). When IL-1 and low dose IL-2 are added in combination, both LAK cytotoxicity and proliferation are increased in short-term (5-6 day) and long-term (12-14 day) cultures compared with cells activated with IL-2 alone. The purpose of this study was to examine the contribution of tumor necrosis factor (TNF-alpha), lymphotoxin (LT, or TNF-beta) and the TNF receptor in the observed IL-1/IL-2 mediated synergy. Analysis of lymphocyte culture supernatants using the L929 bioassay and by specific ELISAs demonstrated an increased production of both TNF and LT in those cells cultured with IL-1 and IL-2. Utilizing specific neutralizing antisera, our experiments demonstrated the biologic activity of both cytokines, with LT-specific antibodies producing the greatest diminution of IL-1/IL-2 stimulated cell proliferation and cytotoxicity. The addition of IL-1 and IL-2 in combination markedly upregulated TNF-receptor expression (measured by Scatchard analysis) in comparison with cells stimulated with IL-2 alone. Characterization of the TNF-R by flow cytometric analysis revealed increased membrane expression of the 75 kDa, but not the 55 kDa, TNF binding protein as a result of IL-1 costimulation.
Antibodies, Monoclonal↗
Implementation of a new DDDR algorithm for tachycardia prevention and treatment utilizing an implantable RAM-based software-controlled pacemaker.
Reentry within the atrioventricular node or over accessory pathways are common causes of symptomatic tachycardia. These arrhythmias are frequently initiated by a spontaneous atrial or ventricular premature beat. Appropriately timed atrial or ventricular extrastimuli can, in some patients, render one limb of the reentrant circuit refractory and prevent induction of tachycardia. Currently available implantable devices are not suitable for this application. The authors have implemented a new implantable pacing algorithm capable of extremely short atrial and ventricular refractory periods, rapid triggered ventricular pacing rates, protection against encroachment on the ventricular vulnerable period, protection against tachycardia induction by ventricular premature beats, automated antitachycardia pacing in either atrium and ventricle, as well as an extensive event storage capability. This application has been made possible by a new, RAM-based microprocessor controlled dual chamber pacemaker (Medtronic Prometheus Model 6100). Its use in intraatrial tachycardia with atrioventricular block as well as Wolff-Parkinson-White syndrome is demonstrated. This device is capable of prevention of tachycardia induction in some patients. Where prevention is not feasible or fails, it is backed up by automated or manually activated antitachycardia pacing. The great flexibility of a completely reprogrammable software based pacemaker has enabled the implementation of a very complex experimental pacemaker that will permit evaluation in the implanted setting of this new pacing strategy.
Algorithms↗
Programmed electrical stimulation of the ventricle: an efficient, sensitive, and specific protocol.
A relatively simple and efficient ventricular programmed electrical stimulation (PES) protocol was developed, capable of achieving high degrees of sensitivity and specificity. In a series of 481 subjects, 1, 2, and 3 extrastimuli (ES) were used successively during sinus rhythm and ventricular pacing at two drive cycle lengths, at one or more ventricular sites, together with rapid ventricular pacing, and other maneuvers such as isoproterenol infusion. Three ES were used immediately after two ES at each drive rate, rather than returning after completion of the protocol with two ES. Using the protocol, appropriate arrhythmias could be induced in 88% of all patients with ventricular fibrillation, 84% of all patients with sustained ventricular tachycardia (91% with underlying coronary disease), and 58% of patients with severe nonsustained ventricular tachycardia. There were significant differences in inducibility between patients whose ventricular arrhythmias were due to coronary artery disease and other causes. In contrast, sustained ventricular arrhythmias (all ventricular fibrillation) could be induced in only 5% of a control group of control patients, for a specificity of 95%. The protocol described is simpler and more efficient than those that use exhaustive testing of two ES before going to three ES. Three ES during sinus rhythm proved to be the most productive step, with a higher yield ratio (true: false-positives) than two ES or three ES during pacing, especially at faster rates. Greater efficiency is also achieved by leaving the timing of an extrastimulus just beyond its effective refractory period when an additional extrastimulus is to be added, compared to protocols in which the extrastimulus is moved later in the cycle and then decremented in tandem with the additional extrastimulus. Coupling intervals less than 200 msec produced some false-positives, but fewer overall than intervals greater than or equal to 200 msec, and with yield ratios comparable to other protocol steps. The protocol described meets NASPE standards for ventricular programmed stimulation protocols, and with its demonstrated specificity and relative simplicity and efficiency may be useful as a model for groups not yet committed to an alternative protocol.
Cardiac Pacing, Artificial↗
Stimulation hierarchy: optimal sequence for double and triple extrastimuli during electrophysiological studies.
To determine the optimal ventricular stimulation sequence, an 11-step programmed electrical stimulation (PES) protocol was completed, even if a ventricular arrhythmia (VA) was induced with earlier steps. The protocol consisted of one, two, and three extrastimuli during sinus rhythm (SR), and at two drive pacing rates (VP1 and VP2) plus rapid burst and ramp pacing. By analyzing the 79 completed protocols that induced the clinical arrhythmia, the following were determined: (1) the frequency of induced clinical and nonclinical VA with each stimulation step; (2) the yield ratio (YR) of each step, defined as the probability of inducing clinical versus nonclinical arrhythmia; (3) the cumulative yield of induced clinical and nonclinical arrhythmia with two widely used stimulation sequences, i.e., triple extrastimuli delivered early in the stimulation protocol (MMC sequence) and triple extrastimuli delayed until after double extrastimuli failed to induce the clinical arrhythmia (B sequence); (4) the relative efficiency of these sequences were determined. The percentage of induced clinical and nonclinical arrhythmia with SR + 3 extrastimuli, VP1 + 2 extrastimuli, and VP2 + 2 extrastimuli were (53%, 5%), (36%, 5%), and (41%, 9%), respectively. The cumulative yield of induced clinical VA with the MMC-type sequence reached 55% by the third step of the protocol, whereas 50% was attained only at the eighth step of the B-type sequence. The cumulative percentage of induced nonclinical VA with either sequence was similar during the early steps of the protocol. The MMC sequence was more efficient, requiring overall 36% of potential steps for clinical arrhythmia induction, compared with 48% for the B sequence (P less than 0.001). For questionable arrhythmia states, e.g., syncope of unknown origin and nonsustained VT, a modified sequence is proposed that may further reduce the induction of uninterpretable arrhythmias.
Anti-Arrhythmia Agents↗
Characterization of early pathogenic effects after experimental infection of calves with bovine immunodeficiency-like virus.
The early pathogenic effects of bovine immunodeficiency-like virus (BIV) were studied in calves experimentally inoculated with BIV. All animals inoculated with BIV R29-infected cells seroconverted by 6 weeks postinoculation, and BIV was recoverable from each animal at 2 weeks postinoculation. However, levels of BIV replication in vivo appeared to be low. In situ hybridization studies indicated that during peak periods of viral replication in vivo, less than 0.03% of peripheral blood mononuclear cells were expressing detectable levels of viral RNA. Moreover, the levels of viral RNA in these cells in vivo were less than 1/10 the levels observed in persistently infected cells in vitro. BIV-inoculated calves had significantly higher numbers of circulating lymphocytes, and follicular hyperplasia was observed in lymph nodes, hemal nodes, and spleen. The histopathological changes observed in BIV-infected calves were similar to changes found early after infection with the immunosuppressive lentiviruses, including human immunodeficiency virus type 1.
Animals↗
Studies on the biological activity of triiodothyronine sulfate.
Hepatic microsomes and isolated hepatocytes in short term culture desulfate T3 sulfate (T3SO4). We, therefore, wished to determine whether T3SO4 could mimic the action of thyroid hormone in vitro. T3SO4 had no thyromimetic effect on the activity of Ca(2+)-ATPase in human erythrocyte membranes at doses up to 10,000 times the maximally effective dose of T3 (10(-10) mol/L). In GH4C1 pituitary cells, T3SO4 failed to displace [125I]T3 from nuclear receptors in intact cells or soluble preparations. Thus, T3SO4 was not directly thyromimetic in either an isolated human membrane system or a pituitary cell system in which nuclear receptor occupancy correlates with GH synthesis. Thyroid hormones inhibit [3H]glycosaminoglycan synthesis by cultured human dermal fibroblasts, and T3SO4 displayed about 0.5% the activity of T3 at 72 h. Human fibroblasts contained roughly the same level of microsomal p-nitrophenyl sulfatase activity as that previously observed in hepatic microsomes. Propylthiouracil (50 mumol/L) did not affect the action of T3SO4, suggesting that deiodination was not important for this activity of T3SO4. Thus, it appears T3SO4 has no intrinsic biological activity, but, under certain circumstances, may be reactivated by desulfation.
Calcium-Transporting ATPases↗
Exercise testing in the evaluation of patients at high risk for complications from lung resection.
Exercise testing was performed on 37 patients with resectable lung lesions who were deemed inoperable because of any of the following risk factors: (1) FEV1 less than or equal to 40 percent of predicted; (2) radionuclide calculated postlobectomy FEV1 less than or equal to 33 percent of predicted; or (3) arterial PCO2 greater than or equal to 45 mm Hg. The patients who reached a peak level of oxygen consumption during exercise (VO2Peak) of greater than or equal to 15 ml/kg/min were offered surgical treatment. Patients with a VO2Peak of less than 15 ml/kg/min were referred for nonsurgical management and excluded from the study. Eight patients underwent lung resection. Their pulmonary function revealed a severe obstructive lung defect with a group mean predicted FEV1 of 40 +/- 6 percent, an FEV1/FVC ratio of 47 +/- 10, a radionuclide calculated postlobectomy FEV1 of 31 +/- 4 percent, and a mean arterial PCO2 of 44 +/- 6 mm Hg. No relationship was found between each patient's exercise performance and spirometric function. Six of the patients had an uncomplicated postoperative course. Two patients had complications but no patient died as a result of surgery or postoperative complications. All patients were discharged from the hospital within 22 days (mean = 9.8 days). We conclude that exercise testing is a useful complement to conventional cardiopulmonary evaluation used in selecting patients for lung resection.
Aged↗
Molecular approaches to prevention and therapy of aerodigestive tract cancers.
We describe studies defining several molecular events in human non-small-cell lung cancer (NSCLC). These include increased growth factor and growth factor receptor expression and oncogene alterations. The epidermal growth factor receptor (EGFR) and erbB2 are expressed by NSCLC cells. Transforming growth factor-alpha (TGF-alpha) is produced by NSCLC and may mediate autocrine growth stimulation. Specific inhibition of K-ras oncogene expression by an antisense K-ras construct reduces the growth rate and tumorigenicity of NSCLC cells. Studies with antisense p53 in NSCLC with a homozygous p53 mutation suggest that the presence of the mutant form contributes to the transformed state.
Carcinoma, Non-Small-Cell Lung↗
Combination immunotherapy for advanced lung cancer.
Therapeutic strategies using cytokines have not been extensively tested in patients with advanced non-small-cell lung cancer (NSCLC). We developed a basic laboratory and clinical research program to investigate the effective immunotherapeutic manipulations for activating the endogenous immune system with biological agents. Our efforts using low-dose interleukin 2 in conjunction with other biologic response modifiers for the treatment of NSCLC are summarized here.
Antineoplastic Combined Chemotherapy Protocols↗