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Biomedical subjects

L R Kaiser

Publications and source records attributed to L R Kaiser.

At least 91 records · Page 5Linked to original sources
PubMed1997

The role of chemotherapy in the treatment of non-small cell carcinoma of the lung.

Within the past 10 years, the role of chemotherapy in the treatment of patients with non-small cell lung cancer has expanded greatly. Previously chemotherapy was used only for patients with disseminated disease and, despite advances in combination therapy with new agents, response rates remained low, response duration was short, and cures were rare. Performance status is an important prognostic indicator both from the standpoint of response and duration of survival. Patients with locally advanced disease who are otherwise candidates for operation have a significantly higher response rate to chemotherapy and tolerate the treatment reasonably well. Combination chemotherapy given preoperatively seems to be associated with improved survival, especially in those patients able to undergo complete resection. Radiation therapy and chemotherapy given preoperatively may be even more efficacious than either modality alone. The question as to whether surgical resection improves on what can be accomplished with radiation therapy and chemotherapy in patients with mediastinal lymph node involvement remains an open one and is currently being evaluated.

Antineoplastic Agents↗
PubMed1997

New therapies in the treatment of malignant pleural mesothelioma.

It can be safely stated that currently there exists no standard therapy for malignant mesothelioma. The "standard" methods of chemotherapy, radiation therapy, and surgery have all been used with little improvement in overall survival. Trimodality therapy that involves a combination of all three standard treatment modalities has been shown to improve survival in selected patients. New and innovative treatment strategies clearly are needed for a disease which, because of the disappointment with standard therapy, is most commonly approached with only palliative intent. The location of this malignancy and its tendency to remain localized make it an ideal target for intracavitary approaches using photodynamic therapy, targeted cytokines, and gene therapy. Strategies using modulation of the immune system in an attempt to elicit a specific response to the tumor have been combined with chemotherapy to optimize response. Lessons learned from treating this localized malignancy with novel therapies may have much broader implications for other tumors in which systemic disease predominates.

Adenoviridae↗
PubMed1996

Safety of intrapleurally administered recombinant adenovirus carrying herpes simplex thymidine kinase DNA followed by ganciclovir therapy in nonhuman primates.

Preclinical safety and toxicity studies of intrapleural administration of recombinant adenovirus carrying the herpes simplex thymidine kinase gene (H5.010RSVtk) were performed. Previously reported experimental evidence has demonstrated the efficacy of this approach in animal models of a localized thoracic cancer, malignant mesothelioma. H5.010RSVtk was delivered at high dose (10(12) pfu) into the pleural cavity of three non-human primates followed by systemic administration of ganciclovir. No clinical toxicity was noted. Although an inflammatory reaction observable by microscopy was noted in the serosal spaces of the chest cavity, these changes were reversible and were not associated with radiographic sequelae. Extrathoracic viral dissemination was minimal and detectable only by sensitive polymerase chain reaction techniques. This low level of viral dissemination was not associated with detectable clinical, biochemical, or pathologic abnormalities.

Adenoviridae↗
PubMed1996

Herpes simplex 1716--an ICP 34.5 mutant--is severely replication restricted in human skin xenografts in vivo.

HSV-1716 is a replication-restricted, neuroattenuated ICP 34.5 gene mutant of herpes simplex virus type 1 (HSV-1). Because of the attenuated phenotype of ICP 34.5 mutants in rodent models of HSV disease, they have been promoted as potential vaccine strains and gene therapy vectors and have been used by us and others as therapeutic agents for the treatment of experimental malignant tumors. However, all data on the phenotype of HSV-1716 and other ICP 34.5 mutants are from animal model systems, while humans are the natural hosts of HSV-1. To achieve an initial characterization of the phenotype of 1716 in human tissue, we have studied its replication in mature human skin xenografts on SCID mice. We find that replication of 1716 is severely restricted in such human skin grafts relative to both parental wild-type HSV-1 strain 17+ and the HSV-1716 revertant virus 1716R, in which the 759-bp ICP 34.5 gene deletions have been repaired. Moreover, the replication of both 1716 and 17+ is significantly better in the human skin grafts than it is in mouse skin. The implications of these findings are discussed.

Animals↗
PubMed1996

Treatment of pleural mesothelioma in an immunocompetent rat model utilizing adenoviral transfer of the herpes simplex virus thymidine kinase gene.

Previously, we have treated malignant mesothelioma (MM) growing in the peritoneal cavity of immunodeficient mice utilizing a recombinant adenovirus vector carrying the herpes simplex virus-thymidine kinase gene (Ad.RSVtk) followed by administration of the anti-viral drug ganciclovir (GCV). To mimic more closely the clinical situation in human MM, a syngeneic model of pleural MM was developed in immunocompetent Fischer rats. Administration of Ad.RSVtk into the pleural space of animals with established multifocal tumor followed by systemic GCV therapy resulted in significant tumor regression at 20 days in HSVtk/GCV-treated animals (average tumor weight 0.6 +/- 0.2 gram; n = 12) versus control animals (average weight 5.4 +/- 0.2 grams; n = 21; p < 0.001). In additional studies, Ad.RSVtk/GCV-treated animals had a mean survival of 34 days (average tumor weight 1.0 +/- 0.3 gram at death) versus 26 days in control animals (average tumor weight 6.2 +/- 0.6 grams at death). A significant reduction in tumor burden was also seen when more advanced, bulkier disease was treated. These studies demonstrate the Ad.RSVtk/GCV system is effective in the treatment of pleural-based tumors in an immunocompetent host. However, there are limitations to this treatment approach that result in only small increments in survival.

Adenoviruses, Human↗
PubMed1996

Lepidic intrapulmonary growth of malignant mesothelioma presenting as recurrent hydropneumothorax.

We report a case of malignant mesothelioma with unusual clinical and histological findings. The patient presented with recurrent hydropneumothorax and minimal pleural thickening on chest computed tomography (CT). Histologically, the pleura was involved by the malignant mesothelioma, albeit to a limited degree. Unexpectedly, the lung parenchyma from two different lobes showed focal nests of mesothelioma cells filling the alveolar spaces and growing on the luminal surface of the alveolar septa, closely resembling the multicentric growth pattern of bronchioloalveolar adenocarcinoma. Immunohistochemical and ultrastructural studies confirmed that the pulmonary lesions were an extension of the malignant mesothelioma. This case illustrates clinically, the importance of a high index of suspicion for malignancy in older patients with unexplained recurrent hydropneumothorax; and histologically the potential of malignant mesothelioma to invade the lung at an early stage of growth.

Aged↗
PubMed1996

Bilateral lung volume reduction surgery for advanced emphysema. A comparison of median sternotomy and thoracoscopic approaches.

STUDY OBJECTIVES: To compare short-term outcomes following bilateral lung volume reduction surgery performed by median sternotomy (MS) and video-assisted thoracoscopic surgery (VATS). METHODS: Bilateral lung volume reduction surgery was performed by MS in 80 patients and by VATS in 40. All patients underwent preoperative assessment with pulmonary function testing, arterial blood gas determination, and 6-min walk test (6MWT). Pulmonary function testing and 6MWT were repeated at 3 to 6 months postoperatively. RESULTS: The mean age of the VATS group was lower than that of the MS group (59.3 +/- 9.4 vs 62.4 +/- 6.9 years; p = 0.001), but there were no differences in baseline functional parameters of disease severity (FEV1, FVC, residual volume [RV], arterial PCO2, or 6MWT). All patients in both groups were extubated at the completion of surgery, but 17.5% of patients in the MS group and 2.5% in the VATS group (p = 0.02) subsequently required reintubation at some point during the postoperative course. Thirty-day operative mortality was 4.2% for the MS group and 2.5% for the VATS group (p = not significant). However, total in-hospital mortality was 13.8% for the MS group, while it remained 2.5% for the VATS group (p = 0.05). Mortality was largely confined to patients 65 years of age or older. There was no significant difference in duration of air leaks or length of hospital stay between the two groups. Functional outcomes achieved with the two techniques were similar. Specifically, there was no difference between the two groups in mean postoperative FEV1, FVC, RV, or 6MWT, or in the magnitude of change in these parameters over preoperative values. CONCLUSIONS: Bilateral lung volume reduction surgery performed by either MS and VATS approaches leads to similar improvements in pulmonary function and exercise tolerance. VATS is associated with a significantly lower incidence of respiratory failure and a trend toward decreased in-hospital mortality and may be the preferred technique, particularly for high-risk patients.

Carbon Dioxide↗
PubMed1996

Health care in the 21st Century.

Our primary agenda for the 21st Century is the reinvention of America. We must reinvent democracy, capitalism, entrepreneurism, and community. Indeed, we must recreate all of our major social institutions. This includes health care. A design for a new society requires a new design for health care. In fact, health care enjoys a special privilege in this regard. It is the gateway to total societal redesign. Health is the common denominator in any society. If you loose your health you cannot work, you cannot play, you cannot study; and, if you lose it sufficiently, you cannot even pray. Health and well-being create the foundation for all other constructive human endeavors. Therefore, the design of healthy communities is the necessary first step in the redesign of total human habitats. This massive redesign effort will take a century. However, it will be launched in the next few years.

Community Health Planning↗
PubMed1996

Thoracoscopic resection of mediastinal tumors and the thymus.

Videothoracoscopic techniques have proven their usefulness in dealing with pathology in the anterior mediastinum and should be considered in many cases as the procedure of choice. The surgeon's judgment, as always, is key in deciding which procedure is best suited for dealing with a particular lesion in any given patient. Thoracic surgeons need to be facile with these techniques in order to be able to provide the best approach for each patient. We need to be vigilant in observing and reporting results with these still relatively new procedures to ensure that outcomes are equivalent to the standard open procedures. The cost effectiveness of these minimally invasive procedures compared with the analogous open procedure still remains to be determined. Despite a shortened hospital stay for many of these procedures the equipment is more expensive and time in the operating room may be longer. It is safe to say, however, that many of these minimally invasive procedures are here to stay even if they fail to show a reduction in costs.

Humans↗
PubMed1996

Gap junctions play a role in the 'bystander effect' of the herpes simplex virus thymidine kinase/ganciclovir system in vitro.

Tumor cells transduced with the herpes simplex virus thymidine kinase (HSVtk) gene are sensitive to the anti-viral drug ganciclovir (GCV). However, nearby untransduced tumor cells are also efficiently killed. The mechanism of this 'bystander effect' was studied by comparing pairs of tumor cell lines transfected with connexin genes that differed only in their degree of gap junctional communication. More efficient cell killing was uniformly seen in connexin transfectants compared with the less coupled cell lines. These results provide direct evidence that gap junctional communication plays an important role in mediating the bystander effect of the HSVtk/GCV system in vitro and have important prognostic and therapeutic implications for future gene therapy trials.

Adenoviruses, Human↗
PubMed1996

GI complications after orthotopic lung transplantation.

OBJECTIVES: Recently, lung transplantation has been performed with increasing frequency and improved outcomes. GI complications have been observed and reported in patients undergoing cardiac and renal transplantations but only recently have been reported in patients after lung transplantation. No large cohort has been systematically analyzed for all GI complications after lung transplantation. The present study describes, categorizes, and assesses risk factors for the development of such GI complications. METHODS: Records of 45 patients who underwent 47 single or bilateral orthotopic lung transplants between November 1991 and January 1994 were reviewed. RESULTS: Twenty-three patients (51%) had 64 GI complications requiring 13 operations on eight patients. The incidence of major abdominal procedures in the entire transplant cohort was 18% (8/45). Their operative mortality rate was 63% (5/8). Eighteen different types of nonoperative complications occurred and were subclassified into major and minor complications. Complications were defined as major if they required medical or surgical intervention and altered patient management. Most GI complications (73%) occurred within 1 month after transplantation. No risk factors were identified to ascertain who will develop GI complications. CONCLUSIONS: GI complications occur in more than one-half of lung transplant recipients early after transplantation and in the absence of identifiable risk factors. Because there are no precedent risk factors to suggest who will develop GI complications, clinicians must be alert to any warning signs and symptoms. The majority of complications are nonoperative, responding to conservative therapy, but there is a higher overall mortality rate for patients requiring operative intervention, necessitating an aggressive search for major, life-threatening complications in these immunosuppressed patients.

Female↗
PubMed1995

Integrin expression in non-small cell carcinoma of the lung.

Alteration of integrin expression in a number of different malignant diseases has been recognized, with a trend of downregulation of collagen-laminin binding integrin expression in epithelial tumor types noted. This study evaluated the expression of a panel of integrin subunits that included subunits that form receptors that bind to collagen and laminin (alpha 2, alpha 3, alpha 6 beta 4) and subunits that form receptors that bind to fibronectin and fibrinogen (alpha 5, alpha V, beta 3, beta 6) in 51 specimens of non-small cell carcinoma (NSCCA) of the lung by use of immunohistochemistry. Integrin expression was then correlated with histologic type (squamous vs. adenocarcinoma), absence or presence of hilar or mediastinal nodal metastasis at resection, and cellular differentiation (well or poorly differentiated). In general, downregulation of the collagen-laminin binding subunits was noted in tumor cells of the NSCCA specimens when compared to the progenitor normal bronchial epithelium. No differences were noted in integrin expression between squamous cell and adenocarcinoma or between node-positive or node-negative tumors. However, downregulation of the integrin subunit alpha 3 was noted to be significantly more common in poorly differentiated tumors (p = 0.02) and several of the other collagen-laminin binding subunits also appeared to be more downregulated in poorly differentiated tumors. No upregulation was seen in the alpha 5 subunit of the fibronectin receptor or the beta 3 subunit of the vitronectin receptor, however, approximately 50% of tumors showed upregulation of the beta 6 subunit, the great majority of these being well-differentiated, node-negative tumors. Downregulation of the collagen-laminin integrins may thus be associated with differentiation of NSCCA, but not metastasis, and may serve as an adjunctive prognostic marker of disease. The beta 6 subunit appears to be associated with malignant transformation, but may serve as a positive prognostic factor.

Antibodies, Monoclonal↗
PubMed1995

Thoracoscopic removal of mediastinal parathyroid adenoma.

Mediastinal parathyroid tissue hyperfunctions in as much as 25% of the patients with primary hyperparathyroidism, and this may be responsible for causing conventional operative procedures to fail in as much as one-third of the cases. When lesions prove to not be accessible through a cervical incision, or when a mediastinal adenoma is diagnosed before cervical procedures, median sternotomy and angiographic ablation have been considered the only options for removal. However, thoracoscopy has theoretic advantages over both. Two patients underwent successful thoracoscopic removal of a hyperfunctioning ectopic mediastinal parathyroid adenoma and their cases are presented here.

Adenoma↗
PubMed1995

Fungal pulmonary abscess in an adult secondary to hyperimmunoglobulin E (Job's) syndrome.

Job's syndrome is characterized by recurring bacterial infections of the skin and sinopulmonary tract. Laboratory evaluation reveals consistent elevation of circulating immunoglobulin E levels. The syndrome has been reported as a rare cause of bacterial pulmonary abscess and pneumatocele formation in childhood; here we present a case of cavitating fungal abscess in an adult with Job's syndrome.

Adult↗
PubMed1995

Pleural-based mesothelioma in immune competent rats: a model to study adenoviral gene transfer.

BACKGROUND: Despite multimodality approaches, pleural-based malignant mesothelioma remains a disease with a very poor prognosis. Novel therapeutic strategies such as gene therapy clearly are needed to improve the survival of patients with this neoplasm. To aid in the evaluation of new treatment strategies, animal models that closely mimic human disease are required. This article describes the establishment of a pleural-based model of malignant mesothelioma in immune-competent Fischer rats. METHODS: Via a modified left anterior lateral thorocotomy, a syngeneic malignant mesothelioma cell line, called II-45, was placed into the pleural cavity of Fischer rats. RESULTS: Placement of II-45 cells into the pleural cavity of Fischer rats results in a model of pleural mesothelioma that closely resembles the disease seen in patients and is highly reproducible, with animals dying within 1 month. We also demonstrate the feasibility of adenoviral-mediated gene transfer to normal mesothelial cells lining the pleural cavity, as well as to malignant cells deep within the substance of pleural-based malignant mesothelioma. CONCLUSIONS: The model described here offers the opportunity to study a variety of new treatment modalities, especially somatic gene transfer, against pleural-based malignant mesothelioma in an immune competent setting.

Adenoviridae↗
PubMed1995

Differential sensitivity of thoracic malignant tumors to adenovirus-mediated drug sensitization gene therapy.

Malignant mesothelioma may prove to be an attractive candidate for somatic gene therapy with replication-deficient recombinant adenovirus transfer of a toxic, or drug sensitization gene. Transfer of the herpes simplex thymidine kinase type I gene (HSVtk), followed by exposure to the acyclic nucleoside drug ganciclovir, has been shown to be an effective tumor cell killing system. To study generalized applicability, we tested a number of thoracic malignant cell lines for their sensitivity to gancyclovir after infection with an adenoviral vector containing the HSVtk gene (Ad.RSVtk). Using the concentration of gancyclovir required to kill 50% of the cells (IC50) as a measure of sensitivity, we detected variable sensitivity among cell lines, with mesothelioma most sensitive (IC50 = 0.075 to 2.8 mumol/L gancyclovir), and non-small-cell carcinoma lines having an intermediate sensitivity (IC50 = 1.5 to 100 mumol/L). In contrast, an ovarian carcinoma line was extremely resistant (IC50 > 2000 mumol/L). To study the possible mechanisms for these differences, we studied cell lines with regard to their ability to be infected with an adenoviral vector containing a marker gene (Ad.CMVlacZ) and expression of the vitronectin receptor alpha v (an integrin cell adhesion molecule shown to be required for adenovirus internalization after initial binding). We found that the degree of lacZ transduction correlated with HSVtk sensitivity, whereas vitronectin receptor expression did not, suggesting that differences in initial viral binding ability, rather than internalization, may explain the sensitivity differences seen in vitro.

Adenoviridae↗