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Biomedical subjects

L R Kaiser

Publications and source records attributed to L R Kaiser.

At least 109 records · Page 6Linked to original sources
PubMed1995

Treatment of experimental human mesothelioma using adenovirus transfer of the herpes simplex thymidine kinase gene.

OBJECTIVE: The authors demonstrate the ability of an adenovirus vector expressing the herpes simplex thymidine kinase (HSVtk) gene to treat human malignant mesothelioma growing within the peritoneal cavity of severe combined immunodeficient (SCID) mice. BACKGROUND DATA: Introduction of the HSVtk gene into tumor cells renders them sensitive to the antiviral drug ganciclovir (GCV). This approach has been used previously to treat experimental brain tumors. Although malignant mesothelioma is refractory to current therapies, its localized nature and the accessibility of the pleural space make it a potential target for a similar type of in vivo gene therapy using adenovirus. METHODS: An adenovirus containing the HSVtk gene (Ad.RSVtk) was used to transduce mesothelioma cells in vitro. These cells were then injected into the flanks of SCID mice. Ad.RSVtk was also injected directly into the peritoneal cavity of SCID mice with established human mesothelioma tumors. Mice were subsequently treated for 7 days with GCV at a dose of 5 mg/kg. RESULTS: Mesothelioma cells transduced in vitro with Ad.RSVtk formed nodules when injected in the subcutaneous tissue. These tumors could be eliminated by the administration of GCV, even when as few as 10% of cells were transduced to express HSVtk (bystander effect). Administration of Ad.RSVtk into the peritoneal space of animals with established multifocal human mesothelioma followed by GCV therapy resulted in the eradication of macroscopic tumor in 90% of animals and microscopic tumor in 80% of animals when evaluated after 30 days. The median survival of animals treated with Ad.RSVtk/GCV was significantly longer than that of control animals treated with similar protocols. CONCLUSION: These results indicate that an adenoviral vector containing the HSVtk gene is effective in treating established malignant mesothelioma in an in vivo setting and raise the possibility of using adenovirus transfer of HSVtk for clinical trials in mesothelioma and other localized tumors.

Adenoviruses, Human↗
PubMed1995

The role of immunosuppression in the efficacy of cancer gene therapy using adenovirus transfer of the herpes simplex thymidine kinase gene.

OBJECTIVE: To determine whether the immune system limits or improves the therapeutic efficacy of an adenovirus vector expressing the herpes simplex thymidine kinase (HSVtk) gene in a subcutaneous tumor model. BACKGROUND DATA: Enhanced immune reactions against tumors may be therapeutically useful. However, recent studies with adenoviral vectors show that immune responses limit the efficacy and persistence of gene expression. The effect of the immune response on cancer gene therapy with HSVtk gene delivery by an adenovirus vector followed by treatment with ganciclovir is unclear. METHODS: After adenoviral transduction of a Fischer rat syngeneic mesothelioma cell line with the HSVtk gene in vitro, subcutaneous flank tumors were established. The ability of the HSVtk/ganciclovir system to inhibit tumor growth was compared among normal Fischer rats, immunodeficient nude rats, and Fischer rats immunosuppressed with cyclosporin. RESULTS: HSVtk/ganciclovir therapy was more effective in nude rats and immunosuppressed Fischer rats than in immunocompetent Fischer rats. CONCLUSION: These results indicate that the immune response against adenovirally transduced cells limits the efficacy of the HSVtk/ganciclovir system and that immunosuppression appears to be a useful adjunct. These findings have important implications for clinical trials using currently available adenovirus vectors as well as for future vector design.

Adenoviridae↗
PubMed1995

Successful nonoperative management of secondarily infected pulmonary pseudocyst: case report.

Pulmonary contusion is a frequent sequelae of blunt chest trauma. If significant shear forces are encountered during energy transfer to the chest wall, pulmonary laceration may result. Most traumatic pulmonary lacerations resolve spontaneously. However, secondary infection of a posttraumatic laceration often leads to serious complications that may be lethal. We report a case of a secondarily infected pulmonary laceration resulting from blunt trauma that was successfully treated by computerized tomogram-guided drainage and review the literature on this unusual complication.

Adult↗
PubMed1995

Adenovirus-mediated gene transfer to human bronchial submucosal glands using xenografts.

The cystic fibrosis (CF) transmembrane conductance regulator has been localized to both submucosal glands and surface epithelium, suggesting that both glandular and surface epithelium may be important targets for gene therapy. To determine the distribution and efficiency of recombinant adenovirus-mediated gene transfer to human airway submucosal glands, an in vivo model was developed by heterotopically transplanting human bronchial segments from both normal and CF lung tissue into severe combined immunodeficient mice. A serotype 5 E1-deleted recombinant adenovirus containing a lacZ reporter gene driven by the cytomegalovirus promoter (H5.010CMVlacZ) was used to infect the xenografts. Transgene expression was correlated with three factors: 1) viral titer, 2) penetration of microspheres, and 3) dwell time of the viral instillate. At viral titers ranging from 10(8) to 10(11) plaque forming units/ml, expression of the lacZ gene was observed in a subpopulation of epithelial cells within approximately 40% of submucosal glands, with more efficient gene transfer to the ducts than the secretory tubules. Within individual glands, gene transfer varied from < 1% to approximately 20% of submucosal cells, including duct, mucous, and serous cells. Adenovirus-sized fluorescent microspheres were found to penetrate only some of the submucosal glands, suggesting that the gene transfer efficiency to submucosal tubules is due to limited viral particle penetration rather than tropism. Gene transfer to surface epithelial cells was inefficient. However, the percentage of transduced surface epithelial cells increased from < 1% to 5-10% as the dwell time of viral solution was increased from 5 min to 1 h, indicating that the time allowed for virus binding and entry is important for gene transfer efficiency.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcysteine↗
PubMed1995

Gene therapy using adenovirus carrying the herpes simplex-thymidine kinase gene to treat in vivo models of human malignant mesothelioma and lung cancer.

Previous studies have shown adenoviral transfer of the herpes simplex virus thymidine kinase (HSVtk) gene followed by the anti-viral drug ganciclovir (GCV) can be used to successfully treat established human mesothelioma tumors growing within the peritoneal cavities of severe combined immune deficient (SCID) mice. These findings raised a number of questions important to the applicability, efficiency, and safety of this treatment strategy. In this report, we have further characterized the use of recombinant adenovirus carrying the HSVtk gene to treat mesothelioma and other localized malignancies. Our results indicate that the Ad.RSVtk/GCV system is effective in causing tumor regression in animals inoculated with another mesothelioma cell line and a lung cancer cell line and that animals with bulky disease can be successfully treated. Effects are seen at a wide range of virus doses and significant anti-tumor activity is present at doses of ganciclovir that are clinically achievable. Finally, this treatment approach appears safe, with limited dissemination of virus using a sensitive RT-PCR detection system. These studies further characterize the use of adenoviral transfer of the HSVtk gene to treat experimental mesothelioma and suggest that clinical trials using this approach may be feasible.

Adenocarcinoma↗
PubMed1995

Video-assisted thoracic surgery: the current state of the art.

Surgical thoracoscopy (or pleuroscopy) has historically been underused in the diagnosis and therapy of diseases of the chest. The rapid developments in laparoscopy in recent years caused thoracic surgeons to reconsider the use of endoscopic techniques in surgery of the chest. Advances in video camera technology and the use of digital processing technology so expanded the potential of thoracoscopy that an entirely new set of procedures, called video-assisted thoracic surgery, has emerged. This article reviews situations in which video-assisted procedures have proven useful, the techniques by which these procedures are performed, and the rationale behind using the video-assisted in lieu of the open approach. Video-assisted surgery often allows one to accomplish the same goal as the comparable open procedure but with less morbidity and a shorter hospital stay. With continued development of instrumentation, increasingly complex procedures continue to be accomplished. It is important for radiologists to be aware of these new developments in minimally invasive surgery, as the techniques have major implications for the practice of chest medicine and surgery as a whole. The evolution of the management of the solitary pulmonary nodule is but one example of the way video-assisted thoracic surgery has called into question the traditional approach to diseases of the chest.

Endoscopy↗
PubMed1994

Use of recombinant adenovirus to transfer the herpes simplex virus thymidine kinase (HSVtk) gene to thoracic neoplasms: an effective in vitro drug sensitization system.

Transfer of the herpes simplex virus thymidine kinase (HSVtk) gene into tumor cells using retroviral vectors followed by administration of ganciclovir provides a potential strategy for the treatment of malignancy. Because of the limitations of using retroviral vectors for clinical application, the feasibility of using a recombinant adenovirus containing HSVtk was examined. Cell lines derived from human malignant mesotheliomas and non-small cell lung cancers infected with a recombinant adenovirus containing HSVtk showed strong expression of HSVtk protein as determined by immunohistochemical staining. Infection with a recombinant adenovirus containing HSVtk rendered cells sensitive to doses of ganciclovir that were 2-3 logs lower than uninfected cells or those infected with a control virus. A strong "bystander effect" was noted in mesothelioma lines; there was no diminution in the efficacy of ganciclovir treatment until the ratio of infected:uninfected cells fell below 1:10. This study thus demonstrates in vitro efficacy of an adenovirus-transduced HSVtk drug sensitization gene therapy system in thoracic malignancies. Recombinant adenovirus transfer of the HSVtk gene followed by ganciclovir may have promise as an in situ treatment for tumors.

Adenoviridae↗
PubMed1994

Successful adenovirus-mediated gene transfer in an in vivo model of human malignant mesothelioma.

Malignant mesothelioma remains a frustrating clinical problem with uniformly poor responses to current therapeutic regimens. However, the localized nature of the disease, the potential accessibility of the tumor, and the relative lack of distant metastases make it a particularly attractive candidate for somatic gene therapy. The purpose of this study was to evaluate the ability of an adenoviral vector system to transfer genetic material to human mesothelioma cells in vitro and in vivo. Using a replication-deficient recombinant adenovirus carrying the Escherichia coli lacZ marker gene, we found that human mesothelioma cell lines were susceptible to adenovirus infection. Furthermore, surprisingly effective gene transfer was accomplished within tumor implants of human mesothelioma growing within the peritoneal cavity of immunodeficient mice after intraperitoneal administration of virus. These studies demonstrate that adenoviral vectors hold promise as vehicles to deliver gene therapy in human malignant mesothelioma.

Abdomen↗
PubMed1994

Esophageal disease in the elderly patient.

Disorders of the esophagus in elderly patients are usually associated with the classic symptoms of dysphagia, regurgitation, chest pain, and heartburn. Pulmonary complaints as a result of undiagnosed esophageal disease are common in this age group. Diagnosis is often delayed because symptoms are attributed to underlying cardiac and pulmonary disease. Elderly patients are more susceptible to the complications of aspiration and malnutrition that often accompany inadequately treated esophageal disease; therefore, prompt and aggressive treatment is indicated. Criteria for surgical intervention in esophageal disease do not change with age. Properly selected elderly patients tolerate esophageal surgery well. Age alone should not constitute a contraindication to surgery of the esophagus.

Aged↗
PubMed1994

Video-assisted thoracic surgery. Current state of the art.

OBJECTIVE: The author reviews the current state of the art of video-assisted thoracic surgery in the context of modern thoracic surgical practice. SUMMARY BACKGROUND DATA: Thoracoscopy has been a part of thoracic surgical practice for many years, but was used mainly for diagnosis of pleural disease. The development of laparoscopic cholecystectomy awakened a new interest in this technique and led to the development of many new therapeutic and diagnostic applications of video-assisted thoracic surgery. METHODS: Current literature and the author's personal experience with more than 500 cases are reviewed. RESULTS: Video-assisted techniques have proven useful for the performance of a broad spectrum of thoracic surgical procedures. Patients may experience less pain and have a shorter hospital stay after a video-assisted procedure. Definitive proof of less morbidity when compared with the analagous open procedure remains to be determined. Patient acceptance has been high, and most thoracic surgeons use these techniques in their practice. CONCLUSIONS: Video-assisted thoracic surgical procedures have made a significant impact on the practice of thoracic surgery. Advantages and disadvantages of specific procedures remain to be definitively determined. Surgeons have learned these techniques and have kept morbidity to acceptance levels during the learning phase. Where these techniques ultimately fit into the overall practice remains to be determined as more experience is gained.

Humans↗
PubMed1994

Expression of endothelial cell adhesion molecules in human bronchial xenografts.

The role of endothelial cell adhesion molecules (CAMs) in the selective recruitment of leukocyte subsets to the airway remains unclear. The goal of the present study was to examine the expression of human endothelial CAM in a cytokine-induced airway inflammatory response. To accomplish this, an in vivo model of human bronchus was developed by heterotopically transplanting intact sections of human airway into severe combined immunodeficient (SCID) mice. Three weeks after transplantation, the xenografts closely resembled normal bronchus with little evidence of rejection. Less than 15% of the submucosal vessels expressed E-selectin and vascular cell adhesion molecule-1 (VCAM-1), whereas intercellular adhesion molecule-1 (ICAM-1) was present constitutively on approximately 35% of bronchial microvessels. Intrabronchial instillation of tumor necrosis factor-alpha (TNF-alpha) significantly increased expression of microvascular E-selectin to 40%, ICAM-1 to 65%, and VCAM-1 to 41%, and was accompanied by an influx of murine leukocytes into the bronchial submucosa. These results demonstrate that the human bronchial microvasculature expresses cytokine-inducible adhesion molecules. Mast cells and other resident or migratory cells that secrete TNF-alpha may thus activate the bronchial microvasculature and thereby recruit leukocytes to the airway.

Animals↗
PubMed1994

Thymoma. The use of minimally invasive resection techniques.

Surgery remains the cornerstone of therapy for thymoma whether the lesion is encapsulated or invasive. Video-assisted thoracic surgical techniques may be applicable in a number of patients with encapsulated thymoma for definitive therapy, especially when combined with a transcervical approach to achieve total thymectomy. Initial experience with a minimally invasive approach for resection of thymomas is described. The development of new instrumentation facilitates the performance of these procedures.

Combined Modality Therapy↗
PubMed1993

Complications of thoracoscopy.

Although thoracoscopy has been a part of thoracic surgical practice for many years, the advent of video-assisted techniques has greatly expanded the indications and the uses of this procedure. Where previously thoracoscopy was performed mainly for diagnostic purposes, it now has assumed a major role in the therapy of chest pathology. In an attempt to inject a modicum of perspective into the tremendous enthusiasm that has accompanied the meteoric rise of video-assisted thoracoscopy, we have reviewed the experience at the Hospital of the University of Pennsylvania accumulated over the 1-year period from December 1991 to December 1992, specifically looking at complications resulting from the thoracoscopic procedure. During this period we performed 266 thoracoscopic procedures with no deaths. The overall incidence of complications was 10%, with the most prevalent complication being prolonged air leak (3.7%). There were five superficial wound infections (1.9%) and 5 patients who bled significantly enough to require either transfusion or reoperation, or both. In 11 patients (4.1%), the proposed thoracoscopic procedure could not be completed as planned, and a thoracotomy was required. The incidence of complications is certainly acceptable and similar to that seen after thoracotomy, although overall hospital stay is shorter and patients seem to have less pain and return to normal activity sooner. One would expect the incidence of complications to further decrease as surgeons acquire more experience with this significant modification and improvement of an old technique.

Aged↗
PubMed1993

Neointimal macrophages colocalize with extracellular matrix gene expression in human atherosclerotic pulmonary arteries.

Vascular remodeling in adult atherosclerotic pulmonary arteries is characterized by discrete areas of neointimal extracellular matrix gene expression, suggesting regulation by local factors. Though the factors responsible for inducing matrix gene expression in atherosclerotic lesions are largely unknown, several observations suggest macrophages may be a focal source of those factors. Immunohistochemistry confirmed the presence of macrophages in the neointima of atherosclerotic elastic pulmonary arteries from patients with unexplained pulmonary hypertension. Areas of neointima containing dense clusters of macrophages were separated by sparsely populated areas. Foamy macrophages resided more deeply within the neointima than nonfoamy macrophages, which were found more often subjacent to the endothelium or within the lumenal one-third of the neointima. Combined immunohistochemistry-in situ hybridization indicated neointimal fibronectin and type I procollagen gene expression was intimately associated only with nonfoamy neointimal macrophages. These observations suggest that: (a) nonfoamy neointimal macrophages participate in the local regulation of extracellular matrix gene expression in atherosclerotic pulmonary arteries; (b) foamy macrophages, which are not associated with matrix gene expression, have undergone modulation of their secretory phenotype.

Arteriosclerosis↗
PubMed1993

Managing in uncertain times.

Radical change, often referred to as a paradigm shift, will occur in the wake of the United States healthcare reform effort currently underway. It will be value-based, community-oriented and patient- and family-centered. These changes will pose great challenges for materiel management. The future will call for integrated healthcare delivery networks that will see hospitals lose their preeminence as providers and, subsequently, needed revenues. Strategies such as implementation of total quality management, and vendor and community partnering will become more pronounced. Materiel managers will see their role change to one of information gathering and disseminating. All healthcare managers will need new skills to help shape the future of healthcare delivery, including the ability to challenge assumptions, understand that there are alternative realities, anticipate business trends, and create and implement a vision of the future of their organization.

Comprehensive Health Care↗
PubMed1993

Active collagen synthesis by pulmonary arteries in human primary pulmonary hypertension.

Immunohistochemistry was performed on lung tissue obtained from patients with severe unexplained pulmonary hypertension using an antibody to the amino-terminal end of the procollagen type I propeptide. This antibody identifies newly synthesized alpha I(I) procollagen before cleavage of the amino-terminal propeptide following secretion and, therefore, can identify sites of active collagen deposition. Procollagen was detected in the media, media and neointima, or neointima alone of a large number of small muscular arteries from hypertensive lungs. Normal adult lungs were negative. Neointimal cells in remodeled small muscular arteries stained positively for alpha-smooth muscle actin and desmin consistent with a smooth muscle lineage. These data suggest smooth muscle-like cells in small muscular arteries are actively synthesizing collagen in patients with severe unexplained pulmonary hypertension.

Actins↗