Biomedical subjects

D J Sugarbaker

Publications and source records attributed to D J Sugarbaker.

123 records · Page 7Linked to original sources

PubMed1992

Multimodality treatment of stage IIIA non-small-cell lung carcinoma: a critical review of the literature and strategies for future research.

PURPOSE AND DESIGN: Stage IIIA non-small-cell lung carcinoma (NSCLC) is composed of regionally advanced yet potentially resectable disease. Many trials have evaluated a variety of therapeutic strategies. Most have been single-arm phase II trials, although a number of comparative phase III trials have also been performed. This review critically evaluates the existing literature on the treatment of stage IIIA NSCLC, particularly the various multimodality approaches that have been used. RESULTS: A review of the existing literature does not establish the optimal treatment of stage IIIA NSCLC. Although radiation therapy alone remains the most commonly administered therapy for apparently unresectable disease, the status of radiation as a "standard" therapy can be seriously challenged based on existing data. Similarly, although a number of studies have established that surgical resection is clearly feasible in selected patients with stage IIIA disease, the efficacy of surgery also remains to be definitively established. Many studies have explored neoadjuvant chemotherapy, either in conjunction with radiation or surgery, with results that are best described as conflicting and controversial. CONCLUSIONS: Without question, randomized phase III trials are required at this time to define what is to be considered optimal treatment. An attempt is made to define the most important questions that should be addressed in future phase III trials. Additionally, a number of study designs are suggested to best answer the therapeutic questions posed.

Carcinoma, Non-Small-Cell Lung↗

PubMed1992

Malignant pleural mesothelioma: value of CT and MR imaging in predicting resectability.

OBJECTIVE: Our objective was to determine if CT or MR imaging findings could be used to accurately predict resectability in patients with biopsy-proved malignant pleural mesotheliomas. SUBJECTS AND METHODS: CT and MR findings in 41 consecutive patients with malignant mesotheliomas who were referred to the thoracic surgery clinic for extrapleural pneumonectomy were studied by thoracic radiologists before surgery. Review of radiologic studies focused on local invasion of three separate regions: the diaphragm, chest wall, and mediastinum. Results of all imaging examinations were carefully correlated with intraoperative, gross, and microscopic pathologic findings. RESULTS: After radiologic and clinical evaluation, 34 patients (83%) had thoracotomy; 24 of these had tumors that were resectable. The sensitivity was high (> 90%) for both CT and MR in each region. Specificity, however, was low, probably because of the small number of patients with unresectable tumors. CONCLUSION: CT and MR provided similar information on resectability in most cases. Sensitivity was high for both procedures. Because CT is more widely available and used, we suggest it as the initial study when determining resectability. In difficult cases, important complementary anatomic information can be derived from MR images obtained before surgical intervention.

Asbestos↗

PubMed1991

Peptidergic innervation of the human esophageal smooth muscle.

Studies were performed to define the peptidergic nature of intramural nerves in the human esophagus. Cryosections of uninvolved surgically resected tissues from 14 individuals were studied by immunofluorescence for the localization of 10 neuropeptides. Myenteric neurons showed bombesin-, calcitonin gene-related peptide-, galanin-, substance P-, vasoactive intestinal polypeptide-, leucine-enkephalin-, methionine-enkephalin-, neuropeptide Y-, and somatostatin-like immunoreactivity. Submucous neurons had all the above except neuropeptide Y, methionine-enkephalin, leucine-enkephalin, and bombesin. Both groups of neurons received nerve terminations positive for calcitonin gene-related peptide, galanin, neuropeptide Y, substance P, and vasoactive intestinal polypeptide. Myenteric neurons additionally received terminations positive for neuropeptide Y, methionine-enkephalin, and somatostatin. All muscle layers had varicose fibers that reacted for calcitonin gene-related peptide, galanin, neuropeptide Y, and substance P. Longitudinal and circular muscle received few nerves reactive for leucine-enkephalin, whereas methionine-enkephalin was localized in a few nerve endings in the circular muscle. Somatostatin- and bombesin-reactive nerves occurred in longitudinal muscle. No cholecystokinin-reactive nerves were found. This study extends the results of previous studies and shows the previously undescribed presence of calcitonin gene-related peptide- and galanin-reactive nerves in the human esophagus and identifies neuropeptides that may serve as motor, sensory, and modulatory neurotransmitters of esophageal nerves.

Adult↗

PubMed1991

High frequency of retinoic acid receptor beta abnormalities in human lung cancer.

One of the three human retinoic acid receptors, RAR-beta, maps to a region on the short arm of chromosome 3 frequently deleted in lung cancer. Because retinoic acid is required for normal epithelial cell growth and regulation, and loss of a retinoic acid receptor might be expected to contribute to oncogenesis, we examined RAR-beta RNA and DNA in normal lung, 33 lung cancer cell lines and nine primary lung tumors. Normally, RAR-beta is expressed as two transcripts, of sizes 3.1 kb and 2.8 kb, which are strongly induced by retinoic acid. At least 50% of the cell lines and 30% of the tumor samples show altered RAR-beta expression and/or inducibility, including examples of absence or specific loss of one of the RAR-beta transcripts. Abnormalities in the expression patterns of RAR-alpha and RAR-gamma also are found, but at a lower frequency than RAR-beta abnormalities. Southern analysis reveals alteration of the RAR-beta gene in three of the cell lines. Our data suggest that abnormalities in structure and expression of the RAR-beta gene may be involved in the pathogenesis of lung cancer.

Carrier Proteins↗

PubMed1991

Extrapleural pneumonectomy, chemotherapy, and radiotherapy in the treatment of diffuse malignant pleural mesothelioma.

Malignant pleural mesothelioma has been considered a uniformly fatal disease associated with a median survival of 4 to 18 months. Extrapleural pneumonectomy alone has proved disappointing in the treatment of this disease, as have chemotherapy and radiotherapy. From 1980 to 1990, 31 patients with pleural mesothelioma underwent multimodality therapy that included extrapleural pneumonectomy with resection of the pericardium and diaphragm. The age of the patients was 53.4 +/- 8.6 years; 26 were male. All patients had the pathologic diagnosis reviewed before treatment. At thoracotomy six patients had residual (unresectable) gross disease, and in 23 there was histologic evidence of disease at the resection margin. The perioperative morbidity and mortality rates were 19% and 6%, respectively. The mean length of hospital stay for the 29 patients who survived the operation was 10.9 +/- 3.5 days. Postoperatively 26 patients received cyclophosphamide, doxorubicin, and cis-platinum chemotherapy with or without radiotherapy. The survival rates were 70% at 1 year and 48% at 2 years. Trends toward improved survival in the patients with complete resections approached but did not reach statistical significance. These data suggest that this multimodality protocol can be administered with acceptable morbidity and mortality. Prospective trials are justified to further clarify the role of this approach.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1990

Developmental expression of plasminogen activator inhibitor type 1 by human alveolar macrophages. Possible role in lung injury.

Urokinase activity is regulated by the specific endogenous plasminogen activator inhibitors type 1 (PAI-1) and type 2 (PAI-2). One of these inhibitors, PAI-1, has been directly implicated in connective tissue metabolism by virtue of its ability to bind extracellular matrix proteins. Because the normal lung is relatively rich in urokinase and abnormalities in urokinase activity have been associated with fibrotic lung diseases, we have explored the possibility of local production of PAI-1 and PAI-2 in human lung. Reverse transcription and subsequent amplification by the polymerase chain reaction of total lung RNA revealed PAI-1 mRNA in each of three normal samples and in two specimens from patients with the adult respiratory distress syndrome (ARDS). In situ hybridizations of lung biopsy specimens from a patient with ARDS with cRNA probes to PAI-1 and PAI-2 indicated that alveolar macrophages express PAI-1 mRNA during the acute injury phase. Subsequent reverse transcription and PCR amplification of normal human monocyte and alveolar macrophage mRNA revealed that neither cell type expressed mRNA for urokinase inhibitors. However, after 24 h stimulation with endotoxin in vitro, monocytes were strongly positive for PAI-2 but negative for PAI-1 mRNA whereas, under the same conditions, alveolar macrophages exhibited mRNA for both PAI-1 and PAI-2. Metabolic labeling of endotoxin-stimulated alveolar macrophages with 35S-methionine followed by immunoprecipitation with PAI-1 and PAI-2 antibodies revealed that macrophages synthesized both PAI-1 and PAI-2. As judged by immunoprecipitation and functional studies, PAI-2 was found to be the major intracellular PA inhibitor whereas PAI-1 was found to predominate outside the cell. Thus, mononuclear phagocytes exhibit a developmental potential for PAI-1 expression. The release of PAI-1 by stimulated macrophages, as observed in the setting of ARDS, may be one mechanism by which these cells promote connective tissue accumulation.

Endotoxins↗

PubMed1990

Primary mediastinal leiomyoma.

An elderly woman was seen with a left mediastinal mass in the region of the aortic arch on chest roentgenography. Further imaging with computed tomography, angiography, and magnetic resonance demonstrated a highly vascular neoplasm adjacent to the aortic arch. Pathological analysis of the resected specimen showed a leiomyoma. A brief review of the 10 previous reported cases of primary mediastinal leiomyoma is provided.

Aged↗

PubMed1989

Cloning of cDNAs that encode human mast cell carboxypeptidase A, and comparison of the protein with mouse mast cell carboxypeptidase A and rat pancreatic carboxypeptidases.

Human skin and lung mast cells and rodent peritoneal mast cells contain a carboxypeptidase in their secretory granules. We have screened human lung cDNA libraries with a mouse mast cell carboxypeptidase A (MC-CPA) cDNA probe to isolate a near-full-length cDNA that encodes human MC-CPA. The 5' end of the human MC-CPA transcript was defined by direct mRNA sequencing and by isolation and partial sequencing of the human MC-CPA gene. Human MC-CPA is predicted to be translated as a 417 amino acid preproenzyme which includes a 15 amino acid signal peptide and a 94 amino acid activation peptide. The mature human MC-CPA enzyme has a predicted size of 36.1 kDa, a net positive charge of 16 at neutral pH, and 86% amino acid sequence identity with mouse MC-CPA. DNA blot analyses showed that human MC-CPA mRNA is transcribed from a single locus in the human genome. Comparison of the human MC-CPA with mouse MC-CPA and with three rat pancreatic carboxypeptidases shows that these enzymes are encoded by distinct but homologous genes.

Amino Acid Sequence↗

PubMed1984

Mechanical and electrical activity of esophageal smooth muscle during peristalsis.

Mechanical events and membrane potential changes in response to evoked swallows and cervical vagal stimulation (10 and 40 Hz) were recorded in anesthetized opossums. Miniature strain-gauge transducers monitored the mechanical activity of the two layers. A suction electrode recorded from the intact esophagus, from a proximally based pedicle flap of longitudinal muscle (LM), and from circular muscle (CM). The onset of swallowing was marked by the onset of mylohyoid activity. During swallows LM contraction preceded CM contraction and was of longer duration. The latencies of LM and CM contraction were 1,980 +/- 38 and 2,250 +/- 101 ms, respectively. The durations of contraction of LM and CM were 5,590 +/- 260 and 3,330 +/- 67 ms, respectively. LM showed no hyperpolarization but showed depolarization and spike burst. The CM showed prompt hyperpolarization followed by depolarization and spike burst. Responses to vagal stimulation were qualitatively similar to swallows. The different components of the responses were quantitatively modified by changes in stimulus frequency. These studies show that, during peristalsis in response to swallows and vagal stimulation, 1) LM contraction occurs before CM and is of longer duration, and 2) unlike CM, LM does not hyperpolarize prior to depolarization.

Animals↗

PubMed1984

Swallowing induces sequential activation of esophageal longitudinal smooth muscle.

We examined the mechanical activity of the longitudinal and circular muscles of the esophagus at three different levels (9, 5, and 1 cm above the lower esophageal sphincter) during peristalsis induced by swallows or vagal stimulation in anesthetized opossums with miniature strain gauges applied in the axis of muscle fibers. The onset of longitudinal muscle contraction occurred in an aboral sequence with swallows but simultaneously with vagal stimulation. The speed of longitudinal muscle activation with swallows was 7.6 +/- 1.7 cm/s. Circular muscle contraction occurred in an aboral sequence with vagal stimulation and swallowing with speeds of 4.1 +/- 0.8 and 2.3 +/- 0.1 cm/s, respectively. Longitudinal muscle contracted before the circular muscle at all sites. The duration of longitudinal muscle contraction increased aborally (P less than 0.05) with swallowing or vagal stimulation. These studies show that 1) during swallowing, esophageal longitudinal and circular smooth muscle contract in a sequential fashion, 2) the longitudinal muscle sequential contraction is due to central mechanisms, whereas circular muscle sequential contraction may be due to both central and peripheral mechanisms, and 3) peripheral neuromuscular mechanisms produce regional differences in the duration of longitudinal muscle contraction.

Animals↗

PubMedDate not supplied

Neoadjuvant and adjuvant therapy in the management of locally advanced non-small-cell lung cancer.

The role of adjuvant therapy in non-small-cell lung cancer continues to be defined. We review the most recent major reports of adjuvant trials. Three large randomized trials of postoperative chemotherapy and/or radiation therapy for stage I and II patients have noted improvement trends in median and long-term survival. Two large preoperative phase II trials for stage IIIA patients have reported high response and surgical resectability rates for preoperative combinations of radiation and chemotherapy, but without significant improvement in survival. In general, most of these protocols require months to complete, and not all patients are able to withstand the associated toxicity. The field of adjuvant therapy is continuing to develop; some of the strategies of ongoing protocols are reviewed.

Carcinoma, Non-Small-Cell Lung↗

PubMedDate not supplied

Histone deacetylation is directly involved in desilencing the expression of the catalytic subunit of telomerase in normal lung fibroblast.

The regulation of telomerase expression in normal cells is poorly understood. Moreover, the molecular mechanism underlying tumor-specific expression of telomerase remains unclear. We investigated the link between histone deacetylation and telomerase activity in normal lung and lung tumor cells. Four non-small-cell lung cancer (NSCLC) lines and one normal lung fibroblast line were tested for telomerase activity with or without Trichostatin A(TSA). The telomerase activity and the expression of telomerase associated components were determined by TRAP assay, RT-PCR analysis and Western blot analysis. All 4 NSCLC cell lines exposed to 1 microM TSA for 24 h had no change in telomerase activity or hTERT mRNA level. Telomerase activity was very low in normal lung fibroblasts (mrc-9) until exposed to 1 microM TSA for 24 h, at which time telomerase activity was readily detectable, with concomitant upregulation of hTERT mRNA (10-fold). The level of other telomerase associated components (hTER and TP1) were unaltered. Furthermore, 1 microM TSA exposure for 24 h did not alter the level of c-Myc or p21 mRNA. Immunodetection reveled that hTERT protein expression increased (approximately 6 fold) compared to c-Myc, p21, or gelsolin. The effect of TSA on hTERT expression is independent of DNA methylation as judged by 5-azacytidine (5aza) treatment. TSA effect on mrc-9 cells is unaltered even in the presence of 200 microg/ml cyclohexamide, suggesting a direct inhibition of histone deacetylation. Collectively, our study indicates that inhibition of histone deacetylation selectively regulates the transcriptional derepression of telomerase catalytic subunit in normal lung fibroblast cells compared to lung tumor cells.

Carcinoma, Non-Small-Cell Lung↗

PubMedDate not supplied

Malignant pleural effusions after resection of pulmonary adenocarcinoma.

OBJECTIVE: To evaluate the clinicopathologic features of malignant pleural effusions secondary to pulmonary adenocarcinoma in patients who have undergone surgical resection of the primary tumor. STUDY DESIGN: Clinical, pathologic and cytologic material from 19 patients who developed malignant pleural effusions after resection of pulmonary adenocarcinoma was reviewed. RESULTS: Malignant effusions developed only in patients with either lymph node or pleural involvement by neoplasm. Time to development of the effusion after resection and overall survival correlated with histologic findings. Malignant effusions in patients who survived > 24 months were secondary to another primary tumor (either breast or a new pulmonary carcinoma). Malignant effusions developed significantly sooner after resection (mean 5.0 +/- 2.0 months, median 5) in patients with lymph nodal metastases than in those with pleural involvement by neoplasm (mean 11.2 +/- 2.5 months, median 12) (Student's t test P = .01, Mann-Whitney U test .04). Nevertheless, survival after resection for patients with lymph node involvement (mean 9.0 +/- 3.6 months, median 8) and those with pleural involvement (mean 12.3 +/- 2.5 months, median 12) was not significantly different. CONCLUSION: Malignant effusions developing in patients more than two years following resection of a pulmonary adenocarcinoma are likely to be secondary to another primary neoplasm. Lymph node and pleural involvement at the time of resection are risk factors for the development of a malignant effusion. Patients with lymph node involvement develop malignant effusions sooner than those with pleural involvement, but the overall survival is not significantly different.

Adenocarcinoma↗

PubMedDate not supplied

Potential mechanism of vasomotor dysregulation after lung transplantation for primary pulmonary hypertension.

BACKGROUND: Vasomotor regulation in the lung is controlled by a dynamic balance between humoral factors and autonomic innervation. Lung transplantation is a unique clinical situation in which vasoregulation is dependent on humoral factors alone. METHODS: We illustrate the problem of vasomotor dysregulation with a lung transplant recipient in whom life-threatening hypoxemia was dramatically reversed with the administration of organic nitrates. The potential mechanism for this dysregulation was explored by exposing human endothelial cells to hypoxic conditions in vitro and analyzing the cells for the expression of pulmonary vasoconstrictor gene transcripts. RESULTS: The hypoxic microenvironment induced a tenfold increase in the transcription of the pulmonary vasoconstrictor genes endothelin-1 and platelet-derived growth factor within 24 hours. The addition of organic nitrates had a dramatic effect on decreasing the levels of vasoconstrictor transcripts within 30 minutes of exposure. CONCLUSION: These findings suggest that a potential mechanism for the clinical effect of organic nitrates is the inhibition of vasoconstrictor synthesis by hypoxic endothelium.

Adult↗

PubMedDate not supplied

Ethical considerations in lung retransplantation.

The decreased survival of patients undergoing lung retransplantation has raised ethical concerns regarding the "fairness" of using organs for retransplantation. This emphasis on organ utility could have important consequences for the doctor-patient relationship and the practice of retransplantation. In an attempt to balance the responsibilities of individual physicians toward their patients and the responsibilities of transplantation programs toward the public resource of donated organs, we propose a limit on the percentage of organs used for experimental or innovative procedures such as retransplantation. This limit would allow the physician to function as the patient advocate, ensure that organs are realistically allocated to patients most likely to benefit from transplantation, and permit an evolving definition of the medical efficacy of retransplantation.

Ethics, Medical↗