Biomedical subjects

S A Yousem

Publications and source records attributed to S A Yousem.

At least 19 recordsLinked to original sources

PubMed1998

Aerosol cyclosporine prevents acute allograft rejection in experimental lung transplantation.

BACKGROUND: The incidence of acute rejection and the morbidity of systemic cyclosporine (INN: cyclosporine) after lung transplantation is significant. Experimental evidence suggests that the allograft locally modulates the immune mechanisms of acute rejection. The purpose of this study was to determine whether aerosolized cyclosporine would prevent acute cellular rejection, achieve effective graft concentrations with low systemic drug delivery, and locally affect production of the inflammatory cytokines involved in acute rejection. METHODS: Unilateral orthotopic left lung transplantation was performed in 64 rats (ACI to Lewis), which were divided into eight groups (each group, n = 8): group A, no treatment; groups B to D, aerosol cyclosporine 1 to 3 mg/kg per day, respectively; group E to H, systemic cyclosporine 2, 5, 10, and 15 mg/kg per day, respectively. After the animals were killed on postoperative day 2, 4, or 6, the transplanted lung, native lung, spleen, and blood were collected. Histologic studies, high-pressure liquid chromatography for trough cyclosporine concentrations, and reverse-transcriptase polymerase chain reaction for cytokine gene expression were performed. RESULTS: Untreated animals showed grade 4 rejection by postoperative day 6. Aerosol cyclosporine prevented acute rejection in a dose-dependent fashion, with group D animals (3 mg/kg per day) showing minimal grade 1 changes. Among animals receiving systemic cyclosporine, only group H (15 mg/kg per day) controlled (grade 1) rejection. However, aerosol cyclosporine, at an 80% lower dose, achieved significantly lower concentrations of cyclosporine in the graft (12,349 vs 28,714 ng/mg, p = 0.002004) and blood (725 vs 3306 ng/ml, p = 0.000378). Group F (systemic 5 mg/kg per day) had higher cyclosporine concentrations in the blood than group D (p = 0.004572) and similar tissue concentrations (p = 0.115180), yet had grade 2 rejection. Reverse-transcriptase polymerase chain reaction demonstrated equivalent suppression of inducible nitric oxide synthase but a 20- to 25-fold higher expression of interleukin-6, interleukin-10, and interferon-gamma in group D versus group H recipient allografts. CONCLUSION: Local delivery of cyclosporine by aerosol inhalation dose-dependently prevented acute pulmonary allograft rejection. Effective graft levels and low systemic drug delivery required significantly lower doses than systemic therapy alone. The gene expression of proinflammatory cytokines involved in allograft rejection was suppressed by aerosol cyclosporine therapy.

Administration, Inhalation↗

PubMed1997

Lung transplantation for respiratory failure resulting from systemic disease.

BACKGROUND: Lung transplantation for pulmonary failure resulting from systemic disease is controversial. We reviewed our transplant experience in patients with sarcoidosis, scleroderma, lymphangioleiomyomatosis, and graft-versus-host disease. METHODS: This retrospective review examined the outcome of 23 patients who underwent pulmonary transplantation for these systemic diseases. Group 1 included 15 patients with pulmonary hypertension who underwent transplantation (9 for sarcoidosis, 6 for scleroderma), and group 2 included 8 patients with normal pulmonary artery pressures who underwent transplantation (5 for lymphangioleiomyomatosis, 3 for graft-versus-host disease). The incidences of infection and rejection, pulmonary function, and survival were measured and compared with those of patients who underwent transplantation for isolated pulmonary disease. RESULTS: Although there were no differences in the rate of infection between patients who underwent transplantation for systemic versus isolated disease, patients with pulmonary hypertension who underwent transplantation for systemic disease had significantly lower rates of rejection. Four patients with sarcoidosis and 2 with lymphangioleiomyomatosis demonstrated recurrence in the allograft. Survival was similar between patients who underwent transplantation for systemic versus isolated disease. CONCLUSIONS: Patients with respiratory failure resulting from these systemic diseases can undergo transplantation with outcomes comparable to those obtained in patients who undergo transplantation for isolated pulmonary disease.

Adult↗

PubMed1997

Primary pulmonary thymoma.

Primary thymomas arising in an intrapulmonary location without an associated mediastinal component are rare entities. The origin of thymomas in this unusual location remains unknown. Knowledge of the natural history and the prognosis of these tumors is also limited because of their rarity.

Aged↗

PubMed1997

Treatment of refractory acute allograft rejection with aerosolized cyclosporine in lung transplant recipients.

Lung transplant recipients who have persistent acute cellular rejection are at increased risk for the development of chronic rejection, the leading cause of reduced long-term survival. This study evaluated the use of aerosolized cyclosporine as rescue therapy for unremitting acute rejection. Between June 1993 and March 1996, 18 patients with rejection that failed to resolve after therapy with pulse steroids and antilymphocyte globulin were enrolled in the study. Aerosolized cyclosporine A (300 mg) treatment was initiated for 10 consecutive days followed by a maintenance regimen of 3 days per week. Efficacy was assessed by graft histologic and pulmonary function testing. With the use of linear regression, results in these patients were compared with those in 23 control patients, matched for histologic acute rejection, who had continued to receive conventional rescue therapy. Two patients were unable to tolerate the treatments and were withdrawn from the study. Significant improvement in histologic rejection occurred in 14 of the remaining 16 patients after a mean of 37 days of aerosolized cyclosporine therapy. Measures of forced vital capacity and forced expiratory volume in 1 second (change in percent predicted/100 days plus or minus the standard error) increased over time in the treated patients whereas the condition of control patients declined despite repeated attempts at conventional rescue (forced vital capacity, aerosolized cyclosporine group, 4.6 +/- 2.9 vs control group -8.1 +/- 1.9, p = 0.001; forced expiratory volume in 1 second, aerosolized cyclosporine group, 2.1 +/- 4.4 vs control group -9.8 +/- 2.6, p = 0.043). Renal and hepatic toxicity during cyclosporine therapy was not observed. The incidence of acute histologic rejection (> or = A2) decreased from 2.49 +/- 0.68 episodes/100 days before aerosolized cyclosporine therapy to 0.72 +/- 0.3 episodes/100 days (p < 0.05). In summary, aerosolized cyclosporine is a safe and effective therapy for acute rejection that has failed to improve with conventional treatment.

Acute Disease↗

PubMed1997

The potential role of mast cells in lung allograft rejection.

To perform a retrospective pilot study of the potential role of mast cells in acute and chronic rejection of the lung allograft, transbronchial biopsies of 29 patients with acute rejection and six patients with bronchiolitis obliterans were stained with antibodies to mast cell tryptase. The number of mast cells per unit area were counted, and compared with a control group of normal lung biopsies stained in a similar fashion. Increasing grades of acute rejection were associated with progressively more mast cells per high-power microscopic field. The presence of bronchiolitis obliterans was accompanied by the greatest numbers of mast cells. Mast cells may play a role in the acute rejection response to the lung allograft and in the development of bronchiolitis obliterans.

Aged↗

PubMed1997

The histological spectrum of chronic necrotizing forms of pulmonary aspergillosis.

Chronic necrotizing pulmonary aspergillosis (CNPA) is a rare locally destructive form of chronic aspergillosis that is recognized as a clinical syndrome, but has been poorly defined histologically. In this study, 10 cases of CNPA were evaluated from a morphological perspective. Three distinct forms of CNPA emerged. One form (n = 4) resembled a necrotizing granulomatous pneumonia centered around a central zone of infarct-like necrosis of parenchyma resulting from angioinvasive aspergillus. The second pattern (n = 4) was that of a granulomatous bronchiectatic cavity with a central fungus ball and subtle tongues of necrosis and inflammation extending into and through the fibrous wall of the cavity. A final form (n = 2) had a bronchocentric granulomatosis-like appearance with a necrotizing granulomatous bronchitis/bronchiolitis associated with luminal necrotic debris and replacement of mucosa by a palisaded histiocytic reaction. Despite the varied histomorphology, all patients survived the aspergillus infection after antifungal therapy and surgical resection. The different forms of pulmonary aspergillosis are briefly discussed, and the differential diagnosis, with particular regard to mycetomas and allergic forms of bronchocentric granulomatosis, is highlighted.

Adult↗

PubMed1997

Alveolar lipoproteinosis in lung allograft recipients.

Three cases of pulmonary alveolar proteinosis developing in lung allograft recipients are reported. In each case, repeated bouts of alveolar damage from harvest/reperfusion injury, rejection, and infection were observed before the development of intraalveolar accumulation of granular, periodic acid-Schiff-positive material in the allograft lungs. It is speculated that iatrogenic immunosuppression combined with defective clearance of alveolar material by alveolar macrophages created a milieu conducive to the accumulation of surfactant, lipoprotein, and fibrinous debris that was morphologically identical to alveolar proteinosis.

Adult↗

PubMed1997

Extracellular matrix expression in metastasizing and nonmetastasizing adenocarcinomas of the lung.

Alterations in extracellular matrix, cell-cell and cell-matrix adhesion, and oncogenes are thought to be important in tumor progression and metastasis. Adenocarcinomas of the lung from 31 patients were studied for immunohistochemical expression of basement membrane molecule type IV collagen, type IV collagenase, and integrins alpha2,3,v adhesion molecules to assess their diagnostic and prognostic importance in pathological stage T2 tumors. The results indicate that with decreasing tumor differentiation, there is a progressive loss of type IV basement membrane collagen (P = .06) and decreased integrin alpha2 expression (P = .03). Type IV collagenase expression was significantly associated with the presence of lymph node metastases, with moderate to strong expression present in 53% T2N1 tumors compared with none (0%) of the T2N0 tumors (P = .008). Integrin alpha(v) was increased in tumors with nodal metastases compared with those without (P = .08). Loss of alpha2 and alpha3 integrins was associated with increased alpha v expression (P = .03). Median survival was 48 months for T2N0 and 20 months for T2N1 (P = .07). In correlating expression of the immunohistochemical markers and survival, type IV collagenase expression was found to be a predictor of survival at a level of P = .07. Measurable alterations in integrins and extracellular matrix, and in particular, expression of matrix-degrading enzyme type IV collagenase may be of prognostic importance in resectable adenocarcinoma of the lung.

Adenocarcinoma↗

PubMed1997

p53 and K-ras mutational genotyping in pulmonary carcinosarcoma, spindle cell carcinoma, and pulmonary blastoma: implications for histogenesis.

In an attempt to understand the molecular pathogenesis of biphasic pulmonary neoplasms, the authors studied 25 cases of carcinosarcoma, spindle cell carcinoma, and pulmonary blastoma using a combined immunohistochemical and topographic genotyping approach for the presence of p53 abnormalities within the different epithelial and mesenchymal components of these tumors. Genotyping involved a search for point mutational damage in p53 exons 5-8, which was correlated with p53 immunoreactivity. This analytical approach demonstrated p53 missense point mutations in four of nine cases of spindle cell carcinoma with a 100% concordance rate between p53 immunopositivity and the presence of DNA mutational damage. One of six carcinosarcomas, heterologous in type, exhibited a p53 mutation. The concordance rate among carcinosarcomas was also 100%. However, the concordance rate among classic biphasic pulmonary blastomas was only 43%, with one of seven cases demonstrating a p53 mutation by DNA genotyping. The lack of concordance in pulmonary blastomas was possibly due to the existence of genotypically distinct subsets of tumor cells likely bearing mutations among largely nonmutated cells. In a similar fashion, among three well-differentiated fetal type adenocarcinomas, no p53 mutations were detected despite the presence of focal p53 immunopositivity in one of the cases. No K-ras mutations were detected in any of the 25 tumors examined. Monoclonal histogenesis from a single totipotential cell in a subset of these neoplasms (six of 22 cases) was supported by the finding of p53 overexpression and identical p53 mutational genotype in both the epithelial and spindle elements of the tumors. Furthermore, the finding of a small percentage of p53-positive tumor cells within one or both components suggests late acquisition of p53 mutational change in a subset of pulmonary blastomas.

Aged↗

PubMed1997

Efficacy of inhaled nitric oxide in oleic acid-induced acute lung injury.

OBJECTIVE: To assess the efficacy of inhaled nitric oxide in improving pulmonary hypertension and gas exchange following oleic acid-induced acute lung injury. DESIGN: Prospective, pharmacologic study. SETTING: Surgical research laboratory at the University of Pittsburgh, Pittsburgh, PA. SUBJECTS: Instrumented, intubated pigs weighing 16 to 27 kg. INTERVENTIONS: Intravenous oleic acid and inhaled nitric oxide. MEASUREMENTS AND MAIN RESULTS: All pigs treated with intravenous oleic acid (0.11 mL/kg) developed a severe lung injury with pulmonary hypertension, accompanied by impaired oxygenation, intrapulmonary shunting, and increased extravascular lung water (p < .05 compared with baseline). Following nitric oxide inhalation, although pulmonary hypertension decreased in a dose-dependent fashion, no amelioration in pulmonary gas exchange was observed, as reflected by PaO2 and intrapulmonary shunt. Plasma nitrite and nitrate concentrations, the stable end products of nitric oxide metabolism, did not increase following nitric oxide exposure in this model of severe lung injury. CONCLUSIONS: The effect of inhaled nitric oxide, restricted to relieving pulmonary vasoconstriction in this model of lung injury, may have limited benefit in improving pulmonary gas exchange when diffusion is impaired by severe lung injury and inflammatory thickening of the alveolar-capillary barrier. Nitric oxide inhalation may have better results when used at an earlier, less severe stage of acute lung injury.

Administration, Inhalation↗

PubMed1997

Spirometry values in stable lung transplant recipients.

To clarify the usefulness of spirometry to assess the function of the lung allograft post-transplant, we retrospectively reviewed 351 sequential spirometry measurements performed by 65 healthy recipients after the 80th postoperative day when the clinical evaluation and fiberoptic bronchoscopy with transbronchial biopsies and bronchoalveolar lavage excluded significant rejection or infection in the allograft. The mean coefficients of variation (CV) and significant values for change (SC) for the FVC, FEV1, and FEF25-75% were calculated according to the type of transplant procedure (heart-lung and double-lung [HL-DL] versus single-lung [SL]), and to the time after transplant when the spirometry measurements were obtained < or = 1 yr versus > 1 yr). The SC for the FVC decreased with time after transplantation for both HL-DL (< or = 1 yr: 17% versus > 1 yr: 7%) and SL recipients (< or = 1 yr: 13% versus > 1 yr: 8%). The higher degree of variability within the first year was primarily due to increasing values especially in the HL-DL recipients. The SC for the FEV1 also decreased over time for HL-DL recipients (< or = 1 yr: 18% versus > 1 yr: 9%) but was similar for SL recipients at both intervals (13%). Our results suggest that decreases of > or = 11% in FVC or 12% in FEV1 in HL-DL recipients and > or = 12% in FVC or 13% in FEV1 for SL recipients indicate a significant decrease in allograft function that may be due to infection or rejection.

Forced Expiratory Volume↗

PubMed1997

Idiopathic bronchiolitis obliterans organizing pneumonia/cryptogenic organizing pneumonia with unfavorable outcome: pathologic predictors.

Idiopathic bronchiolitis obliterans organizing pneumonia (BOOP) and cryptogenic organizing pneumonia (COP) are synonyms for an inflammatory interstitial process characterized by young fibromyxoid connective tissue within airways and air spaces. This clinicopathologic condition is associated with an excellent response to steroidal therapy in more than 80% of patients. In this study, we examined matched groups of 10 patients with steroid-responsive idiopathic BOOP/COP and 9 patients with idiopathic BOOP/COP who fared poorly despite therapy. No significant differences in demographics, symptoms, or radiographic appearances were noted between the two cohorts. Histologic examination revealed that the cases with progressive, idiopathic BOOP/COP were accompanied by scarring and remodeling of the background lung parenchyma in 89% of cases, in contrast to 10% of those with a good prognosis. This finding provided a potential morphologic marker of outcome for therapy in idiopathic BOOP/COP. Steroid-nonresponsive cases of BOOP/COP may have a propensity to cause irreversible injury to the lung, a feature not seen in cases with a good outcome. Another explanation may be that such cases represent a BOOP/COP-like reaction pattern in patients with an associated fibrosing interstitial pneumonia, especially usual interstitial pneumonia. The differential diagnosis of BOOP/COP with organizing diffuse alveolar damage, eosinophilic pneumonia, and other chronic interstitial pneumonias is discussed.

Adrenal Cortex Hormones↗

PubMed1996

Effect of aminoguanidine and cyclosporine on lung allograft rejection.

BACKGROUND: Aminoguanidine, a nitric oxide synthase inhibitor, has been shown to reduce the inflammatory allogeneic response. Here we used it in combination with cyclosporine to evaluate its effect on a clinically relevant immunosuppressive protocol. METHODS: Orthotopic left lung transplantation was performed in 120 rats, of which 24 were syngeneic Lewis to Lewis controls, and allogeneic transplantations were performed across major histoincompatibility barriers (ACI to Lewis). We studied synchronous histologic changes accompanying cytokines and nitric oxide synthase messenger RNA by reverse transcriptase polymerase chain reaction in the grafted lungs. Nitrate/nitrite, oxidized degradation products of nitric oxide, were measured in the whole blood, as were concentrations of cyclosporine. Lung tissue was immunohistochemically stained for nitric oxide synthase protein. Rats receiving allografts were either untreated (24) or received low-dose cyclosporine (232 +/- 105 ng/mL blood by high-performance liquid chromatography), high-dose cyclosporine (2,046 +/- 664 ng/mL), aminoguanidine alone (800 mg. kg-1. day-1 intraperitoneally), or aminoguanidine plus low-dose cyclosporine. RESULTS: The results suggest that aminoguanidine combined with low doses of cyclosporine can reduce the allogeneic response across major histoincompatibilities in rodent lung transplantation. Its biologic effect may not exclusively depend on the inhibition of nitric oxide synthase and may, by other means, reduce proinflammatory cytokines. CONCLUSIONS: Aminoguanidine may be an effective adjuvant to conventional immunosuppression.

Animals↗

PubMed1996

Significance of clinically silent untreated mild acute cellular rejection in lung allograft recipients.

Although acute rejection is a frequent occurrence after transplantation, the clinical behavior and pathological manifestations of untreated mild acute cellular rejection in clinically stable lung allograft recipients is poorly defined. Sixteen patients were identified who had asymptomatic mild acute rejection that was untreated but followed by subsequent pulmonary function tests and repeat transbronchial biopsy. Six patients had spontaneous resolution of their infiltrates; the condition of 10 patients worsened as observed from their biopsies or function studies. Those who worsened had more episodes of acute rejection per patient before the A2 biopsy (2.0 vs 1.3), and 50% developed bronchiolitis obliterans compared with 16% in the spontaneously regressing group. Pathological evaluation showed that patients with persistent or worsening untreated A2 rejection tended to have more large and small airway inflammation, larger numbers of eosinophils and plasma cells in their biopsies, and airway and airspace granulation tissue. These variables may be used to help determine which low grade lung rejection episodes should receive adjunctive immunosuppressive therapy.

Adult↗

PubMed1996

Aerosolized cyclosporine in lung recipients with refractory chronic rejection.

This study evaluated aerosolized cyclosporine as rescue therapy for lung transplant recipients with unremitting chronic rejection. Nine patients with histologic active obliterative bronchiolitis and progressively worsening airway obstruction refractory to conventional immune suppression received aerosolized cyclosporine. Improvement in rejection histology was seen in seven of nine patients. We compared the changes in the FVC and FEV1 over time using linear regression analysis in these seven histologic responders and nine historical control patients. During the pretreatment period for both the experimental and control groups, the FVC and FEV1 declined at comparable rates. After aerosolized cyclosporine there was stabilization of pulmonary function, whereas in the controls there was continued decline. Cyclosporine blood levels were less than 50 ng/ml 24 h after an aerosolized dose of 300 mg in five patients receiving oral tacrolimus. Nephrotoxicity, hepatotoxicity, and a greater than expected rate of infection was not observed. This study suggests that aerosolized cyclosporine is safe and may be effective therapy for refractory chronic rejection in lung transplant recipients.

Adult↗

PubMed1996

Immunohistochemical markers of prolonged survival in small cell carcinoma of the lung. An immunohistochemical study.

OBJECTIVE: To investigate the association of a variety of cell surface and cytoplasmic antigens in small cell carcinoma of the lung with long-term survival (greater than 2 years). DESIGN: Using immunohistochemical analysis of small cell carcinomas, the tissue expression of corticotropin, bcl-2, p-glycoprotein, cathepsin B, cathepsin D, CD44, carcinoembryonic antigen, collagenase IV, Leu-7, neu oncoprotein, p53, S100, and synaptophysin was assessed. RESULTS: Compared with the control group of short-term survivors, tumors from prolonged survivors were unique in their relative absence of staining for cathepsin B (0/13 vs 3/13 [23%], P = .037), cathepsin D (5/13 [38%] vs 13/15 [87%], P = 0.006), carcinoembryonic antigen (5/13 [38%] vs 11/15 [73%], P = .047), and neu oncoprotein (5/13 [38%] vs 14/15 [93%], P = .0014). A variety of histologic characteristics were also compared, and none were shown to be associated with differences in survival in this study. CONCLUSIONS: Negative immunohistochemical staining for cathepsin B, cathepsin D, carcinoembryonic antigen, and neu oncoprotein is associated with prolonged survival in small cell carcinoma of the lung. Evaluation of these antigens should be considered in future attempts to stratify patients with small cell carcinoma of the lung for prognostic or therapeutic purposes, as this study is limited by the small size of the study group and the large number of clinical and pathologic variables.

Adult↗

PubMed1996

Bcl-2, p53, CD44, and CD44v6 isoform expression in neuroendocrine tumors of the lung.

Immunohistochemical expression of p53, bcl-2, CD44 standard (CD44S), and the v6 isoform of CD44 (CD44v6) proteins were studied in 14 typical carcinoid tumors (TCs), 11 atypical carcinoids (ACs), and eight small cell carcinomas (SCLCs) in an attempt to use these markers of mutational events and cellular adhesion to discriminate neoplasms demonstrating neuroendocrine differentiation. p53 and bcl-2 overexpression were associated with more aggressive neuroendocrine cell types. p53 nuclear staining was weakly positive in 21% of the TCs, whereas strong nuclear staining was seen in 64% of the ACs and 88% of the SCLCs (P = 0.0047). bcl-2 was present in 21% of the TCs, 91% of the ACs, and 100% of the SCLCs (P = 0.0001). In contrast, CD44S and CD44v6 were inversely correlated with more aggressive types of neuroendocrine tumors. CD44S expression was moderate to strong in all of the TCs and 91% of the ACs but in only 37% of the SCLCs (P = 0.0018). There was no correlation between expression of these markers and tumor size or nodal status, although loss of CD44v6 was associated with lymph node metastases in the TC group only. In the spectrum of neuroendocrine tumors of the lung, p53 and bcl-2 overexpression correlates with more aggressive histologic cell types. The decreasing CD44S expression in AC and SCLC is similar to findings in cancer of the colon and in non-small cell carcinoma of the lung, where loss of CD44S is associated with poor prognosis. In AC and SCLC, but not in cancer of the colon, loss of CD44v6 correlates with more aggressive neoplasms and might correlate with lymph node metastases in TCs.

Adult↗

PubMed1996

Revision of the 1990 working formulation for the classification of pulmonary allograft rejection: Lung Rejection Study Group.

In 1990, an international grading scheme for the grading of pulmonary allograft rejection was instituted. The use of this classification has resulted in a uniformity of grading which has allowed inter-institutional collaborations and communication unique in allograft monitoring. In 1995 an expanded group of international pathologists convened and revised the original proposal. This article summarizes the updated classification for pulmonary allograft rejection. In brief, acute rejection is based on perivascular and interstitial mononuclear infiltrates. Each grade of acute rejection should mention the presence of coexistent airway inflammation, the intensity of which may also be graded. Chronic rejection is divided into bronchiolitis obliterans--active or inactive--and vascular atherosclerosis--accelerated arterial or venous sclerosis.

Acute Disease↗