Felix G. Fernandez

Five-Year Survival After Resection of Hepatic Metastases From Colorectal Cancer in Patients Screened by Positron Emission Tomography With F-18 Fluorodeoxyglucose (FDG-PET)

Objective:To report the first 5-year overall survival results in patients with colorectal carcinoma metastatic to the liver who have undergone hepatic resection after staging with [18F] fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET). Summary Background Data:The 5-year overall survival after hepatic resection for colorectal cancer metastases without preoperative FDG-PET has been established in 19 studies (6070 patients). The median 5-year overall survival rate in these studies is 30% and has not improved over time. FDG-PET detects unsuspected tumor in 25% of patients considered to have resectable hepatic metastasis by conventional staging. Methods:From March 1995 to June 2002, all patients having hepatic resection for colorectal cancer metastases had preoperative FDG-PET. A prospective database was maintained. Results:One hundred patients (56 men, 44 women) were studied. Metastases were synchronous in 52, single in 63, unilateral in 78, and <5 cm in diameter in 60. Resections were major (>3 segments) in 75 and resection margins were ≥1 cm in 52. Median follow up was 31 months, with 12 actual greater than 5-year survivors. There was 1 postoperative death. The actuarial 5-year overall survival was 58% (95% confidence interval, 46–72%). Primary tumor grade was the only prognostic variable significantly correlated with overall survival. Conclusions:Screening by FDG-PET is associated with excellent postresection 5-year overall survival for patients undergoing resection of hepatic metastases from colorectal cancer. FDG-PET appears to define a new cohort of patients in whom tumor grade is a very important prognostic variable.

Immune mechanisms in the pathogenesis of bronchiolitis obliterans syndrome after lung transplantation

Abstract:u2002 Lung transplantation is recognized as the only viable treatment option in a variety of end‐stage pulmonary diseases. However, the long‐term survival after lung transplantation is limited by the development of obliterative bronchiolitis, and its clinical correlate bronchiolitis obliterans syndrome (BOS), which is considered to represent chronic lung allograft rejection. Histopathologically, BOS is an inflammatory process that leads to fibrous scarring of the terminal and respiratory bronchioles and subsequent total occlusion of the airways. The specific etiology and pathogenesis of BOS are not well understood. The current premise is that BOS represents a common lesion in which different inflammatory insults such as ischemia‐reperfusion, rejection, and infection can lead to a similar histological and clinical outcome. However, the low incidence of BOS in non‐transplanted individuals and the observation that early development of BOS is predicted by the frequency and severity of acute rejection episodes indicate that alloimmune‐dependent mechanisms play a crucial role in the pathogenesis of BOS. The evidence presented in this review indicates that BOS is the result of humoral and cellular immune responses developed against major histocompatibility complex molecules expressed by airway epithelial cells of the lung allograft. This process is aggravated by alloimmune‐independent mechanisms such as ischemia‐reperfusion and infection. Currently, treatment of BOS is frequently unsuccessful. Therefore, a better understanding of the immunopathogenesis of BOS is of paramount importance toward improving long‐term patient and graft survival after lung transplantation.

Lymph node evaluation in video-assisted thoracoscopic lobectomy versus lobectomy by thoracotomy.

BACKGROUNDnWith the emergence of video-assisted thoracic surgery (VATS) lobectomy, concern remains regarding the adequacy of nodal assessment versus thoracotomy.nnnMETHODSnAll clinical stage I non-small cell lung cancer patients treated with VATS or open lobectomy were retrospectively evaluated. Total nodes, N2 nodes, and nodes at each station were evaluated for associations with surgery type and location of involved lobe.nnnRESULTSnThere were 79 VATS and 464 open lobectomy or segmental resections for stage I tumors. Overall, fewer lymph nodes were sampled with VATS compared with thoracotomy (7.4 +/- 0.6 vs 8.9 +/- 0.2, respectively; p = 0.029), and fewer N2 nodes were sampled with VATS versus thoracotomy as well (2.5 +/- 3.0 vs 3.7 +/- 3.3, p = 0.004). There were no differences in N1 node sampling between the two groups (5.2 +/- 3.6 vs 4.9 +/- 4.2, p = 0.592). Furthermore, there were more station 7 nodes with thoracotomy versus VATS (1.2 +/- 0.1 vs 0.6 +/- 0.1, p = 0.002). Among right-sided lesions, there was no difference in 4R nodes between groups (1.4 +/- 0.4 vs 1.6 +/- 0.2, p = 0.7) although there was a trend toward more level 7 nodes with thoracotomy (1.0 +/- 0.2 vs 1.4 +/- 0.2, p < 0.08). Among left-sided resections there were more station 7 nodes with thoracotomy versus VATS (1.0 +/- 0.1 vs 0.4 +/- 0.1, p < 0.001) and more station 5/6 nodes (1.1 +/- 0.1 vs 0.5 +/- 0.1, p < 0.04). For upper lobe resections, the total nodes (8.9 +/- 0.3 vs 7.4 +/- 0.7, p = 0.05) and station 7 nodes (1.0 +/- 0.1 vs 0.6 +/- 0.1, p < 0.01) were higher with thoracotomy than VATS. There was no difference in 2-year survival between groups (81% vs 83%, p = 0.4).nnnCONCLUSIONSnOur early experience with VATS has been associated with fewer lymph nodes sampled compared with open lobectomy although there was no survival difference. Analysis of these differences has directed us toward a more focused lymph node sampling with VATS lobectomy.

Airway Epithelium is the Primary Target of Allograft Rejection in Murine Obliterative Airway Disease

Murine heterotopic tracheal allografts develop obliterative airway disease (OAD), a suitable model of chronic lung allograft rejection. This model, however, fails to account for the behavior of the allograft when adjacent to recipient airway tissues, particularly the epithelium. This study was performed to determine the immunologic role of the epithelium in development of OAD. BALB/c (H2d) tracheal allografts were transplanted orthotopically into C57BL/6 (H2b) mice and harvested 14–150 days post‐transplantation. The phenotype of the allograft epithelium after orthotopic transplantation was determined with immunofluorescent staining. Orthotopic BALB/c tracheal allografts harvested at 28 days were re‐transplanted heterotopically into BALB/c or C57BL/6 mice, harvested after 28 days, and assessed for OAD. Orthotopic allografts displayed mild cellular infiltration, no fibrosis and preserved epithelium at 28 days post‐transplant. The presence of recipient‐derived epithelium within the allograft was demonstrated with immunofluorescent staining at day 14. Significantly, BALB/c orthotopic allografts re‐transplanted heterotopically into BALB/c mice developed OAD by day 28, whereas BALB/c orthotopic allografts re‐transplanted heterotopically into C57BL/6 mice did not. Repopulation of orthotopic tracheal allografts with recipient‐derived epithelium confers a protective effect against OAD after heterotopic re‐transplantation. This indicates that the airway epithelium plays a crucial role in OAD development.

Large-cell neuroendocrine carcinoma of the lung.

BACKGROUNDnLarge-cell neuroendocrine carcinoma (LCNEC) of the lung displays morphologic and immunohistochemical characteristics common to neuroendocrine tumors and morphologic features of large-cell carcinomas. Because surgical resection of LCNEC in many series has been described with 5-year actuarial survival that is far worse than that reported for other histologic variants of non-small-cell lung cancer (NSCLC), considerable debate has emerged as to whether these tumors should be classified and treated as NSCLC or small-cell lung cancer.nnnMETHODSnThe initial evaluation and diagnosis, tumor classification, surgical treatment, results of therapy, and long-term prognosis of patients with LCNEC based on our experience are discussed, and a review of the literature is presented.nnnRESULTSnPatients with LCNEC are more likely to develop recurrent lung cancer and have shorter actuarial survival than patients with other histologic types of NSCLC, even in those with stage I disease.nnnCONCLUSIONSnAccurate differentiation of LCNEC from other types of NSCLC is important because it identifies those patients at highest risk for developing recurrent disease. Efforts to identify effective adjuvant therapies are needed to improve treatment outcomes with this aggressive type of lung cancer.

Inhibition of Obliterative Airway Disease Development in Murine Tracheal Allografts by Matrix Metalloproteinase-9 Deficiency

This study was designed to define the roles of matrix metalloproteinase (MMP)‐2 and MMP‐9 in obliterative airway disease (OAD) in heterotopic murine tracheal allografts, considered a suitable animal model for chronic lung allograft rejection. BALB/c tracheal allografts were transplanted into MMP‐2‐deficient (−/−) and MMP‐9−/− mice. Also, wild‐type recipients were treated with doxycycline, a nonspecific MMP inhibitor. After 10, 20 and 30 days, allografts were analyzed for OAD development, intragraft levels of MMP‐2 and MMP‐9 and the frequency and cytokine/chemokine production profile of alloreactive T cells. Allografts transplanted into wild‐type mice developed OAD lesions within 30 days. These allografts revealed significant upregulation of both MMP‐2 and MMP‐9. Allografts transplanted into MMP‐9−/− and doxycycline‐treated recipients did not develop OAD. In contrast, allografts transplanted into MMP‐2−/− mice developed OAD lesions with normal kinetics. Interestingly, MMP‐9−/− recipients showed an enhanced T cell alloreactivity associated with an abnormal profile of cytokine/chemokine production. The enhanced T cell alloreactivity in MMP‐9−/− mice was mediated by enhanced dendritic cell stimulatory capacity as well as enhanced T cell responsive capacity. These results suggest that MMP‐9 plays an important role in the pathogenesis of OAD and may represent a target for the therapeutic intervention of chronic lung allograft rejection.

Pirfenidone inhibits obliterative airway disease in a murine heterotopic tracheal transplant model1

Background. Chronic lung allograft rejection in the form of bronchiolitis obliterans syndrome and its histopathologic correlate, obliterative bronchiolitis (OB), are a major source of morbidity and mortality after lung transplantation. Murine heterotopic tracheal transplants into fully allogeneic mismatched recipients develop obliterative airway disease (OAD), which is a suitable model of OB. Using this murine heterotopic tracheal allograft model, we evaluated the effect of pirfenidone, a novel antifibrotic agent, on the development of OAD. Methods. Mice transplanted with complete MHC-mismatched tracheal allografts received pirfenidone (0.5%) in pulverized food according to different schedules: daily for the first 14 days after transplantation or daily for the duration of the study beginning on posttransplantation days 0, 5, or 10. Results. Mice on a continuous daily regimen of pirfenidone failed to develop evidence of chronic allograft rejection at the termination of the study (60 days). Mice receiving pirfenidone limited to the early posttransplantation period had delayed onset of OAD to 60 days. Forty percent (2/5) of mice receiving a continuous regimen of pirfenidone beginning on day 5 after transplantation had no evidence of OAD at 28 days. However, when the drug was started on day 10, all mice developed OAD by 28 days. Conclusions. Our results demonstrate a delay of onset or abrogation of OAD when pirfenidone is administered in the early posttransplantation period. These findings suggest that pirfenidone is a candidate drug to be evaluated for prevention of the fibrotic changes seen in OB in human recipients of lung transplants.

Molecular mechanisms of chronic rejection following transplantation.

Although significant advances have been made in the field of organ transplantation, chronic rejection remains a major limiting factor for prolonged graft survival. The long-term survival and function of transplanted lungs are limited by the development of bronchiolitis obliterans syndrome (BOS). The 10-yr lung graft survival rate is only 18.6%. Aside from results of several clinical studies that strongly support the concept that BOS results from alloimmune-mediated injury, little is known regarding specific immune effectors or target molecules involved in the pathogenesis of BOS. Studies from our laboratory have provided evidence for the seminal role of CD4+ T-cells in the pathogenesis of obliterative airway disease (OAD) seen in BOS. Prior to any clinically detectable lesions, there is indirect antigen presentation of mismatched major histocompatibility complex (MHC) class I antigen and production of antibodies to these MHC antigens. Both MHC and minor histocompatibility antigen disparities can result in the development of OAD in animal models and preliminary results strongly suggest that peptide vaccination strategies may prevent OAD following heterotopic tracheal transplants. Using a newly developed orthotopic tracheal transplant model, we have obtained evidence for an important and probably exclusive role for airway epithelial cell injury as a primary mechanism for the immunopathogenesis of the development of OAD.

Animal models for bronchiolitis obliterans syndrome following human lung transplantation.

Lung transplantation is the only viable treatment option that can improve survival and enhance the quality of life of patients with end-stage lung diseases such as emphysema, cystic fibrosis, idiopathic pulmonary fibrosis, and primary pulmonary hypertension. However, the long-term survival of lung allografts is still limited by the development of bronchiolitis obliterans syndrome (BOS), an irreversible condition unresponsive to therapy. BOS is the most significant cause of long-term morbidity and mortality after lung transplantation. Over the past decade, several animal models have been developed to investigate BOS. These are valuable to elucidate the immunologic and pathologic mechanisms that lead to BOS and to test treatment options for BOS. In this review, we discuss the advantages and disadvantages of different animal models and highlight work that has been done with each model.

Unique site- and time-specific patterns of recurrence following resection of colorectal carcinoma hepatic metastases in patients staged by FDG-PET

BACKGROUND/PURPOSEnWe recently reported that patients staged by positron emission tomography (PET) with F-18 fluorodeoxyglucose (FDG) prior to liver resection for metastatic colorectal cancer had an excellent 5-year survival. In this study, the site- and time-specific patterns of recurrence were examined in patients staged by FDG-PET and the results compared to historical literature control data.nnnMETHODSnFrom March 1995 to June 2002, all patients having hepatic resection for colorectal cancer metastases had preoperative FDG-PET. A prospective database was maintained.nnnRESULTSnOne hundred patients were studied; 48 patients had no evidence of recurrence, 30 patients had recurrence within 12 months of resection, and 22 patients had recurrence after 12 months. Seventy percent of patients with recurrence within 1 year of resection had intrahepatic recurrence. Furthermore, 86% of patients with recurrence more than 1 year after resection had extrahepatic recurrence. We reviewed all published case series of conventionally staged patients. This pattern of early recurrence in the liver and later recurrence in extrahepatic sites has not been reported in any of the conventionally staged series.nnnCONCLUSIONSnThere is an interesting difference in the pattern of recurrence of FDG-PET-staged patients and conventionally staged patients who undergo liver resection. Several explanations seem possible. One potential explanation requiring further study is that the pattern of recurrence is due to the convergence of two factors-that FDG-PET more effectively detects extrahepatic disease than conventional staging and that liver resection gives a growth spurt to hepatic metastases.