Timothy M. Anderson

Thyroid transcription factor-1 expression prevalence and its clinical implications in non-small cell lung cancer: a high-throughput tissue microarray and immunohistochemistry study.

Thyroid transcription factor 1 (TTF-1), a homeodomain-containing transcription factor, plays a pivotal role in lung development, cell growth, and differentiation processes. The current literature reports considerable variation in frequency of TTF-1 protein expression in human non-small cell lung cancer (NSCLC). TTF-1 expression has not been extensively investigated as a prognostic marker in NSCLC. To assess the prevalence of TTF-1 expression, and to evaluate its potential role in disease prognosis, 140 stage I-IIIA NSCLCs with long-term follow-up were studied under uniform conditions using high-density tissue microarray (TMA) combined with immunohistochemistry. Patient survival and association of TTF-1 expression with clinicopathologic parameters were analyzed. One hundred twenty-six tumor samples were fully assessable after tissue processing. Sixty-four samples (50.8%) expressed TTF-1 and 62 (49.2%) displayed no expression. TTF-1 expression was significantly (P < 0.001) correlated with histological subtype: 51 adenocarcinomas (AdCs) (51 of 75; 68%) versus 9 squamous cell carcinomas (SCCs) (9 of 43; 21%) were TTF-1 positive. TTF-1 expression, performance status, nodal status, and tumor stage were significantly related to patient survival. In multivariate analysis, positive TTF-1 expression tended to favor a better patient outcome (P = 0.05). Overall, NSCLC patients with positive TTF-1 expression had a median survival of greater than 57.3 months, whereas those with negative expression had a median survival of 39.4 +/- 5.2 months (log-rank test, P = 0.0067). In this study we found that TTF-1 is predominately expressed in adenocarcinoma. The loss of TTF-1 expression was associated with aggressive behavior of NSCLCs. The results from this study strongly indicate that further investigation is warranted to better define the role of TTF-1 as a prognostic factor in this malignancy.

The surgical management of pulmonary metastasis: current concepts

Lung metastases have been found in 25-30% of all patients with cancer at autopsy. Those patients satisfying criteria for surgical resection represent a much smaller subgroup. Given the potentially curative nature of pulmonary metastasectomy in the absence of disseminated disease, it has become widely accepted as an important treatment option for a variety of malignancies with metastasis to the lungs. A standardized approach remains unfounded however, given limited numbers of patients, various histologic subtypes and few published studies utilizing randomized prospective methodology.Ultimately, the development of metastasis represents a major determinant of survival for patients with cancer. Pulmonary metastasectomy is an important treatment modality for patients with metastatic pulmonary disease. The indications for pulmonary metastasectomy and the surgeons role in pulmonary metastatic disease continue to evolve. Future prospective studies and the compilation of comparable data yielding prognostic factors for specific histologies will better define indications for resection.

Human CD4+ T Cells Present Within the Microenvironment of Human Lung Tumors Are Mobilized by the Local and Sustained Release of IL-12 to Kill Tumors In Situ by Indirect Effects of IFN-γ

By implanting nondisrupted pieces of human lung tumor biopsy tissues into SCID mice, it has been possible to establish viable grafts of the tumor, as well as the tumor-associated microenvironment, including inflammatory cells, fibroblasts, tumor vasculature, and the extracellular matrix. Using this xenograft model, we have evaluated and characterized the effects of a local and sustained release of human rIL-12 (rhIL-12) from biodegradable microspheres. In response to rhIL-12, the human CD45+ inflammatory cells present within the xenograft mediate the suppression or the complete arrest of tumor growth in SCID mice. Analysis of the cellular events reveals that human CD4+ and CD8+ T cells are induced by rhIL-12 to produce and secrete IFN-γ. Serum levels of human IFN-γ in mice bearing rhIL-12-treated tumor xenografts correlate directly with the degree of tumor suppression, while neutralizing Abs to human IFN-γ abrogate the IL-12-mediated tumor suppression. Gene expression profiling of tumors responding to intratumoral rhIL-12 demonstrates an up-regulation of IFN-γ and IFN-γ-dependent genes not observed in control-treated tumors. Genes encoding a number of proinflammatory cytokines, chemokines (and their receptors), adhesion molecules, activation markers, and the inducible NO synthase are up-regulated following the introduction of rhIL-12, while genes associated with tumor growth, angiogenesis, and metastasis are decreased in expression. NO contributes to the tumor killing because an inhibitor of inducible NO synthase prevents IL-12-induced tumor suppression. Cell depletion studies reveal that the IL-12-induced tumor suppression, IFN-γ production, and the associated changes in gene expression are all dependent upon CD4+ T cells.

HER-2/neu Protein Expression and Gene Alteration in Stage I-IIIA Non-Small-Cell Lung Cancer: A Study of 140 Cases Using a Combination of High Throughput Tissue Microarray, Immunohistochemistry, and Fluorescent In Situ Hybridization

Regarding HER-2/ neu expression (gene or protein level) in lung cancer, several studies with inconsistent results have been recently reported, partially due to variable techniques used and/or heterogeneous populations examined. The objective of this study was to examine HER-2/ neu expression in a well-defined cohort of non–small-cell lung cancers (NSCLC) and in nonneoplastic lung tissue utilizing a combination of high-density tissue microarray, immunohistochemistry (IHC), and fluorescent in situ hybridization (FISH) under uniform test conditions. One hundred forty stage I-IIIA primary NSCLCs and 38 non-neoplastic lung samples were examined. IHC, using an FDA-approved Hercept monoclonal antibody kit, was performed and HER-2/ neu gene alteration was assessed by FISH. The association of expression of HER-2/ neu with clinicopathologic parameters was analyzed. Ninety-four percent of tumor samples (131/140) were fully interpretable after tissue processing. Twenty-five of them (19%) overexpressed (2+, 3+) HER-2/ neu, while 106 (81%) had no or weak expression. All thirty-four interpretable non-neoplastic lung samples were negative for HER-2/ neu alteration at protein and gene level. HER-2/ neu protein overexpression correlated well with HER-2/ neu gene amplification (r =.83, P < 0.001). HER-2/ neu overexpression was significantly associated with histologic subtype: 19 adenocarcinomas (19/82, 23%) versus 4 squamous cell carcinomas (4/44, 9%) overexpressed Her-2/ neu (P = 0.04). Statistical significance was observed between HER-2/ neu expression and tumor differentiation, with strong positive (3+) expression observed more frequently in poorly differentiated tumors (P = 0.01). Patients with HER-2/ neu abnormalities, particularly HER-2/ neu gene amplification, exhibited a shorter survival (P = 0.043). The statistically significant difference (P < 0.005) between HER-2/ neu alteration in tumor samples(25/131, 19%) and in the nonneoplastic tissue (0/34, 0%) implies that HER-2/ neu may have a role in the carcinogenesis of NSCLC. The findings provide evidence supporting the hypothesis that the HER-2/ neu receptor may represent a useful molecular target in the treatment of NSCLC. The significant association of HER-2/ neu expression and gene amplification with poorly differentiated carcinoma compared with well differentiated carcinoma suggests that HER-2/ neu may be involved in NSCLC tumor evolution. Patients with HER-2/ neu gene amplification and strong positive expression of HER-2/ neu protein showed a strong tendency toward shorter survival.

Resection of invasive pulmonary aspergillosis in immunocompromised patients.

Background: Immunocompromised patients are prone to develop invasive pulmonary aspergillosis (IPA). Relapse and high mortality rates are seen in those patients who receive subsequent immunotoxic therapy. Standard antifungal regimens often fail to completely eradicate IPA, which then warrants an aggressive surgical approach.Methods: We performed a retrospective chart review of 13 immunocompromised patients who were considered to have IPA and who underwent surgery between 1988 and 1998.Results: Twelve patients had a hematological malignancy and one patient had breast cancer. The diagnosis of IPA was based on a chest computed tomographic scan in all patients. A preoperative diagnosis of aspergillosis was made in three patients, and mucormycosis in one patient, by bronchoalveolar lavage. Before surgery, seven patients received chemotherapy, one patient underwent bone marrow transplantation, and five patients received a combination of chemotherapy and bone marrow transplantation. Symptoms included cough (54%), fever (54%), hemoptysis (30%), and shortness of breath (8%). Three patients (23%) were asymptomatic. The mean preoperative absolute neutrophil count was 4881 cells/ml. Seventeen thoracic operations were performed, i.e., 12 wedge resections, 4 lobectomies, and 1 pneumonectomy. One patient also underwent nephrectomy for invasive aspergillosis and one patient underwent craniotomy to resect an aspergillus brain mass. Surgical pathology revealed IPA in 13 (76%), invasive mucormycosis in 2 (15%), aspergilloma in 1, and diffuse alveolar hemorrhage in 1. Postoperative complications included the following: operative bleeding requiring transfusion, three patients; prolonged air leak, two patients; death because of hepatic/renal failure, one patient; and death because of overwhelming multisystem aspergillosis, one patient. Seven (54%) patients underwent further immunotoxic treatment with no aspergillosis recurrence. After a mean follow-up of 12 months, five (38%) patients are alive and seven (54%) have died without evidence of aspergillosis and/or mucormycosis.Conclusions: Surgical resection, in combination with antifungal agents, is a safe and effective form of therapy for invasive mycoses. It prevents recurrence and allows for subsequent cytotoxic therapies.

Prognostic implications of pulmonary satellite nodules: Are the 1997 staging revisions appropriate?1

In the 1992 AJCC and 1993 UICC staging systems, primary lobe satellite nodules increased the T designation of the primary by one level and ipsilateral non-primary lobe satellite nodules raised the T designation to T4. The recent 1997 UICC and AJCC staging revisions assign a T4 (IIIb) designation to satellite nodules in a primary lobe, and a M1 (IV) designation to satellites in ipsilateral non-primary lobes. There is abundant evidence showing that satellite nodules are negative prognostic factors, but their inclusion in stage IIIb and IV may not be appropriate. The English-language medical literature was searched for papers reporting survival after surgical resection of lung cancer with satellite nodules (primary and non-primary ipsilateral lobe locations). Eleven articles were retrieved and their data pooled for analysis. Of 568 resected patients with satellite nodules, actuarial 5-year survival was 20%. Five articles gave separate survival data for satellite nodules in primary versus ipsilateral non-primary lobes. All five articles showed better survival for satellite nodules in a primary lobe. Satellite nodules in a primary lobe have a better prognosis than those in ipsilateral non-primary lobes. Survival for resected lung cancer with satellite nodules in a primary lobe is better than that usually observed for T4 (IIIB) disease. The 1997 staging revisions may unduly upstage patients with satellite nodules in a primary cancer lobe. However, satellite nodules in ipsilateral non-primary lobes share metastatic mechanisms and have survival results consistent with M1 stage disease. Their 1997 MI designation may be appropriate.

Pulmonary malignant granular cell tumor

BackgroundMalignant granular cell tumor (MGCT) is a rare disease entity. Forty-one well-documented MGCTs have been reported in the world literature.Case ReportThis report describes a patient who presented with a MGCT of the lung and reviews the preoperative evaluation, pathologic features and differential diagnosis of the disease. This case represents the first report of resected primary pulmonary MGCT.ConclusionsDiagnosis of MGCT is based on histology of the primary tumor, immunohistochemistry, and exclusion of tumors that may mimic granular cell tumor.

Malignant pleural mesothelioma: a problematic review

Malignant pleural mesothelioma is a rare tumor that has been difficult to study. Because of disappointing treatment results, malignant pleural mesothelioma has remained an area of active research and development. A clinicopathologic review is performed in light of several problematic issues involving diagnosis, staging, natural history, and treatment. Multimodality treatment with surgery followed by adjuvant local and systemic therapy remains the most optimal therapy. Many controversial issues still exist in the treatment of malignant pleural mesothelioma. In the ensuing years newer staging systems, better preoperative staging, newer experimental therapies, and the localization of patients at expert centers will undoubtedly have an impact on disease management.

Pulmonary Lymphatic Mapping in Dogs: Use of Technetium Sulfur Colloid and Isosulfan Blue for Pulmonary Sentinel Lymph Node Mapping in Dogs

Lung cancer is the most frequent cause of cancer death in the United States. The pattern of regional lymph node involvement is a major prognostic factor in a patient with nonsmall cell lung cancer. The accuracy of information obtained about the lymph node status of lung cancer patients can be potentially increased by sentinel node lymphatic mapping. This technique has been well studied in melanoma and breast cancer. It may be useful in increasing the detection of micrometastases and in decreasing the morbidity from complete mediastinal lymphadenectomy. We report an animal pilot study of pulmonary lymphatic mapping. The aim of our study was to gain experience in the surgical techniques for pulmonary sentinel node lymphatic mapping in an animal model prior to its application in humans. Technetium sulfur colloid and isosulfan blue dye were injected into different lobes of the lung followed by attempts to identify the sentinel node draining that specific portion of the lung. Technetium sulfur colloid identified the sentinel node in five of six dogs within 20 min after the radiotracer was injected into the lung parenchyma. Isosulfan blue dye identified the sentinel node in three of six dogs within 5 min. Both the agents are potentially useful, but we found greater technical ease in identifying the sentinel node with technetium sulfur colloid. Two single-institution pilot studies in humans have been performed. A multi-centered study to validate and further refine this technique is necessary. Advanced pathologic techniques such as immunohistochemistry and reverse transcriptase-polymerase chain reaction can be used to enhance the accuracy of staging. This may facilitate proper application of novel therapeutic strategies to improve the current dismal prognosis of this disease.

Comparison of human lung cancer/SCID mouse tumor xenografts and cell culture growth with patient clinical outcomes.

Leukemic cell growth in SCID mice has been reported as a predictor of disease relapse. However, there is a paucity of literature regarding xenograft growth and clinical outcomes in non-small cell lung cancer (NSCLC). Seventy-nine specimens from patients with NSCLC were either subcutaneously implanted into SCID mice and/or placed in tissue culture. Retrospective chart review was correlated with stage, histology, necrosis, disease-free interval, and survival. Tumor xenografts were successfully established with 17 of 37 (46%) tumor biopsy tissues. Thirteen of 59 (22%) specimens grew in cell culture. Patients whose tumors grew in SCID mice had no difference in survival compared to those with no growth (n=20, p=0.42). Median survival was 36 months in 13 patients whose tumors grew in cell culture compared to 39 months in 46 patients without growth. Eight of 12 (67%) patients with metastasis showed SCID/human xenograft growth, whereas nine of 25 (36%) without metastases did so (p=0.08). Growth of tumor cells in vitro occurred in 11 of 31 (35%) adenocarcinomas, one of 25 (4%) squamous cell carcinomas, and one of three (33%) large cell carcinomas (p=0.02). Well or moderately differentiated tumors grew in cell culture in only two of 22 (9%), whereas poorly or undifferentiated tumors grew in 11 of 32 (34%) cases (p=0.03). We conclude that neither the ability of a tumor to engraft and grow in SCID mice nor its ability to grow in vitro in cell culture is a reliable predictor of disease outcome or survival in patients with NSCLC. The ability to propagate tumors in vitro appears to be more dependent upon the histological type of tumor and its degree of differentiation.