Biomedical subjects

David J Sugarbaker

Publications and source records attributed to David J Sugarbaker.

49 records · Page 3Linked to original sources

PubMed2003

Section V: techniques of esophageal resection.

Esophagectomy the treatment of choice for esophageal cancer, is a procedure which, nationwide, carries a mortality rate of 10% and a morbidity rate of 50%. The five-year survival rate for esophagectomy for cancer remains at 20%. With great care in surgical planning, technique, and patient care, the mortality rate has been lowered to 3% at several large academic centers. The methods of esophagectomy including Ivor-Lewis, transhiatal, left thoracoabdominal, and cervical exenteration are discussed. The technique of tri-incisional esophagectomy is detailed in this chapter. This technique combines the best aspects of the Ivor-Lewis and transhiatal approaches, those being a cervical anastomosis (avoiding an intrathoracic leak, minimizing reflux, and allowing for a complete esophagectomy) and transthoracic dissection of the esophagus (allowing for a safe dissection and complete lymphadenectomy).

Esophageal Neoplasms↗

PubMed2003

A prognostic test for adenocarcinoma of the lung from gene expression profiling data.

Until recently, it has been impossible to determine which patients with resected stage I lung cancer are among the 30% who will die of metastatic cancer within 5 years of surgery. Bioinformatics tools applied to lung cancer expression profiling data have identified prognostic genes that have been used to develop predictor models, but thus far, these models have not been incorporated into routine clinical use because of their inherent complexity and requirement for relatively large numbers of genes. We have used ratios of gene expression to overcome these limitations. Here, we evaluate the ability of this technique to identify patients with stage I lung adenocarcinoma at risk for recurrence. We derived candidate ratio-based tests from analysis of 36 stage I lung adenocarcinoma samples using previously published expression profiling data. Eleven of these tests were identified for additional study and assessed for classification accuracy in an independent set of 60 stage I lung adenocarcinoma samples. We then evaluated the optimal ratio-based test in the independent samples using Kaplan-Meier survival analysis. Finally, we examined the ability of this test to predict outcome in a set of 97 stage I breast adenocarcinoma. We found that subsets of the independent lung cancer samples predicted to be associated with either good or poor outcome using the optimal ratio-based test differed significantly (P=0.0056) in terms of survival with a classification accuracy of 74% (P=0.0043, Fisher's exact test). When this test was applied to stage II and III lung cancers, most specimens were classified as poor outcome cancers. Interestingly, we found that the same test significantly (P=0.0417) predicted recurrence of stage I breast tumors, suggesting that at least some of the marker genes we identified may have generalized prognostic significance for adenocarcinoma. Our results provide additional evidence that expression ratios are highly accurate in predicting cancer recurrence and may be used in a simple test to predict response to surgical therapy in early-stage lung adenocarcinoma.

Adenocarcinoma↗

PubMed2002

Missense mutations of the BRAF gene in human lung adenocarcinoma.

Mutations of the BRAF protein serine/threonine kinase gene have recently been identified in a variety of human cancers, most notably melanomas. We sought to determine the frequency of BRAF mutations in human lung cancer pathogenesis. Analysis of BRAF sequence from 127 primary human lung adenocarcinomas revealed mutations in two tumor specimens, one in exon 11 (G465V), and a second in exon 15 (L596R). These specimens belong to the same adenocarcinoma subgroup as defined by clustering of gene expression data. BRAF may provide a target for anticancer chemotherapy in a subset of lung adenocarcinoma patients.

Adenocarcinoma↗

PubMed2002

Translation of microarray data into clinically relevant cancer diagnostic tests using gene expression ratios in lung cancer and mesothelioma.

The pathological distinction between malignant pleural mesothelioma (MPM)and adenocarcinoma (ADCA) of the lung can be cumbersome using established methods. We propose that a simple technique, based on the expression levels of a small number of genes, can be useful in the early and accurate diagnosis of MPM and lung cancer. This method is designed to accurately distinguish between genetically disparate tissues using gene expression ratios and rationally chosen thresholds. Here we have tested the fidelity of ratio-based diagnosis in differentiating between MPM and lung cancer in 181 tissue samples (31 MPM and 150 ADCA). A training set of 32 samples (16 MPM and 16 ADCA) was used to identify pairs of genes with highly significant, inversely correlated expression levels to form a total of 15 diagnostic ratios using expression profiling data. Any single ratio of the 15 examined was at least 90% accurate in predicting diagnosis for the remaining 149 samples (e.g., test set). We then examined (in the test set) the accuracy of multiple ratios combined to form a simple diagnostic tool. Using two and three expression ratios, we found that the differential diagnoses of MPM and lung ADCA were 95% and 99% accurate, respectively. We propose that using gene expression ratios is an accurate and inexpensive technique with direct clinical applicability for distinguishing between MPM and lung cancer. Furthermore, we provide evidence suggesting that this technique can be equally accurate in other clinical scenarios.

Adenocarcinoma↗

PubMed2002

Current surgical management of malignant pleural mesothelioma.

Malignant pleural mesothelioma is a rare and very aggressive malignancy with an increasing incidence. Single-modality therapy has failed to improve median survival. Current surgical therapies include palliative and cytoreductive procedures. The rarity of the disease, the lack of randomized surgical studies, and the lack of a universally accepted and validated staging system make it difficult to reach consensus and establish stage-specific protocols. However, with strict criteria, subsets of patients can be identified who can benefit from aggressive cytoreductive surgical approaches, such as extrapleural pneumonectomy, and adjuvant chemoradiation protocols. Our experience with this type of protocol in carefully selected patients has resulted in increased median survival. The lack of cure in any of the published protocols demonstrates the need for new therapies and approaches for this disease.

Asbestosis↗

PubMed2002

Multimodality treatment of diffuse malignant pleural mesothelioma.

Diffuse malignant pleural mesothelioma (DMPM) is a challenging disease in all of its aspects, from presentation and diagnosis to staging and treatment. Single-modality therapy was the initial approach to this disease. It generally has not been effective in changing the natural history of DMPM. As a result, multimodality regimens involving surgery with radiation, chemotherapy, or immunotherapy delivered regionally or systemically have been evaluated. Randomized controlled studies comparing various strategies are lacking and, thus, the debate continues regarding the effectiveness of different treatment approaches.

Combined Modality Therapy↗

PubMed2002

Inhibitor of apoptosis protein-1 promotes tumor cell survival in mesothelioma.

Malignant pleural mesothelioma (MPM) is a highly lethal pleural neoplasm that is often resistant to chemotherapeutic drugs, including cisplatin, and for which little is known regarding carcinogenic pathways. We used differential display to compare gene expression patterns in mesothelioma, normal pleura and normal lung, in order to better understand MPM pathobiology, and to search for genes that may facilitate drug resistance in this cancer. The human inhibitor of apoptosis protein-1 gene (IAP-1/MIHC/cIAP2) was discovered to be highly expressed in MPM. We confirmed overexpression of IAP-1 mRNA and protein in 39 additional human MPM tumor specimens and 3/5 (60%) MPM cell lines by multiple methods, including real time quantitative reverse transcription-PCR and western blot analysis. Using an antisense targeting approach, we found that attenuation of IAP-1 mRNA levels decreases baseline cell viability and increases the sensitivity of MPM cell lines to cisplatin by nearly 20-fold. Reduced IAP-1 gene expression also results in a concordant increase of the pro-apoptotic cleavage product of caspase 9 and a reduction in the number of viable tumor cells. Our observations strongly suggest that IAP-1 is at least partly responsible for promoting carcinogenesis and mediating resistance to cisplatin in many MPM tumors and that further study of this apoptotic pathway is warranted.

Cell Survival↗

PubMed2002

Cardiac decortication (epicardiectomy) for occult constrictive cardiac physiology after left extrapleural pneumonectomy.

Constrictive cardiac physiology typically does not occur in the absence of parietal pericardium. However, we report eight patients who, after left extrapleural pneumonectomy and removal of the parietal pericardium for malignancy, presented with dyspnea, jugular venous distension, and peripheral or generalized edema unresponsive to diuretics. Cardiac decortication (epicardiectomy) was performed whereby a thickened peel encasing the heart was surgically excised, resulting in vigorous contraction and expansion of the heart. In one patient, decortication occurred early after pneumonectomy and was incomplete. Acute signs of inflammation were present, and recurrence necessitated repeat decortication. When patients present with dyspnea, hepatojugular reflux, and peripheral edema refractory to diuretics, constrictive cardiac physiology should be considered in the differential diagnosis, even in the absence of parietal pericardium.

Constriction, Pathologic↗

PubMed2002

Radiotherapy versus chemotherapy plus radiotherapy in surgically treated IIIA N2 non-small-cell lung cancer.

Preoperative chemotherapy in patients with stage III non-small-cell lung cancer (NSCLC) remains controversial. Phase II trials utilizing preoperative chemotherapy in selected patients have achieved complete resection rates of 50%-70% with 3-5 year failure-free survival rates of 15%-33%. Between October 1992 and November 1994, 57 adults (50 of whom were evaluable) with surgically staged IIIA NSCLC and pathologically documented ipsilateral mediastinal nodal involvement (N2) were enrolled in a Cancer and Leukemia Group B randomized trial. Preoperative therapy was thought to be critical to facilitating surgical resectability. For patients randomized to the radiotherapy/surgery/radiotherapy (RSR) arm (n = 24), treatment consisted of preoperative radiation therapy (RT) at 40 Gy, surgery, and then additional RT at 14-20 Gy. For patients randomized to the chemotherapy/surgery/chemotherapy/radiotherapy (CSCR) arm (n = 26), treatment consisted of 2 cycles of cisplatin/etoposide with filgrastim support (PE) followed by surgery, 2 more cycles of PE, then RT 54-60 Gy. The total dose of RT on either arm was 54 Gy if completely resected or 60 Gy if incompletely resected or unresected. Clinical characteristics were well balanced between the two arms. Thoracotomy was performed in 42 patients (84%), 28 (67%) of whom had complete resection. The median failure-free and overall survival rates were 12 months (95% confidence interval [CI], 9-23 months) and 23 months (95% CI, 19 months-infinity) for the RSR arm and 11 months (95% CI, 5-20 months) and 18 months (95% CI, 12-32 months) for the CSCR arm. The rates of overall and complete surgical resection, downstaging of nodal involvement, and failure-free (P = 0.92) and overall survival (P = 0.41) did not differ between the two treatment arms. Moreover, in this trial, the chemotherapy regimen was sufficiently toxic to have had a lower completion rate of prescribed therapy in the CSCR arm than in the RSR arm.

Clinical Trial↗

PubMed2002

Diffuse malignant mesothelioma of the pleural space and its management.

Diffuse malignant pleural mesothelioma is a rare and aggressive malignancy of the pleura that is usually caused by exposure to asbestos. Between 2,000 and 3,000 new cases are expected to be diagnosed annually in the United States. Difficulties in diagnosis, staging, and treatment set this disease apartfrom other malignancies. The variable clinical presentation and problems in establishing a definite histopathologic diagnosis result in significant delays in treatment. Three histologic subtypes of the disease are described in this review: epithelial, sarcomatous, and mixed histologies. The Butchart, International Mesothelioma Interest Group, and Brigham staging systems are the most commonly used staging systems. The disease's natural history involves aggressive local growth, invasion of vital mediastinal structures, and death within 4 to 12 months without treatment. Single-modality therapy of any kind has failed to substantially alter this natural history. Aggressive, multimodality regimens that include surgery, radiation, and chemotherapy have resulted in improved survival in properly selected patients. However, innovative therapies are still needed to prolong survival in patients with early and advanced disease.

Aged↗

PubMed2002

Assessment of malignant pleural mesothelioma with (18)F-FDG dual-head gamma-camera coincidence imaging: comparison with histopathology.

UNLABELLED: Malignant pleural mesothelioma is an aggressive primary neoplasm for which early detection and accurate staging are known diagnostic challenges. The role of (18)F-FDG dual-head gamma-camera coincidence imaging ((18)F-FDG-CI) is yet to be defined. The purpose of this study was to evaluate the usefulness of (18)F-FDG-CI in the assessment of malignant pleural mesothelioma using histopathology as the gold standard. METHODS: Fifteen consecutive patients with CT scan evidence of pleural thickening, fluid, plaques, or calcification underwent (18)F-FDG imaging 1.5 h after the intravenous administration of 370 MBq (18)F-FDG. Imaging was performed with a dual-head gamma camera equipped with 2.54-cm-thick NaI crystals operating in coincidence mode. Using an iterative algorithm, whole-body images were reconstructed as transaxial, sagittal, and coronal images. No attenuation correction was applied. The results of (18)F-FDG-CI scans were compared with CT and with histopathologic diagnosis. RESULTS: Eleven of 15 patients had histologically proven malignant mesotheliomas (10 epithelial, 1 sarcomatoid). All 11 primary tumors were detected by (18)F-FDG, and absence of disease was confirmed in the 4 patients who were disease free. Thirty-four lesions were biopsied; among these, 29 were found to be positive for tumor. (18)F-FDG was true-positive in 28 lesions, true-negative in 4, false-negative in 1 (0.5 cm in diameter), and false-positive in 1 (inflammatory pleuritis). The smallest lesion detected was 0.8 cm. For biopsied lesions, overall sensitivity, specificity, and accuracy for (18)F-FDG-CI were 97%, 80%, and 94% respectively, compared with 83%, 80%, and 82% for CT. Twenty-one of 29 positive lesions involved the pleura, lung parenchyma, or chest wall and were all (18)F-FDG avid. In the mediastinum, (18)F-FDG-CI detected 7 of 8 biopsy-positive lesions (88%), whereas CT was positive in 6 of 8 lesions (75%). (18)F-FDG identified extrathoracic metastases in 5 patients, excluding them from surgical therapy. CONCLUSION: These preliminary results suggest that (18)F-FDG-CI appears to be an accurate method to diagnose and to define the extent of disease in patients with diffuse malignant pleural mesothelioma.

Algorithms↗

PubMedDate not supplied

Activation of focal adhesion kinase in human lung cancer cells involves multiple and potentially parallel signaling events.

Integrins are adhesion receptors that transmit signals bidirectionally across the plasma membrane. In our previous report we have shown that the squamous lung cancer cell line, Calu-1, binds to collagen type IV (Coll IV) through beta1-integrin and results in phosphorylation of focal adhesion kinase (FAK) (Ann Thorac Surg 2004; 78:450-457). Considering the critical role of FAK in cell migration, proliferation, and survival, here we investigated potential mechanisms of its activation and regulation in Calu-1 cells. We observed the phosphorylation of Tyr397 of FAK (the autophosphorylation site of FAK) and paxillin, the immediate downstream substrate of FAK following the adhesion of Calu-1 cells to Coll IV. FAK remains phosphorylated during proliferation either on Coll IV or on uncoated plates for 72 h, as determined by peroxivanadate treatment. Exposure of Calu-1 cells with 60 microM genistein, reduces FAK phosphorylation (7.6 fold) and cell proliferation. Extracellular signal regulated kinases (ERKs) were also phosphorylated after Coll IV attachment. Disruption of Calu-1 cell cytoskeleton integrity by 1-5 muM Cytochalasin D resulted in the inhibition of cell adhesion (50% to 75%, p<0.19 - 6.6 x 10(7)) and ERKs phosphorylation (2 fold) without any effect on FAK phosphorylation. Protein Kinase C inhibitor, Calphostin C at 100 and 250 nM concentrations did not block Coll IV induced FAK phosphorylation but activated the ERKs in a dose dependent manner. beta1-integrin is essential for Coll IV induced FAK activation, but it is not physically associated with FAK as determined by immunodetection assay. Collectively, this report defines the existence of multiple and potentially parallel Coll IV/beta1-integrin mediated signaling events in Calu-1 cells, which involve FAK, ERKs, and PKC.

Cell Adhesion↗

PubMedDate not supplied

Detection and quantification of SV40 large T-antigen DNA in mesothelioma tissues and cell lines.

SV40 viral DNA sequences, particularly large T-antigen (T-ag) DNA, have been reported in malignant pleural mesothelioma (MPM) and suggested to play a role in the tumorigenesis of this cancer. These results remain somewhat controversial owing to variability among a number of laboratories in reported SV40 DNA and protein detection in MPM tissues. This could be explained in part if SV40 DNA is present in relatively low abundance in many MPM tissues determined to contain viral sequences and is therefore difficult to detect. To this end, we investigated the efficacy of real time quantitative PCR in detecting low copy number SV40 DNA sequences, then we quantified SV40 copy number in MPM tissues and cell lines at our institution. Quantitative PCR demonstrated consistent precision and accuracy in detecting SV40 DNA sequences over a large logarithmic range of viral copy number. In addition, SV40 sequences were found in 2/35 tissues and 3/7 cell lines in relatively low abundance. We conclude that SV40 is not a contributing factor in the pathobiology of the majority of MPM tumors from patients at our institution.

Animals↗