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Mark B Orringer

Publications and source records attributed to Mark B Orringer.

At least 37 records · Page 2Linked to original sources
PubMed2003

Protein profiles associated with survival in lung adenocarcinoma.

Morphologic assessment of lung tumors is informative but insufficient to adequately predict patient outcome. We previously identified transcriptional profiles that predict patient survival, and here we identify proteins associated with patient survival in lung adenocarcinoma. A total of 682 individual protein spots were quantified in 90 lung adenocarcinomas by using quantitative two-dimensional polyacrylamide gel electrophoresis analysis. A leave-one-out cross-validation procedure using the top 20 survival-associated proteins identified by Cox modeling indicated that protein profiles as a whole can predict survival in stage I tumor patients (P = 0.01). Thirty-three of 46 survival-associated proteins were identified by using mass spectrometry. Expression of 12 candidate proteins was confirmed as tumor-derived with immunohistochemical analysis and tissue microarrays. Oligonucleotide microarray results from both the same tumors and from an independent study showed mRNAs associated with survival for 11 of 27 encoded genes. Combined analysis of protein and mRNA data revealed 11 components of the glycolysis pathway as associated with poor survival. Among these candidates, phosphoglycerate kinase 1 was associated with survival in the protein study, in both mRNA studies and in an independent validation set of 117 adenocarcinomas and squamous lung tumors using tissue microarrays. Elevated levels of phosphoglycerate kinase 1 in the serum were also significantly correlated with poor outcome in a validation set of 107 patients with lung adenocarcinomas using ELISA analysis. These studies identify new prognostic biomarkers and indicate that protein expression profiles can predict the outcome of patients with early-stage lung cancer.

Adenocarcinoma↗
PubMed2003

Gene amplification in esophageal adenocarcinomas and Barrett's with high-grade dysplasia.

PURPOSE: The purpose of this study was to determine the frequency and overall contribution of specific gene amplification events in the formation of Barrett's adenocarcinomas. The relationship of gene amplification to clinical-pathological variables and its potential usefulness as a marker for early cancer detection were also examined. EXPERIMENTAL DESIGN: We used quantitative PCR and Southern blot analysis to screen 87 cases of Barrett's adenocarcinoma for the presence or absence of 13 distinct gene amplification events. Gene amplification was then examined for correlation with other amplification events and clinical variables (survival, stage, nodal involvement, tumor invasion, smoking history, and gender). Additionally, 22 specimens of Barrett's with high-grade dysplasia (HGD) were examined for the presence of gene amplification. RESULTS: One or more amplification events were present in 50 of 87 (57%) adenocarcinomas. The ERBB2 gene was amplified in 19 of 87 (21.8%), CCNE1 in 11 of 87 (12.6%), GATA4 in 9 of 87 (10.3%), KRAS in 9 of 87 (10.3%), EGFR in 7 of 87 (8.0%), CCND1 in 6 of 87 (6.8%), HNF3alpha in 5 of 87 (5.7%), PIK3CA in 5 of 87 (5.7%), C-MYC in 4 of 87 (4.6%), DYRK2 in 2 of 87 (2.3%), and AIB1, AKT1, and IGF1R were amplified in 0 of 87 (0%) of the tumors. CCND1 amplification was found to correlate negatively with survival (P < 0.05). In addition, the ERBB2 amplicon positively correlated (P < 0.05) with GATA4 amplification. Increased copy number of the ERBB2 (1 of 22), GATA4 (1 of 22), KRAS (2 of 22), C-MYC (1 of 22), CCNE1 (2 of 22), and CCND1 (2 of 22) genes was also observed in one or more Barrett's adenocarcinomas with HGD. CONCLUSIONS: The high frequency of gene amplification in esophageal adenocarcinomas and HGD indicates the important role of these events in esophageal adenocarcinoma development. Additionally, these results underscore the possible usefulness of early detection approaches and chemotherapeutic strategies (ErbB2 and cyclin D1) targeted against amplified gene products.

Adenocarcinoma↗
PubMed2003

Increased C-CRK proto-oncogene expression is associated with an aggressive phenotype in lung adenocarcinomas.

The C-CRK gene, cellular homolog of the avian v-crk oncogene, encodes two alternatively spliced adaptor signaling proteins, CRKI (28 kDa) and CRKII (40 kDa). Both CRKI and CRKII have been shown to activate kinase signaling and anchorage-independent growth in vitro and CRKI transformed cells readily form tumors in nude mice. Affymetrix oligonucleotide arrays were used to analyse 86 lung adenocarcinomas and 10 uninvolved lung tissues. C-CRK mRNA expression was increased in more advanced (stage III versus stage I), larger (T(2-4) versus T(1)), and poorly differentiated tumors and in tumors from patients demonstrating poor survival (P=0.00034). An overlapping series of 93 lung adenocarcinomas (64 stage I and 29 stage III) and 10 uninvolved lung specimens were measured for quantitative differences in CRKI and CRKII protein levels using 2-D PAGE. CRK protein spots were identified using mass spectrometry and 2-D Western blotting. A significant increase in levels of the CRKI oncoprotein and the phosphorylated isoform of CRKII was observed in tumors (P<0.05). No difference in protein level was evident between stages. Concordant with mRNA expression, CRKI and CRKII were increased in poorly differentiated tumors (P<0.05). CRK immunohistochemical analysis of tumor tissue arrays using the same tumor series also demonstrated increased abundance of nuclear and cytoplasmic CRK in more proliferative tumors (P<0.05). This study provides the first quantitative analysis of discrete CRKI and CRKII protein isoforms in human lung tumors and provides evidence that the C-CRK proto-oncogene may foment a more aggressive phenotype in lung cancers.

Adenocarcinoma↗
PubMed2003

Amplification and overexpression of the dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 2 (DYRK2) gene in esophageal and lung adenocarcinomas.

Genomic amplification can lead to the activation of cellular proto-oncogenes during tumorigenesis, and is observed in most, if not all, human malignancies, including adenocarcinomas of lung and esophagus. Using a two-dimensional restriction landmark genomic scanning technique, we identified five NotI/HinfI fragments with increased genomic dosage in an adenocarcinoma of the gastroesophageal junction. Four of these amplified fragments were matched within three contigs of chromosome 12 using the bioinformatics tool, Virtual Genome Scan. All three of the contigs map to the 12q13-q14 region, and the regional amplification in the tumor was verified using comparative genomic hybridization analysis. The 12q14 amplicon was characterized using sequence tagged site-amplification mapping with DNA from paired normal-tumor tissues of 75 gastroesophageal and 37 lung adenocarcinomas. The amplicon spans a region of >12 Mb between genes DGKA and BLOV1. The core-amplified domain was determined to be <0.5 Mb between marker WI-12457 and gene IFNG. However, MDM2, a well-documented oncogene of the region, is outside the core-domain. Eleven genes and expressed sequence tags within the amplicon were selected for quantitative reverse transcription-PCR, and DYRK2, a member of the dual-specificity kinase family, was overexpressed in all of the tumors showing gene amplification. Among the sequence tagged site/expressed sequence tag/gene markers tested, DYRK2 demonstrated the highest DNA copy number and the highest level of mRNA overexpression in the tumors. Moreover, DYRK2 mRNA overexpression (>2.5-fold of normal mean) was found in 18.6% of additional 86 lung adenocarcinomas in an assay using oligonucleotide microarrays. DYRK2 mRNA overexpression occurs more frequently than gene amplification in both esophageal and lung adenocarcinomas. This is the first report of amplification and overexpression of DYRK2 in any tumor type.

Adenocarcinoma↗
PubMed2003

Overexpression of oncoprotein 18 correlates with poor differentiation in lung adenocarcinomas.

We examined the expression of oncoprotein 18 (Op18) in 93 lung adenocarcinomas and 10 uninvolved lung samples using quantitative two-dimensional PAGE analysis with confirmation by mass spectrometry and two-dimensional Western blot analysis. mRNA expression was examined using oligonucleotide microarrays, and the cellular localization of the Op18 protein was examined using immunohistochemical analysis of tissue microarrays. Three phosphorylated forms and one unphosphorylated form of the Op18 protein were identified and found to be overexpressed in lung adenocarcinomas as compared with normal lung. The percentage of phosphorylated to total Op18 protein isoforms increased from 3.2% in normal lung to 7.9% in lung tumors. Both the phosphorylated and unphosphorylated Op18 proteins were significantly increased in poorly differentiated tumors as compared with moderately or well differentiated lung adenocarcinomas (p<0.03), suggesting that up-regulated expression of Op18 reflects a poor differentiation status and higher cell proliferation rates. This was further verified in A549 and SKLU1 lung adenocarcinoma cell lines by examining Op18 levels and phosphorylation status following treatment that altered either cell proliferation or differentiation. The increased expression of Op18 protein was significantly correlated with its mRNA level indicating that increased transcription likely underlies elevated expression of Op18. The overexpression of Op18 proteins in poorly differentiated lung adenocarcinomas and the elevated expression of the phosphorylated forms of Op18 may offer a new target for drug- or gene-directed therapy and may have potential utility as a tumor marker.

Adenocarcinoma↗
PubMed2003

Proteomic analysis of eIF-5A in lung adenocarcinomas.

We examined the eIF-5A protein expression in 93 lung adenocarcinomas and 10 uninvolved lung samples using quantitative two-dimensional polyacrylamide gel electrophoresis (2-D PAGE) analysis with identification by mass spectrometry and 2-D Western blots. The same tissue samples were examined for the eIF-5A mRNA expression using oligonucleotide microarrays, and the cellular localization of the eIF-5A protein was examined using immunohistochemical analysis on tissue arrays. Higher eIF-5A protein expression was present in tumors showing poor differentiation, 12/13(th) codon K-ras mutations, p53 nuclear accumulation, and tumors with positive lymphocytic response. The eIF-5A mRNA was also significantly increased in lung adenocarcinomas compared to normal lung, but the eIF-5A protein expression was not correlated to its mRNA levels indicating that the increase in the eIF-5A protein expression in lung tumors is post-transcriptionally/translationally/post-translationally regulated. Patients having a higher eIF-5A protein expression showed a relatively poorer survival suggesting the use of eIF-5A as prognostic marker in lung adenocarcinoma. Moreover, the investigation on agents that inhibit eIF-5A function is encouraged.

Adenocarcinoma↗
PubMed2003

Challenges in reversing esophageal discontinuity operations.

BACKGROUND: After catastrophic esophageal or gastric disruption results in esophageal discontinuity, operations to restore swallowing are surgical challenges. METHODS: A retrospective review and assessment of functional results was performed in 40 patients (average age 59.9 years) who had 42 operations to reverse esophageal discontinuity between 1973 and 2002. RESULTS: Esophageal discontinuity resulted from gastric necrosis after esophagectomy and esophagogastrostomy (n = 10) or hiatal hernia repair (n = 4), esophageal perforation complicating dilatation (n = 5), failed colonic or jejunal interpositions (n = 5), caustic ingestion (n = 4), Boerhaave syndrome (n = 4), esophagogastric anastomotic leak (n = 3), and other causes (n = 6). Eighteen patients (43.9%) required prolonged mechanical ventilation. Thirty-one (75.6%) had an end cervical esophagostomy; 6, an anterior thoracic esophagostomy; 2, lateral esophagostomy and in situ native esophagus stapled and divided distally; and 1 each, a stapled, divided esophagus without esophagostomy and a stapled undivided esophagus without esophagostomy. Twenty-six patients (63.4%) had undergone partial or total gastrectomy. Ten (24.4%) had vocal cord paralysis. Operations reestablishing continuity included colonic interposition in 23 (56.1%), substernal gastric interposition in 7 (17.1%), esophagectomy and cervical anastomosis in 6, esophageal reanastomosis in 3, staged jejunal interposition in 1, and Roux-en-Y esophagojejunostomy in 1. There were no hospital deaths. Twenty-eight patients (68.3%) had postoperative complications. Length of stay averaged 20.6 days. Follow-up for 40 patients averaged 54.5 months. Functional results (39 patients) were excellent in 12 (30.8%), good in 15 (38.5%), fair in 10 (25.6%), and poor in 2 (5.1%). CONCLUSIONS: Successful reversal of esophageal discontinuity requires individualized assessment and ingenuity. Despite appreciable morbidity, the ultimate result is generally gratifying.

Adult↗
PubMed2003

Macrophage migration inhibitory factor and CXC chemokine expression in non-small cell lung cancer: role in angiogenesis and prognosis.

PURPOSE: The purpose of this study was to determine whether expression of migration inhibitory factor (MIF) is increased in non-small cell lung cancer, and whether it correlates with angiogenesis and/or prognosis. EXPERIMENTAL DESIGN: We measured vessel density, and levels of MIF, angiogenic CXC chemokines, and vascular-endothelial growth factor (VEGF; by ELISA) in tumor and normal lung tissue from 87 patients after resection of lung cancer. We compared vessel density with levels of MIF, VEGF, or angiogenic CXC chemokines in the corresponding tumor homogenate. Disease-free survival was analyzed in a Cox proportional hazards model. RESULTS: Levels of MIF in lung cancer demonstrated a bimodal distribution, with some having "normal" values (relative to normal lung tissue) and a second cluster with markedly high values. The increased levels of MIF in lung cancer were statistically significant in both paired and unpaired comparisons (P < 0.05). The strongest correlation of vessel density was with the sum of angiogenic CXC chemokines. MIF correlated very strongly with levels of angiogenic CXC chemokines. Tumors in the high MIF group had a strong correlation between MIF level and vessel density. Risk of recurrence was associated with high levels of glutamic acid-leucine-arginine amino acid motif CXC chemokines, MIF, and/or VEGF in a Cox proportional hazards model. CONCLUSIONS: MIF expression in non-small cell lung cancer occurs in a bimodal distribution, and is closely associated with tumor levels of angiogenic CXC chemokines and with vessel density. High levels of tumor-associated CXC chemokines, MIF, or VEGF are associated with risk of recurrence after resection of lung cancer.

Carcinoma, Non-Small-Cell Lung↗
PubMed2002

The hepatocyte nuclear factor 3 alpha gene, HNF3alpha (FOXA1), on chromosome band 14q13 is amplified and overexpressed in esophageal and lung adenocarcinomas.

Genomic amplification is observed in many, if not all, types of human malignancy and is one of the mechanisms for the activation of dominant-acting oncogenes in tumorigenesis. In the present study, three amplified restriction fragments were identified in an esophageal adenocarcinoma (P16) using the restriction landmark genome scanning two-dimensional gel technique. These fragments were cloned, sequenced, and mapped to chromosome band 14q13. Using the sequence tagged site-amplification mapping approach, we defined the core-amplified domain by screening 75 normal-tumor paired esophageal samples. The frequency of 14q13 amplification is 6.7% in esophageal tumors, and the amplicon spans >6 Mb in 1 tumor but is contained in a region <0.3 Mb in all of the remaining amplified tumors. Quantitative reverse transcription-PCR (RT-PCR) of 8 genes and expressed sequence tags located within the core-amplified domain revealed that the HNF3alpha (FOXA1)(4) gene, a forkhead gene family member, was overexpressed in all of the amplified esophageal tumors. HNF3alpha amplification was confirmed by Southern blot and interphase fluorescence in situ hybridization analyses, and the results of real-time RT-PCR were consistent with that of the regular quantitative RT-PCR. Increased immunohistochemical nuclear staining of the HNF3alpha protein was detected in all of the tumors containing 14q13 amplification. Affymetrix oligonucleotide microarrays of 86 lung adenocarcinomas demonstrated that expression of the HNF3alpha mRNA was elevated (> or =2.5-fold of mean expression in normal lung) in 37% (32 of 86) of the tumors analyzed. Gene amplification of HNF3alpha was detected in 2 of the 5 overexpressed lung tumors examined. This is the first report of HNF3alpha amplification, and overexpression in esophageal and lung adenocarcinomas. Amplification of HNF3alpha in esophageal and lung tumors may suggest a potential oncogenic role for this gene in tumorigenesis.

Adenocarcinoma↗
PubMed2002

Gene-expression profiles predict survival of patients with lung adenocarcinoma.

Histopathology is insufficient to predict disease progression and clinical outcome in lung adenocarcinoma. Here we show that gene-expression profiles based on microarray analysis can be used to predict patient survival in early-stage lung adenocarcinomas. Genes most related to survival were identified with univariate Cox analysis. Using either two equivalent but independent training and testing sets, or 'leave-one-out' cross-validation analysis with all tumors, a risk index based on the top 50 genes identified low-risk and high-risk stage I lung adenocarcinomas, which differed significantly with respect to survival. This risk index was then validated using an independent sample of lung adenocarcinomas that predicted high- and low-risk groups. This index included genes not previously associated with survival. The identification of a set of genes that predict survival in early-stage lung adenocarcinoma allows delineation of a high-risk group that may benefit from adjuvant therapy.

Adenocarcinoma↗
PubMed2002

Development of a CD-ROM Internet Hybrid: a new thoracic surgery curriculum.

The TSDA Prerequisite Curriculum Committee has successfully developed the content for a didactic curriculum to be mastered by the residents before their matriculation in a thoracic surgical residency program. In addition the committee assembled an innovative electronic format consisting of a CD-ROM Internet Hybrid to teach this curricular material. By use of a serialized CD-ROM Internet Hybrid it is possible to store relatively dense high bandwidth portions of the curriculum including video and audio materials on the CD-ROM and yet allow constant updating and interaction of the other portions of the curriculum. In addition, it is possible to track the performance and utilization by the residents during the entire course of their residency program. By studying the relationship between the utilization of the curriculum, particularly as it relates to certain subject areas, and comparing that to performance or standardized examinations as well as other measurements of resident satisfaction, the efficacy of the prerequisite curriculum will be tracked during the upcoming years. It is anticipated that the process of developing the content of the prerequisite curriculum will allow the residents and program directors to focus on the subject material currently deemed necessary for successful initiation of a thoracic surgery residency, and that by keeping this subject material outline up-to-date, the changing spectrum of what we anticipate our residents will know at the time of their matriculation will continue to mature. Although electronic-based education has been available for a number of years, a prospective randomized study comparing it with traditional textbook-based learning is novel. Multiple attempts have been made to implement Web-based or CD-ROM-based educational tools in other specialties with variable results. It is our anticipation that successful completion of this project will not only allow for the use of an innovative highly technical means of education for our residents but may in turn become broadly applicable to many other types of educational projects within thoracic surgery education. This may also be applicable to other types of educational projects in the postgraduate education industry and other venues as well. The conduct of a scientific study monitoring the impact of this curriculum project as well as the acceptance of the project by the resident is also relatively unique and will be scrutinized by numerous professional medical and educational groups.

CD-ROM↗
PubMed2002

Diagnostic thoracoscopic lung biopsy: an outpatient experience.

BACKGROUND: Tissue diagnosis of either interstitial lung disease or indeterminate pulmonary nodules can be obtained by either limited thoracotomy or thoracoscopic lung biopsy. Both procedures traditionally have required hospital admission. We report a series of patients undergoing outpatient thoracoscopic lung biopsy to demonstrate the safety and efficacy of this practice. METHODS: Sixty-two ambulatory patients with a clinical diagnosis of either interstitial lung disease or indeterminate pulmonary nodule(s) underwent thoracoscopic lung biopsy between June 2000 and June 2001. All procedures were performed with double-lumen endotracheal anesthesia and stapled wedge resection. Chest tubes were removed if no air leak was present and if chest radiograph demonstrated no residual pneumothorax. RESULTS: Of 62 patients undergoing thoracoscopic lung biopsy, 45 (72.5%) were discharged home within 8 hours of observation on the day of operation. Fourteen (22.5%) were discharged within 23 hours of their operation. Reasons for 23-hour observation included significant comorbidity (8), pain management (4), postoperative air leak (1), and conversion to muscle-sparing thoracotomy (1). Three (5%) required admission for prolonged air leak (2) or conversion to muscle-sparing thoracotomy (1). Diagnoses were obtained in 61 patients, including neoplasm (25), interstitial lung disease (18), granulomatous disease (7), and other (11). One patient was readmitted for pneumothorax. Patients diagnosed with nonbronchogenic pulmonary metastases were more likely to be discharged on the day of operation. No differences in age, smoking status, or preoperative pulmonary function testing were observed between patients requiring short-stay observation and those discharged immediately after operation. CONCLUSIONS: Outpatient thoracoscopic lung biopsy is safe and effective, and has become our procedure of choice for diagnosis of either interstitial or focal lung disease.

Adult↗
PubMed2002

Discordant protein and mRNA expression in lung adenocarcinomas.

The relationship between gene expression measured at the mRNA level and the corresponding protein level is not well characterized in human cancer. In this study, we compared mRNA and protein expression for a cohort of genes in the same lung adenocarcinomas. The abundance of 165 protein spots representing 98 individual genes was analyzed in 76 lung adenocarcinomas and nine non-neoplastic lung tissues using two-dimensional polyacrylamide gel electrophoresis. Specific polypeptides were identified using matrix-assisted laser desorption/ionization mass spectrometry. For the same 85 samples, mRNA levels were determined using oligonucleotide microarrays, allowing a comparative analysis of mRNA and protein expression among the 165 protein spots. Twenty-eight of the 165 protein spots (17%) or 21 of 98 genes (21.4%) had a statistically significant correlation between protein and mRNA expression (r > 0.2445; p < 0.05); however, among all 165 proteins the correlation coefficient values (r) ranged from -0.467 to 0.442. Correlation coefficient values were not related to protein abundance. Further, no significant correlation between mRNA and protein expression was found (r = -0.025) if the average levels of mRNA or protein among all samples were applied across the 165 protein spots (98 genes). The mRNA/protein correlation coefficient also varied among proteins with multiple isoforms, indicating potentially separate isoform-specific mechanisms for the regulation of protein abundance. Among the 21 genes with a significant correlation between mRNA and protein, five genes differed significantly between stage I and stage III lung adenocarcinomas. Using a quantitative analysis of mRNA and protein expression within the same lung adenocarcinomas, we showed that only a subset of the proteins exhibited a significant correlation with mRNA abundance.

Adenocarcinoma↗
PubMed2002

Proteomic analysis of lung adenocarcinoma: identification of a highly expressed set of proteins in tumors.

PURPOSE: The goal of this study was to identify potential protein markers in lung adenocarcinomas. EXPERIMENTAL DESIGN: A series of 93 lung adenocarcinomas (64 stage I and 29 stage III) and 10 uninvolved lung samples were examined for quantitative differences in protein expression using two-dimensional PAGE. Candidate proteins were identified using matrix-assisted laser desorption/ionization mass spectrometry or peptide sequencing. The levels of the individual isoforms of nine proteins found to be overexpressed in the lung tumors were examined. Potential mechanisms for overexpression were examined by comparing mRNA expression levels, assessed using oligonucleotide arrays, to the protein values in the same samples. RESULTS: Antioxidant enzyme AOE372, ATP synthase subunit d (ATP5D), beta1,4-galactosyltransferase, cytosolic inorganic pyrophosphatase, glucose-regulated M(r) 58,000 protein, glutathione-S-transferase M4, prolyl 4-hydroxylase beta subunit, triosephosphate isomerase, and ubiquitin thiolesterase (UCHL1) were identified as being significantly overexpressed in lung adenocarcinomas. The expression of these proteins was increased from 1.4- to 10.6-fold as compared with uninvolved lung tissue. The expression of the individual protein isoforms was correlated with 10 clinicopathological variables as well as with each gene's mRNA level in the same sample. Both isoforms of glucose-regulated M(r) 58,000 protein were found to be significantly correlated with their mRNA expression profiles (P < 0.05), indicating that increased transcription likely underlies the increased expression of these proteins. CONCLUSIONS: Two-dimensional PAGE and mass spectrometry can identify proteins showing increased expression in lung adenocarcinoma. The association of specific isoforms of these proteins with clinical variables and understanding the regulation of their expression will aid in determination of their potential use as biomarkers in this cancer.

Adenocarcinoma↗
PubMed2002

RANTES expression is a predictor of survival in stage I lung adenocarcinoma.

PURPOSE: The presence of an active lymphocytic response (ALR) in non-small cell lung cancer (NSCLC) tumors has previously been associated with a more favorable prognosis. The purpose of this study was to identify differences in global gene expression profiles between stage I NSCLC tumors with ALR (ALR+) and those without ALR (ALR-). EXPERIMENTAL DESIGN: Sixty-three stage I lung adenocarcinomas were analyzed for gene expression using Affymetrix oligonucleotide microarrays. Tumors were stratified into ALR+ and ALR- groups and compared for statistically significant differences in gene expression. Identified candidate genes were validated using both ELISA and immunohistochemistry. Follow-up data for these patients were collected and used to assess patient prognosis. RESULTS: Of the 63 tumors studied, 27 were ALR+ and 36 were ALR-. A total of 303 genes showed significant differences in gene expression between the two populations (t test, P < 0.02). Three of the genes overexpressed by ALR+ tumors were the chemokines: small inducible cytokine A4 (MIP-1beta), RANTES, and interferon inducible protein 10 (IP-10). Immunohistochemistry analysis showed that the tumor cells expressed these cytokines. ELISA showed that MIP-1beta and RANTES were overexpressed at the protein level by ALR+ tumors. Univariate Cox proportional hazards analysis showed that RANTES was a predictor of survival in stage I lung adenocarcinomas (P = 0.002). CONCLUSION: When tested in the Cox univariate proportional hazards model, RANTES expression by lung adenocarcinoma cells is a predictor of survival in stage I NSCLC patients and may be useful as a prognostic factor in lung cancer.

Adenocarcinoma↗
PubMedDate not supplied

L-type amino acid transporter-1 overexpression and melphalan sensitivity in Barrett's adenocarcinoma.

The L-type amino acid transporter-1 (LAT-1) has been associated with tumor growth. Using cDNA microarrays, overexpression of LAT-1 was found in 87.5% (7/8) of esophageal adenocarcinomas relative to 12 Barrett's samples (33% metaplasia and 66% dysplasia) and was confirmed in 100% (28/28) of Barrett's adenocarcinomas by quantitative reverse transcription polymerase chain reaction. Immunohistochemistry revealed LAT-1 staining in 37.5% (24/64) of esophageal adenocarcinomas on tissue microarray. LAT-1 also transports the amino acid-related chemotherapeutic agent, melphalan. Two esophageal adenocarcinoma and one esophageal squamous cell line, expressing LAT-1 on Western blot analysis, were sensitive to therapeutic doses of melphalan (P <.001). Simultaneous treatment with the competitive inhibitor, BCH [2-aminobicyclo-(2,1,1)-heptane-2-carboxylic acid], decreased sensitivity to melphalan (P <.05). In addition, confluent esophageal squamous cultures were less sensitive to melphalan (P <.001) and had a decrease in LAT-1 protein expression. Tumors from two esophageal adenocarcinoma cell lines grown in nude mice retained LAT-1 mRNA expression. These results demonstrate that LAT-1 is highly expressed in a subset of esophageal adenocarcinomas and that Barrett's adenocarcinoma cell lines expressing LAT-1 are sensitive to melphalan. LAT-1 expression is also retained in cell lines grown in nude mice providing a model to evaluate melphalan as a chemotherapeutic agent against esophageal adenocarcinomas expressing LAT-1.

Adenocarcinoma↗