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Biomedical subjects

Mark B Orringer

Publications and source records attributed to Mark B Orringer.

At least 19 recordsLinked to original sources
PubMed2006

Diversity of the angiogenic phenotype in non-small cell lung cancer.

Angiogenesis is crucial for tumor biology. There are many mechanisms by which tumors induce angiogenesis. We hypothesize that each individual tumor develops a unique mechanism to induce angiogenesis, and that activation of a particular angiogenic pathway suppresses the evolution of alternative pathways. We characterized 168 human non-small cell lung cancer (NSCLC) specimens for levels of angiogenic factors (angiogenic CXC chemokines, basic fibroblast growth factor, and vascular endothelial growth factor). We also induced lung tumor formation in A/J mice by injecting the tobacco carcinogen NNK. We dissected individual lung tumors and measured expression of angiogenic factors from three distinct families using real-time PCR. Finally, we controlled the angiogenic milieu using in vivo models to determine the resultant phenotype of the angiogenic factors expressed by NSCLC cells. Human tumors displayed marked variation in the expression of angiogenic factors. Individual mouse tumors, even from within the same mouse, displayed variability in their pattern of expression of angiogenic factors. In a sponge model of angiogenesis using murine lung cancer cells, implanting LLC cells with an angiogenic factor suppressed the expression of other angiogenic factors in implanted sponges. This suppressive effect was not seen in vitro. We conclude that lung cancer tumors evolve a unique and dominant angiogenic phenotype. Once an angiogenic pathway is activated, it may allow for tumor growth to proceed in the absence of a selection pressure to activate a second pathway.

Angiogenic Proteins↗
PubMed2006

Multiple forms of genetic instability within a 2-Mb chromosomal segment of 3q26.3-q27 are associated with development of esophageal adenocarcinoma.

Gene amplification is one of the mechanisms to activate oncogenes in many cancers, including esophageal adenocarcinoma (EA). In the present study, we used two-dimensional restriction landmark genome scanning to clone a NotI/DpnII fragment that showed increased genomic dosage in 1 of 44 EAs analyzed. This fragment maps to 3q26.3-q27, and subsequent experiments identified two intrachromosomal amplicons within a 10-Mb DNA segment in 7 of 75 (9%) EAs. The distal amplified-core region maps centromeric to the PIK3CA locus, and a microsatellite (D3S1754) within this region exhibited significant instability (MSI), in stark contrast to the genomewide microsatellite stability found in EA. D3S1754-MSI arises in premalignant Barrett's dysplastic cells and preceded amplification of the nascent MSI allele in the corresponding EA. Seven ESTs within the amplified-core were overexpressed in amplicon-containing EAs. One of these, EST AW513672, represents a chimeric transcript that initiated from an antisense promoter sequence in the 5'UTR of a full-length LINE-1 element (L1-5'ASP). Similar chimeric transcripts encoding portions of the MET oncogene and the BCAS3 gene also were overexpressed in EAs, suggesting that L1-5'ASP activation may occur at a broad level in primary EAs. Thus, the fine dissection of a 2-Mb amplified DNA segment in 3q26.3-q27 in EA revealed multiple genetic alterations that had occurred sequentially and/or concurrently during EA development.

5' Untranslated Regions↗
PubMed2006

Tension chylothorax.

Thoracic duct injury resulting in chylothorax is a well-known and documented complication of thoracic surgery. However, chylothorax under tension is a rarely reported complication that results in respiratory and hemodynamic collapse. Early recognition and treatment of this entity are essential for optimal patient outcome. Herein we present two cases of postoperative tension chylothorax followed by a review of the diagnostic work-up and therapy for this complication.

Aged↗
PubMed2006

Awake tracheobronchial dilation without the use of rigid bronchoscopy.

Benign tracheal strictures have been treated by repeated dilations using rigid bronchoscopy and general anesthesia. An alternative approach using conscious sedation, fluoroscopy, flexible bronchoscopy, and Savary-Gilliard esophageal dilators (Cook Endoscopy, Inc, Winston-Salem, NC) is reported. All patients undergoing dilation while awake had lesions due to inflammatory disease or lesions that were not amenable to resection. This method may be less traumatic than rigid bronchoscopy and can be accomplished on an outpatient basis without the use of general anesthesia.

Adult↗
PubMed2006

Expression and effect of inhibition of the ubiquitin-conjugating enzyme E2C on esophageal adenocarcinoma.

Ubiquitin-dependent proteolysis of cyclins plays a critical role in cell cycle progression and tumorigenesis. We examined the expression of ubiquitin-conjugating enzyme E2C (UBE2C) during progression from Barrett's metaplasia to esophageal adenocarcinoma (EA) and the effects of targeting this enzyme on EA-derived cell lines. Using oligonucleotide microarrays UBE2C expression was elevated in 73% (11 of 15) of EAs relative to Barrett's metaplasia. Tissue microarray showed elevated UBE2C in 70% (7 of 10) of dysplastic samples and in 87% (58 of 67) of tumors relative to metaplastic samples. Transfection of dominant-negative UBE2C into Seg-1 cells decreased proliferation (P = .04) and increased mitotic arrest compared to vector controls (63.5% vs 6.8%; P < .001). Transfection of UBE2C small interfering RNA also caused inhibiton of cell proliferation and distortion of the cell cycle, with maximal increase of G(2) cells (155% of mock cells) at 72 hours and of S-phase cells (308% of mock cells) at 24 hours. Treatment of Seg-1 cells with the proteasome inhibitor MG-262 (1 nM-1 microM) showed decreased proliferation (P = .02). EA-derived cells expressing UBE2C are sensitive to treatment with MG-262 and to silencing of UBE2C, suggesting that patients with EAs overexpressing UBE2C may benefit from agents targeting this ubiquitin-conjugating enzyme.

Adenocarcinoma↗
PubMed2005

Phosphorylated FADD induces NF-kappaB, perturbs cell cycle, and is associated with poor outcome in lung adenocarcinomas.

In an effort to identify a clinical biomarker for lung cancer, we used cDNA microarray and 2D protein analyses to demonstrate that increased Fas-associated death domain (FADD) mRNA and protein were significantly associated with poor survival. Analyses of copy number and sequence of the FADD gene in 24 independent tumors ruled out the existence of an amplified and/or mutated FADD gene in aggressive lung cancers. Immunohistochemistry-based tissue microarray analysis showed that nuclear localization of FADD and elevation of the phosphorylated form of FADD (p-FADD) correlated with poor outcome (P = 0.003). Tumors with increased p-FADD expression showed elevated NF-kappaB (P = 0.004) activation, a frequent molecular alteration associated with tumorigenesis and metastasis in a variety of cancers. To provide a link between p-FADD and NF-kappaB, cell culture studies demonstrated that overexpression of p-FADD leads to an increase in NF-kappaB activity and a decrease in the number of cells in the G2 phase of the cell cycle, compared with cells expressing the nonphosphorylatable form of FADD or the vector control. Furthermore, cDNA microarray analyses of lung tumor samples showed that increased levels of FADD transcripts were significantly correlated with overexpression of cyclins D1 (P < 0.01) and B1 (P < 0.01), genes that are involved in the regulation of cell cycle progression and are inducible by NF-kappaB. These studies demonstrate that induction of NF-kappaB activity and its effects on cell-cycle progression may represent a molecular basis underlying the aggressive tumor behavior associated with elevated p-FADD expression in lung adenocarcinoma.

Adaptor Proteins, Signal Transducing↗
PubMed2005

National trends in outcomes for esophageal resection.

BACKGROUND: Case-series reports from tertiary centers report improved outcomes for esophageal resection in recent years. The objective of the current study was to determine trends in short-term outcomes after esophageal resection in a representative sample of United States (US) hospitals. METHODS: Observational study of all adult patients in the Nationwide Inpatient Sample who underwent esophageal resection from 1988 to 2000 (N = 8,657). Temporal trends of in-hospital mortality and prolonged length of stay were determined. Analyses were performed for all hospitals after stratifying by hospital volume. The proportion of patients having surgery at high volume hospitals was used to assess changes in referral patterns. RESULTS: The overall mortality rate was 11.3% and revealed a modest but significant decline from 13.6% to 10.5% during the study period (p = 0.001). Low volume hospitals had markedly higher mortality rates and showed no improvement over time (15.3% vs 14.5%). In contrast, high volume hospitals indicated significant reduction in mortality over time (11.0% vs 7.5%, p = 0.003). Referral patterns changed over time with the proportion of esophageal resections performed at high volume hospitals increasing from 40% (1988 to 1991) to 57% (1997 to 2000). CONCLUSIONS: The operative mortality rate for esophageal resection has declined over the past 13 years, particularly at high volume hospitals. Efforts should be made to understand the processes of care underlying this improvement.

Adult↗
PubMed2005

Nontraumatic chest wall systemic-to-pulmonary artery fistula.

A congenital chest wall systemic-to-left pulmonary artery fistula fed by the left internal mammary and left gastric arteries in a 31-year-old man is reported. Attempted sclerosis was complicated by rupture of the communicating vessel, hemothorax, and deep vein thrombosis of the legs. Fistula resection and pulmonary decortication were successfully performed.

Adult↗
PubMed2005

Specialty training and mortality after esophageal cancer resection.

BACKGROUND: Surgeons with advanced training have lower mortality rates with some surgical procedures. The objective of the current study was to investigate the impact of thoracic surgery training on mortality rates of esophageal cancer resection. METHODS: We studied esophageal cancer resection in the national Medicare population during 1998 and 1999. Operative mortality rates (in-hospital or 30-day) were compared for thoracic surgeons and other surgeons, adjusting for patient characteristics, hospital volume, and surgeon volume. Surgeons with specialty training in thoracic surgery were those certified by the American Board of Thoracic Surgery. RESULTS: Of the 1,946 patients, 625 (32%) had their operation performed by a thoracic surgeon. After adjustment for patient characteristics, mortality rates were 37% (odds ratio, 1.37; 95% confidence interval, 1.02 to 1.82) higher for surgeons without specialty training compared with thoracic surgeons (adjusted mortality 16.5% versus 12.4%; p = 0.01). However, differences in mortality between high-volume and low-volume hospitals (24.3% versus 11.4%; p < 0.001) and surgeons (20.7% versus 10.7%; p < 0.001) were larger than those between thoracic and general surgeons. Although thoracic surgeons had lower mortality rates after adjusting for hospital volume, the effect of thoracic surgery training was no longer significant after accounting for surgeon volume (odds ratio, 1.23; 95% confidence interval, 0.92 to 1.63). CONCLUSIONS: Specialty training in thoracic surgery has an independent association with lower mortality after esophageal resection. But specialty training appears to be less important than hospital and surgeon volume.

Aged↗
PubMed2005

Evaluation of web-based learning tools: lessons learned from the thoracic surgery directors association curriculum project three-year experience.

BACKGROUND: In 2001 the Thoracic Surgery Directors Association implemented a web-based curriculum for prematriculated TS residents containing 75 learning modules organized into 13 sections Each module contains an audio/video presentation, a summary, frequently asked questions, references, a self-assessment, and a critique. Curriculum content was provided as a randomized prospective trial one year prior to matriculation to residents matching into a TS program from 2001 to 2004. METHODS: Over 3 years the utilization and impact of this curriculum was evaluated by 8 different methods including resident surveys, faculty surveys, web tracking, examination scores, and individual online learning module critiques. Each completed critique evaluated the resident's perception of the relevance, content quality and presentation quality of the module on a scale corresponding to low, average and high. RESULTS: A total of 11,117 learning modules were used through the end of 2004 with complete critiques available on 1458 (13%). Utilization and measured quality continue to increase over the 3-year interval. The average rating scores for relevance, content and presentation tracked together and were overall rated as good or excellent (92%). There were large variations in utilization and perceived quality by section subject. As the average module rating score improved, the utilization increased and the variability of the rating decreased substantially. CONCLUSIONS: Module specific learner evaluation of educational content is one of several important feedback tools for monitoring ongoing curricular development and refinement. These studies, based upon web tracking, demonstrate increasing resident use and strong resident satisfaction. This educational format will hopefully lend itself to many important improvements in web-based Thoracic Surgery education.

Computer-Assisted Instruction↗
PubMed2004

Melanoma-associated antigens in esophageal adenocarcinoma: identification of novel MAGE-A10 splice variants.

PURPOSE: The melanoma-associated antigens (MAGEs) are tumor-specific antigens recognized by cytotoxic T lymphocytes. In this study, expression of MAGE family A members was evaluated during the development of esophageal adenocarcinoma (EA) as potential targets for immunotherapy. EXPERIMENTAL DESIGN: MAGE-A mRNA expression was evaluated in 46 samples including Barrett's metaplasia (BM), dysplasia, and EA using oligonucleotide microarrays. Expression of MAGE-A proteins was confirmed by immunohistochemistry on tissue microarrays containing 59 EA, 11 dysplasia, and 9 BM samples and by Western blot. To further evaluate MAGE-A10 expression, reverse transcription-polymerase chain reaction (RT-PCR) products were sequenced, and protein expression was determined using a specific antibody. RESULTS: Overexpression of MAGE-A1, MAGE-A2b, MAGE-A3, MAGE-A4, MAGE-A6, MAGE-A9, MAGE-A10, and MAGE-A12 was found in EAs relative to BM on oligonucleotide microarrays. MAGE-A3 overexpression was confirmed by real-time RT-PCR in 21.4% (6 of 28) of esophageal tumors. Immunohistochemistry on tissue microarray revealed MAGE-A proteins in 20.3% (12 of 59) of EAs and MAGE-A10 staining in 16.9% (10 of 59) of EAs. MAGE-A expression was confirmed by Western blot in several esophageal tumors and in two EA cell lines, Flo-1 and Seg-1, whereas Flo-1 also expressed MAGE-A10. Tumors produced from these cell lines in nude mice retained MAGE-A expression. Interestingly, RT-PCR in primary tumors expressing MAGE-A10 protein revealed additional PCR products that were identified as novel MAGE-A10 alternative splice variants using DNA sequencing. CONCLUSIONS: This is the first report of these MAGE-A10 alternative splice sequences, and characterization of MAGE-A expression may provide potential targets for immunotherapy in patients with EA.

Adenocarcinoma↗
PubMed2004

Reduced selenium-binding protein 1 expression is associated with poor outcome in lung adenocarcinomas.

The effects of selenium, an essential nutrient with anti-carcinogenic properties, are mediated by selenium-binding proteins. The protein expression status of human selenium-binding protein 1 (SBP1) in human tumours and the exact function of this protein are not known. In this study, quantitative two-dimensional polyacrylamide gel electrophoresis (2-D PAGE) was used on 93 lung adenocarcinomas and ten uninvolved lung samples. Two likely isoforms of a 56 kD protein that showed a significantly decreased abundance in lung adenocarcinomas were observed. Tandem mass spectrometry and 2-D western blot analysis identified these two proteins as human SBP1. Tumour tissue microarrays were utilized to examine the cellular expression patterns of SBP1 using immunohistochemistry. The same tissue samples were examined for SBP1 mRNA expression using oligonucleotide microarrays. Two major SBP1 isoforms were detected, with an acidic isoform (457) being significantly down-regulated in lung adenocarcinomas compared with normal lung (p = 0.02). Two additional more acidic SBP1 isoforms were only observed in normal lung. SBP1 protein isoforms and SBP1 mRNA levels were significantly decreased in poorly differentiated (versus moderately and well-differentiated), T2-T4 (versus T1), and bronchus-derived (versus bronchioloalveolar) tumours. Low levels of SBP1 protein (native form, 460) correlated significantly with poor survival (p = 0.007). The lack of SBP1 expression was not due to gene deletion. Treatment of A549 lung adenocarcinoma cells with the methylation inhibitor 5-azacytidine did not affect expression of the SBP1 protein. Analysis of the tumour proliferation status using Ki-67 suggests that down-regulated expression of SBP1 may reflect increased cell proliferation and decreased differentiation in lung adenocarcinomas.

Adenocarcinoma↗
PubMed2004

A 25-year experience with open primary transthoracic repair of paraesophageal hiatal hernia.

OBJECTIVE: The optimal surgical treatment of paraesophageal hiatal hernia is in debate. Our experience with a traditional transthoracic approach was reviewed to provide "benchmark" data against which newer surgical techniques can be measured. METHODS: Between 1977 and 2001, 240 patients had primary transthoracic repair of paraesophageal hiatal hernia. Presenting complaints included reflux (69%), pain (67%), dysphagia (36%), and bleeding or anemia (33%). Preoperative esophageal function testing showed abnormal reflux in 86%. Hernia types were combined (type III) in 92% and type IV in 8%. All patients had reduction of the hernia and a concomitant antireflux procedure. An esophageal lengthening Collis gastroplasty was performed in 96%. RESULTS: There were 3 perioperative deaths (1.7%). The median length of hospital stay was 7 days. Early complications requiring reoperation occurred in 12 patients (5%) and included recurrent hernia in 4, leak in 3, and a tight hiatal closure in 3. Mean follow-up in 226 patients was 42 months (median 27.8 months). Satisfactory results were obtained in 86% of patients. Follow-up complaints (moderate or persistent symptoms) included dysphagia (4), reflux (1), dumping (3), and post-thoracotomy pain (1). Routine postoperative barium radiographs showed intact repair in 71% (108/153). Of 19 patients with an anatomic recurrence, 4 (2%) had more than a partial asymptomatic migration of the fundoplication and required reoperation. Postoperative esophageal function testing, obtained in 28% of the patients, showed abnormal gastroesophageal reflux in 2. CONCLUSION: Open transthoracic repair of paraesophageal hiatal hernia provides good to excellent long-term control of both the hernia and gastroesophageal reflux with relatively low early morbidity.

Adult↗
PubMed2004

Genomic and proteomic analyses of vascular endothelial growth factor and insulin-like growth factor-binding protein 3 in lung adenocarcinomas.

Vascular endothelial growth factor (VEGF) is regulated by the hypoxia-inducible factor 1 (HIF1) pathway and is implicated in tumor progression and patient survival in many types of cancer. Insulin-like growth factor-binding protein 3 (IGFBP3) is also regulated by HIF1 but works in a completely different manner by modulating the activities of insulin-like growth factors and inducing apoptosis. In this study, 2-dimensional (2D) polyacrylamide gel electrophoresis (PAGE) was used to analyze the protein expression profiles of VEGF and IGFBP3 isoforms in 93 lung adenocarcinomas and 10 uninvolved lung samples. The same samples were examined for messenger RNA (mRNA) expression with use of oligonucleotide arrays. Correlation analysis in the lung adenocarcinomas between mRNA expression levels of VEGF and all 4966 other genes was used to identify other biologic processes that may be associated with increased VEGF expression. Two-dimensional gel separations revealed 7 VEGF protein isoforms and 5 isoforms of IGFBP3. VEGF and IGFBP3 mRNA were found to be overexpressed in bronchial-derived lung adenocarcinomas (P < 0.0001), and expression was decreased in well-differentiated lung adenocarcinomas (P < 0.0002). There was a significant correlation (P < 0.01) between VEGF and IGFBP3 mRNA in lung adenocarcinomas; however, no correlation was detected in uninvolved lung samples. Forty genes were identified as the most significantly associated with VEGF expression (r > 0.38, P < 0.001), 17 of which were also associated with IGFBP3, and 12 were known to be induced through the HIF1 pathway. Among other highly correlated genes, several, including bradykinin receptor B2, suggest additional cellular processes that were not previously known to be associated with VEGF expression in lung adenocarcinoma.

Adenocarcinoma↗
PubMed2003

Concurrent cisplatin, paclitaxel, and radiotherapy as preoperative treatment for patients with locoregional esophageal carcinoma.

BACKGROUND: A Phase II trial was conducted at the University of Michigan to determine the efficacy of a preoperative regimen of concurrent cisplatin, paclitaxel, and radiation for patients with locoregional esophageal carcinoma. METHODS: Sixty-nine patients with esophageal carcinoma were treated with cisplatin 75 mg/m(2) on Day 1, paclitaxel 60 mg/m(2) on Days 1, 8, 15, and 22, and radiation 1.5 Gray (Gy) twice per day on Days 1-5, 8-12, and 15-19, for a total dose of 45 Gy. Transhiatal esophagectomy was performed on approximately Day 50. RESULTS: The treatment regimen was well tolerated. Only 13% of patients developed Grade 3 or 4 neutropenia and 17% of patients required feeding tubes. Ninety percent of all patients had complete tumor resection at the time of surgery. Nineteen percent of patients achieved a complete histologic response in the resected specimen. The median survival period was 24 months. One-, 2-, and 3-year survival probabilities were 75%, 50%, and 34%, respectively. CONCLUSIONS: This cisplatin-based preoperative regimen, which contained paclitaxel rather than 5-fluorouracil, was well tolerated. The survival data compared favorably with other previously reported combinations. This regimen is a reasonable preoperative approach for patients with localized esophageal carcinoma.

Adult↗