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ABSTRACT: Accumulating evidence suggests that the extracellular matrix play important roles in intercellular communications and contribute to the development of a number of diseases, including diseases of the gastrointestinal tract. The present study examined the structural characteristics and alterations of the extracellular matrix of the mucosa stroma in the Barrett's esophagus metaplasia-dysplasia-adenocarcinoma sequence.
A total of 41 esophageal tissue specimens (15 esophageal adenocarcinoma, 10 Barrett's esophagus intestinal metaplasia, seven dysplasia and nine normal esophagus) were studied. The present study used transmission electron microscopy and computerized quantitative electron-microscopic analysis in order to investigate the characteristics of the extracellular matrix of the mucosa.
The study revealed that marked structural alterations of the mucosa stroma, relating to changes in the distribution and appearance of collagen fibers as well as to changes in numbers of matrix microvesicles, occur in Barrett's esophagus and esophageal adenocarcinoma. It was found that there were 3.1 times more microvesicles in the stroma in Barrett's esophagus than in the stroma of the normal esophagus (P<0.0001) and that there were 5.8 times more microvesicles in esophageal adenocarcinoma than in the normal esophagus (P<0.0001). There were 1.9 times more microvesicles in esophageal adenocarcinoma than in Barrett's esophagus (P=0.0043).
The study demonstrates distinctive alterations of the mucosa stroma extracellular matrix in the metaplasia-dysplasia-adenocarcinoma sequence. The findings suggest that the redistribution of collagen fibers and increases in numbers of matrix microvesicles may play roles in the formation of specialized intestinal metaplasia and the development of adenocarcinoma.
Journal of Gastroenterology and Hepatology 05/2012; 27(9):1498-504. · 2.87 Impact Factor
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Reginald V. N. Lord,
Dennis Salonga,
Kathleen D. Danenberg,
Jeffrey H. Peters,
Tom R. DeMeester,
Ji Min Park,
Jan Johansson,
Kristin A. Skinner,
Para Chandrasoma,
Steven R. DeMeester,
Cedric G. Bremner,
Peter I. Tsai,
Peter V. Danenberg
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ABSTRACT: Barrett’s esophagus is a multistage polyclonal disease that is associated with the development of adenocarcinoma of the esophagus
and csophagogastric junction. Telomerase activation is associated with cellular immortality and carcinogenesis, and increased
expression of the telomerase reverse transcriptase catalytic subunit (hTERT) has been used for the early detection of malignant
diseases. To identify’ biomarkers associated with each stage of the Barrett’s process, relative mRNA expression levels of
hTERT were measured using a quantitative reverse transcription-polymerase chain reaction method (ABI 7700 Sequence Detector
(TaqMan system) in Barrett’s intestinal metaplasia (n —14), Barrett’s dysplasia (n =10), Barrett’s adenocarcinoma (n = 14),
and matching normal squamous esophagus tissues (n = 32). hTERT expression was significantly increased at all stages of Barren’s
esophagus, including the intestinal metaplasia stage, compared to normal tissues from patients without cancer (intestinal
metaplasia vs. normal esophagus, P <0.0001; dysplasia, P = 0.001; adenocarcinoma, P = 0.007; all Alann-Whitney U test). hTERT
expression levels were significantly higher in adenocarcinoma tissues than in intestinal metaplasia tissues (P = 0.003), and
were higher in dysplasia compared with intestinal metaplasia tissues (P = 0.056). hTERT levels were also significantly higher
in histologically normal squamous esophagus tissues from cancer panents than in normal esophagus tissues from patients vrith
no cancer (P = 0.013). Very high expression levels ([hTERT × 100: β-actin] >20) were found only in patients with cancer. These
findings suggest that telomerase activation is an important early event in the development of Barrett’s esophagus and esophageal
adenocarcinoma, that very high telomerase levels may be a clinically useful biomarker for the detection of occult adenocarcinoma,
and that a widespread cancer ‘field’ effect is present in the esophagus of patients with Barrett’s cancer.
Journal of Gastrointestinal Surgery 04/2012; 4(2):135-142. · 2.83 Impact Factor
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ABSTRACT: The origin of smooth muscle cells in developing atherosclerotic lesions is a controversial topic with accumulating evidence indicating that at least some arterial smooth muscle cells might originate from bone marrow-derived smooth muscle cell precursors circulating in the blood. The stem cell markers currently used for the identification of stem cells in the arterial intima can be expressed by a number of different cell types residing in the arterial wall, such as mast cells, endothelial cells and dendritic cells, which can make interpretation of the data obtained somewhat ambiguous. In the present study we examined whether the putative intestinal stem cell marker Musashi-1 is expressed in the arterial wall. Using a multiplexed tandem polymerase chain reaction method (MT-PCR) and immunohistochemistry, Musashi-1 expression was revealed in human coronary arterial wall tissue segments, and this finding was followed by the demonstration of significantly higher expression levels of Musashi-1 in atherosclerotic plaques compared with those in undiseased intimal sites. Double immunohistochemistry demonstrated that in the arterial wall Musashi-1 positive cells either did not display any specific markers of cells that are known to reside in the arterial intima or Musashi-1 was co-expressed by smooth muscle α-actin positive cells. Some Musashi-1 positive cells were found along the luminal surface of arteries as well as within microvessels formed in atherosclerotic plaques by neovascularization, which supports the possibility that Musashi-1 positive cells might intrude into the arterial wall from the blood and might even represent circulating smooth muscle cell precursors.
Atherosclerosis 01/2011; 215(2):355-65. · 3.79 Impact Factor
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ABSTRACT: Widespread applicability of tissue-based mRNA expression screening for Barrett esophagus (BE) is likely to require (1) accurate methods for assaying archival formalin-fixed, paraffin-embedded (FFPE) histopathology specimens taken at endoscopy, and (2) validation studies of promising biomarkers in different patient cohorts.
30 genes were significantly differentially expressed by histopathology tissue type. The direction and magnitude of the differences were very similar to those found in previous studies using fresh frozen tissues. Novel upregulated genes were TSPAN8 (also known as CO-029), TSPAN24 (CD151), EGR1 and TCIRG1. Novel downregulated genes were DPYD, TSPAN29 (CD9) and Ets1. Strong associations between histopathology type and gene expression were observed with the overexpressed genes: cyclo-oxygenase-2 (COX-2), for which histopathology type explained 77.7% of the variation in expression, TSPAN1 (73.5%), TSPAN8 (62.9%), SPARC (62.1%), MMP7 (50.8%); and the under-expressed genes ADH7 (53.7%), APC (58.2%), RAR-gamma (51.3%).
mRNA was isolated from 54 FFPE small endoscopic biopsies from patients with Barrett intestinal metaplasia (BE), esophageal adenocarcinoma (EAC), or control patients with a normal squamous-lined esophagus. Multiplexed tandem PCR (MT-PCR) was used to quantitate 50 selected candidate genes for BE and control genes in duplicate. Principal component analysis (PCA) was conducted to explore the presence of global differences in gene expression profiles. One-way analysis of variance (ANOVA) of the transformed data was used to identify genes that were differentially expressed between different histological subtypes. Differentially expressed genes with a fold change of ≥2 (upregulated) or ≤-2 (downregulated) are reported with the p value for each comparison (EAC vs. normal, EAC vs. BE and BE vs. normal). The Benjamini-Hochberg method was used to control the false discovery rate at 0.01 for all comparisons.
Alterations in expression of select genes are strongly associated with BE or EAC or both. This study's findings for many highly differentially expressed genes are very similar to those previously reported, suggesting that these genes should be tested further in longitudinal studies for their potential role as biomarkers of progression to more advanced Barrett disease.
Cancer biology & therapy 07/2010; 10(2):172-9. · 2.64 Impact Factor
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ABSTRACT: C1q, an element of the first component of complement, is known to be expressed by interdigitating and follicular dendritic cells in the spleen, where it has been suggested that C1q is involved in capturing immune complexes. The present study investigated whether C1q is expressed in Barrett's esophagus and esophageal adenocarcinoma and, if so, whether its expression is associated with dendritic cells.
Endoscopic biopsy or operative surgical specimens were obtained from 15 patients with Barrett's esophagus, 13 patients with esophageal adenocarcinoma and 12 patients whose biopsy specimens did not show the presence of specialized intestinal metaplasia or adenocarcinoma. Barrett's esophagus was diagnosed by the presence of a macroscopic area of columnar-lined esophagus as well as microscopic intestinal metaplasia with goblet cells. Immunohistochemistry utilizing anti-C1q and markers for dendritic cells and macrophages was performed on sections of tissue samples embedded in paraffin. Double immunostaining with C1q/CD83 and C1q/CD68 was used to analyze the possible co-localization of C1q with dendritic cells and macrophages. The expression of C1q by dendritic cells and macrophages was also examined in in vitro studies using reverse transcriptase polymerase chain reaction (RT-PCR) and Western blotting.
In all specimens studied, C1q expression was detected as being distributed irregularly throughout the lamina propria. A computerized quantitative analysis showed that C1q expression was significantly higher in tissue specimens without specialized intestinal-type metaplasia than in Barrett's esophagus specimens and specimens with adenocarcinoma. Double immunostaining revealed that dendritic cells and macrophages expressed C1q in all analyzed esophageal specimens. The expression of C1q by dendritic cells and macrophages was also demonstrated in in vitro studies using RT-PCR and Western blotting.
The findings suggest that reduced levels of the expression of C1q by dendritic cells and macrophages in the esophagus may play a role in the formation of immune responses associated with the formation of specialized intestinal metaplasia and the development of adenocarcinoma.
Journal of Gastrointestinal Surgery 05/2010; 14(8):1207-13. · 2.83 Impact Factor
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ABSTRACT: The CDX2 (caudal-related homeobox gene 2) and PITX1 (pituitary homeobox 1) genes have essential roles in human development. Forced expression of Cdx2 alone in the murine stomach results in gastric intestinal metaplasia (IM). This study was undertaken to investigate the expression pattern of these critical morphogenesis genes in the Barrett's multistage carcinogenesis model.
CDX2 and PITX1 messenger RNA (mRNA) expression levels, relative to the control gene beta-actin, were measured by reverse transcription-polymerase chain reaction in specimens of Barrett's IM (n = 21), dysplasia (n = 18), adenocarcinoma (n = 20), and matching normal squamous esophagus tissues (n = 39) collected from 19 patients with Barrett's esophagus and 20 patients with esophageal adenocarcinoma. CDX2 protein expression was assessed by immunohistochemistry in specimens of normal squamous esophagus (n = 13), IM (n = 10), dysplasia (n = 8,) and adenocarcinoma (n = 5).
The median relative CDX2 mRNA expression was approximately 200 times higher in Barrett's esophagus tissues (0.83) than in matching normal squamous esophagus (0.004) in the patients with Barrett's esophagus (P < .001). The mRNA expression in cancer tissues (0.49) was also higher than in matching normal squamous esophagus specimens (0.009, P < .001). There was no significant difference between the mRNA expression levels in Barrett's esophagus and adenocarcinoma. There was no CDX2 protein expression in normal squamous esophagus, but moderate to strong protein expression was seen in all Barrett's tissues and in a majority of the dysplasia and adenocarcinoma cells. Relative median PITX1 mRNA expression was decreased in Barrett's esophagus (8.02 for all specimens), compared with normal esophagus specimens (47.46 for all specimens, P < .001), and was further reduced in cancer specimens (2.21), compared with either Barrett's esophagus or normal esophagus (both P < .001). Wilcoxon testwas used for all P values shown.
CDX2 mRNA and CDX2 protein expression are upregulated in Barrett's IM tissues, compared with normal squamous esophagus, and remain elevated in dysplasia and adenocarcinoma tissues. In contrast, PITX1 mRNA expression is decreased in Barrett's esophagus, compared with matching normal squamous esophagus specimens, and is further decreased in Barrett's-associated cancer. These descriptive findings suggest a possible role for these genes in the Barrett's metaplasia-dysplasia-adenocarcinoma sequence.
Surgery 11/2005; 138(5):924-31. · 3.10 Impact Factor
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Jan Brabender,
Paul Marjoram, Reginald V N Lord,
Ralf Metzger,
Dennis Salonga,
Daniel Vallböhmer,
Hartmut Schäfer,
Kathleen D Danenberg,
Peter V Danenberg,
Florin M Selaru,
Stefan E Baldus,
Arnulf H Hölscher,
Stephen J Meltzer,
Paul M Schneider
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ABSTRACT: Genetic alterations in the normal tissues surrounding various cancers have been described, but a comprehensive analysis of this carcinogenic field effect in Barrett's-associated adenocarcinoma of the esophagus disease has not been reported. The aim of this study was to analyze the gene expression profile of a panel of highly selected genes in the normal squamous esophagus epihelium of patients with Barrett's esophagus, patients with Barrett's-associated adenocarcinoma, and a healthy control group to define the existence of a carcinogenic field effect, and to investigate the clinical importance of such a field effect in the management of Barrett's disease.
Forty-nine histologic normal squamous esophageal epithelia collected from 19 patients with Barrett's esophagus, 20 patients with Barrett's-associated esophageal adenocarcinoma, and a healthy control group of 10 patients were studied. A quantitative real-time reverse transcription-PCR method (TaqMan) was used to measure the expression of a panel of genes with known associations with gastrointestinal carcinogenesis.
A widespread carcinogenic field effect was detected for more than 50% of the genes analyzed including Bax, BFT, CDX2, COX2, DAPK, DNMT1, GSTP1, RARalpha, RARgamma, RXRalpha, RXRbeta, SPARC, TSPAN, and VEGF. Based on the expression signature of the normal appearing squamous esophagus, a linear discriminant analysis was able to distinguish between the three groups of patients with an error rate of 0%.
This study provides the first comprehensive investigation of a carcinogenic field effect in Barrett's esophagus disease. Based on the gene expression signature of the normal esophagus, patients could be correctly characterized according to their pathologic classification by applying a linear discriminant analysis. Our results provide evidence that a molecular classification might have clinical importance for the diagnosis and treatment of patients with Barrett's esophagus disease.
Cancer Epidemiology Biomarkers & Prevention 10/2005; 14(9):2113-7. · 4.12 Impact Factor
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ABSTRACT: The cervical esophagus is normally lined by squamous epithelium and is usually not exposed to gastroesophageal reflux. The aims of this study were, first, to investigate whether cardiac mucosa can be acquired in the remnant cervical esophagus after esophagectomy and cervical esophagogastrostomy and, second, to characterize this mucosa if present.
The medical records of 100 patients who had undergone esophagectomy with gastric pull-up reconstruction were studied retrospectively to identify those who had biopsies from the cervical esophagus proximal to the gastroesophageal anastomosis during postoperative follow-up. The histopathology and immunohistochemical stains were reviewed to assess similarity to Barrett's mucosa (cytokeratins [CK] 7 and 20 and DAS-1), cellular proliferation (topoisomerase 2alpha), and the potential for dysplasia (cyclo-oxygenase 2 [COX-2] and ornithine decarboxylase [ODC]).
Supra-anastomotic biopsies were performed in 20 patients. Cardiac mucosa was present in 10 of 20 (50%) patients in whom biopsies were performed. Four patients had areas of intestinal metaplasia, and dysplasia, and adenocarcinoma developed in 1 patient. The CK7/20 and DAS-1 staining of the columnar mucosa showed a pattern similar to Barrett's mucosa. Topoisomerase 2alpha protein expression was present in 50% of patients with cardiac mucosa. DAS-1 protein was expressed in cervical columnar mucosa but not in normal squamous esophagus mucosa. The cardiac mucosa stained weakly for COX-2 and ODC.
Cardiac mucosa can be acquired. Its expression profile is similar to cardiac mucosa and intestinal metaplasia found in Barrett's esophagus, and different from normal esophageal or gastric mucosa. The development of cardiac mucosa is likely to be related to reflux of acid into the remnant cervical esophagus as the first step in the development of Barrett's esophagus. These findings are applicable to the development of similar changes at the gastroesophageal junction.
Surgery 10/2004; 136(3):633-40. · 3.10 Impact Factor
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ABSTRACT: To determine the safety and efficacy of the duodenal switch procedure as surgical treatment of morbid obesity.
The longitudinal gastrectomy and duodenal switch procedure as performed for morbid obesity involves a 75% subtotal greater curvature gastrectomy and long limb suprapapillary Roux-en-Y duodenoenterostomy. This results in a restricted caloric intake and diversion of bile and pancreatic secretions to induce fat malabsorption. Broad acceptance of this procedure has been impeded because of concerns that the malabsorptive component may produce serious nutritional complications.
Review of data collected prospectively from all patients who underwent duodenal switch as the primary surgical treatment of morbid obesity at a single institution during the 10-year period beginning September 1992. Operative morbidity and mortality, weight loss, volume of food intake, and bowel function were recorded. Sequential measurements of serum albumin, hemoglobin, and calcium levels were obtained to assess metabolic function and nutrient absorption.
Duodenal switch was performed as the primary operation in 701 (81%) of a total 863 patients undergoing bariatric surgery during the period of study. The average body mass index (BMI) was 52.8 (range, 34-95). Perioperative mortality was 1.4%, and morbidity (including leaks, wound dehiscence, splenectomy, and postoperative hemorrhage) occurred in 21 patients (2.9%). Weight loss averaged 127 pounds at 1 year, 131 at 3 years, and 118 at 5 or more years (% EBWL of 69%, 73%, and 66%, respectively). The mean number of bowel movements was fewer than 3 per day. Patients reported and maintained a mean restriction of 63% of their preoperative intake (approximately 1600 calories), with no specific food intolerance, at 3 or more years follow-up. At 3 years, serum albumin remained at normal levels in 98% of patients, hemoglobin in 52%, and calcium in 71%. No patients reported dumping, and marginal ulcers were not seen.
The longitudinal gastrectomy with duodenal switch is a safe and effective primary procedure for the treatment of morbid obesity. It has the advantage of allowing acceptable alimentation with a minimum of side effects while producing and maintaining significant weight loss. These results are achieved without developing significant dietary restrictions or clinical metabolic or nutritional complications.
Annals of Surgery 11/2003; 238(4):618-27; discussion 627-8. · 7.49 Impact Factor
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Rafael Rosell,
Giorgio Scagliotti,
Kathleen D Danenberg, Reginald V N Lord,
Gerold Bepler,
Silvia Novello,
Janine Cooc,
Lucio Crinò,
José Javier Sánchez,
Miquel Taron,
Corrado Boni,
Filippo De Marinis,
Maurizio Tonato,
Maurizio Marangolo,
Felice Gozzelino,
Franceso Di Costanzo,
Massimo Rinaldi,
Dennis Salonga,
Craig Stephens
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ABSTRACT: Non-small-cell lung cancer patients with locally advanced or metastatic disease at the time of diagnosis show marginal response to chemotherapy in terms of tumor shrinkage, time to progression and median survival. The identification and implementation of predictive genetic markers of response-specific cytotoxic drugs is a priority of current research and future trials. In this study, we have used quantitative PCR to analyse expression of beta-tubulin III, stathmin, RRM1, COX-2 and GSTP1 in mRNA isolated from paraffin-embedded tumor biopsies of 75 nonsmall-cell lung cancer patients treated as part of a large randomized trial. In total, 22 patients were treated with gemcitabine/cisplatin, 25 with vinorelbine/cisplatin and 28 with paclitaxel/carboplatin. There were no differences in clinical characteristics and transcript levels in the pretreatment biopsies according to treatment arm. Patients with low beta-tubulin III levels had better response in the paclitaxel/carboplatin arm (P=0.05), and those with low RRM1 levels showed a tendency to better response in the gemcitabine/cisplatin arm. Time to progression was influenced by beta-tubulin III (P=0.03) and stathmin (P=0.05) levels in the vinorelbine/cisplatin arm, and there was a tendency toward correlation between beta-tubulin III levels and time to progression in the paclitaxel/carboplatin arm. RRM1 levels influenced time to progression (P=0.05) and even more so, survival (P=0.0028) in the gemcitabine/cisplatin arm. The predictive value of beta-tubulin III, stathmin and RRM1 should be tested in prospective customized chemotherapy trials, the results of which will help tailor chemotherapy to improve patient survival.
Oncogene 07/2003; 22(23):3548-53. · 6.37 Impact Factor
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Reginald V N Lord
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ABSTRACT: Barrett's oesophagus is usually the result of severe reflux disease. Relief of reflux symptoms is the primary aim of treatment in patients with Barrett's oesophagus who do not have high-grade dysplasia. Some studies with medium-term (2-5 years) follow up show that antireflux surgery can provide good or excellent symptom control, with normal oesophageal acid exposure, in more than 90% of patients with Barrett's oesophagus. Antireflux surgery, but not medical therapy, can also reduce duodenal nonacid reflux to normal levels. There is no conclusive evidence that antireflux surgery can prevent the development of dysplasia or cancer, or that it can reliably induce regression of dysplasia, and patients with Barrett's oesophagus should therefore remain in a surveillance programme after operation. Some data suggest that antireflux surgery can prevent the development of intestinal metaplasia (IM) in patients with reflux disease but no IM. The combination of antireflux surgery plus an endoscopic ablation procedure is a promising treatment for patients with Barrett's oesophagus with low-grade dysplasia.
ANZ Journal of Surgery 05/2003; 73(4):234-6. · 1.25 Impact Factor
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Reginald V N Lord,
Ji Min Park,
Kumari Wickramasinghe,
Steven R DeMeester,
Stefan Oberg,
Dennis Salonga,
Jon Singer,
Jeffrey H Peters,
Kathleen D Danenberg,
Tom R Demeester,
Peter V Danenberg
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ABSTRACT: This study was undertaken to investigate the role of the angiogenic factors vascular endothelial growth factor and basic fibroblast growth factor in the development and progression of Barrett esophagus and adenocarcinomas of the esophagus and gastroesophageal junction.
Vascular endothelial growth factor and basic fibroblast growth factor messenger RNA expression levels, relative to the control gene encoding beta-actin, were measured by using a quantitative reverse transcription-polymerase chain reaction method (ABI 7700 Sequence Detector system) in specimens of Barrett intestinal metaplasia (n = 16), dysplasia (n = 11), adenocarcinoma (n = l 5), and matching normal squamous esophageal tissues (n = 35). Vascular endothelial growth factor and basic fibroblast growth factor protein expression and CD31(+) microvessel density were assessed by means of immunohistochemistry in 25 tissue sections that included representative areas for each of these Barrett stages.
Expression levels were significantly increased in adenocarcinoma compared with in either normal squamous mucosa (P <.0001 for both genes) or intestinal metaplasia (vascular endothelial growth factor, P =.002; basic fibroblast growth factor, P <.0001). Vascular endothelial growth factor levels were also significantly higher in cancer tissues compared with dysplasia tissues (P =.024, Mann-Whitney U test). Basic fibroblast growth factor expression was also significantly increased in Barrett dysplastic mucosa compared with in intestinal metaplasia or normal esophageal mucosa. Microvessel density was generally higher in adenocarcinoma compared with in preneoplastic Barrett tissues. The pattern of vascular endothelial growth factor and basic fibroblast growth factor protein expression was similar to the messenger RNA expression pattern, with the exception that mucin-containing goblet cells stained intensely for vascular endothelial growth factor and only weak vascular endothelial growth factor staining was present in some adenocarcinomas.
Vascular endothelial growth factor and basic fibroblast growth factor messenger RNA expression levels are significantly upregulated in esophageal and gastroesophageal junction adenocarcinomas, suggesting a role for these angiogenic factors in the development of these cancers. Vascular endothelial growth factor and basic fibroblast growth factor messenger RNA expression levels are also increased in some Barrett esophagus tissues, with this increase occurring at an earlier stage for basic fibroblast growth factor than for vascular endothelial growth factor. Basic fibroblast growth factor protein expression pattern is similar to the messenger RNA expression pattern, but unlike the messenger RNA findings, vascular endothelial growth factor protein expression is strongest in goblet cells.
Journal of Thoracic and Cardiovascular Surgery 02/2003; 125(2):246-53. · 3.41 Impact Factor
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ABSTRACT: The results of cisplatin-based chemotherapy seem to have reached a plateau, and empirical approaches are targeting the inclusion of novel biological agents with different mechanisms of action, but their clinical benefit is still unknown. In preparing this review of cisplatin resistance, we posed two questions: Who are we writing for and why? We believe that medical oncologists should be involved in the reality of the growing list of genetic mechanisms of cancer and chemoresistance. Only by becoming familiar with these mechanisms will we be able to circumvent them. In this review, we provide some insight into DNA repair defects involved in non-small-cell lung cancer (NSCLC) and cisplatin effect. Some DNA repair genes, like ERCC1, have been shown to be crucial in predicting cisplatin resistance and can be used for tailoring cisplatin-based chemotherapy.
Lung Cancer 01/2003; 38(3):217-27. · 3.43 Impact Factor
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ABSTRACT: The normal histology at the gastroesophageal junction, and in particular the nature of cardiac mucosa, remains in dispute. Likewise, the relationship of intestinal metaplasia at the gastroesophageal junction (CIM) to Barrett's and intestinal metaplasia of the stomach (GIM) is unclear. The aim of this study was to assess the immunostaining characteristics of cardiac mucosa and CIM and compare their staining pattern with that of other foregut mucosal types. We hypothesized that the immunostaining patterns of these foregut tissues would provide insight into the nature and etiology of cardiac mucosa and CIM.
Paraffin-embedded biopsy specimens from 50 patients with normal antral or fundic mucosa, cardiac mucosa, squamous mucosa, CIM, GIM, or Barrett's were obtained and immunostained with a panel of monoclonal antibodies including those for cytokeratins 7 and 20 (CK7/CK20) and DAS-1.
Biopsies from normal gastric antral and fundic mucosa and squamous esophageal mucosa all showed a non-Barrett's type CK7/CK20 immunostaining pattern, whereas in 85% of patients, cardiac mucosa had a Barrett's type CK7/CK20 pattern (p < 0.001). A Barrett's type CK7/ CK20 staining pattern was seen in 100% of Barrett's, 78% of CIM, and 0% of GIM patients. Likewise, DAS-1 staining was similar in patients with CIM and Barrett's and significantly different in patients with GIM.
Cytokeratin immunostaining of cardiac mucosa demonstrates significant differences from recognized normal gastric and esophageal mucosa but a similarity to Barrett's. This suggests that cardiac mucosa, like Barrett's, may be acquired. Likewise, immunostaining similarities between CIM and Barrett's biopsies point to the possibility of a reflux etiology for CIM in some patients.
The American Journal of Gastroenterology 10/2002; 97(10):2514-23. · 7.28 Impact Factor
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Reginald V N Lord,
Jan Brabender,
David Gandara,
Vicente Alberola,
Carlos Camps,
Manuel Domine,
Felip Cardenal,
José M Sánchez,
Paul H Gumerlock,
Miquel Tarón,
José J Sánchez,
Kathleen D Danenberg,
Peter V Danenberg,
Rafael Rosell
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ABSTRACT: Overexpression of the excision repair cross-complementing 1 (ERCC1) gene, which is crucial in the repair of cisplatin (CDDP)-DNA adducts, is reported to negatively influence the effectiveness of CDDP-based therapy for gastric and ovarian cancers. Recent evidence indicates that Gemcitabine (Gem) may modulate ERCC1 nucleotide excision repair activity, and down-regulation of DNA repair activity by ERCC1 antisense RNA reportedly inhibits synergism of CDDP/Gem. We investigated whether ERCC1 mRNA expression levels were associated with clinical outcomes after treatment with a combination Gem/CDDP regimen for patients with advanced stage non-small cell lung cancer (NSCLC).
Response and survival were correlated with the level of ERCC1 expression in 56 patients with advanced (stage IIIb or IV) NSCLC treated as part of a multicenter randomized trial with Gem 1250 mg/m(2) days 1 and 8 plus CDDP 100 mg/m(2) on day 1 every 3 weeks. mRNA was isolated from paraffin-embedded pretreatment primary tumor specimens, and relative expression levels of ERCC1/beta-actin were measured using a quantitative reverse transcription-PCR (Taqman) system.
ERCC1 expression was detectable in all tumors. There were no significant differences in ERCC1 levels by gender, age, performance status, weight loss, or tumor stage. The overall response rate was 44.7%. There were no significant associations between ERCC1 expression and response. Median overall survival was significantly longer in patients with low ERCC1 expression tumors (61.6 weeks; 95% confidence interval, 42.4-80.7 weeks) compared to patients with high expression tumors (20.4 weeks, 95% confidence interval, 6.9-33.9 weeks). ERCC1 expression, Eastern Cooperative Oncology Group performance status, and presence of weight loss were significant prognostic factors for survival in a Cox proportional hazards multivariable analysis.
These data suggest that ERCC1 expression is a predictive factor for survival after CDDP/Gem therapy in advanced NSCLC. Although there was a trend toward decreased response with high ERCC1 mRNA levels, this difference failed to reach statistical significance. This result may reflect the impact of Gem and the requirement for ERCC1 expression for CDDP/Gem synergism or may be attributable to the relatively small patient sample size in this study. Prospective studies of ERCC1 as a predictive marker for activity of CDDP-based regimens in NSCLC are warranted.
Clinical Cancer Research 08/2002; 8(7):2286-91. · 7.74 Impact Factor
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ABSTRACT: Recent studies have shown that many patients use acid suppression medications after antireflux surgery. The aim of this study was to determine the frequency of gastroesophageal reflux disease in a cohort of surgically treated patients with postoperative symptoms and a high prevalence of acid suppression medication use. The study group consisted of 86 patients who had symptoms following Nissen fundoplication that were sufficient to merit evaluation with 24-hour distal esophageal pH monitoring. All completed a detailed symptom questionnaire. The mean postoperative follow-up period was 28 months (median 18 months). Thirty-seven patients (43%) were taking acid suppression medications after fundoplication. Only 23% (20 of 86) of all the patients and only 24% (9 of 37) of those taking acid suppression medications had abnormal esophageal acid exposure on the 24-hour pH study. Heartburn and regurgitation were the only symptoms that were significantly associated with an abnormal pH study. Endoscopic assessment of the fundoplication was the most significant factor associated with an abnormal pH study. Multivariable logistic regression analysis showed that patients with a disrupted, abnormally positioned fundoplication had a 52.6 times increased risk of abnormal esophageal acid exposure. Most patients who use acid suppression medications after antireflux surgery do not have abnormal esophageal acid exposure, and the use of these medications is thus often inappropriate. Because of the limited predictive power of symptoms, objective evidence of reflux disease should be obtained before prescribing acid suppression medication for patients who have undergone antireflux surgery.
Journal of Gastrointestinal Surgery 6(1):3-9; discussion 10. · 2.83 Impact Factor
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ABSTRACT: The aim of this study was to define the clinical presentation, motility characteristics, and prevalence and patterns of gastroesophageal reflux in patients with hypertensive lower esophageal sphincter (HTLES). HTLES was defined by a resting pressure measured at the respiratory inversion point on stationary manometry of greater than 26 mm Hg (ninety-fifth percentile of normal). One hundred consecutive patients (80 women, 20 men; mean age 54.7 years, range 23 to 89 years), diagnosed with HTLES at our institution between September 1996 and October 1999, were studied. Patients with achalasia or other named esophageal motility disorders or history of foregut surgery were excluded, but patients with both HTLES and "nutcracker esophagus" were included. The most common symptoms in patients with HTLES were regurgitation (75%), heartburn (71%), dysphagia (71%), and chest pain (49%). The most common primary presenting symptoms were heartburn and dysphagia. The intrabolus pressure, which is a manometric measure of outflow obstruction, was significantly higher in patients with HTLES compared to normal volunteers. The residual pressure measured during LES relaxation induced by a water swallow was also significantly higher than in normal persons. There were no significant associations between any of the relaxation parameters studied (residual pressure, nadir pressure, duration of relaxation, time to residual pressure) and either the presence or severity of any symptoms or the presence of abnormal esophageal acid exposure. Seventy-three patients underwent 24-hour pH monitoring, and 26% had increased distal esophageal acid exposure. Compared to a cohort of patients with gastroesophageal reflux disease but no HTLES (n=300), the total and supine periods of distal esophageal acid exposure were significantly lower in the patients with HTLES and abnormal acid exposure. Patients with HTLES frequently present with moderately severe dysphagia and typical reflux symptoms. Approximately one quarter of them have abnormal esophageal acid exposure on pH monitoring. Patients with HTLES have significantly elevated intrabolus and residual relaxation pressures on liquid boluses, suggesting that outflow obstruction is present.
Journal of Gastrointestinal Surgery 7(5):692-700. · 2.83 Impact Factor
