Biomedical subjects

Alexandra Giatromanolaki

Publications and source records attributed to Alexandra Giatromanolaki.

At least 19 recordsLinked to original sources

PubMed2007

Metastatic cancer cells from c-erbB-2 negative primary breast cancer maintain the original c-erbB-2/HIF1alpha phenotype.

The expression of c-erbB-2 and HIF1alpha proteins is linked with an aggressive tumor phenotype and poor survival in breast cancer. In the present study we investigated whether this ominous effect is a result of c-erbB-2/HIF1alpha expressing clone appearance within the primary tumor, by examining the c-erbB-2/HIF1alpha expression status in the primary tumor, node metastasis and cancer cells invading into the lymphovascular spaces. The metastasizing cancer cell clones, whether migrating to the lymph nodes or entering into the systemic circulation maintained the original c-erbB-2/HIF1alphaphenotype of the primary tumor. Migrating c-erbB-2/HIF1alpha negative tumors do so through activation of alternative biologic pathways and not through positive clone appearance. These results strongly support the concept that targeted therapies against c-erbB-2 or against HIF1alpha can be guided with precision by the primary tumor c-erbB-2/HIF1alpha status without demanding the detection of the metastatic tumor phenotype.

Breast Neoplasms↗

PubMed2006

Lactate dehydrogenase 5 expression in operable colorectal cancer: strong association with survival and activated vascular endothelial growth factor pathway--a report of the Tumour Angiogenesis Research Group.

PURPOSE: Lactate dehydrogenase 5 (LDH-5) regulates, under hypoxic conditions, the anaerobic transformation of pyruvate to lactate for energy acquisition. Several studies have shown that serum LDH may be an ominous prognostic marker in malignant tumors. The clinical significance of tissue LDH-5, however, remains largely unexplored. PATIENTS AND METHODS: We investigated the immunohistochemical expression of LDH-5 in a series of 128 stage II/III colorectal adenocarcinomas treated with surgery alone. In addition, markers of tumor hypoxia (hypoxia-inducible factor 1 alpha [HIF1alpha]), angiogenesis (vascular endothelial growth factor [VEGF] and phosporylated kinase domain receptor [pKDR]/flk-1 receptor) and the tumor vascular density (CD31 positive standard vascular density [sVD] and pKDR positive activated vascular density [aVD]) were assessed. RESULTS: The expression of LDH-5, together with that of HIF1alpha and pKDR, was both nuclear and cytoplasmic. Assessment, with minimal interobserver variability, was achieved using a previously described scoring system. LDH-5 was significantly associated with HIF1alpha (P = .01), aVD (P = .001) and, particularly, with pKDR expression in cancer cells (P = .0001). Tissue LDH-5 expression was linked with elevated serum LDH levels, but serum levels failed to reflect tissue expression in 71% of LDH-5 positive cases. In univariate analysis tissue LDH-5 was associated with poor survival (P = .0003, HR 15.1), whereas in multivariate analysis this isoenzyme was the strongest independent prognostic factor (P = .0009). VEGF, pKDR, aVD, sVD and vascular invasion were all significantly related to unfavorable prognosis. CONCLUSION: The immunohistochemical assessment of tissue LDH-5 and pKDR provides important prognostic information in operable colorectal cancer. The strong association between LDH-5 and pKDR expression would justify their use as surrogate markers to screen patients for tyrosine kinase inhibitor therapy.

Adenocarcinoma↗

PubMed2006

Clear cell sarcoma of the scapula. A case report and review of the literature.

BACKGROUND: Clear cell sarcoma of tendons and aponeuroses (CCSTA) appears usually in the extremities and rarely in the trunk. CASE PRESENTATION: We present an unusual case of CCSTA overlying the scapular region and with secondary osseous extension in the lower scapula. The patient underwent a wide local excision with removal of the tumor and the lower two thirds of the scapula. He had no local recurrences but he developed lung metastases after 5 months in spite of postoperative chemotherapy. He finally died ten months later. CONCLUSION: The patients with CCSTA have a variable unpredictable course. Despite treatment the overall prognosis is poor.

Journal Article↗

PubMed2006

C2028T polymorphism in exon 12 and dinucleotide repeat polymorphism in intron 13 of the HIF-1alpha gene define HIF-1alpha protein expression in non-small cell lung cancer.

OBJECTIVES: In this study, we investigated whether polymorphisms of the HIF-1alpha gene may account for the patterns of HIF-1alpha protein expression in non-small cell lung carcinomas (NSCLC) and the expression of HIF-1alpha down-stream proteins. METHODS: Specific HIF-1alpha polymorphisms were assessed in a series of patients with NSCLC: (a) the C to T transition at nucleotide 1744 (position 2028 according to sequence with accession number , which gives rise to Pro/Ser variation at codon 582), (b) the G to A nucleotide substitution at point 1790 (position 2046 according to sequence with accession number , which gives rise to Ala/Thr variation at codon 588), and (c) the dinucleotide GT repeat polymorphism in intron 13. Immunohistochemistry for HIF-1alpha and down-stream proteins (VEGF, LDH-5, GLUT-1) was also performed in tumor material. RESULTS: A strong association of the P582S polymorphism and of GT repeat polymorphism higher than 14/14 with increased HIF-1alpha expression was noted. HIF-1alpha polymorphism did not relate to the expression of the HIF-1alpha downstream proteins analysed, but significant association of HIF-1alpha expression with LDH-5 was confirmed (p=0.008). CONCLUSIONS: HIF-1alpha polymorphisms may have an important impact on HIF-protein stability and, eventually, function.

Aged↗

PubMed2006

Lactate dehydrogenase 5 (LDH-5) expression in endometrial cancer relates to the activated VEGF/VEGFR2(KDR) pathway and prognosis.

PURPOSE: Lactate dehydrogenase (LDH-5) is a major lactate dehydrogenase isoenzyme catalyzing the transformation of pyruvate to lactate for anaerobic acquisition energy. In this study, the expression of LDH-5 was assessed in the normal and malignant endometrium. Its role in prognosis and tumor angiogenesis and hypoxia was also examined. EXPERIMENTAL DESIGN: Tissue specimens from 68 patients with clinical stage I endometrial adenocarcinoma of the endometrioid cell type and 20 samples from normally cycling endometrium were investigated immunohistochemically for the expression of LDH-5. The vascular density and the expression of angiogenesis/hypoxia-related proteins (VEGF, HIF1alpha, HIF2alpha, phosphorylated VEGFR2/KDR, VEGF/KDR complex) were also assessed. RESULTS: Unlike other normal epithelia, the glandular endometrial cells consistently expressed LDH-5 suggesting a role of this enzyme in the normal menstrual cycle. Endometrial adenocarcinomas displayed LDH-5 expression in 31/68 (45.5%) cases with those having a high LDH-5 expression being connected with a low lymphocytic response; this may suggest an important role of LDH-5 and, presumably, lactate release in tumor escape from host immuno-surveillance. More importantly, LDH-5 was significantly associated with the expression of phosphorylated VEGFR2/KDR receptors in cancer cells and tumor-associated vasculature. LDH-5 was one of the most powerful and independent prognostic variables. CONCLUSIONS: LDH-5 expression is an independent prognostic marker in endometrial cancer, linked with impaired host immune response and activation of VEGFR2/KDR receptors in both cancer cells and tumor-associated vasculature. Adjuvant radio-chemotherapy may, therefore, be useful in these cases, while the administration of VEGF- tyrosine kinase receptor inhibitors emerges as a therapeutic option.

Adenocarcinoma↗

PubMed2006

Endogenous markers of two separate hypoxia response pathways (hypoxia inducible factor 2 alpha and carbonic anhydrase 9) are associated with radiotherapy failure in head and neck cancer patients recruited in the CHART randomized trial.

PURPOSE: Randomized controlled trials have generally shown a benefit from accelerated radiotherapy in head and neck squamous cell carcinoma (HNSCC). However, the large randomized United Kingdom trial CHART (Continuous Hyperfractionated Accelerated Radiotherapy) failed to show a benefit of strongly accelerated over standard radiotherapy (RT) in 918 patients with HNSCC. In this study, we investigated the impact of tumor hypoxia on the outcome of HNSCC patients in the CHART trial. There are two distinct hypoxia inducible factors (HIFs) that control different gene response pathways and we assessed them both with endogenous markers of hypoxia, hypoxia inducible factor HIF-2 alpha (HIF-2) and carbonic anhydrase CA9, an indicator of HIF-1 alpha (HIF-1) function. METHODS: Tissue from pre-RT biopsies performed in 198 of 918 patients recruited was analyzed for the immunohistochemical expression of HIF-2 and CA9. RESULTS: A significant association of high HIF2 and of high CA9 reactivity with poor locoregional control (P < .0001 and P = .0002, respectively) and poor survival (P = .0004 and 0.002, respectively) was noted. In multivariate analysis, HIF-2 and CA9 maintained their independent prognostic significance. Coexpression of both pathways had an additive effect, supporting their independent role. The uni-directional hypothesis, that a benefit from randomization to CHART should be seen in the nonhypoxic tumors, was supported by the data (one-tailed P = .04). CONCLUSION: Expression of endogenous markers of hypoxia for the HIF-1 and HIF-2 pathway is strongly associated with radiotherapy failure. Using immunohistochemical methods it is possible to identify subgroups of HNSCC patients who are highly curable with radiotherapy, or who are excellent candidates for clinical trials on hypoxia-targeting drugs in two distinct pathways.

Antigens, Neoplasm↗

PubMed2006

Comparison of metabolic pathways between cancer cells and stromal cells in colorectal carcinomas: a metabolic survival role for tumor-associated stroma.

Understanding tumor metabolism is important for the development of anticancer therapies. Immunohistochemical evaluation of colorectal adenocarcinomas showed that cancer cells share common enzyme/transporter activities suggestive of an anaerobic metabolism [high lactate dehydrogenase 5 (LDH5)/hypoxia-inducible factor alphas (HIFalphas)] with high ability for glucose absorption and lactate extrusion [high glucose transporter 1 (GLUT1)/monocarboxylate transporter (MCT1)]. The tumor-associated fibroblasts expressed proteins involved in lactate absorption (high MCT1/MCT2), lactate oxidation (high LDH1 and low HIFalphas/LDH5), and reduced glucose absorption (low GLUT1). The expression profile of the tumor-associated endothelium indicated aerobic metabolism (high LDH1 and low HIFalphas/LDH5), high glucose absorption (high GLUT1), and resistance to lactate intake (lack of MCT1). It is suggested that the newly formed stroma and vasculature express complementary metabolic pathways, buffering and recycling products of anaerobic metabolism to sustain cancer cell survival. Tumors survive and grow because they are capable of organizing the regional fibroblasts and endothelial cells into a harmoniously collaborating metabolic domain.

Adenocarcinoma↗

PubMed2006

The significance of p53 and bcl-2 overexpression and other prognostic factors in transitional cell carcinoma of the bladder.

The aim of this study was to investigate the expression of bcl-2 and p53 oncoproteins in a series of transitional cell bladder carcinomas and its relation to traditional prognostic indicators and patients' survival. Specimens from 59 patients who underwent transurethral resection from March 1992 to February 1997 were included in this study. Tumors were graded based on WHO grades 1-3 and staged according to the 1997 TNM classification. Three patients lost to follow-up were excluded from the analysis. We could not establish a statistically significant relation between bcl-2 and p53 and other parameters such as sex, age, stage and grade. Tumor grade and stage were the most important factors for predicting tumor recurrence and aggressiveness. Only sex seems to significantly affect the statistics of the risk of death (p<0.05). Women had quadruple risk of death compared to men.

Age Factors↗

PubMed2006

Loss of expression and nuclear/cytoplasmic localization of the FOXP1 forkhead transcription factor are common events in early endometrial cancer: relationship with estrogen receptors and HIF-1alpha expression.

The FOXP1 gene has been identified as a new member of the winged helix family of transcription factors that have important roles in cellular transformation, differentiation and proliferation. In this study, we examined the expression of FOXP1 in the normal and malignant endometrium (stage I endometrioid adenocarcinoma cases), showing a frequent deregulation of its expression in cancer. Proliferative endometrium showed predominantly nuclear localization of FOXP1, while exclusively weak cytoplasmic staining was present in the secretory phase. Loss of nuclear expression was the most striking event in endometrial adenocarcinoma. Nuclear expression ranged from 0 to 20% (median 0%). Cytoplasmic expression was noted more frequently, ranging from 0 to 90% of cancer cells (median 30%). Overall, 24/82 cases (29.3%) were observed to lack both nuclear and cytoplasmic FOXP1 expression. Tumors with exclusively cytoplasmic expression of FOXP1 were linked with deep myometrial invasion and hypoxia-inducible factors 1alpha (HIF-1alpha) expression. On the other hand, the presence of nuclear FOXP1 expression was significantly linked with ER-alpha reactivity. Survival analysis did not reveal significant differences among patients grouped by FOXP1 expression, presumably due to the high curability of stage I disease. This study provides evidence on pathways to be investigated to elucidate the interplay between FOXP1, ER-alpha and HIF-1alpha in hormone dependent cancers.

Cell Nucleus↗

PubMed2006

Phosphorylated KDR expression in endometrial cancer cells relates to HIF1alpha/VEGF pathway and unfavourable prognosis.

Vascular endothelial growth factor (VEGF) is a potent angiogenic factor for many malignant neoplasms exerting its function through activation of specific membrane receptors, that is, KDR/flk-1, residing in endothelial cells. Several recent reports indicate that VEGF receptors are also expressed in cancer cells, suggesting that specific VEGF-originated cancer cell reactions may parallel the endothelial response. Using a novel monoclonal antibody, recognizing the activated (phosphorylated) form of the KDR receptor (pKDR), we assessed the expression of pKDR in normal and malignant endometrium. A strong and consistent cytoplasmic and nuclear pKDR expression was noted in the normally cycling endometrium, including epithelial, stromal and endothelial cells, suggesting a role in the normal menstrual cycle. Approximately, one-third of the 70 stage I endometrioid adenocarcinomas analysed exhibited an intense cytoplasmic and nuclear pKDR expression in both cancer cells and peritumoral vessels. It was noted that such pKDR reactivity in cancer cells was related directly to VEGF, VEGF/KDR complexes and HIF1alpha (hypoxia inducible factor 1alpha) expression. Furthermore, pKDR expression was significantly associated with poor prognosis. It is concluded that the VEGF/KDR pathway is activated in both normally cycling and malignant endometrium, suggestive of an important role in the biology of this tissue. The unfavourable prognosis that VEGF confers to endometrial adenocarcinomas could be attributed to its angiogenic activity, but also to a direct effect on cancer cells through an autocrine VEGF/KDR loop.

Endometrial Neoplasms↗

PubMed2006

The angiogenetic effect of intramuscular administration of b-FGF and a-FGF on cardiac muscle: the influence of exercise on muscle angiogenesis.

Although angiogenetic therapy using recombinant growth factors holds much hope for the treatment of ischaemic diseases, there are still many unanswered questions, including the method of administration, the correct dose of these factors, and the duration of the therapeutic approach. Exercise has also been suggested to induce neovascularizaiton in muscles. We evaluated the angiogenetic effects of the intramuscular administration of basic-fibroblast growth factor (b-FGF) and acidic-fibroblast growth factor (a-FGF) in rat heart, compared with rats who exercised daily. In conclusion, both the intramuscular administration of b-FGF and exercise increased significantly angiogenesis in the heart in contrast to the intramuscular administration of a-FGF, which was ineffective.

Animals↗

PubMed2006

Angiogenesis in colorectal cancer: prognostic and therapeutic implications.

Angiogenesis is important for tumor growth and metastasis. This account reviews the clinicopathological studies conducted in the field of angiogenesis in colorectal cancer, the methods of assessing vascular-related characteristics in tissue sections and provides a background for the usefulness of antiangiogenic policies along with chemotherapy and radiotherapy. Highly angiogenic colorectal tumors are associated with aggressive histopathological features and poor patients' survival. Similarly, factors stimulating angiogenesis, such as vascular endothelial growth factor (VEGF), thymidine phosphorylase (TP), and others, are commonly related to increased vascular density (VD) and, therefore, to an unfavorable clinical course. Anti-VEGF agents have improved prognosis in patients with metastatic colorectal cancer, when added to standard chemotherapy. It is expected that, in addition to adjuvant chemotherapy and radiotherapy, agents blocking the stimulatory effect of VEGF on endothelial cells would prove beneficial to the patient.

Angiogenesis Inhibitors↗

PubMed2006

Hypoxia-inducible factor-2 alpha (HIF-2 alpha) induces angiogenesis in breast carcinomas.

Hypoxia-inducible factors-1alpha (HIF-lalpha) and HIF-2alpha are important proteins initiating tumor cell responses to hypoxia. Specifically, the transcription of genes related to erythropoiesis, glycolysis, and angiogenesis depends on the rate of HIFalpha binding to DNA at the hypoxia response elements of target genes. In this study, the authors evaluated the immunohistochemical expression of HIF-2alpha in 62 infiltrating ductal carcinomas of the breast, not otherwise specified, in relation to estrogen and progesterone receptors, the MIB1 proliferation index, the vascular density, and the proteins c-erbB-2, bcl-2, and p53. Extensive and strong cytoplasmic and/or nuclear expression of HIF-2alpha was noted in 23 of the 64 (35.9%) cases, and this was associated with increased vascular density (P=0.0002), increased c-erbB-2 membrane expression (P=0.02), and secondary deposits to multiple axillary lymph nodes (>3). In multivariate analysis, HIF-2alpha and T stage were the only variables related to extensive nodal metastasis. The authors conclude that HIF-2alpha overexpression, a common event in infiltrating ductal carcinomas of the breast, is related to high metastatic potential via increased angiogenic and c-erbB-2 activity.

Basic Helix-Loop-Helix Proteins↗

PubMed2006

Endogenous markers of hypoxia/anaerobic metabolism and anemia in primary colorectal cancer.

Anemia has been implicated in the decreased oxygen tension noted within the tumor environment. In a series of 79 colorectal adenocarcinomas we investigated the role of anemia in activating molecular pathways regulated by hypoxia. Preoperative Hb levels were correlated with the immunohistochemical expression of HIF1alpha and HIF2alpha, LDH5, GLUT1, VEGF, DEC1 and BNIP3, and with angiogenesis and the cancer cell proliferation index. Upregulation of HIF1alpha and HIF2alpha proteins, found in 43% and 44.3% of cases, respectively, was not related to anemia (Hb < 10 g%). This is in agreement with other studies suggesting that HIF activation occurs for various reasons, such as poor or irregular vascularity, or oncogene activation. Nevertheless, low Hb levels (<10 g%) were linked to activated anaerobic metabolism (LDH5 overexpression) in a subset of tumors not expressing HIF1alpha (P < 0.01). Overexpression of HIFs, whether linked to anemia or not, was associated with a number of factors related to tumor aggressiveness (assessed as local invasion and nodal metastasis), anaerobic metabolism and intratumoral acidosis (LDH5, GLUT1; increased glucose metabolism to lactate), activation of genes related to necrosis (BNIP3) and angiogenesis (VEGF). Expression of BNIP3 emerged as the strongest independent factor related to transmural invasion and metastasis to lymph nodes. Identification of specific patterns of the hypoxia molecular cascade activated in cancer cells might help in developing specific therapeutic policies.

Adenocarcinoma↗

PubMed2006

Oxygen and glucose consumption in gastrointestinal adenocarcinomas: correlation with markers of hypoxia, acidity and anaerobic glycolysis.

This study gives an insight into tumor metabolic activity by investigating oxygen and glucose content, together with their metabolic products carbon dioxide and acids-pH, in the arterial and venous blood of a tumor. Nineteen patients with gastrointestinal adenocarcinomas undergoing surgery were studied. Biochemical analysis showed that in a large subgroup of tumors, oxygen consumption was reduced while that of glucose was increased in malignant, as compared to normal tissues; these features were more evident in tumors overexpressing lactate dehydrogenase (LDH-5) and hypoxia inducible factors (HIF1alpha/2alpha). An increase in carbon dioxide production in the tumor environment was linked with overexpression of carbonic anhydrase 9 (CA9). The simultaneous overexpression of CA9 and LDH-5 was related to very low pH levels in the veins draining the tumor, suggesting an intense acidification of the tumor microenvironment in such cases. These in vivo data confirm the importance of HIFs and their downstream regulated genes in tumor metabolism, particularly in glycolysis and carbon dioxide buffering.

Acidosis↗

PubMed2005

Inclusion of vasculature-related variables in the Dukes staging system of colon cancer.

PURPOSE: The Dukes stage is used to stratify colorectal cancer patients into groups of different prognosis and need of adjuvant radiotherapy and chemotherapy. However, approximately 80% of patients with Dukes stage C colorectal cancer receive cytotoxic therapy without any expected benefit, for such patients would either not relapse without adjuvant therapy or they would inevitably do so because of tumor resistance to the available regimens. On the other hand, as 20% of Dukes stage B patients would relapse after surgery, adjuvant therapy could improve their survival. Improvement of the Dukes stage predictive accuracy is necessary to better assign patients for adjuvant therapies, especially nowadays when antiangiogenic agents are being incorporated in the clinical practice. PATIENTS AND METHODS: In this study, we examined the prognostic role of Dukes staging system in parallel with three vasculature-related variables (vascular invasion, tumor angiogenic activity, and vascular survival ability) in a series of 130 stage B/C patients with colorectal cancer treated with surgery alone (without adjuvant radiotherapy or chemotherapy). RESULTS: Inclusion of vasculature-related variables in the Dukes staging system significantly improved the prognostic categorization of patients, identifying subgroups of B-stage and C-stage patients with an up to 40% and 60% 5-year survival difference, respectively. CONCLUSIONS: Preliminary results show that the prognostic value of Dukes staging system is significantly improved after taking into account vasculature-related variables, which may be useful in stratifying patients for adjuvant therapies, highlighting also subgroups that may benefit the most from antiangiogenic agents.

Blood Vessels↗

PubMed2005

Node-related factors and survival in node-positive breast carcinomas.

The number of positive lymph nodes (+LNs) is the only node-related prognostic factor recognized by the American Joint Committee TNM system for breast cancer. In this study, we evaluated additional node-related prognostic factors in node-positive breast carcinomas. One hundred and thirty-four patients with infiltrating ductal carcinomas and axillary +LNs, who had been treated with modified radical mastectomy, were analyzed. Metastatic lymph nodes were evaluated for traditional prognostic factors, i.e., the number of involved nodes and the extranodal extension, but also for a variety of other node-related characteristics, such as nodal tumor burden and maximum size of tumor deposits, necrosis, stromatogenesis, extranodal vascular involvement, and nodal matting. The results reaffirmed the prognostic significance of metastasis in 1-3 vs. 4-7 axillary lymph nodes and, in addition, revealed the importance of 4 +LNs as a cut-off point for breast tumor aggressiveness, given that survival curves for 4-7 vs. >7 +LNs were indifferent. Interestingly, nodal tumor burden, when extensive, was statistically an adverse prognostic factor. Prognosis was equally poor if metastases to regional nodes showed extensive nodal necrosis or extensive nodal stromatogenesis, if there was extranodal spread, extranodal vascular involvement, or if the axillary +LNs were matted. In multivariate analysis, intranodal necrosis and extranodal vascular involvement were the only node-related features with a significant and independent prognostic function. Node-related pathological features in node-positive breast carcinomas are important in determining prognosis. Intranodal necrosis and extranodal tumor emboli should be considered, in parallel with the number of +LNs, in subsequent treatment design.

Breast Neoplasms↗

PubMed2005

Impact of hiatal hernia on histological pattern of non-erosive reflux disease.

BACKGROUND: Hiatus hernia (HH) has major pathophysiological effects favoring gastroesophageal reflux and hence contributing to esophageal mucosa injury, especially in patients with severe gastroesophageal disease. However, prospective studies investigating the impact of HH on the esophageal mucosa in non-erosive reflux disease (NERD) are lacking. This study evaluated the association between the presence of (HH) and the histological findings in symptomatic patients with NERD. METHODS: Fifty consecutive patients with gastroesophageal reflux disease (GERD) were enrolled. After conventional endoscopy, Lugol solution was applied and biopsy specimens were obtained. Histological parameters including basal zone hyperplasia, papillary length and cellular infiltration were evaluated. The chi-square test with Yates' correlation was used for comparing discrete parameters between groups. However, Fisher's exact probability test was used where the expected frequencies were lower than 5. Wilcoxon's test for unpaired samples was preferred in cases of semi-quantitative parameters. RESULTS: The presence of HH along with more severe findings (0.01 <P < 0.05) was confirmed in 18 patients. NERD was observed in 29 (58%) patients. Basal zone hyperplasia and loss of glycogen accompanied HH in all cases, and the correlation was significant in NERD (P < 0.001). The remaining histological patterns were similar between erosive reflux disease and NERD in the presence of HH. CONCLUSION: The presence of HH is correlated with more severe endoscopy findings, and predisposes for severe histological abnormality in cases of NERD.

Adult↗