Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The incidence of oesophageal cancer has been rising for the past decades in the western world due to the rapid increase of oesophageal adenocarcinoma. Strategy and extent of the diagnostic work up in case of suspected oesophageal cancer should be focussed on the therapeutic consequences which have to be drawn in the individual patient. Upper endoscopy including biopsy will provide the diagnosis and the location of the tumour, computed tomography and transcutaneous sonography are used to rule out distant metastases. Endoscopic ultrasound is the tool of choice to obtain an exact locoregional staging - an experienced investigator may correctly classify the tumour according to the T-N-categories in about 80% of the cases. To define early cancers restricted to the mucosa, which may be suitable for local ablative therapy, high-resolution endosonography is essential. Intravital staining methods may help to delineate flat or multifocal cancers, they are also used to better recognise dysplastic foci in a Barrett-segment. To rule out osseous metastases a bone scintigraphy is indicated. In tumours located proximal to the bifurcation a bronchoscopy completes the diagnostic procedures, in case of advanced tumours of the oesophagogastric junction laparoscopy may be performed to rule out peritoneal carcinosis.
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PMID:[Oesophageal cancer--diagnosis]. 1563 Sep 86

Endoscopy with biopsy, endoscopic ultrasonography and computed tomography (CT) are prerequisites for an exact preoperative staging of patients with oesophageal cancer. Diagnosing an early adenocarcinoma limited to the mucosa (pT1m), the risk of lymph node metastase is nearly zero. Therefore, consideration could be given to ablate endoscopically the metaplastic mucosa including the pT1m-area. On the other hand, an adenocarcinoma that is invading into the submucosa (pTlsm) has an 18 to 50% likelihood of associated lymphnode metastases. In these patients with a highly curable form of oesophageal cancer only oesophageal resection with systematic abdominal and mediastinal lymph node dissection represents the standard of care. This seems to be also true for more advanced tumours without or with neoadjuvant chemoradiation. Because of substantial complications and long-term side effects the need for extensive resection in patients with early tumour stage (pT1) or down staged 'early' carcinoma (yT1) is questionable. Therefore, a limited resection of distal oesophagus and proximal stomach with two-field lymphadenectomy and jejunal interposition is an attractive alternative in early Barrett's carcinoma providing a low morbidity and mortality and resulting in a more than 90% chance of cure, perhaps in successfully down staged yT1-patients as well. Therefore, the extent of oesophageal resection should be tailored to the patient and the known extent of tumour disease. Although, there is no clear evidence at present that RCTx prolongs survival in patients with potentially resectable oesophageal cancer, preoperative treatment appears to increase the chance for a curative resection. Generally, in case of a T4-tumour or distant metastasis a surgical treatment is not indicated.
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PMID:[Surgical treatment of early adenocarcinoma arising in Barrett's oesophagus]. 1563 Sep 87

With regard to esophageal tumors, important reports on several topics have been published recently. 1) The place of endoscopic ultrasonography (EUS) as the best locoregional staging technique for cancer of the esophagus has been further consolidated. The addition of fine-needle aspiration makes EUS more sensitive than computed tomography (CT) and more accurate than CT or EUS alone for nodal staging. 2) High-resolution endoscopy with chromoendoscopy has been found to be very effective for mucosal lesions, but not for submucosal lesions. In combination with EUS, the sensitivity for submucosal tumors increases up to 60 %. 3) Autofluorescence-guided biopsy has been reported to be a good tool for detecting high-grade dysplasia. A narrow-band imaging system improved the overall accuracy for depth of invasion. 4) The incidence of hypopharyngeal cancer increases after resection for esophageal carcinoma. Patients with a scattered staining pattern after application of Lugol's solution are more prone to develop upper lesions. 5) Fluorescence imaging makes it possible to detect low-grade intraepithelial neoplasia in Barrett's mucosa, with fewer biopsies. 6) Patients with Barrett's esophagus with a length of over 3 cm had a significantly greater prevalence of dysplasia in comparison with those in the whom the Barrett's segment was shorter than 3 cm (23 % vs. 9 %, P = 0.0001). With regard to gastric tumors, 1) Helicobacter pylori eradication can significantly reduce the development of gastric cancer, but only in patients without precancerous lesions. 2) Intestinal metaplasia types II and III have been shown to have a higher rate of progression to low-grade dysplasia than type I. 3) With regard to screening in asymptomatic individuals, serum pepsinogen may represent an alternative to conventional fluoroscopy methods. 4) In patients who have undergone esophagectomy for esophageal cancer, annual follow-up endoscopies are vital for detecting early secondary gastric cancer and ulcerations in which curative treatment is possible. 5) High-resolution endoscopy allows more precise diagnosis of early gastric cancer. The presence of irregular minute vessels and variations in vessel caliber were found to be specific of early gastric cancer. The small regular pattern of sulci and ridges was observed significantly more frequently in differentiated carcinoma than in undifferentiated carcinoma. 6) Infrared-ray electronic endoscopy combined with indocyanine green injection appears to be effective in detecting sentinel nodes that contain metastases in patients with gastric cancer. 7) Gastric adenocarcinoma was found to show specific changes in the fluorescence spectra emitted, in comparison with normal gastric mucosa. However, there was wide variation in the emitted autofluorescence spectra in gastric cancer with signet-ring cells in comparison with normal mucosa.
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PMID:Diagnosis of esophagogastric tumors. 1565 54

Esophageal adenocarcinoma arises through well-defined precursor lesions (Barrett esophagus), although only a subset of these lesions advances to invasive adenocarcinoma. The lack of markers predicting progression in Barrett esophagus, typical presentation at advanced stage, and limitations of conventional chemotherapy result in >90% mortality for Barrett-associated adenocarcinomas. To identify potential prognostic markers and therapeutic targets, we compared gene expression profiles from Barrett-associated esophageal adenocarcinoma cell lines (BIC1, SEG1, KYAE, OE33) and normal esophageal epithelial scrapings utilizing the Affymetrix U133_A gene expression platform. We identified 560 transcripts with >3-fold up-regulation in the adenocarcinoma cell lines compared with normal epithelium. Utilizing tissue microarrays composed of normal esophageal squamous mucosa (n = 20), Barrett esophagus (n = 10), low-grade dysplasia (n = 14), high-grade dysplasia (n = 27), adenocarcinoma (n = 59), and node metastases (n = 27), we confirmed differential up-regulation of three proteins (Cdc2/Cdk1, Cdc5, and Igfbp3) in adenocarcinomas and Barrett lesions. Protein expression mirrored histologic progression; thus, 87% of low-grade dysplasias had at least focal surface Cdc2/Cdk1 and 20% had >5% surface staining; 96% of high-grade dysplasias expressed abundant surface Cdc2/Cdk1, while invasive adenocarcinoma and metastases demonstrated ubiquitous expression. Esophageal adenocarcinoma cell lines treated with the novel CDC2/CDK1 transcriptional inhibitor, tetra-O-methyl nordihydroguaiaretic acid (EM-1421, formerly named M4N) demonstrated a dose-dependent reduction in cell proliferation, paralleling down-regulation of CDC2/CDK1 transcript and protein levels. These findings suggest a role for CDC2/CDK1 in esophageal adenocarcinogenesis, both as a potential histopathologic marker of dysplasia and a putative treatment target.
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PMID:CDC2/CDK1 expression in esophageal adenocarcinoma and precursor lesions serves as a diagnostic and cancer progression marker and potential novel drug target. 1572 9

Barrett's oesophagus is the premalignant precursor of oesophageal adenocarcinoma. Non-dysplastic metaplasia can progress to low-grade dysplasia, high-grade dysplasia, and finally to invasive cancer. Although the frequency of adenocarcinoma in patients with Barrett's oesophagus is low, surveillance is justified because the outcome of adenocarcinoma is poor. Oesophagectomy remains the standard treatment for patients with high-grade dysplasia and superficial carcinoma. However, it has been associated with substantial morbidity and mortality and some patients are judged unfit for surgery. In this review, the present status of less invasive procedures is discussed. Endotherapy preserves the integrity of the oesophagus and allows a better quality of life to patients at low risk of developing lymph-node metastases. Opposition to endoscopic treatment is based mainly on the identification of undetected foci of cancer and high-grade dysplasia in oesophagectomy samples. The current ablative techniques used are photodynamic therapy, argon plasma coagulation, laser treatment, and endoscopic mucosal resection.
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PMID:Endoscopic treatment of high-grade dysplasia and early cancer in Barrett's oesophagus. 1586 79

Vascular endothelial growth factors (VEGF)-A, -C and -D are members of the proangiogenic VEGF family of glycoproteins. VEGF-A is known to be the most important angiogenic factor under physiological and pathological conditions, while VEGF-C and VEGF-D are implicated in the development and sprouting of lymphatic vessels, so called lymphangiogenesis. Local tumor progression, lymph node metastases and hematogenous tumor spread are important prognostic factors for esophageal carcinoma (EC), one of the most lethal malignancies throughout the world. We found solid evidence in the literature that VEGF expression contributes to tumor angiogenesis, tumor progression and lymph node metastasis in esophageal squamous cell carcinoma (SCC), and many authors could show a prognostic value for VEGF-assessment. In adenocarcinoma (AC) of the esophagus angiogenic properties are acquired in early stages, particularly in precancerous lesions like Barrett's dysplasia. However, VEGF expression fails to give prognostic information in AC of the esophagus. VEGF-C and -D were detected in SCC and dysplastic lesions, but not in normal mucosa of the esophagus. VEGF-C expression might be associated with lymphatic tumor invasion, lymph node metastases and advanced disease in esophageal SCC and AC. Therapeutic interference with VEGF signaling may prove to be a promising way of anti-angiogenic co-treatment in esophageal carcinoma. However, concrete clinical data are still pending.
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PMID:Clinical significance of VEGF-A, -C and -D expression in esophageal malignancies. 1586 86

SUMMARY. Esophageal cancer is one of the most deadly forms of gastrointestinal cancer with a mortality rate exceeding 90%. The major risk factors for esophageal adenocarcinoma are gastroesophageal reflux disease (GERD) and its sequela, Barrett's esophagus. GERD commonly leads to esophagitis. In a minority of patients however, ongoing GERD leads to replacement of esophageal squamous mucosa with metaplastic, intestinal-type Barrett's mucosa. In the setting of continued peptic injury, Barrett's mucosa can give rise to esophageal adenocarcinoma. Despite the widespread use of potent acid suppressive therapies for patients with GERD, the incidence of esophageal adenocarcinoma, among white men in the USA, the UK and Europe has continued to rise. Cancers in Barrett's esophagus arise through a sequence of genetic events that endow the cells with six essential physiologic hallmarks of cancer as described by Hanahan and Weinberg in 2000. These cancer hallmarks include the ability to proliferate without exogenous stimulation, to resist growth-inhibitory signals, to avoid triggering the programmed death mechanism (apoptosis), to resist cell senescence, to develop new vascular supplies (angiogenesis), and to invade and metastasize. While the acquisition of these essential attributes is not specific to the neoplastic progression of Barrett's esophagus, this review will focus on the genetic alterations that occur in Barrett's cells that contribute to the acquisition of each of the hallmarks. Moreover, potential diagnostic and therapeutic strategies for Barrett's patients aimed at each of these cancer hallmarks will be reviewed.
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PMID:Molecular targets for treatment of Barrett's esophagus. 1605 81

Endoglin (CD105), a member of transforming growth factor beta1 receptor complex, has been shown to be a more useful marker to identify tumor angiogenesis than panendothelial markers such as CD31. We investigated endoglin and vascular endothelial growth factor (VEGF) expression as possible prognostic markers in esophageal adenocarcinoma. Surgical specimens from 75 patients with esophageal adenocarcinoma treated with esophagectomy were immunostained for endoglin, CD31, and VEGF. We also included 10 cases of Barrett's esophagus with high-grade dysplasia and 10 cases with Barrett's esophagus low-grade dysplasia. Positively stained microvessels (MVs) were counted in hot spots at magnification of x400. Results were expressed as the highest number of MV identified. For VEGF, intensity of staining was scored on 3-tiered scale. Endoglin demonstrated significantly more vessels than the CD31 (mean, 28.9 +/- 13.2 versus 19.0 +/- 9.4, P < .001). Both endoglin and CD31 MV counts showed significant correlation with stage of the disease (r = 0.59, P < .001; r = 0.52, P < .001, respectively) and patient survival (log rank P < .01). Only endoglin MV count was significantly correlated with the presence of angiolymphatic invasion (r = 0.34, P < .05) and lymph node (LN) metastases (r = 0.48, P < .001). Univariate analysis showed that endoglin MV count is an independent prognostic factor. Endoglin showed a significant increase in MV count in Barrett's esophagus with high-grade dysplasia when compared with Barrett's esophagus low-grade dysplasia (P < .01), whereas CD31 did not show any significant difference. VEGF was expressed in 48 (64%) of 75 cases of adenocarcinoma and was significantly correlated with angiolymphatic invasion, LN metastases, and survival. In conclusion, endoglin is a specific and sensitive marker for tumor angiogenesis. Endoglin staining also showed prognostic significance with positive correlation with the presence of angiolymphatic invasion, LN metastases, tumor stage, and survival.
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PMID:Endoglin (CD105) and vascular endothelial growth factor as prognostic markers in esophageal adenocarcinoma. 1615 57

The gene that encodes methylthioadenosine phosphorylase (MTAP), an enzyme involved in adenine and methionine salvage pathways, is located on chromosome 9p21 telomeric to the p16INK4A/CDKN2A tumor suppressor gene. Inactivation of the p16INK4A/CDKN2A gene occurs by three different mechanisms: hypermethylation of the gene promoter, intragenic mutation coupled with loss of the second allele, and homozygous deletion. Immunohistochemical labeling for the p16INK4A/CDKN2A gene product parallels gene status but does not elucidate the mechanism of gene inactivation. Since the MTAP gene is often co-deleted with p16INK4A/CDKN2A, concurrent immunolabeling for both proteins can identify cases with homozygous p16INK4A/CDKN2A gene deletion. MTAP loss itself has therapeutic implications since it may confer selective sensitivity to inhibitors of de novo purine biosynthesis, such as L-alanosine. Twelve tissue microarrays were constructed from 92 cases of Barrett-associated adenocarcinomas and precursor lesions and 112 cases of gastric adenocarcinoma and precursor lesions comprising 1161 individual cores. Multiple cores were arrayed from any given case, and when available, included the entire histologic spectrum of intestinal metaplasia-dysplasia-carcinoma. Tissue microarrays were labeled with monoclonal antibodies against MTAP protein (clone 6.9, Salmedix, Inc) and p16 (clone 16P07, Neomarkers). Complete loss of labeling was considered negative, while any labeling (p16: nuclear; MTAP: cytoplasmic and nuclear) was considered positive. Loss of MTAP labeling occurred exclusively in conjunction with loss of p16 labeling, confirming that the previous findings from this group that concurrent loss of MTAP and p16 labeling is a surrogate marker of 9p21 homozygous deletions. Complete loss of MTAP and p16 was seen in 4 of 25 (16%) patients with Barrett's esophagus, 4 of 18 (22%) with low-grade dysplasia, 5 of 39 (13%) with high-grade dysplasia, 17 of 78 (22%) with invasive adenocarcinoma, and 8 of 36 (22%) of metastases. There were 7 cases of esophageal adenocarcinoma with loss of both MTAP and p16 for which precursor lesions were available. In 6 on these 7 cases (85%), the precursor lesion(s) had loss of both MTAP and p16. Lack of MTAP and p16 expression was seen in 11 of 106 (10%) cases of gastric adenocarcinoma. All metaplastic (30 biopsies from 20 cases) and dysplastic (15 biopsies from 13 cases) gastric tissues had both intact MTAP and p16INK4A/CDKN2A gene products. No precursor lesions were available from the gastric cancers that had loss of both MTAP and p16. Two benign gastric hyperplastic polyps also had intact p16 and MTAP. Concurrent MTAP and p16 loss detected by immunohistochemistry can serve as a convenient surrogate for p16INK4A/CDKN2A gene homozygous deletion in archival tissues. Inactivation of p16INK4A/CDKN2A by homozygous deletion appears to be an early event in Barrett carcinogenesis, occurring in noninvasive precursor lesions, including nondysplastic Barrett mucosa, in subsets of cases. In the absence of MTAP, cells depend exclusively on the de novo synthesis pathway for production of adenosine. This loss of MTAP during 9p21 homozygous deletion might be exploited therapeutically using de novo purine synthesis antimetabolites to treat a subset of invasive gastroesophageal adenocarcinomas and esophageal precursor lesions.
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PMID:Concordant loss of MTAP and p16/CDKN2A expression in gastroesophageal carcinogenesis: evidence of homozygous deletion in esophageal noninvasive precursor lesions and therapeutic implications. 1622 17

Current treatment recommendations for early esophageal adenocarcinoma range from radical esophagectomy with extensive lymphadenectomy, limited surgical resection with/without regional lymphadenectomy to endoscopic mucosectomy or ablation. A comparison of treatment associated morbidity, tumor recurrence rates, and functional outcome suggests that none of these alternatives can be universally recommended. Rather, an individualized strategy should be employed based on depth of tumor penetration into the mucosa/submucosa, presence of lymph node metastases, multicentricity of tumor growth, length of the underlying Barrett mucosa and comorbidity of the affected patient. Endoscopic mucosectomy may suffice for an isolated focus of high-grade neoplasia or mucosal cancer, provided the neoplasia and underlying Barrett mucosa can be removed completely. Surgical resection is the treatment of choice for tumors invading the submucosa, multicentric tumors and recurrence after endoscopic mucosectomy. The extent of surgical resection must be guided by the length of the Barrett mucosa. In most instances a complete tumor resection and removal of the entire Barrett mucosa can be achieved by a limited transabdominal approach, and therefore subtotal esophagectomy may not be necessary. Application of the sentinel node technology may in the future allow to limit systematic lymphadenectomy to the rather small subgroup of patients who in fact have lymph node metastases.
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PMID:Surgery for early stage esophageal adenocarcinoma. 1629 89


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