Oesophageal cancer: hope for the future?
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Clinical Trials as Topic↗
Biomedical subjects
A G Casson
Publications and source records attributed to A G Casson.
Osteopontin expression in lung cancer.
Osteopontin (OPN), an integrin-binding, transformation-associated protein, is secreted by tumor cell lines in culture and is associated with increased malignancy in some experimental tumor systems. Little is known, however, about the significance of OPN expression in human cancers. The aims of this study were to determine if OPN was expressed in a series of surgically resected lung cancers, and if there was a relationship between OPN expression and clinico-pathologic findings or outcome. Twenty-five patients who underwent curative pulmonary resection were studied prospectively. RNA was extracted from primary tumor and distant normal lung tissue for each patient. OPN RNA levels were evaluated by northern blotting. Immunohistochemistry on paraffin-embedded tissue, using an anti-OPN monoclonal antibody, was performed to assess tissue distribution of OPN protein. OPN RNA and protein were over-expressed in the majority of tumors, relative to paired normal tissue. There was variation in the cells of the tumor that were OPN-immunopositive. In some cases OPN was present in tumor cells, while in the majority of cases OPN was detected primarily in tumor-infiltrating macrophages and necrotic areas. Over-expression of OPN RNA or protein generally was not related to clinico-pathological findings. However, there was a statistically significant association between OPN-immunopositivity in the tumor and patient survival. These findings suggest that OPN levels in lung tumors have the potential to provide clinically important predictive information on patient outcome, and that OPN may play a role in the biology of lung cancer.
Adult↗
Mutations of p53 in Barrett's esophagus and Barrett's cancer: a prospective study of ninety-eight cases.
We had previously identified p53 mutations in Barrett's esophagus and therefore began a multiinstitutional study to determine their significance as a marker for malignancy. Ninety-eight patients from four institutions were studied. Forty-eight patients (37 men and 11 women, mean age 56.2 years) had Barrett's esophagus with metaplasia or dysplasia but no evidence of malignancy at a mean follow-up of 2.2 years. Barrett's esophagus was classified as metaplasia with no evidence of dysplasia in 32 patients, as low-grade dysplasia in 13, and as high-grade dysplasia in three. The other 50 patients (46 men and four women, mean age 60.2 years) had adenocarcinoma arising in Barrett's esophagus. Tissues from normal stomach or esophagus, tumor, and Barrett's esophagus were obtained for deoxyribonucleic acid analysis by endoscopic biopsy from patients with Barrett's esophagus or cancer or during operations on some patients with Barrett's cancer. Exons 5 through 9 of the p53 gene were studied for mutations by single-strand conformational polymorphism analysis after polymerase chain reaction amplification. Mutations detected by single-strand conformational polymorphism analysis were confirmed by deoxyribonucleic acid sequencing. None of the tissue samples from patients with Barrett's esophagus alone and no dysplasia or low-grade dysplasia had any p53 mutations, but one of the three patients with high-grade dysplasia and no evidence of invasive malignancy did have a p53 mutation. Of the 50 patients with Barrett's cancer, however, 23 (46%) had p53 mutations in Barrett's epithelium, tumors, or both. Twenty of these patients had p53 mutations in the tumor only (n = 16) or in both tumor and Barrett's epithelium (n = 4), suggesting that the mutation plays a direct role in carcinogenesis. Mutations in Barrett's epithelium were found in one patient in the group without malignancy and in seven patients with cancer (one with no dysplasia, two with low-grade dysplasia, and five with high-grade dysplasia). In three patients with cancer, mutations occurred only in Barrett's epithelium, suggesting that such mutations may also be a marker for genomic instability. Mutations were predominantly found in exons 5, 7, and 8, and transitions from guanine to adenine were the most frequent changes. Mutations of p53 are clearly involved in the pathogenesis of Barrett's cancer for a subset of patients (46%), and the fact that we could detect mutations in premalignant Barrett's epithelium supports the hypothesis that p53 mutations may be a useful marker for patients at increased risk for development of invasive cancer.
Adenocarcinoma↗
Dysphagia lusoria: extrathoracic surgical management.
OBJECTIVE: To report a case of dysphagia lusoria managed by an extrathoracic approach. DESIGN: Case report and literature review. SETTING: A university hospital. PATIENT: A 39-year-old man, who presented with weight loss and dysphagia. Aortography and computed tomography revealed an aberrant subclavian artery compressing the esophagus against the aortic arch. INTERVENTION: The right subclavian artery was divided at its origin and reimplanted onto the right carotid artery. The operation was performed through a right supraclavicular incision without opening the chest. RESULTS: There was no operative morbidity. Six months postoperatively the patient was asymptomatic and had gained weight. There was no radiologic evidence of esophageal compression. CONCLUSIONS: Based on the results of our case of dysphagia lusoria and the reports of others that have started to appear in the literature, consideration should be given to repairing a symptomatic, nonaneurysmal aberrant right subclavian artery through an extrathoracic approach.
Adult↗
Thymoma found during routine cardiac imaging.
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Chest Pain↗
Prognostic value of DNA index, S-phase fraction and p53 protein accumulation after surgical resection of esophageal squamous-cell carcinomas in Thailand.
The prognostic value of cell nuclear DNA content, S-phase fraction and p53 protein accumulation in esophageal squamous-cell carcinomas was studied in a consecutive series of 80 patients from a high-incidence region of southern Thailand, who underwent esophagectomy between 1983 and 1993. Flow cytometry was used to determine tumor ploidy, DNA index and S-phase fraction, while p53 protein accumulation was evaluated immunohistochemically using the monoclonal anti-p53 antibody, CO7. Biomarkers were correlated with clinico-pathologic findings and survival by univariate and multivariate analysis. p53 protein was found in 40 tumors (50%), and was associated with significantly reduced overall survival. In patients with immunopositive tumors, depth of primary tumor invasion, lymph-node status. TNM stage and tumor grade were also significant prognostic factors. Additional predictors of reduced overall survival after esophagectomy, determined by flow cytometry, included S-phase fraction above 10%, aneuploidy (DNA index 1.2-1.8) and multiploidy (DNA index > 2.2). This study further implicates p53 in the pathogenesis of esophageal squamous-cell carcinoma. Prognostic factors such as p53 protein, S-phase fraction and DNA index may be useful in stratifying patients for adjuvant therapies in future clinical trials of esophageal cancer.
Adult↗
Prognostic value of p53 protein in esophageal adenocarcinoma.
The p53 tumor suppressor gene has recently been implicated in the pathogenesis of human esophageal cancer. To assess potential clinical applications for this molecular marker, 52 patients with primary esophageal adenocarcinoma were studied prospectively. p53 protein accumulation was evaluated immunohistochemically in surgically resected esophageal tissues, and correlated with clinicopathologic findings and survival. All patients underwent total esophagectomy with reconstruction, completely resecting all gross disease. Immunopositivity was seen in 28 of 52 (54%) primary adenocarcinomas, and was associated with a trend towards reduced postoperative survival (P = 0.06; log-rank). Regional lymph node metastases were found in 30 (58%) patients. Thirteen of 30 (43%) regional lymph node metastases were immunopositive, which was the most significant predictor of overall survival by univariate (P = 0.02; log-rank) and multivariate analysis (P = 0.05; Cox regression). This study further implicates p53 in esophageal tumor development and progression. The immunohistochemical finding of p53 protein in primary esophageal adenocarcinomas and regional lymph node metastases appears to be associated with reduced overall survival for this disease. If these preliminary observations are confirmed in larger prospective studies, p53 may prove to be a clinically useful molecular marker in future clinical trials of esophageal cancer.
Adenocarcinoma↗
Adenocarcinoma of the neo-esophagus after Collis gastroplasty.
The development of an invasive adenocarcinoma arising from gastric mucosa within the neo-esophagus of a Collis gastroplasty is uncommon. We report 1 patient in whom an adenocarcinoma developed 18 years postoperatively, and who was treated by total gastrectomy. We suggest accurate preoperative evaluation and staging to distinguish tumors arising in the distal esophagus from those arising in the gastric mucosa of the neo-esophagus, and recommend an approach to management of these tumors.
Adenocarcinoma↗
Genetic modulation in the pathogenesis and treatment of cancer.
Recent advances in molecular biology have improved our understanding of the pathogenesis of cancer. Molecular genetic alterations have been characterized in lung and esophageal tumors, and have potential clinical application in tumor diagnosis, staging, prevention, and therapy.
DNA, Neoplasm↗
p53 mutation, expression, and DNA ploidy in evolving gliomas: evidence for two pathways of progression.
BACKGROUND: Two lines of evidence indirectly implicate the tumor suppressor p53 (also known as TP53) gene in glioma development. First, germline mutations of the p53 gene are associated with increased susceptibility to glioma. Second, chromosome 17p deletions and p53 gene mutations are found frequently in sporadic gliomas of all malignancy stages. These observations suggest that mutations of the p53 gene may be early events in glioma development. PURPOSE: Our purpose was to analyze 15 low-grade astrocytic gliomas that progressed to higher-grade gliomas, examining the status of the p53 gene in both the initial and recurrent tumors. Also, we explored the relationships between p53 status, DNA ploidy, tumor grade, and patient survival. METHODS: Fifteen low-grade gliomas that recurred as tumors of higher grade 17-102 months after initial treatment (biopsy, resection, radiotherapy, or chemotherapy) were identified from hospital records of patients (eight male and seven female) aged 31-68 years. Pathologic diagnosis was re-evaluated. Polymerase chain reaction (PCR)-single-strand conformation polymorphism and DNA sequencing were performed on tissue samples from the initial and recurrent tumors of each patient, using oligonucleotide PCR primers directed to exons 5-9 of the p53 gene. p53 expression was determined by immunohistochemistry and DNA ploidy evaluated by DNA flow cytometry. RESULTS: Eight (53%) of fifteen tumors had p53 mutations in exons 5-9. Nine (64%) of fourteen were immunopositive initially, and eight of these were also immunopositive at recurrence. p53 gene status was significantly associated with p53 expression in the initial tumor (P = .02), and p53 expression at initial diagnosis was significantly related to tumor pathology at recurrence (P = .03). Patients with p53 mutant tumors survived nearly twice as long as those without mutations (median survival, 61 versus 33 months; P = .031). There was no significant difference in recurrence-free survival between patients with p53 mutant and nonmutant tumors (48 versus 33 months; P = .37), but there was a significant difference in postrecurrence survival (17 versus 2 months; P = .019). CONCLUSION: Low-grade tumors that recurred as anaplastic gliomas were characterized by p53 gene mutation, immunopositivity, and DNA non-diploidy. Low-grade tumors that recurred as glioblastomas generally had intact p53 genes and were immunonegative. These findings suggest that histologically indistinguishable, low-grade astrocytic gliomas that are destined to progress to higher grades, do so along two distinct clinicopathologic pathways (either stepwise to anaplastic glioma, then glioblastoma, or directly to glioblastoma) marked by the presence or absence of p53 mutation.
Adult↗
Prognostic value and clinicopathologic correlation of p53 gene mutations and nuclear DNA content in human lung cancer: a prospective study.
The aim of this prospective study was to determine whether use of a combination of biomarkers, p53 and nuclear DNA content, led to improved prognosis and clinicopathologic correlation in human non-small cell lung cancer. Nineteen patients undergoing curative resection of primary non-small cell lung cancer were evaluated. Resected tumors were studied by polymerase chain reaction/single strand conformation polymorphism analysis (p53 gene mutations), flow cytometry (nuclear DNA content and cell cycle analysis), and immunohistochemically (p53 oncoprotein). Histologically normal lung was used as an internal control for each patient. Minimum postoperative follow-up was 4 years. p53 gene mutations (5/19 tumors; 26%), tumor ploidy (5/19 diploid), patterns of immunoreactivity, or combination of biomarkers did not appear to correlate with clinicopathologic findings or clinical outcome. Two of three patients with associated second primary malignancies, had squamous cell diploid tumors with p53 gene mutations. We conclude that p53 gene mutations and tumor ploidy may represent different biologic markers for human non-small cell lung cancer. Although trends in improved predictive accuracy were not seen when both markers were incorporated into the tumor analysis, flow cytometry and molecular analysis of the p53 gene may identify patients at increased risk of the development of a second primary malignancy.
Adult↗
p53 immunoreactivity in carcinosarcoma of the esophagus.
The case of a primary esophageal carcinosarcoma, shown to express p53 protein, is presented. The patient, a 57-year-old male, presented with fever, weight loss, and clubbing, but without swallowing difficulties. A large intraesophageal tumor was found on radiologic imaging, and sarcoma was diagnosed on esophagoscopic biopsy. Despite total esophagectomy and adjuvant chemo-radiotherapy, pleural metastases developed 3 months postoperatively. Histologically, the tumor was composed of epithelial and sarcomatous elements. Using monoclonal and polyclonal anti-p53 antibodies, p53 protein was distributed heterogenously throughout the sarcomatous elements of the primary tumor. Immunoreactivity was also found in regional lymph node metastases. These observations further implicate the p53 tumor suppressor gene in the pathogenesis of human esophageal cancers.
Carcinosarcoma↗
Clinical implications of p53 gene mutation in the progression of Barrett's epithelium to invasive esophageal cancer.
The p53 tumor suppressor gene has been implicated in human esophageal tumorigenesis, and mutations are reported in primary esophageal adenocarcinomas and associated Barrett's epithelium. To evaluate the potential clinical significance of this molecular genetic marker in the progression of Barrett's epithelium to invasive esophageal cancer, we studied 20 patients with Barrett's epithelium, 10 of whom had an associated adenocarcinoma. p53 gene mutations were screened using polymerase chain reaction (PCR)/single-strand conformation polymorphism (SSCP) analysis and p53 oncoprotein distribution by immunohistochemistry. Point mutations were localized to exons 5 and 7 of the p53 gene, previously recognized as "hot spots." p53 gene mutations and immunoreactivity were detected in 7 of 10 patients with primary esophageal adenocarcinomas and in 6 patients with associated Barrett's epithelium, 3 of whom had high-grade dysplasia. Little correlation was observed between p53 positivity and clinicopathologic findings or outcome, although two patients with p53 mutations subsequently developed second primary cancers. Of 10 patients with Barrett's epithelium alone, 6 had p53 mutations, with mild or no dysplasia histologically, suggesting that p53 gene mutation may be an early event in progression to invasive cancer. No patient has developed invasive cancer to date, with a median follow-up of 8 years. These studies further implicate the p53 gene in the Barrett's epithelium-to-carcinoma sequence. Prospective surveillance studies incorporating molecular analysis of the p53 gene are warranted to further evaluate p53 as a predictor of patients at high risk for developing malignancy.
Adenocarcinoma↗
Lymph node mapping of esophageal cancer.
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Esophageal Neoplasms↗
p53 and ras gene expression in human esophageal cancer and Barrett's epithelium: a prospective study.
To assess potential clinical applications for molecular genetic markers associated with human esophageal tumorigenesis, ten patients with primary esophageal adenocarcinomas were studied prospectively to evaluate expression of the p53 and H-ras genes. Total RNA was extracted from tumor, Barrett's epithelium, and histologically normal esophageal mucosa obtained at surgical resection, and gene expression investigated by Northern blot analysis. p53 was overexpressed, relative to normal tissue from the same patient, in seven tumor and six Barrett's specimens, whereas high levels of H-ras were found in only four tumor and one Barrett's specimen. Clinical correlative data were obtained for all patients, with a median follow-up of 14 months. Advanced pathologic stage was associated with poor survival. No association was found between gene expression and outcome. Three patients with low p53 and H-ras levels developed metastatic disease 7 to 12 months following resection. We conclude that both p53 and ras are implicated in the progression of Barrett's epithelium to invasive cancer, and that further clinical correlative studies are warranted to evaluate potential clinical application for such molecular markers.
Adenocarcinoma↗
Laparoscopic appendicectomy.
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Adenocarcinoma↗
Predictors of survival following surgical resection of thymoma.
The aim of this study was to determine the predictors of long-term survival following surgical resection of thymoma. Forty-one patients with a histologically proven diagnosis of thymoma were evaluated and treated over a 30-year period (1961 to 1991) at our institution. Seven patients (Masaoka stage III or IV) were unresectable and were treated by radiotherapy and/or chemotherapy, with an overall 5 year survival of 50%. Thirty-four patients underwent primary surgical excision of the thymoma, most often through a median sternotomy, with 5- and 10-year survivals of 90%. Complete excision of the thymoma was achieved in 31 patients with a median survival of 54 months vs. 17 months if incomplete. Independent prognostic factors influencing survival were stage, histology, and patients judged to have a benign thymoma at surgery. Although the thymoma was associated with myasthenia gravis (8 patients) and second primary cancers (8 patients), neither factor was associated with overall survival. We conclude that the most significant predictors of long-term survival of thymoma include complete excision, Masaoka stage I disease, and lymphocytic histology. Multivariate analysis suggested that postoperative chemoradiotherapy may impact on survival.
Adolescent↗
Blunt cardiac trauma: survival after bichamber rupture.
Rupture of cardiac chambers after nonpenetrating blunt thoracic trauma is being recognized with increasing frequency. Despite a high mortality rate, survival after repair of a single-chamber rupture is widely reported. Bichamber cardiac rupture is less frequent, and we report a patient who survived this injury.
Adult↗