Flow cytometric analysis of cellular DNA content in Barret's esophagus. A study of 66 cases]

Dysplasia is the only marker for malignant potential in Barrett's esophagus. The histologic interpretation of dysplasia is sometimes difficult, particularly when attempting to distinguish dysplastic changes from those of a regenerating and inflammatory mucosa. In order to find an objective marker to identify patients with high risk of malignant transformation, the authors evaluated 497 biopsies from 66 patients with Barrett's esophagus with flow cytometry. The aim of the study was to correlate DNA content and proliferative abnormalities with histology. All biopsies classified histologically as negative for dysplasia had a diploid DNA content. The percentage of biopsies with an aneuploid DNA content increased with the histologic grade of dysplasia: 2 percent of indefinite dysplasia, 11 percent of low grade dysplasia, 44 percent of high grade dysplasia and 78 percent of biopsy specimens with cancer biopsies were aneuploid. Mean S and G2M fractions of diploid biopsy specimens increased with the severity of histologic changes. The S and G2M fraction threshold values that could differentiate patients that were negative for dysplasia from those with high grade dysplasia or cancer were 9 percent and 6 percent, respectively. Aneuploidy or G2M fraction greater than 6 percent was the best discriminating criteria between those two distinct groups of patients. All 6 patients with high grade dysplasia or cancer had aneuploid cell populations or increased G2M fraction, whereas none of the 35 patients whose biopsies were histologically negative for dysplasia had evidence of genomic instability or increased G2M fraction. Flow cytometric abnormalities were found in 10 out of 25 patients whose biopsies were classified as indefinite for dysplasia or low grade dysplasia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Molecular analysis of the TP53 gene in Barrett's adenocarcinoma

The TP53 gene is the most frequently mutated gene in human cancers. Barrett's esophagus provides an excellent model by which to understand the genetic events that lead from dysplasia to cancer. We screened for mutations in the TP53 gene by a combination of denaturing gradient gel electrophoresis and DNA sequencing in ten cases of adenocarcinoma arising in Barrett's mucosa. We have identified missense mutations in five of the ten samples, three transitions (R282W, G245S, R248W) and two transversions (E286Q and C176F). In one case we have analyzed biopsy specimens taken from the same site, one year before the patient developed an intra mucosal carcinoma. The mutation that was identified in this high grade dysplastic area was identical to that detected in the cancer. This would suggest TP53 mutations occur as an early genetic event in the development of Barrett's adenocarcinoma. © 1996 Wiley-Liss, Inc.     

p53 and VEGF expression are independent predictors of tumour recurrence and survival following curative resection of gastric cancer

This study was undertaken to determine the value of tumour microvessel density (MVD) and the expression of p53 and vascular endothelial growth factor (VEGF) as prognostic markers in patients with gastric cancer operated on for cure. In all, 156 patients with curatively resected gastric cancer constituted the basis of this blinded retrospective evaluation. Patients were treated with either surgery alone (n=53) or surgery plus adjuvant chemotherapy (n=103). Tumour MVD, p53 expression, and VEGF expression were assayed using immunohistochemical techniques. After a mean follow-up of 43 months, 64 (41%) patients had died and 55 (35%) patients developed tumour recurrence. Positive correlations between MVD and both p53 (P=0.005) and VEGF (P=0.005) expression were observed. Both MVD >/=100 (P=0.05) and positive VEGF expression (P<0.02) were associated with shorter disease-free survival, and positive VEGF expression (P=0.01) was also associated with shorter overall survival. Multivariate analysis confirmed that, in addition to the pathological tumour stage, lymph node ratio, the extent of lymphadenectomy and perineural invasion, p53 expression, and VEGF expression were independently associated with both disease-free survival (P<0.0005 and 0.02, respectively) and overall survival (P<0.02 and 0.01, respectively). Finally, patients whose tumours did not show p53 expression had a survival benefit compared to those expressing p53 when treated with adjuvant chemotherapy (P=0.01).This investigation demonstrates that p53 expression and VEGF expression are independent prognostic factors for both disease-free survival and overall survival in patients with curatively resected gastric cancer, and that p53 status may also influence response to chemotherapy.     

Detection of colorectal carcinoma by emission-computerized tomography after injection of 123I-labeled Fab or F(ab'')2 fragments from monoclonal anti-carcinoembryonic antigen antibodies

This clinical study was based on experimental results obtained in nude mice grafted with human colon carcinoma, showing that injected 131I-labeled F(ab')2 and Fab fragments from high affinity anti-carcinoembryonic antigen (CEA) monoclonal antibodies (MAb) gave markedly higher ratios of tumor to normal tissue localization than intact MAb. 31 patients with known colorectal carcinoma, including 10 primary tumors, 13 local tumor recurrences, and 21 metastatic involvements, were injected with 123I-labeled F(ab')2 (n = 14) or Fab (n = 17) fragments from MAb anti-CEA. The patients were examined by emission-computerized tomography (ECT) at 6, 24, and sometimes 48 h after injection using a rotating dual head scintillation camera. All 23 primary tumors and local recurrences except one were clearly visualized on at least two sections of different tomographic planes. Interestingly, nine of these patients had almost normal circulating CEA levels, and three of the visualized tumors weighed only 3-5 g. Among 19 known metastatic tumor involvements, 14 were correctly localized by ECT. Two additional liver and several bone metastases were discovered by immunoscintigraphy. Altogether, 86% of the tumor sites were detected, 82% with F(ab')2 and 89% with Fab fragments. The contrast of the tumor images obtained with Fab fragments suggests that this improved method of immunoscintigraphy has the potential to detect early tumor recurrences and thus to increase the survival of patients. The results of this retrospective study, however, should be confirmed in a prospective study before this method can be recommended for the routine diagnosis of cancer.     

Ivor Lewis' operation for epidermoid cancer of the esophagus. Immediate and late results. Apropos of 168 cases]

168 Ivor Lewis operations for squamous carcinoma of the lower esophagus are reviewed. 155 men and 13 women with a mean age of 59 years were operated on. 46 tumors were stage I and II, and 122 were stage III. Operations were considered to be curative for 120 patients and only palliative for 48. An esophagectomy associated with lymphadenectomy was performed through laparotomy and right thoracotomy. Feeding jejunostomy and pyloroplasty were routine. EEA or ILS 25 staplers were used to perform esophagogastric anastomosis and the gastroplasty tube was fashioned by TA 90 stapler. In every case an extended esophagectomy was performed with anastomosis between 3 ans 7 cm below the pharyngo-esophageal junction. Postoperative mortality was 4.7%. There were 10 leaks (6%) and 28 pulmonary complications. Median actuarial survival is 17 months. Actuarial survival at 2 years is significantly greater for stages I and II (68.4%) than for stage III (23.2%) (p < 0.01). Ivor Lewis esophagectomy is a reliable procedure to treat squamous carcinoma of the lower two thirds of the esophagus ensuring a good quality of life.     

Optimal combination of early biomarkers for infection and sepsis diagnosis in the emergency department: The BIPS study

Objective: To define the best combination of biomarkers for the diagnosis of infection and sepsis in the emergency room.Methods: In this prospective study, consecutive patients with a suspicion of infection in the emergency room were included. Eighteen different biomarkers measured in plasma, and twelve biomarkers measured on monocytes, neutrophils, B and T-lymphocytes were studied and the best combinations determined by a gradient tree boosting approach.Results: Overall, 291 patients were included and analysed, 148 with bacterial infection, and 47 with viral infection. The best biomarker combination which first allowed the diagnosis of bacterial infection, included HLA-DR (human leukocyte antigen DR) on monocytes, MerTk (Myeloid-epithelial-reproductive tyrosine kinase) on neutrophils and plasma metaloproteinase-8 (MMP8) with an area under the curve (AUC) = 0.94 [95% confidence interval (IC95): 0.91;0.97]. Among patients in whom a bacterial infection was excluded, the combination of CD64 expression, and CD24 on neutrophils and CX3CR1 on monocytes ended to an AUC = 0.98 [0.96;1] to define those with a viral infection.Conclusion: In a convenient cohort of patients admitted with a suspicion of infection, two different combinations of plasma and cell surface biomarkers were performant to identify bacterial and viral infection.