Alan G. Casson

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 Barretts epithelium. To evaluate the potential clinical significance of this molecular genetic marker in the progression of Barretts epithelium to invasive esophageal cancer, we studied 20 patients with Barretts 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 Barretts 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 Barretts 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 Barretts 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.

What is the optimal distal resection margin for esophageal carcinoma

BACKGROUNDnWhereas a proximal resection margin of 12 cm is recommended for complete resection of esophageal cancer, the extent of distal resection is unclear.nnnMETHODSnWe examined distal resection margins in a consecutive series of patients who underwent esophagectomy for squamous cell carcinomas (n = 50), primary esophageal adenocarcinomas (n = 100), and adenocarcinomas of the cardia (n = 39), in whom all macroscopic tumor was judged to be completely resected.nnnRESULTSnMicroscopic tumor was found at a 3-cm distal resection margin for one multifocal squamous cell carcinoma. Positive distal resection margins were seen in 12% (12 of 100 patients) of primary esophageal adenocarcinomas (median, 2 cm versus 4 cm if negative; p = 0.002, Wilcoxon) and 28% (11 of 39 patients) of cardia adenocarcinomas (median, 1 cm versus 3 cm if negative; p = 0.02, Wilcoxon). Although pathologic stage was shown to be the only significant predictor of overall survival (Hazard ratio [HR] 1.8; 95% confidence interval 1.2 to 2.6; p = 0.007), there was a trend toward reduced postoperative survival for patients with histologically positive distal resection margins, in particular for patients with cardia adenocarcinomas (median, 15.4 months versus 5.7 months if negative; p = 0.0001).nnnCONCLUSIONSnTo achieve consistently negative distal resection margins, we recommend resection of at least 5 cm of macroscopically normal foregut below the distal margin of the primary tumor.

Preoperative Mitomycin, Ifosfamide, and Cisplatin Followed by Esophagectomy in Squamous Cell Carcinoma of the Esophagus: Pathologic Complete Response Induced by Chemotherapy Leads to Long-Term Survival

PURPOSEnSquamous cell carcinoma of the esophagus remains an aggressive disease with a poor prognosis, even after curative-intent surgery. This article analyzes the impact of preoperative chemotherapy with mitomycin, ifosfamide, and cisplatin (MIC) on a cohort of 68 patients.nnnPATIENTS AND METHODSnFrom 1988 to 1994, 68 patients with potentially operable squamous cell carcinoma of the esophagus were entered onto two phase II trials of neoadjuvant chemotherapy with mitomycin 6 mg/m2, ifosfamide 3 g/m2, and cisplatin 50 mg/m2 and received between two and four cycles of treatment at 3-weekly intervals. Two patients were removed from the analysis when they were found to have malignancy other than squamous cell carcinoma of the esophagus.nnnRESULTSnForty (61%) of 66 patients had a radiologic response to chemotherapy (18 complete responses and 22 partial responses), and 52 (79%) of 66 patients went on to have the primary tumor resected. There were nine pathologic complete responders, seven of whom remain fit and well after at least 60 months of follow-up. The overall median survival was 12.4 months (95% confidence interval, 9.6 to 18.8 months). The complete response and node-negative patients survived significantly longer than those in other categories (log-rank chi2 = 18.8; P <.001): on average 13 months longer than the node-positive or nonresected category (22.0 v 9.4 months). The toxicity of the regimen was low.nnnCONCLUSIONnMIC is an easily administered, well-tolerated, and efficacious regimen as neoadjuvant therapy for patients with squamous cell carcinoma of the esophagus. These results warrant further investigation.

Functional results of gastric interposition following total esophagectomy.

Functional results of gastric interposition were evaluated in 35 patients at 3 to 84 months following esophagectomy. All patients were satisfied with the results of surgery, although 14 (40%) still experienced some degree of dysphagia. Transit times for radiolabeled solids across the cervical esophagus and anastomosis were not significantly different for the 14 symptomatic patients (mean 77 seconds) versus 21 asymptomatic patients (mean 55 seconds). Spontaneous emptying of the vagotomized intrathoracic stomach appeared complex, with mean percentage radionuclide clearances at 30 minutes (semisolid meal) calculated at 37% for 23 patients with early satiety (versus 42% asymptomatic) and at 38% for nine patients with reflux (versus 39% asymptomatic), all values comparable to emptying of the normal intra-abdominal stomach (35% clearance at 30 minutes). Our data suggest that the interposed stomach appears to retain its gastric identity rather than act as an inert conduit, and that although little correlation exists between postoperative symptoms and objective findings, the stomach remains a satisfactory esophageal substitute.

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.