Arlene M. Correa

Endoscopic ultrasound-guided fine needle aspiration and multidetector spiral CT in the diagnosis of pancreatic cancer

INTRODUCTION:Endoscopic ultrasound (EUS) is now established as a valuable imaging test for diagnosing and staging pancreatic cancer. But, with significant recent improvements in spiral CT scanners, particularly higher resolution and ability to reconstruct 3D images, spiral CT is now increasingly accepted as being better for pancreatic cancer staging. The debate continues, however, about the best diagnostic test or combination of tests in patients with suspected pancreatic cancer. Spiral CT is more readily available than EUS-FNA and, therefore, more frequently used. In this study, we evaluated the use of EUS-FNA in conjunction with spiral CT for suspected pancreatic cancer.METHODS:We retrospectively evaluated 81 consecutive patients who underwent EUS and EUS-FNA for clinical suspicion of a pancreatic cancer from November 2000 to November 2001. All patients had spiral CT with a multiphasic pancreatic protocol using multidetector spiral CT scanners. In all patients, EUS-FNA and spiral CT examinations were performed less than 3 wk apart.RESULTS:Overall, the accuracy of spiral CT, EUS, and EUS-FNA was 74% (n = 60/81, CI 63–83%), 94% (n = 76/81, CI 87–98%), and 88% (n = 73/81, CI 81–96%), respectively, for diagnosing pancreatic cancer. In patients without an identifiable mass on spiral CT, the diagnostic accuracy of EUS and EUS-FNA for pancreatic tumors was 92% (n = 23/25, CI 74–99%). Absence of a focal “mass” lesion on EUS reliably excluded pancreatic cancer irrespective of clinical presentation (NPV 100% n = 5/5, CI 48–100%). The negative predictive value of EUS-FNA was only 22% (n = 2/9, CI 3–60%) in patients with obstructive jaundice and biliary stricture. However, in patients without obstructive jaundice at initial presentation, EUS-FNA was highly accurate (accuracy 97%, n = 33/34, CI 85–100%) and was reliable for ruling out malignancy (NPV 89%, n = 8/9, CI 52–100%). Cytologic assessment of EUS-FNA specimens was 89% accurate for identifying malignancy in suspicious lesions visualized on EUS.CONCLUSIONS:The EUS with FNA can be a valuable adjunct to newer high-resolution multidetector spiral CT for diagnostic evaluation of patients with suspected pancreatic cancer.

Treatment outcomes of resected esophageal cancer.

ObjectiveTo assess the evolution of treatment and outcome for resected esophageal cancer at a single institution. Summary Background DataStrategies for optimizing the treatment of resected esophageal cancer continue to evolve over time. The outcomes of these evolving treatments in the context of improved diagnostic staging and changing epidemiology have not been carefully analyzed in a single institution. MethodsOne thousand ninety-seven consecutive patients with primary esophageal cancer underwent surgery during the period 1970 to 2001. Nine hundred ninety-four patients underwent curative esophagectomy and were analyzed for changing demographics. Eight hundred seventy-nine patients who did not have systemic metastases and survived the perioperative period were assessed by multivariate analysis for factors associated with long-term survival. ResultsDuring the study period the overall median survival increased from 17 to 34 months, and combined hospital and 30-day mortality decreased from 12% to 6%. The R0 resection rate increased from 78 to 94%, and adenocarcinoma replaced squamous cell carcinoma as the predominant histology (83% vs. 17%). No change in survival with time was noted for patients treated with surgery alone having the same postoperative pathologic stage (pTNM). An increased proportion of patients had preoperative chemoradiation in the last 4 years of the study (59% vs. 2%). Preoperative chemoradiation was associated with a longer survival and increased likelihood of achieving a complete resection. Multivariate analysis showed that long-term survival was associated with a complete resection and the preoperative staging strategy used, while the use of preoperative chemoradiation was the most significant factor associated with ability to achieve an R0 esophageal resection. ConclusionsThis study shows favorable trends in the survival of patients with resected esophageal cancer over time. The increased use of preoperative chemoradiation, better preoperative staging, and other time-dependent factors may have contributed to the observed increase in survival.

Genetic Variations in Radiation and Chemotherapy Drug Action Pathways Predict Clinical Outcomes in Esophageal Cancer

PURPOSE Understanding how specific genetic variants modify drug action pathways may provide informative blueprints for individualized chemotherapy. METHODS We applied a pathway-based approach to examine the impact of a comprehensive panel of genetic polymorphisms on clinical outcomes in 210 esophageal cancer patients. RESULTS In the Cox proportional hazards model, MTHFR Glu429Ala variant genotypes were associated with significantly improved survival (hazard ratio [HR] = 0.56; 95% CI, 0.35 to 0.89) in patients treated with fluorouracil (FU). The 3-year survival rates for patients with the variant genotypes and the wild genotypes were 65.26% and 46.43%, respectively. Joint analysis of five polymorphisms in three FU pathway genes showed a significant trend for reduced recurrence risk and longer recurrence-free survival as the number of adverse alleles decreased (P = .004). For patients receiving platinum drugs, the MDR1 C3435T variant allele was associated with significantly reduced recurrence risk (HR = 0.25; 95% CI, 0.10 to 0.64) and improved survival (HR = 0.44; 95% CI, 0.23 to 0.85). In nucleotide excision repair genes, there was a significant trend for a decreasing risk of death with a decreasing number of high-risk alleles (P for trend = .0008). In base excision repair genes, the variant alleles of XRCC1 Arg399Gln were significantly associated with the absence of pathologic complete response (odds ratio = 2.75; 95% CI, 1.14 to 6.12) and poor survival (HR = 1.92; 95% CI, 1.00 to 3.72). CONCLUSION Several biologically plausible associations between individual single nucleotide polymorphisms and clinical outcomes were found. Our data also strongly suggest that combined pathway-based analysis may provide valuable prognostic markers of clinical outcomes.

Expression of epidermal growth factor receptor in esophageal and esophagogastric junction adenocarcinomas: Association with poor outcome

The prognosis for patients with esophageal and esophagogastric junction (EGJ) adenocarcinoma remains poor, even after surgical resection. Pathologic assessment of depth of invasion and lymph node status are the primary prognostic factors in these patients. In patients with esophageal squamous cell carcinoma, increased epidermal growth factor receptor (EGFR) expression has been associated with a worse prognosis. It is not known whether EGFR plays a similar role in esophageal and EGJ adenocarcinomas.

Synchronous Overexpression of Epidermal Growth Factor Receptor and HER2-neu Protein Is a Predictor of Poor Outcome in Patients with Stage I Non-Small Cell Lung Cancer

Purpose: Despite maximal therapy, surgically treated patients with stage I non-small cell lung cancer (NSCLC) are at risk for developing metastatic disease. Histopathologic findings cannot adequately predict disease progression, so there is a need to identify molecular factors that serve this purpose. Because the ErbB receptors play an important role in lung cancer progression, we analyzed the expression of epidermal growth factor receptor (EGFR), phosphorylated EGFR, transforming growth factor α (TGFα), and HER2-neu as potential prognostic factors in stage I NSCLC. Experimental Design: Using immunohistochemical techniques, we retrospectively analyzed formalin-fixed, paraffin-embedded samples from 111 patients with resected pathological stage I NSCLC. Then we correlated these data with patient clinical outcome. Results: Median follow-up was 69.3 months. EGFR overexpression (defined as >10% membranous staining) was found in 66 tumors (59.5%). It was significantly more common in T2 tumors than in T1 tumors (P = 0.001), and in more squamous cell carcinomas than in adenocarcinomas (P = 0.07). HER2-neu overexpression was found in 19 tumors (17.1%) and was significantly more common in adenocarcinomas than in squamous cell carcinomas (P = 0.035). Synchronous overexpression of EGFR and HER2-neu was found in 11 tumors (9.9%). Patients with these tumors had a significantly shorter time to recurrence (P = 0.006) and a trend toward shorter overall survival (P = 0.093). Phosphorylated EGFR and transforming growth factor α were detected but were not related to prognosis. Conclusions: Synchronous overexpression of EGFR and HER2-neu at the protein level predicts increased recurrence risk and may predict decreased survival in patients with stage I NSCLC. This suggests that important interactions take place among the different members of the ErbB family during tumor development and suggests a method for choosing targeted therapy. A prospective study is planned.

Management of Primary Pulmonary Artery Sarcomas

The objective of this review is to determine the outcome of patients with sarcomas involving the main pulmonary artery, pulmonic valve, or right ventricular outflow tract. Survival data were analyzed using an aggregate series derived from the published literature in conjunction with a current series. Median survival was 36.5 +/- 20.2 months for patients undergoing an attempt at curative resection compared with 11 +/- 3 months for those undergoing incomplete resection. Median survival was 24.7 +/- 8.5 months for patients undergoing multimodality treatment compared with 8.0 +/- 1.7 months for patients having single-modality therapy. A complete review of diagnosis, evaluation, treatment, and surveillance of primary pulmonary artery sarcomas follows.

Proposed revision of the esophageal cancer staging system to accommodate pathologic response (PP) following preoperative chemoradiation (CRT)

Objective:To determine the impact of pathologic response following preoperative chemoradiation (CRT) on the AJCC esophageal cancer staging system. Summary Background Data:Increasing numbers of locoregionally advanced esophageal cancer patients are treated with preoperative CRT prior to surgical resection. Methods:Five hundred ninety-three pts from 1985 to 2003 with esophageal cancer who underwent surgery with (n = 239) or without CRT (n = 354) were reviewed. Resected esophageal tumors were assessed for pathologic response by determining extent of residual tumor following CRT (P0, 0% residual; P1, 1%–50% residual; P2, >50% residual). Results:After CRT down-staging, pTNM specific survival was similar, irrespective of treatment group (P = 0.98). The pTNM stage distribution was more favorable in the CRT group (P < 0.001) despite a more advanced initial cTNM stage distribution (P < 0.001). Following CRT, the pathologic response (pP) at the primary tumor as defined by extent of residual tumor predicted overall survival (3 years: P0, 0% residual = 74%; P1, 1%–50% residual = 54%; P2, >50% residual = 24%, P < 0.001) and stage specific survival with greater accuracy than pTNM stage alone. Conclusions:Our analyses demonstrate that following CRT, pTNM continues to predict survival. The extent of pathologic response following CRT is an independent risk factor for survival (pP) and should be incorporated in the pTNM esophageal cancer staging system to better predict patient outcome in esophageal cancer.

Prognostic significance of differentially expressed miRNAs in esophageal cancer

Altered microRNA (miRNA) expression has been found to promote carcinogenesis, but little is known about the role of miRNAs in esophageal cancer. In this study, we selected 10 miRNAs and analyzed their expression in 10 esophageal cancer cell lines and 158 tissue specimens using Northern blotting and in situ hybridization, respectively. We found that Let‐7g, miR‐21 and miR‐195p were expressed in all 10 cell lines, miR‐9 and miR‐20a were not expressed in any of the cell lines, and miR‐16‐2, miR‐30e, miR‐34a, miR‐126 and miR‐200a were expressed in some of the cell lines but not others. In addition, transient transfection of miR‐34a inhibited c‐Met and cyclin D1 expression and esophageal cancer cell proliferation, whereas miR‐16‐2 suppressed RAR‐β2 expression and increased tumor cell proliferation. Furthermore, we found that miR‐126 expression was associated with tumor cell dedifferentiation and lymph node metastasis, miR‐16‐2 was associated with lymph node metastasis, and miR‐195p was associated with higher pathologic disease stages in patients with esophageal adenocarcinoma. Kaplan‐Meier analysis showed that miR‐16‐2 expression and miR‐30e expression were associated with shorter overall and disease‐free survival in all esophageal cancer patients. In addition, miR‐16‐2, miR‐30e and miR‐200a expression were associated with shorter overall and disease‐free survival in patients with esophageal adenocarcinoma; however, miR‐16‐2, miR‐30e and miR‐200a expression were not associated with overall or disease‐free survival in squamous cell carcinoma patients. Our data indicate that further evaluation of miR‐30e and miR‐16‐2 as prognostic biomarkers is warranted in patients with esophageal adenocarcinoma. In addition, the role of miR‐34a in esophageal cancer also warrants further study.

Intrathoracic Leaks Following Esophagectomy Are No Longer Associated With Increased Mortality

Objectives:Assess outcomes following intrathoracic leaks after esophagectomy from 1970 to 2004 to evaluate the impact of evolving surgical and perioperative techniques on leak-associated mortality (LAM). Summary Background Data:An intrathoracic leak following esophagectomy has historically been considered a catastrophic event, with mortality as high as 71%. Concerns about this complication often affect choice of surgical approach for esophagectomy. Methods:A retrospective review of all esophagectomies for cancer from 1970 to 2004 (n = 1223) was performed. Outcomes following intrathoracic anastomoses (n = 621) were analyzed by era: historical 1970–1986 (n = 145) and modern 1987–2004 (n = 476). Results:There was no difference in the frequency of leak between the time intervals (4.8% versus 6.3%, P = 0.5). Despite a significant increase in the use of preoperative chemoradiation (1% versus 42%, P < 0.001) in the historical versus modern era, the overall mortality decreased from 11% to 2.5% (P < 0.001). The LAM was markedly reduced from 43% to 3.3% (P = 0.016). Factors associated with LAM included failure to use enteral nutrition (HR 13.22, CI 1.8–96.8) and era in which the surgery was performed (HR 18.3, 1.9–180). Other differences included an increased proportion of successful reoperations for leak control (11/30 versus 0/7, P = 0.08) and use of reinforcing muscle flaps (7/11). In the modern era, perioperative mortality is not significantly different for patients with or without intrathoracic leaks (3.3% versus 2.5%, P = 0.55), nor is long-term survival (P = 0.16). Conclusions:Modern surgical management of intrathoracic leaks results in no increased mortality and has no impact on long-term survival. Clinical decisions regarding the use of intrathoracic anastomoses should not be affected by concerns of increased mortality from leak.

Failure patterns correlate with the proportion of residual carcinoma after preoperative chemoradiotherapy for carcinoma of the esophagus

The current study was conducted to test the hypothesis that patterns of failure are correlated with the degree of residual carcinoma after preoperative chemoradiotherapy (CRT) in patients with esophageal carcinoma.