Mark D. Iannettoni

RANDOMIZED TRIAL OF PREOPERATIVE CHEMORADIATION VERSUS SURGERY ALONE IN PATIENTS WITH LOCOREGIONAL ESOPHAGEAL CARCINOMA

PURPOSE A pilot study of 43 patients with potentially resectable esophageal carcinoma treated with an intensive regimen of preoperative chemoradiation with cisplatin, fluorouracil, and vinblastine before surgery showed a median survival of 29 months in comparison with the 12-month median survival of 100 historical controls treated with surgery alone at the same institution. We designed a randomized trial to compare survival for patients treated with this preoperative chemoradiation regimen versus surgery alone. MATERIALS AND METHODS One hundred patients with esophageal carcinoma were randomized to receive either surgery alone (arm I) or preoperative chemoradiation (arm II) with cisplatin 20 mg/m2/d on days 1 through 5 and 17 through 21, fluorouracil 300 mg/m2/d on days 1 through 21, and vinblastine 1 mg/m2/d on days 1 through 4 and 17 through 20. Radiotherapy consisted of 1.5-Gy fractions twice daily, Monday through Friday over 21 days, to a total dose of 45 Gy. Transhiatal esophagectomy with a cervical esophagogastric anastomosis was performed on approximately day 42. RESULTS At median follow-up of 8.2 years, there is no significant difference in survival between the treatment arms. Median survival is 17.6 months in arm I and 16.9 months in arm II. Survival at 3 years was 16% in arm I and 30% in arm II (P = .15). This study was statistically powered to detect a relatively large increase in median survival from 1 year to 2.2 years, with at least 80% power. CONCLUSION This randomized trial of preoperative chemoradiation versus surgery alone for patients with potentially resectable esophageal carcinoma did not demonstrate a statistically significant survival difference.

Discordant Protein and mRNA Expression in Lung Adenocarcinomas

The relationship between gene expression measured at the mRNA level and the corresponding protein level is not well characterized in human cancer. In this study, we compared mRNA and protein expression for a cohort of genes in the same lung adenocarcinomas. The abundance of 165 protein spots representing 98 individual genes was analyzed in 76 lung adenocarcinomas and nine non-neoplastic lung tissues using two-dimensional polyacrylamide gel electrophoresis. Specific polypeptides were identified using matrix-assisted laser desorption/ionization mass spectrometry. For the same 85 samples, mRNA levels were determined using oligonucleotide microarrays, allowing a comparative analysis of mRNA and protein expression among the 165 protein spots. Twenty-eight of the 165 protein spots (17%) or 21 of 98 genes (21.4%) had a statistically significant correlation between protein and mRNA expression (r > 0.2445; p < 0.05); however, among all 165 proteins the correlation coefficient values (r) ranged from −0.467 to 0.442. Correlation coefficient values were not related to protein abundance. Further, no significant correlation between mRNA and protein expression was found (r = −0.025) if the average levels of mRNA or protein among all samples were applied across the 165 protein spots (98 genes). The mRNA/protein correlation coefficient also varied among proteins with multiple isoforms, indicating potentially separate isoform-specific mechanisms for the regulation of protein abundance. Among the 21 genes with a significant correlation between mRNA and protein, five genes differed significantly between stage I and stage III lung adenocarcinomas. Using a quantitative analysis of mRNA and protein expression within the same lung adenocarcinomas, we showed that only a subset of the proteins exhibited a significant correlation with mRNA abundance.

Eliminating the cervical esophagogastric anastomotic leak with a side-to-side stapled anastomosis.

BACKGROUND Although the acute postoperative complications of a cervical esophagogastric anastomosis are less than those with an intrathoracic esophageal anastomosis, the long-term sequelae of a cervical anastomotic leak are not as minor as initially reported. Nearly 50% of cervical anastomotic leaks result in an anastomotic stricture, and the subsequent need for chronic dilatations negates the merits of an operation intended to restore comfortable swallowing. OBJECTIVE This study was undertaken to determine whether construction of a side-to-side stapled cervical esophagogastric anastomosis after transhiatal esophagectomy could reliably eliminate the majority of anastomotic leaks. METHODS In 114 consecutive patients undergoing transhiatal esophagectomy, a functional side-to-side cervical esophagogastric anastomosis was constructed with the Auto Suture Endo-GIA II stapler (United States Surgical Corporation, Auto Suture Company Division, Norwalk, Conn) applied directly through the cervical wound. This side-to-side stapled anastomosis has 3 rows of staples. Early postoperative anastomotic morbidity, subsequent need for anastomotic dilatations, and patient satisfaction with swallowing were evaluated. RESULTS Before the side-to-side stapled anastomosis, the incidence of cervical esophagogastric anastomosis leak in over 1000 patients undergoing transhiatal esophagectomy having a manually sewn anastomosis varied from 10% to 15%. Among the 111 survivors of transhiatal esophagectomy and a side-to-side stapled anastomosis, there were 3 (2.7%) clinically significant anastomotic leaks. This lowered incidence of leaks has contributed to reduction in the average length of stay after an uncomplicated transhiatal esophagectomy to 7 days and has provided more comfortable swallowing, ease of subsequent esophageal dilatations, and greater patient satisfaction. CONCLUSIONS Construction of the cervical esophagogastric anastomosis with a side-to-side stapled anastomosis greatly reduces the frequency of anastomotic leaks and later strictures. The side-to-side stapled anastomosis is a major technical advance in the progression of refinements of transhiatal esophagectomy and a cervical esophagogastric anastomosis.

Protein profiles associated with survival in lung adenocarcinoma

Morphologic assessment of lung tumors is informative but insufficient to adequately predict patient outcome. We previously identified transcriptional profiles that predict patient survival, and here we identify proteins associated with patient survival in lung adenocarcinoma. A total of 682 individual protein spots were quantified in 90 lung adenocarcinomas by using quantitative two-dimensional polyacrylamide gel electrophoresis analysis. A leave-one-out cross-validation procedure using the top 20 survival-associated proteins identified by Cox modeling indicated that protein profiles as a whole can predict survival in stage I tumor patients (P = 0.01). Thirty-three of 46 survival-associated proteins were identified by using mass spectrometry. Expression of 12 candidate proteins was confirmed as tumor-derived with immunohistochemical analysis and tissue microarrays. Oligonucleotide microarray results from both the same tumors and from an independent study showed mRNAs associated with survival for 11 of 27 encoded genes. Combined analysis of protein and mRNA data revealed 11 components of the glycolysis pathway as associated with poor survival. Among these candidates, phosphoglycerate kinase 1 was associated with survival in the protein study, in both mRNA studies and in an independent validation set of 117 adenocarcinomas and squamous lung tumors using tissue microarrays. Elevated levels of phosphoglycerate kinase 1 in the serum were also significantly correlated with poor outcome in a validation set of 107 patients with lung adenocarcinomas using ELISA analysis. These studies identify new prognostic biomarkers and indicate that protein expression profiles can predict the outcome of patients with early-stage lung cancer.

Epithelial-neutrophil activating peptide (ENA-78) is an important angiogenic factor in non-small cell lung cancer

We report here the role of the CXC chemokine, epithelial neutrophil activating peptide (ENA-78), as an angiogenic factor in human non-small cell lung cancer (NSCLC). In freshly isolated human specimens of NSCLC, elevated levels of ENA-78 were found that strongly correlated with the vascularity of the tumors. In a SCID mouse model of human NSCLC tumorigenesis, expression of ENA-78 in developing tumors correlated with tumor growth in two different NSCLC cell lines. Furthermore, passive immunization of NSCLC tumor-bearing mice with neutralizing anti-ENA-78 antibodies reduced tumor growth, tumor vascularity, and spontaneous metastases, while having no effect on the proliferation of NSCLC cells either in vitro or in vivo. These findings suggest that ENA-78 is an important angiogenic factor in human NSCLC.

Distribution of distant metastases from newly diagnosed non-small cell lung cancer

BACKGROUND The purpose of our study was to determine the incidence and locations of M1 disease at presentation in patients with non-small cell lung cancer to help design appropriate preoperative imaging algorithms. METHODS All patients with non-small cell lung cancer seen between 1991 and 1993 were identified, and records were reviewed. For patients with M1 disease, the sites of distant metastases and the methods of diagnosis were recorded. RESULTS Of 348 patients identified, 276 (79%) had M0 disease and 72 (21%) had M1 disease. In 40 of 72 patients (56%), M1 disease was detected via chest or abdominal computed tomography (CT). Brain, bone, liver, and adrenal glands were the most common sites of metastatic disease, in decreasing order. Brain metastases often occurred as an isolated finding, although isolated liver metastases were uncommon. CONCLUSIONS M1 disease was common at presentation, and was often detectable via chest CT. The incremental yield of abdominal CT over chest CT was very small, and therefore abdominal CT is not an effective method of screening for metastases if chest CT has been performed.

Transhiatal Esophagectomy for Treatment of Benign and Malignant Esophageal Disease

Since our initial 1978 report, we have performed transhiatal esophagectomy (THE) in 1085 patients with intrathoracic esophageal disease: 285 (26%) benign lesions and 800 (74%) malignant lesions (4.5% upper, 22% middle, and 73.5% lower third/cardia). THE was possible in 97% of patients in whom it was attempted; reconstruction was performed at the same operation in all but six patients. The esophageal substitute was positioned in the original esophageal bed in 98%, stomach being used in 782 patients (96%) and colon in those with a prior gastric resection. Hospital mortality was 4%, with three deaths due to uncontrollable intraoperative hemorrhage. Major complications included anastomotic leak (13%), atelectasis/pneumonia prolonging hospitalization (2%), recurrent laryngeal nerve paralysis, chylothorax, and tracheal laceration (< 1% each). There were five reoperations for mediastinal bleeding within 24 hours of THE. Intraoperative blood loss averaged 689 ml. Altogether, 78% of the patients had no postoperative complications. Actuarial survival of the cancer patients mirrors that reported after transthoracic esophagectomy. Late functional results are good or excellent in 80%. Approximately 50% have required one or more anastomotic dilatations. With intensive preadmission pulmonary and physical conditioning, use of a side-to-side staple technique (which has reduced the cervical esophagogastric anastomotic leak rate to less than 3%), and postoperative epidural anesthesia, the need for an intensive care unit stay has been eliminated and the length of hospital stay was reduced to 7 days. We concluded that THE can be achieved in most patients requiring esophageal resection for benign and malignant disease and with greater safety and less morbidity than the traditional transthoracic approaches.

The CXC chemokine, monokine induced by interferon-gamma, inhibits non-small cell lung carcinoma tumor growth and metastasis.

Angiogenesis is an absolute requirement for tumor growth beyond 2 mm3 in size. The balance in expression between opposing angiogenic and angiostatic factors controls the angiogenic process. The CXC chemokines are a group of chemotactic cytokines that possess disparate activity in the regulation of angiogenesis. Non-small cell lung carcinoma (NSCLC) has an imbalance in expression of ELR+ (angiogenic) compared with ELR- (angiostatic) CXC chemokines that favors angiogenesis and progressive tumor growth. We found that the level of the ELR- CXC chemokine MIG (monokine induced by interferon gamma) in human specimens of NSCLC was not significantly different from that found in normal lung tissue. These results suggested that the increased expression of ELR+ CXC chemokines found in these tumor samples is not counterregulated by a concomitant increase in the expression of the angiostatic ELR-CXC chemokine MIG. This would result in an even more profound imbalance in the expression of regulatory factors of angiogenesis that would favor neovascularization. We hypothesized that MIG might be an endogenous inhibitor of NSCLC tumor growth in vivo and that reconstituion of MIG in the tumor microenvironment would result in the inhibition of tumor growth and metastasis. In support of this hypothesis, we demonstrate here that overexpression of the ELR-CXC chemokine MIG, by three different strategies including gene transfer, results in the inhibition of NSCLC tumor growth and metastasis via a decrease in tumor-derived vessel density. These findings support the importance of the ELR- CXC chemokine MIG in inhibiting NSCLC tumor growth by attenuation of tumor-derived angiogenesis. Furthermore, these findings demonstrate the potential of gene therapy as an alternative means to deliver and overexpress a potent angiostatic CXC chemokine.

Esophagectomy for achalasia: patient selection and clinical experience

BACKGROUND In 1989, we predicted an increasing number of esophagectomies for megaesophagus and for recurrent symptoms after prior esophagomyotomy or balloon dilatation for achalasia. Patient selection in this group is challenging, as the potential operative morbidity of an esophagectomy must be weighed against the expected clinical outcome after a redo esophagomyotomy or alternative procedures designed to salvage the native esophagus. METHODS The hospital records of 93 patients undergoing esophagectomy for achalasia during the past 20 years were reviewed retrospectively and the results of operation assessed using our prospectively established Esophageal Resection Database and follow-up information obtained through personal contact with the patients. RESULTS Patient age averaged 51 years. Indications for esophagectomy included tortuous megaesophagus (64%), failure of prior myotomy (63%), and associated reflux stricture (7%). Ninety-four percent of the patients underwent a transhiatal esophagectomy. Stomach was used as the esophageal substitute in 91% cases. Intraoperative blood loss averaged 672 mL. Postoperative length of stay averaged 12.5 days. Major complications included anastomotic leak (10%), recurrent laryngeal nerve injury (5%), delayed mediastinal bleeding requiring thoracotomy (2%), and chylothorax (2%). There were 2 hospital deaths (2%) from respiratory insufficiency and sepsis. Follow-up has averaged 38 months. In all, 95% of patients eat well; nearly 50% have required an anastomotic dilatation; troublesome regurgitation has been rare; and 4% have refractory postvagotomy dumping. CONCLUSIONS Esophagectomy, preferably through a transhiatal approach, is generally safe and effective therapy in selected patients with achalasia. Unique technical considerations include difficulty encircling the dilated cervical esophagus, deviation of the esophagus into the right chest, large aortic esophageal arteries, and adherence of the exposed esophageal submucosa to the adjacent aorta after prior myotomy.

Intrathoracic esophageal perforation: The merit of primary repair

Between 1976 and 1993, 22 patients with intrathoracic esophageal perforations, none associated with carcinoma, underwent primary repair regardless of the interval between perforation and the time of repair. Eighteen perforations were iatrogenic and four were spontaneous. The interval from perforation to operation was less than 12 hours in 10 patients, 12 to 24 hours in 3, and more than 24 hours in 9. Principles of repair included (1) a local esophagomyotomy proximal and distal to the tear to expose the mucosal defect and normal mucosa beyond, (2) debridement of the mucosal defect and closure over a bougie, and (3) reapproximation of the muscle. The repair was buttressed with muscle or pleura in five patients. Associated distal obstruction caused by reflux stricture was treated with dilation and fundoplication in four patients. Of the four patients with achalasia, two underwent esophagomyotomy with a fundoplication and one underwent myotomy alone. There was one death. The esophageal repair healed primarily in 17 patients (80%). Four patients, three of whom underwent repair more than 24 hours after the perforation, had leaks at the site of repair. All four fistulas eventually healed with drainage alone, two with simple tube thoracostomy and two with rib resection and empyema tube placement. In the absence of cancer or an irreversible distal obstruction, meticulous repair of an intrathoracic esophageal perforation is the preferred approach, regardless of the duration of the injury, inasmuch as primary healing is likely, and the morbidity associated with prolonged drainage or diversion may be avoided.