Minimally invasive esophagectomy: results of a prospective phase II multicenter trial-the eastern cooperative oncology group (E2202) study.

OBJECTIVE: The primary aim of this trial was to assess the feasibility of minimally invasive esophagectomy (MIE) in a multi-institutional setting. BACKGROUND: Esophagectomy is an important, potentially curative treatment for localized esophageal cancer, but is a complex operation. MIE may decrease the morbidity and mortality of resection, and single-institution studies have demonstrated successful outcomes with MIE. METHODS: We conducted a multicenter, phase II, prospective, cooperative group study (coordinated by the Eastern Cooperative Oncology Group) to evaluate the feasibility of MIE. Patients with biopsy-proven high-grade dysplasia or esophageal cancer were enrolled at 17 credentialed sites. Protocol surgery consisted of either 3-stage MIE or Ivor Lewis MIE. The primary end point was 30-day mortality. Secondary end points included adverse events, duration of hospital-stay, and 3-year outcomes. RESULTS: Protocol surgery was completed in 95 of the 104 patients eligible for the primary analysis (91.3%). The 30-day mortality in eligible patients who underwent MIE was 2.1%; perioperative mortality in all registered patients eligible for primary analysis was 2.9%. Median intensive care unit and hospital stay were 2 and 9 days, respectively. Grade 3 or higher adverse events included anastomotic leak (8.6%), acute respiratory distress syndrome (5.7%), pneumonitis (3.8%), and atrial fibrillation (2.9%). At a median follow-up of 35.8 months, the estimated 3-year overall survival was 58.4% (95% confidence interval: 47.7%-67.6%). Locoregional recurrence occurred in only 7 patients (6.7%). CONCLUSIONS: This prospective multicenter study demonstrated that MIE is feasible and safe with low perioperative morbidity and mortality and good oncological results. This approach can be adopted by other centers with appropriate expertise in open esophagectomy and minimally invasive surgery.

Esophageal stenting and radiotherapy: a multimodal approach for the palliation of symptomatic malignant dysphagia.

BACKGROUND: Esophageal stents provide immediate palliation of malignant dysphagia; however, radiotherapy (RT) is a superior long-term option. We review the outcomes of combined esophageal stenting and RT for patients with malignant dysphagia. METHODS: We retrospectively reviewed patients with esophageal stents placed for palliation of malignant dysphagia from esophageal stricture, esophageal extrinsic compression, or malignant tracheoesophageal fistula (TEF). We excluded patients with radiation-induced TEF in the absence of tumor. We analyzed and compared outcomes between patients with no RT, RT before stent placement, and RT after stent placement. RESULTS: We placed stents in 45 patients for esophageal stricture from esophageal cancer (n = 30; 66.7 %), malignant TEF (n = 8; 17.7 %), and esophageal compression from airway, mediastinal, or metastatic malignancies (n = 7; 15.6 %). Twenty patients (44.4 %) had no RT; 25 patients had RT before stent placement (n = 16; 35.6 %), RT after stent placement (n = 8; 17.8 %), or both (n = 1; 2.2 %). Median follow-up was 30 days. Complications requiring stent revision were similar with or without RT. Subjective symptom relief was achieved in 68.9 % of all patients, with no differences noted between groups (p = 0.99). The 30-day mortality was 15.6 %. Patients with RT after stent placement had a longer median survival compared to those without RT (98 vs. 38 days). CONCLUSIONS: Esophageal stent placement with RT is a safe approach for malignant dysphagia.

T1/T2 non-small-cell lung cancer treated by lobectomy: does tumor anatomic location matter?

BACKGROUND: The effect of tumor location on long-term survival after lobectomy for stage I non-small-cell lung cancer is unclear. Current data are limited to a retrospective single-institution series. We sought to determine if tumor anatomic location (i.e., the particular lobe that was involved) confers a survival advantage based on population-based data. METHODS: Using the Surveillance, Epidemiology and End Results database (1988-2007), we identified patients who underwent lobectomy for pathologic T1/T2 adenocarcinoma or squamous cell carcinomas. Wedge resections, segmentectomies, and pneumonectomies were excluded. We evaluated the association between the particular lobe that was involved, lymph node (LN) yield, and survival using the Kaplan-Meier method. To adjust for potential confounders, we used a Cox proportional hazards regression model. RESULTS: We identified 13,650 patients who met our inclusion criteria. There were significant differences in unadjusted overall (P=0.03) and cancer-specific survivals (P=0.03) based on tumor location. However, after adjusting for patient factors, geographic location of treatment, and tumor characteristics, we found that tumor location was not associated with significant differences in survival. We found that male gender, black race, squamous cell histology, increasing grade, and age were independent negative predictors of survival. Higher LN yields were independently associated with improved survival. Although adjusted survival rates were not significantly different, there were significant differences (P<0.0001) in LN yield based on tumor location; right middle lobe had the lowest yield (5.1 nodes), and left upper lobe had the highest yield (eight nodes). CONCLUSIONS: LN counts are independent predictors of survival. Although it is associated with significant difference in LN yield, tumor location is not an independent predictor of survival. Age, race, gender, tumor size, histology, and grade appear to be more important prognostic factors. These data suggest that treatment of T1/T2 non-small-cell lung cancer should be dictated by the same oncologic principles, regardless of tumor location.

The long-term impact of surgical complications after resection of stage I nonsmall cell lung cancer: a population-based survival analysis.

OBJECTIVE: Surgical morbidity may influence long-term cancer survival. Because resection of early stage nonsmall cell lung cancer (NSCLC) is primary therapy, we sought to determine the survival impact of surgical complications for elderly patients undergoing resection of stage I NSCLC. METHODS: Using the linked Surveillance Epidemiology and End Results-Medicare database (2000-2005), we identified elderly patients who underwent lobectomy for stage I NSCLC. We then assessed the unadjusted association between in-hospital, postoperative complications, and long-term survival for patients who survived more than 30 days after resection using the Kaplan-Meier method. Finally, we used Cox proportional hazards regression to evaluate the relationship between postoperative complications and 5-year cancer-specific (CSS) and overall survival (OS) after adjusting for patient, tumor, and treatment characteristics. RESULTS: We identified 3996 eligible patients. The overall in-hospital, postoperative complication rate was 54.2%. Pulmonary complications were the most common (n = 1464) followed by cardiac (n = 916). Unadjusted 5-year CSS was significantly worse for those who had an in-hospital, postoperative complication (70.9%) compared to those who did not (78.9%, P < 0.001). OS was also significantly worse (P < 0.001) for patients who developed a complication. Complications continued to predict worse 5-year CSS and OS after adjusting for patient, tumor, and treatment characteristics (HR: 1.38, 95% CI, 1.17-1.64). CONCLUSIONS: The occurrence of in-hospital postoperative complications was an independent predictor of worse 5-year CSS after resection of stage I NSCLC. Importantly, the impact of surgical complications extends well after the initial perioperative period. These findings may help identify important targets for best practice guidelines and quality-of-care measures.

Being an effective surgical educator.

Training in thoracic surgical residencies has evolved in the past several years, with significant advances in simulation technology, heightened pressure regarding work-hour reforms, and initiation of integrated training programs. This article highlights current concepts in surgical education and methods of incorporating teaching opportunities into practice. General strategies on how to be a better teacher and increase student feedback evaluation scores are addressed. Finally, the evolving roles and responsibilities of a mentor in assisting residents and colleagues in developing successful thoracic surgical careers are explored.

Minimally invasive versus open Roux-en-Y gastric bypass: effect on immune effector cells.

BACKGROUND: Minimally invasive surgery (MIS) has several potential benefits compared with the open approach, including potentially less perioperative immunosuppression. Data characterizing the differential stress responses have been limited to serum cytokine analyses and animal studies. We hypothesized that the open approach to Roux-en-Y gastric bypass (RYGB) has a more deleterious, negative, quantifiable effect on the peripheral blood mononuclear cells than does the MIS approach. METHODS: Patients undergoing open and MIS RYGB for morbid obesity had blood samples collected preoperatively and postoperatively on days 1 and 2 and at the first follow-up visit. The peripheral blood mononuclear cells were isolated and analyzed for phenotype using flow cytometry, natural killer cell cytotoxicity using 51-chromium release assay, and gene expression using Affymetrix U133 Plus 2.0 microarray. RESULTS: Patient age and body mass index were similar between the 2 groups. Postoperatively, differences within the open group were seen for CD3+/CD16- (T lymphocytes), CD3-/CD16+ (natural killer cells), CD3+/CD4+ (T-helper lymphocytes), and CD4/CD8 subsets (P<.05). No differences were seen within the open group CD3+/CD8+ (cytotoxic T lymphocytes) or within the MIS subsets. Between the 2 approaches, no phenotypic differences were found, except for the postoperative day 1 CD3+/CD16- (P<.05). Within each group, significant decreases were found in cytotoxicity on days 1 and 2 compared with preoperatively (P<.05). The cytotoxicity seen after MIS had returned to the preoperative levels at the first follow-up visit, but the cytotoxicity after open RYGB had not (P<.05). Between the 2 groups, the open group had greater cytotoxic decreases than did the MIS group at postoperative days 1 and 2 (P<.05). Microarray analysis of the preoperative (n=20) and day 2 (n=20) specimens identified a 20-gene signature that correlated with the surgical approach. CONCLUSION: Open RYGB surgery causes greater inhibition of innate immunity than does MIS. This inhibition was not accounted for by phenotypic changes. Gene expression changes from surgical stress might represent the molecular basis of this differential immune response.

Recommendations for optimal use of imaging studies to clinically stage mediastinal lymph nodes in non-small-cell lung cancer patients.

Appropriate clinical staging of mediastinal lymph nodes in non-small-cell lung cancer (NSCLC) patients has important therapeutic and prognostic implications. Because of the wide variations in practice patterns among community and academic physicians, we reviewed the literature so that we could provide evidence-based recommendations on the use of imaging studies in the pretreatment clinical staging of NSCLC patients. We concluded that the most sensitive and accurate method of noninvasive mediastinal nodal staging is a positron emission tomography/computed tomography fusion scan; we believe this tool should be a component of clinical staging of all NSCLC patients. Given insufficient sensitivity with currently available imaging studies, mediastinal nodal staging should also include histologic evaluation.

Radiographic staging of mediastinal lymph nodes in non-small cell lung cancer patients.

In conclusion, accurate pretreatment staging of NSCLC patients is essential so that they undergo the most appropriate treatment. Imaging studies play an integral part in clinical staging. The preferred imaging method for staging the mediastinum is PET/CT, preferably integrated. Until the sensitivity and accuracy of imaging studies are equivalent to the available MLN biopsy techniques, all candidates for definitive therapy require histologic assessment of the mediastinum.

Thoracoscopic lingulectomy for invasive pulmonary aspergillosis.

Invasive pulmonary aspergillosis (IPA) is associated with a high mortality rate in immunocompromised patients. Surgery has a therapeutic role for selected patients when the main objective is to achieve infection control with minimal lung resection. Large or deep-seated lesions may require an anatomic resection such as segmentectomy, lobectomy, or pneumonectomy. Thoracoscopic lobectomy has been described as a treatment of localized IPA; however, thoracoscopic anatomic segmentectomy has not been reported until now. Herein, we describe a case of thoracoscopic lingulectomy for localized IPA in an immunocompromised patient: this operation minimized the delay in resuming therapy for the patient's underlying acute myeloid leukemia. Video-assisted thoracoscopic segmentectomy can be safely performed for localized IPA.

Open lobectomy for patients with stage I non-small cell lung cancer.

Until additional multi-institutional, randomized, controlled trials provide evidence to the contrary, open lobectomy with mediastinal lymphadenectomy should be considered the gold standard for treating patients with stage I NSCLC with sufficient cardiopulmonary reserve, including older patients. It is the operation with which alternative pulmonary resections, including video-assisted thoracoscopic lobectomy and sublobar resection, should be compared. In treating stage I NSCLC patients, sublobar resection should be reserved for patients with inadequate physiologic reserve to tolerate lobectomy and for those enrolled in clinical trials.

Evolution of clipping for thoracoscopic sympathectomy in symptomatic hyperhidrosis.

BACKGROUND: Severe hyperhidrosis is treated by thoracic sympathetic chain interrupting through chain transection or clipping. Our study compared the efficacy of these 2 methods. METHODS: Retrospectively, patients who underwent thoracoscopic sympathectomy from 1999 to 2005 had demographic, operative, and postoperative data analyzed. RESULTS: Fifty-four operations were performed for refractory sweating of the palm (72%), axilla (66%), foot (53%), and head/neck (19%). Thirty-seven (69%) underwent clipping; 17 (31%) underwent chain transection. There was no difference in age, sex, or blood loss. One ganglion level was interrupted in 24.1% and 2 levels in 75.4%. Bothersome compensatory hyperhidrosis occurred in 13% (5-clipping and 2-transection). One patient underwent clip removal for debilitating symptoms. Three small pneumothoraces occurred (all in the transection group); all treated expectantly. CONCLUSIONS: Thoracoscopic sympathectomy is a safe outpatient procedure. Both methods yield excellent results with minimal compensatory hyperhidrosis. Thoracoscopic sympathetic chain clipping and transection are equivalent.

The use of real-time polymerase chain reaction in thoracic malignancies.

Recent progress in the molecular analysis of NSCLC tumors and lymph node status will likely translate into a clearer understanding of the variables and predictors of tumor recurrence. This understanding may lead to more appropriate therapeutic decisions both in the operating room and in the clinic. With these analyses at the molecular level, a more precise molecular classification is on the horizon which includes a molecular substaging. All of these aspects of NSCLC biology await testing or final analysis of prospective multi-institutional trials such as that set forth in CALGB 9761.

Selective activation of insulin receptor substrate-1 and -2 in pleural mesothelioma cells: association with distinct malignant phenotypes.

Molecular mechanisms active in transforming human pleural cells remain incompletely understood. Our previous microarray analysis of malignant pleural mesothelioma revealed alterations in components of the insulin-like growth factor (IGF) system, implicating this signaling axis in tumorigenesis. Therefore, in this current study, we characterized the molecular phenotype and investigated the key signaling pathways of the IGF system in malignant pleural mesothelioma specimens. For the major IGF components, we assessed mRNA abundance and total protein levels. We measured IGF-I ligand-dependent activation of signaling pathways downstream of the type I IGF receptor in a subset of malignant pleural mesothelioma cell lines and determined the corresponding biological consequences. At the transcriptional level, we observed consistent changes in IGF components that may contribute to a malignant phenotype. IGF-I stimulation of cells resulted in enhanced activation of type I IGF receptor and IRS adaptor proteins. Differential activation of IRS-1 signaling was associated with cell growth, whereas IRS-2 signaling was associated with cell motility. Thus, these data suggest that multiple mechanisms likely contribute to malignant pleural mesothelioma tumorigenesis. Therefore, IGF system components represent novel malignant pleural mesothelioma therapeutic targets for investigation.

Detection of Occult Micrometastases in Patients With Clinical Stage I Non-Small-Cell Lung Cancer: A Prospective Analysis of Mature Results of CALGB 9761 (Alliance).

PURPOSE: Outcomes after resection of stage I non-small-cell lung cancer (NSCLC) are variable, potentially due to undetected occult micrometastases (OM). Cancer and Leukemia Group B 9761 was a prospectively designed study aimed at determining the prognostic significance of OM. MATERIALS AND METHODS: Between 1997 and 2002, 502 patients with suspected clinical stage I (T1-2N0M0) NSCLC were prospectively enrolled at 11 institutions. Primary tumor and lymph nodes (LNs) were collected and sent to a central site for molecular analysis. Both were assayed for OM using immunohistochemistry (IHC) for cytokeratin (AE1/AE3) and real-time reverse transcriptase polymerase chain reaction (RT-PCR) for carcinoembryonic antigen. RESULTS: Four hundred eighty-nine of the 502 enrolled patients underwent complete surgical staging. Three hundred four patients (61%) had pathologic stage I NSCLC (T1, 58%; T2, 42%) and were included in the final analysis. Fifty-six percent had adenocarcinomas, 34% had squamous cell carcinomas, and 10% had another histology. LNs from 298 patients were analyzed by IHC; 41 (14%) were IHC-positive (42% in N1 position, 58% in N2 position). Neither overall survival (OS) nor disease-free survival was associated with IHC positivity; however, patients who had IHC-positive N2 LNs had statistically significantly worse survival rates (hazard ratio, 2.04, P = .017). LNs from 256 patients were analyzed by RT-PCR; 176 (69%) were PCR-positive (52% in N1 position, 48% in N2 position). Neither OS nor disease-free survival was associated with PCR positivity. CONCLUSION: NSCLC tumor markers can be detected in histologically negative LNs by AE1/AE3 IHC and carcinoembryonic antigen RT-PCR. In this prospective, multi-institutional trial, the presence of OM by IHC staining in N2 LNs of patients with NSCLC correlated with decreased OS. The clinical significance of this warrants further investigation.

Poor correspondence between clinical and pathologic staging in stage 1 non-small cell lung cancer: results from CALGB 9761, a prospective trial.

PURPOSE: A major problem with the staging system for non-small cell lung cancer (NSCLC) is clinical underestimation of the extent of disease. Many patients with clinical stage 1 disease do not retain that designation following surgical resection. Herein, we present data from Cancer and Leukemia Group B (CALGB) protocol 9761 evaluating the correspondence between clinical and pathologic analysis in early stage NSCLC. METHODS: Five hundred and two patients with suspected or biopsy-proven NSCLC classified as clinical stage 1 (T1-2, N0) by computed tomography (CT) scan or cervical mediastinoscopy were prospectively enrolled in CALGB 9761. The purpose of CALGB 9761 was to prospectively evaluate molecular markers of micrometastatic disease in stage 1 NSCLC. Enrollment occurred at 11 selected institutions within the CALGB. Patients with clinically suspected resectable early stage lung cancer were eligible for enrollment if they had no evidence of mediastinal or hilar adenopathy on CT scan or if they had CT evidence of potential N2 or N3 disease (lymph node > or =1.0 cm) but with negative mediastinoscopy. No prior chemotherapy or radiotherapy was permitted. RESULTS: Of the 502 patients felt to have clinical stage 1 NSCLC enrolled in CALGB 9761, 489 underwent resection with complete surgical staging and routine histopathologic analysis. From these 489 patients, only 422 (86.3%) turned out to have pathologically documented NSCLC. Of these 422 patients, 302 (71.6%) had pathologic stage 1 disease (173 stage 1A and 129 stage 1B). Despite clinical assessment of stage 1 disease, 59 (14%) patients had pathologic stage 2 disease, 57 (13.5%) had stage 3 disease, and four (0.9%) patients had stage 4 disease. Of the patients undergoing resection for clinical stage 1 NSCLC, 65 patients did not have NSCLC (44 had benign disease and 21 had malignancies other than NSCLC) and two additional patients had dual synchronous primary NSCLC tumors and were not eligible for the study. Overall, only 61.7% (302 of 489) of patients with suspected stage 1 NSCLC disease retained that stage and diagnosis after complete surgical staging, while 38.3% had an inaccurate pre-operative clinical stage or diagnosis. CONCLUSIONS: The results from this prospective trial demonstrate the poor predictive value of current clinical staging techniques in early stage NSCLC. These findings will serve as a benchmark for comparison of future clinical imaging modalities and other tests evaluating early stage NSCLC.

Short esophagus and esophageal stricture.

Short esophagus and peptic esophageal stricture are complications of chronic severe GERD. Short esophagus is properly diagnosed by an objective,intraoperative assessment after appropriate dissection of the GEJ. A laparoscopic Collis gastroplasty combined with an antireflux procedure comprises effective therapy. Peptic stricture should be addressed with an initial course of dilator therapy and optimization of antiacid medication. Consideration is given to an antireflux procedure if conservative therapy fails. Laparoscopic techniques have proven to be safe and effective in treating short esophagus and peptic stricture.

Immunohistochemical detection of occult lymph node metastases in non-small cell lung cancer: anatomical pathology results from Cancer and Leukemia Group B Trial 9761.

PURPOSE: Our purpose was to study the detection of occult metastases (OM) in regional lymph nodes using immunohistochemical stain for cytokeratin, and for this study we targeted clinical stage I patients with non-small cell lung cancer. EXPERIMENTAL DESIGN: The study comprised the first 193 patients entered onto Cancer and Leukemia Group B protocol 9761. All had clinically staged T(1-2)N(0)M(0) non-small cell lung cancer, and all underwent curative resections of their primary tumors. Samples of the primary tumor and lymph nodes were taken from lymph node stations 2-12 and shipped to a central laboratory, where each lymph node was histologically processed and stained with H&E as well as with immunohistochemical stain using antibodies to cytokeratin (AE1/3). RESULTS: Altogether, we examined 825 lymph nodes. Whereas routine H&E staining allowed us to detect 18 positive lymph nodes, immunohistochemical staining allowed us to detect 45 positive lymph nodes (P < 0.0001). There were 28 OM [i.e., those detectable only by immunohistochemistry (IHC)], and there was 1 metastasis detected only by H&E staining. The OM included 9 OM in N1 stations and 19 OM in N2 stations. Twelve patients with OM had skip metastases. Routine H&E staining upstaged six patients to N1, and IHC added another five. Routine H&E upstaged 9 patients to N2, and IHC added another 11. We also uncovered new details about the way in which H&E detection depends on metastatic tumor burden. Specifically, for the probability of detecting metastases by H&E to exceed 0.50, the maximum diameter of the metastasis must be greater than 0.23 mm. CONCLUSIONS: IHC detects greater than twice as many positive regional lymph nodes as does H&E staining, and the foci of tumor it detects are significantly smaller than those detected by H&E staining.

Gene expression profiling identifies matriptase overexpression in malignant mesothelioma.

STUDY OBJECTIVE: We investigated the gene expression profiles of malignant pleural mesothelioma (MPM) specimens to identify novel genes that are potentially involved in the oncogenic transformation of human pleural cells. DESIGN: Complementary DNA (cDNA) microarray transcriptional profiling studies of 10 MPM cell lines and 4 MPM primary tumor specimens were performed using hierarchic clustering. To confirm microarray data, we used real-time polymerase chain reaction and immunoblotting. RESULTS: Cluster analysis differentiated among epithelial (E), sarcomatoid, and biphasic MPM variants. Expression profiling identified common overexpressed or underexpressed genes in MPM. Notably, matriptase messenger RNA was found to be overexpressed by 826-fold in E MPM, with protein expression subsequently confirmed by immunoblot analysis. This recently characterized trypsin-like serine protease has been implicated in tumor invasion and metastasis of E-derived cancers, but has not been described until now in MPM. We also identified other novel genes, such as insulin-like growth factor binding protein 5 and a cDNA clone similar to proteolipid MAL2. CONCLUSIONS: Thus, further large-scale profiling of MPM may elucidate previously unrecognized molecular mechanisms by identifying novel genes that are involved in malignant transformation. Our study has now found matriptase to be one of these mesothelioma-associated genes, with potential pathogenic and therapeutic significance.

Expression profiling of non-small cell lung carcinoma identifies metastatic genotypes based on lymph node tumor burden.

OBJECTIVE: This study hypothesized that non-small cell lung carcinoma cells from primary tumors isolated by laser capture microdissection would exhibit gene expression profiles associated with graded lymph node metastatic cell burden. METHODS: Non-small cell lung carcinoma tumors (n = 15) were classified on the basis of nodal metastatic cell burden by 2 methods, obtaining 3 groups: no metastasis, micrometastasis, and overt metastasis. We then performed microarray analysis on microdissected primary tumor cells and identified gene expression profiles associated with graded nodal tumor burden using a correlation-based selection algorithm coupled with cross-validation analysis. Hierarchical clustering showed the regrouping of tumor specimens; the classification inference was assessed with Fisher's exact test. We verified data for certain genes by using another independent assay. RESULTS: The 15 specimens clustered into 3 groups: cluster A predominated in specimens with overt nodal metastasis; cluster B had more specimens with nodal micrometastases; and cluster C included only specimens without nodal metastases. Cluster assignment was based on a validated 75-gene discriminatory subset. Notably, genes not previously associated with positive non-small cell lung carcinoma lymph node status were encountered in the profiling analysis. CONCLUSIONS: Microdissection, combined with microarray analysis, is a potentially powerful method to characterize the molecular profile of tumor cells. The 75-gene expression profiles representative of clusters A and B may define genotypes prone to metastasize. Overall, the 3 groups of tumor specimens clustered separately, suggesting that this approach may identify graded metastatic propensity. Further, genes singled out in clustering may yield insights into underlying metastatic mechanisms and may represent new therapeutic targets.

Molecular staging of lung cancer: real-time polymerase chain reaction estimation of lymph node micrometastatic tumor cell burden in stage I non-small cell lung cancer--preliminary results of Cancer and Leukemia Group B Trial 9761.

OBJECTIVE: The 5-year survival for patients with surgically resected stage I non-small cell lung cancer is only 60% to 70%, probably because of undetected systemic occult micrometastases. Detection of occult micrometastases in lymph nodes by reverse-transcriptase polymerase chain reaction for carcinoembryonic antigen messenger RNA in non-small cell lung cancer has not been reported. Detection of occult micrometastases by standard reverse-transcriptase polymerase chain reaction provides only yes or no answers about their presence, whereas quantitative real-time reverse-transcriptase polymerase chain reaction permits reproducible quantitation of target molecules. This study evaluated the ability of quantitative reverse-transcriptase polymerase chain reaction to quantitate lymph node occult metastases with carcinoembryonic antigen messenger RNA as a tumor marker. METHODS: Standard reverse-transcriptase polymerase chain reaction and quantitative reverse-transcriptase polymerase chain reaction for carcinoembryonic antigen messenger RNA were performed on 232 lymph nodes from 53 patients with stage I disease (node negative according to histologic examination). Quantitative reverse-transcriptase polymerase chain reaction determined carcinoembryonic antigen messenger RNA quantity by detecting fluorescence increase at a threshold polymerase chain reaction cycle. Threshold polymerase chain reaction cycle values were correlated with standard curves created from serially diluted carcinoembryonic antigen-positive HTB-174 tumor cells to estimate the number of micrometastatic tumor cells in a lymph node. RESULTS: Detection rates of occult metastases were similar for standard reverse-transcriptase polymerase chain reaction and quantitative reverse-transcriptase polymerase chain reaction at 38 of 232 (16.4 %) and 59 of 232 (25.4 %), respectively. Upstaging rates among 53 cases of stage I non-small cell lung cancer were also similar for standard reverse-transcriptase polymerase chain reaction and quantitative reverse-transcriptase polymerase chain reaction at 23 of 53 (43.4 %) and 30 of 53 (56.6%), respectively. Comparison of positive lymph node stations according to quantitative reverse-transcriptase polymerase chain reaction (threshold polymerase chain reaction cycle <45) with HTB-174 tumor cell standard curves yielded estimates of metastatic tumor cell burden of 1.07 x 10(3)to 3.24 x 10(5)cells per lymph node station (median 7190 tumor cells per lymph node station). CONCLUSIONS: Standard and quantitative real-time reverse-transcriptase polymerase chain reaction for carcinoembryonic antigen detected occult metastases in patients with stage I non-small cell lung cancer at similar rates; both upstaged about 50% of cases. Quantitative reverse-transcriptase polymerase chain reaction allows estimation of the number of metastatic cells per lymph node, however, which potentially allows greater precision in predicting recurrence risk.