Frequency and features of myasthenia gravis developing after thymectomy.

BACKGROUND AND PURPOSE: Thymectomy is an effective treatment for myasthenia gravis (MG) with anti-acetylcholine receptor (AChR) antibodies. We rarely encounter patients who develop MG after surgery for thymic tumors. This study aimed to investigate the characteristics and frequency of post-thymectomy onset (PostTx) MG. METHODS: We reviewed the clinical information of thymoma-associated MG in 158 patients. Of these, 18 (11%) patients with PostTx MG were identified. RESULTS: The presence of anti-AChR antibodies (82%) and electrophysiological abnormalities (50%) was confirmed before thymectomy in patients with PostTx MG. The clinical characteristics of PostTx MG were similar to those of pre-thymectomy onset (PreTx) MG. In PostTx MG, the duration between thymectomy and MG onset were distributed as < 6 months (early-onset PostTx MG) and ≥ 6 months (late-onset PostTx MG). Notably, some patients with late-onset PostTx MG were associated with thymoma relapse. CONCLUSION: Our results suggest that approximately 11% of patients with thymoma-associated MG were PostTx MG and pre-surgical assessment of anti-AChR antibody titer or electrophysiological testing may predict PostTx MG development. However, no difference in clinical manifestation and prognosis was observed between PreTx MG and PostTx MG.

Feasibility of cytological diagnosis of sarcoidosis with endobronchial US-guided transbronchial aspiration.

BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has a high diagnostic value in sarcoidosis if the obtained histological specimen is indicative of a non-caseating epithelioid-cell granuloma. However, EBUS-TBNA in sacoidosis sometimes affords solely cytological specimens. OBJECTIVE: To investigate the relevance of EBUS-TBNA cytology specimens in diagnosing sarcoidosis. DESIGN: The study population comprised 72 patients with sarcoidosis and 116 patients who had thoracic malignancies and intrathoracic lymphadenopathy but were eventually proven to be metastasis-free (controls). The EBUS-TBNA samples obtained for these subjects were blindly evaluated for the presence of epithelioid cell clusters by 2 independent cytoscreeners and a pathologist. RESULTS: Interobserver variability in the specimen grading was minimal. The sensitivity and specificity were 65.3% and 94.0%, respectively. The sensitivity was high, at 87.5%, for the combined cytological and histological examinations. Of 7 controls whose cytological specimens showed epithelioid cell clusters, 3 were also deemed positive for sarcoidosis on histological examination, which indicated that they had sarcoid reaction to cancer. CONCLUSIONS: Cytological evaluation of the EBUS-TBNA specimens had higher sensitivity than histological evaluation alone for intrathoracic lymphadenopathy due to sarcoidosis. It should be recognized, however, that up to 6% of patients with thoracic malignancy may have sarcoid reaction in non-metastatic lymph nodes.

Nuclear survivin in pN2 nonsmall cell lung cancer: prognostic and clinical implications.

Patients with N2 nonsmall cell lung cancer (N2-NSCLC) represent heterogeneous groups. Survivin is a member of the inhibitor of apoptosis family. If N2-NSCLC patients could be stratified, based on survivin expression and/or its relation to cell cycle proteins, into homogeneous subgroups, certain therapies could be selected for those patients. Survivin expression in 78 surgically resected primary pathological N2-NSCLC tumours was evaluated using immunohistochemistry. Relationships of survivin expression to overall survival, clinical features and expression of six cell cycle-related proteins (pRb, cyclin D1, p16(INK4A), p53, p21(Waf1) and Ki-67) were analysed. Nuclear survivin and the number of mediastinal lymph node (LN) stations were independent prognostic factors. The patient group with combined negative survivin/single mediastinal LN station were the most favourable prognostic group, and was related to the clinical nodal factor. Indeed, patients with negative survivin/low Ki-67 labelling indices had the best survival, especially in nonsquamous histopathology. The current authors conclude that nuclear survivin is strongly related to lymph node metastasis and proliferative potentials in pathological N2 nonsmall cell lung cancer patients. Pre-operative N2 nonsmall cell lung cancer patients with combined negative nuclear survivin and a single mediastinal lymph node station, or low proliferative indices, particularly in clinical N0-1 disease and nonsquamous histopathology, respectively, are expected to have a favourable post-operative prognosis and may be candidates for primary resection.

Long-term surgical outcome in patients with lung cancer and coexisting severe COPD.

BACKGROUND: The functional criteria for curative surgery for patients with non-small cell lung cancer (NSCLC) and coexisting chronic obstructive pulmonary disease (COPD) remain controversial. We aimed to clarify long-term outcomes after resection. METHODS: Between January 1990 and April 2005, 36 consecutive patients with NSCLC and severe COPD underwent pulmonary resection. All had severe (30-50 % pred FEV1) or very severe COPD (30 % > pred FEV1) preoperatively. Survival, short- and long-term complications were analyzed retrospectively. Prognostic factors were also analyzed. RESULTS: The 5-year survival rate of these patients was significantly worse than that of patients with better pulmonary function (50 % < pred FEV1) ( P < 0.0001). Patients with interstitial pneumonia (IP) had a significantly poorer prognosis ( P = 0.0099). With regard to long-term complications three months after surgery, 30 % of patients reported worsening of dyspnea, and 20 % experienced pneumonia recurrence. No deaths were related to COPD progression. CONCLUSION: Patients with stage IA NSCLC and severe COPD may undergo curative surgical resection; however, postoperative complications and long-term survival remain unsolved problems. IP is a contraindication for surgery in patients with severe COPD.

Cytolytic potential of peripheral blood T-lymphocytes following adoptive immunotherapy with lymphokine-activated killer cells and low-dose interleukin 2.

In this study, we investigated the cytolytic activity of peripheral blood T-cells (PBT) obtained from nine patients with primary lung cancer treated by surgical adjuvant adoptive immunotherapy (AIT) with lymphokine-activated killer cells and low-dose recombinant interleukin 2 at the time of rebound lymphocytosis (24-48 h after AIT). In eight of nine patients, nonspecific cytotoxicity of peripheral blood lymphocytes significantly increased as compared with that of pre-AIT peripheral blood lymphocytes. However, purified PBT showed much less activity to kill tumor cells although they increased in number and were activated well in terms of increases in the expression of HLA-DR and interleukin 2 receptor. The cytolytic activity of post-AIT PBT was significantly enhanced when they were targeted to Fc receptor-bearing tumor cells (K562 or Daudi) with anti-CD3 (NU-T3) or anti-T-cell receptor (TCR)alpha beta (WT31) monoclonal antibody in all five patients examined. Phenotypically, the targeted cytotoxicity was predominantly mediated by CD8+ cells. The results indicated that in vivo-activated PBT by AIT could not exhibit direct cytotoxicity, but they acquired cytolytic potential, the effect of which was expressed by targeting to tumor cells.

Tumor-reactive T-cells accumulate in lung cancer tissues but fail to respond due to tumor cell-derived factor.

The purpose of this study was to elucidate a possible immune response to tumor cells mediated by tumor-infiltrating lymphocytes (TIL) in lung cancer. In flow cytometry, the majority of T-cells of TIL were CD45RA-, CD45RO+, and CDw29high, and expressed HLA-DR. The expression of interleukin 2 receptor beta chain increased in both CD4+ and CD8+ TIL compared with both types of T-cells in peripheral blood. These results indicate that the major population of TIL is activated memory T-cells. The TIL preparation, which was usually contaminated with 5 to 10% tumor cells, did not exhibit any response in autologous mixed lymphocyte-tumor culture even in the presence of interleukin 2 (IL-2) in all five cases tested. Although purified T-cells from TIL showed the positive response in only 1 of 10 cases tested without addition of IL-2, it occurred in 7 of 10 cases in the addition of a low concentration of IL-2. The IL-2-dependent response to irradiated autologous tumor cells was suppressed when nonirradiated autologous tumor cells were added to the culture. Culture supernatants of four lung cancer cell lines and freshly prepared lung cancer cells obtained from 6 cases exhibited suppressive activity against anti-CD3 antibody-induced mitogenesis of peripheral blood mononuclear cells from healthy donors. We suggest that, taken together, (a) the major population of TIL in lung cancer are activated memory T-cells, and they include tumor-reactive ones, and that (b) the function of the TIL is impaired by unavailability of IL-2 and/or by suppression due to lung cancer cell-derived factor(s).

HER2/neu-derived peptides are shared antigens among human non-small cell lung cancer and ovarian cancer.

Previously, we have reported a correlation between the expression of HER2/neu and sensitivity to HLA-A2-restricted cytotoxic T-cells (CTL) in ovarian cancer. To investigate the role of HER2/neu in human non-small cell lung cancer (NSCLC), we established autologous tumor-specific CTL from tumor-infiltrating lymphocytes of HLA-A2+ HER2/neu+ NSCLC patients. These CTL lines specifically recognized HLA-A2+ HER2/neu+ autologous and allogeneic NSCLC cell lines as well as HLA-A2+ HER2/neu+ heterologous ovarian cancer cell lines. Furthermore, these CTL recognized an overexpressed, HER2/neu-derived peptide. From these results, we conclude that HLA-A2 serves as a restriction element in NSCLC. More importantly, at least one HER2/neu-derived peptide is a tumor-associated antigen in NSCLC and ovarian cancer.

Clinicopathological and molecular evidence indicating the independence of bronchioloalveolar components from other subtypes of human peripheral lung adenocarcinoma.

Although human lung adenocarcinoma has diverse histological subtypes, the correlation between histological subtypes and occurrence of the p53 gene mutation has been given less attention. We investigated 145 surgically resected lung adenocarcinomas to search for the incidence of p53 mutations and for record data on survival in each histological subtype, according to the new WHO criteria (1999). The frequency of p53 mutation in bronchioloalveolar carcinoma (BAC; 0% in 17 cases) and BAC with invasive growth component (BAC-invasive; 11% in 27 cases), which is conventionally categorized as the mixed subtype in WHO typing, were apparently significantly lower than in other types (non-BAC including acinar, papillary, solid, or mixed histology with these subtypes; 48% in 101 cases; P < 0.01). Multivariate analysis revealed that the histological subtype including BAC-invasive was a strong, independent, and significant prognostic factor (P < 0.03), as were tumor size and pathological stage (P < 0.001 and 0.002, respectively) for overall survival. However, the occurrence of p53 mutation itself was seen to be significant only in case of the univariate analysis. Therefore, histological subtyping may be a better prognostic indicator than is p53 mutation. These findings suggest that the WHO classification with the BAC and BAC-invasive from other histological subtypes may prove useful to predict the outcome for surgically treated patients with lung adenocarcinoma.

Primary culture of chicken hepatocytes in serum-free medium (pH 7.8) secreted albumin and transferrin for a long period in free gas exchange with atmosphere.

To study liver functions of chicken, we examined the primary culture of chicken hepatocytes, and found an easy method of long-term culture with free atmosphere exchange. Chicken hepatocytes were obtained by collagenase perfusion and cultured at 37 degrees C as a monolayer without substratum in serum-free L-15 medium (pH 7.8) with free atmosphere exchange. The amounts of albumin and transferrin in medium were assayed by ELISA. The culture of chicken hepatocytes was maintained in the serum-free L15-medium )pH 7.) and 37 degrees C with free atmosphere exchange for 20 days. The amount of albumin secreted in the medium decreased to low levels early in culture; however, this was followed by marked increase from day 9 to day 17 of culture. The amount of transferrin was constant until day 6, then it too increased with further culture. We reported an easy method for the simple monolayer culture of chicken hepatocytes in serum-free L12 medium (pH 7.8) with free atmosphere exchange over an extended period. Expression of liver-specific functions, viz. albumin and transferrin synthesis, was observed after 1 week of culture.

Molecular cloning and expression of human caldecrin.

Earlier we reported the primary structure of serum calcium-decreasing factor (caldecrin) from rat pancreas, a protein which is considered to be a member of the elastase family. In this report, we describe the isolation of the two homologous cDNA clones encoding caldecrin from human pancreas, the structures of which are identical except for one base and the corresponding amino acid residue. These human caldecrin isoforms are composed of a signal peptide of 16 amino acids, a propeptide of 13 amino acids, and a mature form of 239 amino acids. Both recombinant caldecrins showed the same chymotrypsin-type protease activity and hypocalcemic activity. The hypocalcemic activity of both remained intact even after treatment with PMSF to abolish their protease activity. These results suggest that human caldecrin possesses hypocalcemic activity that has no connection with its protease activity.

Fas expression in non-small cell lung cancer: its prognostic effect in completely resected stage III patients.

The aim of this study was to examine Fas expression in non-small cell lung cancer (NSCLC) and examine its correlation with clinicopathological features and prognosis. Fas expression was determined by an immunohistochemical analysis using the labelled streptavidin-biotin method from 220 paraffin specimens of completely resected primary stage I-III NSCLC. 80 (36%) of 220 cases were positive for Fas immunostaining. These 80 cases included 44 adenocarcinomas (33%) and 30 squamous cell carcinomas (40%). 33 stage I (33%) 13 (43%) stage II and 34 (37%) stage III tumours were Fas positive. No statistically significant differences were observed regarding the Fas status with respect to age, sex, histological type, or stage of disease. There was no significant difference in survival between early stage (stages I-II) disease patients with positive Fas expression and those with a negative expression (P = 0.719). However, for patients with completely resected stage III tumours, the patients with positive Fas staining were found to survive for a longer period than those with negative staining (P = 0.026).

Prognostic factors obtained by a pathologic examination in completely resected non-small-cell lung cancer. An analysis in each pathologic stage.

We attempted to clarify what factors predominantly influence the survival of patients with non-small-cell lung cancer in each pathologic stage on the basis of information generally obtained by a pathologic examination of completely resected non-small-cell lung cancer. The subjects included 243 patients with stage I, 63 with stage II, and 108 with stage IIIA disease. Pathologic features used in the analysis were as follows: the greatest tumor size (< or = 3.0 cm versus > 3.0 cm), the histologic cell type (squamous versus nonsquamous cell carcinoma), the grade of differentiation, and tumor invasion of pleura and vessels. In stage IIIA, the extent of the metastasis to the lymph nodes was also included in the analysis. The significant prognostic factors (p < 0.05) in stage I demonstrated by a univariate analysis of the survival curves included the tumor size, the grade of differentiation (well differentiated versus moderately and poorly differentiated tumor), pleural involvement, and invasion of the artery and vein. In addition, the histologic cell type and the pleural involvement in stage II and invasion of the vein and the extent of metastasis to the lymph nodes (N0 and N1 versus N2) in stage IIIA were also found to be significant prognostic factors. A multivariate prognostic factor analysis showed that the grade of differentiation, pleural involvement, and venous invasion in stage I; the histologic cell type and pleural involvement in stage II; and venous invasion and mediastinal lymph node metastasis in stage IIIA were all predominant prognostic factors. These observations therefore suggest that a pathologic examination can identify the patients with a poor prognosis, which is different among the stages.

Unfavorable prognosis of patients with stage II non-small cell lung cancer associated with macroscopic nodal metastases.

BACKGROUND: Patients with stage II-N1 non-small cell lung cancer (NSCLC) make up an intermediate group of patients with an unsatisfactory prognosis even though complete resection is usually possible. We retrospectively analyzed postoperative prognostic factors to devise guidelines for the proper management of this patient population. STUDY DESIGN: Among 546 patients with NSCLC who underwent surgical resection from 1979 to 1995, 43 patients were pathologically defined to be at stage II-N1 (T1-2N1M0). The influence of the following variables on postoperative survival was analyzed: gender, age, cell type, pathologic T factor, number of metastatic nodes, station of metastatic nodes (hilar or pulmonary nodes), status of nodal metastasis (macroscopic, gross involvement confirmed histologically; or microscopic, metastasis first defined by histologic examination), surgical methods, and adjuvant therapy (including 18 of chemotherapy and 2 of radiotherapy). RESULTS: The 5-year survival rates (5YSRs) of patients with microscopic (n = 21) and macroscopic nodal metastasis (n = 22) were 76.0% and 27.6%, respectively (p = 0.001). The 5YSRs of 20 patients who received adjuvant therapy and 23 who did not receive adjuvant therapy were 57.6% and 46.6%, respectively (p = 0.036). Other variables did not affect survival. The Cox proportional hazards model analysis indicated that the presence of a macroscopic nodal metastasis and postoperative adjuvant therapy were independent prognostic factors. Among patients with macroscopic N1 NSCLC, 9 patients who had undergone adjuvant therapy showed a more favorable prognosis than the 13 patients who had not received adjuvant therapy (3-year survival rate, 55.6% vs 18.5%; p = 0.037; and recurrence rate, 30.0% vs 77.8%), whereas no significant influence of adjuvant therapy on survival was observed among patients with microscopic N1 NSCLC. CONCLUSIONS: Stage II-N1 NSCLC was categorized into microscopic and macroscopic N1 diseases. The latter had a poor prognosis, which might be improved by adjuvant therapy, although a suitable regimen has not been established.

Bronchial arterial infusion is an effective therapeutic modality for centrally located early-stage lung cancer: results of a pilot study.

OBJECTIVE: This pilot study was done to assess the effectiveness of bronchial arterial infusion (BAI) as a therapeutic modality for centrally located early-stage lung cancer. PATIENTS AND METHODS: Seven patients who had endoscopically evaluated, centrally located early-stage squamous cell lung carcinoma, including three patients with synchronous multiple primary lung cancers, were offered BAI with cis-diamminedichloroplatinum (CDDP; dosage, 50 to 150 mg/body, 35 to 100 mg/m2), a radical therapeutic method, as an alternative to a resection. RESULTS: All early-stage lesions showed complete remission within 1 to 6 weeks (median, 3.3 weeks) after BAI. In the three patients with multiple lung cancers, BAI was used to treat accessible early-stage lesions, although a surgical resection was required for advanced lesions. Three of the seven patients suffered from severe bronchial ulcers after BAI. Six of the patients in the study had no disease relapse to date at a median follow-up time of 19.8 months (range, 11 to 32 months), but the other patient died of a pulmonary hemorrhage 3 months after BAI. CONCLUSION: Based on our findings, BAI with CDDP should be reappraised as an effective therapeutic modality for centrally located early-stage lung cancer and as an acceptable primary treatment.

Phenotypes of lymphocytes infiltrating non-small cell lung cancer tissues and its variation with histological types of cancer.

We investigated surface markers of lymphocytes infiltrating four different histological non-small cell lung cancer tissues obtained at surgery and the corresponding peripheral blood lymphocytes (PBL) of 40 clinical cases, who had undergone no prior anti-cancer treatment, by flowcytometry. In estimation of the mean proportion of each lymphocyte subset, a paired Wilcoxon test revealed that tumor-infiltrating lymphocytes (TIL) exhibited significantly higher values of CD3+ cells (P < 0.05), CD8+ cells (P < 0.05) and CD20+ cells (P < 0.01), and lower value of CD16+cells (P < 0.05), as compared with those in PBL. The Spearman test revealed that none of the values of surface markers in TIL statistically correlated with those in the corresponding PBL (r < 0.6, P > 0.05). Although there was no significant difference between the mean CD4/CD8 ratio of total TIL and that of PBL, TIL of 12 patients with squamous cell carcinoma almost always showed lower values of CD4/CD8 ratio than those in PBL (P < 0.05), while the CD4/CD8 ratio was similar between TIL and PBL in adenocarcinoma. These results suggest that TIL of lung cancers represent specific immunological responses, whose characteristic depend on the histological types of lung cancers.

The clinical significance of serum soluble interleukin-2 receptors in lung cancer.

It has been recently reported that the soluble interleukin-2 receptor (IL-2R) levels in the sera of cancer patients were higher than those of normal controls. The present study was conducted in order to clarify the clinical significance of serum soluble IL-2R in patients with lung cancer. Using commercially available EIA kits, we measured the serum levels of soluble IL-2R in 102 lung cancer patients and 18 normal controls. The serum level of IL-2R was higher than 100 pM (mean +3 S.D. in the normal controls) in 14 of 58 patients with adenocarcinoma and in 13 of 32 patients with squamous cell carcinoma. In both adenocarcinoma and squamous cell carcinoma, the mean level of soluble IL-2R was higher in advanced stages (Stages IIIA, IIIB and IV) than in early stages (Stages I and II). In contrast, no patients with small cell carcinoma exhibited a serum level of soluble IL-2R higher than 100 pM, whereas almost all of those patients were in advanced-stage diseases. These results first demonstrated that the serum level of soluble IL-2R increased in association with both the disease stage and the histological type in lung cancer.

Alpha-fetoprotein-producing adenocarcinoma of the lung.

We herein present a case of metachronous primary lung cancers, the first of which was adenosquamous cell carcinoma and the second of which was poorly differentiated adenocarcinoma. At the time the second lung cancer was detected 5 years after being operated on for the first cancer, a high level of serum alpha-fetoprotein (AFP) was noticed, but no elevation of other tumor markers was observed. In addition, no liver metastases, chronic liver diseases or other systemic abnormalities were seen either. The serum AFP level was 696 ng/ml, and the profile of lectin affinity showed a tumor-derived pattern. Two weeks after the operation, the serum AFP level decreased to a normal level. An immunohistochemical analysis confirmed that the exact origin of AFP was the tumor tissue. A specimen taken from the first lung cancer was not stained by the same procedures, which thus indicated this case to be a double primary lung cancer.

Postoperative adjuvant adoptive immunotherapy with lymph node-LAK cells and IL-2 for pathologic stage I non-small cell lung cancer.

We conducted a clinical trial of adoptive immunotherapy with lymph node-lymphokine-activated killer (LN-LAK) cells and recombinant interleukin 2 (rIL-2) for a surgical adjuvant therapy of pathologic stage I non-small cell lung cancer. The regimen consisted of the subcutaneous administration of low-dose rIL-2 for 6 consecutive days and the transfer of ex vivo generated LAK cells from regional lymph node lymphocytes, obtained at the time of surgical operation. A group of 19 patients with primary lung cancer received the immunotherapy about 2 weeks after surgery (pulmonary lobectomy). The regimen was postoperatively well tolerated by the patients. In peripheral blood lymphocytes (PBL) obtained after the treatment, the proportion of CD3+ T cells predominantly increased with the increase of CD4+ T cell subsets. On the other hand, the proportion of CD20+ B cells decreased. Both NK and LAK activity of PBL significantly increased. However, the immunomodulatory effects did not result in a prolongation of the postoperative survival time in comparison to the postoperative survival of patients (n = 21) with surgery alone during the same period. These results suggested that the treatment with low-dose LN-LAK cells and concurrent low-dose IL-2 could, therefore, neither reduce nor eradicate minimal micrometastatic diseases.

High vascularity in the peripheral region of non-small cell lung cancer tissue is associated with tumor progression.

OBJECTIVES: We attempted to determine if the degree of angiogenesis can serve as a prognostic factor in the case of completely resected non-small cell lung cancer patients, with special reference to the center and the periphery of the tumor tissue. METHOD: For 255 Japanese patients who underwent completely resected non-small cell lung cancer (NSCLC), micro vessel density (MVD) was assessed by visual quantification of microvessels immunostained with anti-CD34 monoclonal antibody in 5 m section. Vascular endothelial growth factor (VEGF) was also immunostained on the same paraffin block specimen. RESULTS: MVD at the center (MVD-c) and that at the periphery (MVD-p) were frequently different in each individual although a weak positive correlation was observed (r=0.499, P<0.0001). One hundred and one patients with high MVD-p, but not the 107 patients with high MVD-c, showed a significantly higher proportion of advanced stage, larger tumor size and nodal metastasis as compared with MVD. The 5 year survival rate and median survival time for the high MVD-p group were significantly lower than that of low the MVD-p group (43.0%/31 months vs 48.6%/54 months, P=0.0256). As to the relationship among vascular endothelial growth factor (VEGF) and MVD, expression of VEGF was not associated with the degree of MVD. However, patients with high grade MVD-p showed an unfavorable prognosis in cases of high expression of VEGF. CONCLUSION: High MVD-p is associated with advancement of NSCLC, and it was particularly apparent in conjunction with high VEGF expression.

Skip metastasis to the mediastinal lymph nodes in non-small cell lung cancer.

BACKGROUND: Whether any difference exists in clinical characteristics between resected non-small cell lung cancer with either skip or ordinary mediastinal lymph node metastases (N2 disease) needs to be clarified. METHODS: There were 110 patients with stage IIIA N2 disease. Thirty-three patients demonstrating no metastasis at the hilar nodes [skip (+) group] were compared with the other 77 patients [skip (-) group]. To investigate the extent of nodal involvement, we classified the mediastinal lymph nodes into three regions (superior, inferior, or aortic). RESULTS: There were no significant differences regarding histologic type, T status, or the site of the primary tumors between the skip (+) and the skip (-) N2 groups. In the skip (+) group, mediastinal node metastasis was found in only one region (level 1) in 30 patients (90.9%) and in two regions (level 2) in 3 (9.1%), whereas 28 patients (36.4%) from the skip (-) group revealed mediastinal metastasis at two or three regions (level 2 or 3). The overall survival rate at 5 years after operation was 35% in the skip (+) group and 12.7% in the skip (-) group (p = 0.054). This favorable clinical outcome in the skip (+) group could be explained partially by the higher proportion of patients with level 1 metastases. Furthermore, regarding patients with level 1 disease, the skip (+) group tended to have a better prognosis than the skip (-) group (p = 0.096). CONCLUSIONS: These results suggest that patients with skip mediastinal lymph node metastases represent a unique subgroup of N2 disease.