Comparison of the efficacy of novel two covering methods for spontaneous pneumothorax: a multi-institutional study.

OBJECTIVES: The postoperative recurrence rate after thoracoscopic bullectomy for primary spontaneous pneumothorax (PSP) is not satisfactory. This retrospective study was conducted to elucidate an effective technique for improving the postoperative recurrence rate. METHODS: The present study included 373 patients who underwent thoracoscopic bullectomy for PSP at three hospitals from January 2013 to May 2020. We compared the recurrence rate according to two methods that were used to cover the staple line after thoracoscopic bullectomy. Group A (146 patients) was treated with an absorbable polyglycolic acid (PGA) sheet plus fibrin glue and oxidised regenerated cellulose (ORC). Group B (227 patients) was treated with ORC alone. RESULTS: There was no significant difference in preoperative characteristics of the patients. The postoperative recurrence rate of pneumothorax was 3.4% (5/146) in Group A and 17.2% (39/227) in Group B, respectively. Among 23 patients (Group A, n=3 and Group B, n=20) who received reoperation for recurrent pneumothorax, the site of recurrence was around the stapler line of the first operation in 1 of 5 (20%) patients in Group A and 28 of 39 (71.8%) patients in Group B. The 1-year recurrence-free rate was 97.4% (median follow-up period, 73 days (range, 2-3952 days)) in Group A and 80.9% (median follow-up period, 71 days (range 2-2648 days)) in Group B. CONCLUSIONS: Coverage with a PGA sheet may prevent the postoperative recurrence of PSP. A large-scale prospective randomised study should be conducted to clarify the most effective treatment for PSP.

Feasibility and prognostic benefit of induction chemoradiotherapy followed by surgery in patients with locally advanced non-small cell lung cancer.

BACKGROUND: The optimal treatment for patients with resectable non-small cell lung cancer (NSCLC) involving adjacent organs (T3 or T4) and/or cN2 remains unclear. We investigated whether or not induction chemoradiotherapy (ICRT) followed by surgery improves the survival. METHODS: We retrospectively analyzed 84 patients with NSCLC involving the adjacent organs and/or cN2 who underwent ICRT followed by surgery at our hospital from 2006 to 2018. Presurgical treatment consisted of 2 courses of platinum-doublet and concurrent radiotherapy (40-50 Gy) to the tumor and involved field. RESULTS: All 84 patients completed ICRT. One patient died after completion of ICRT due to bacterial pneumonia. Radiological responses to ICRT were a complete response (CR), n=1; partial response (PR), n=48; stable disease (SD), n=32; and progressive disease (PD), n=2 (overall response rate: 58.3%). Eighty-one patients underwent radical surgery. The procedures included lobectomy, n=66; bilobectomy, n=7; pneumonectomy, n=6; and segmentectomy, n=2 (including 49 extended resections). Seventy-three patients (90%) underwent complete resection. The postoperative morbidity rate was 30%. The 30- and 90-day mortality rates were 1.2% and 2.4%, respectively. A pathological CR (Ef3) and major response (Ef2) were achieved in 17 (21.0%) and 38 (46.9%) patients, respectively; a minor response (Ef1) was observed in 26 (32%). The 5-year overall survival (OS) and recurrence-free survival (RFS) rates were 58.0% and 45.6%, respectively. The median survival time was 73.2 months. Based on the response to ICRT, patients with radiological CR or PR showed better 5-year OS than those with SD (63.7% vs. 40.0%, P=0.020). Patients with Ef3 or Ef2 demonstrated a much better 5-year OS than those with Ef1 (65.0% vs. 24.4%, P=0.005). CONCLUSIONS: ICRT followed by surgery for patients with NSCLC involving the adjacent organs and/or cN2 was feasible and improved the survival. A CR/PR or Ef2/Ef3 after ICRT led to a better prognosis.

Micronodular thymoma with lymphoid stroma diagnosed 10 years after the first operation: a case report.

INTRODUCTION: Micronodular thymoma with lymphoid stroma is a rare subtype of thymoma. Here we report a case of micronodular thymoma with lymphoid stroma that was completely resected after incomplete resection 10 years earlier. CASE PRESENTATION: A 70-year-old Japanese woman who had undergone resection for a thymic cyst 10 years earlier was found to have a solid nodule with a multilocular lesion at the site of the previous operation. We suspected that the tumor was a malignant tumor and performed trans-sternal radical thymectomy and diagnosed the lesion as micronodular thymoma with lymphoid stroma pathologically. When we reassessed the thymic cyst that had been resected 10 years earlier, a few lesions of micronodular thymoma with lymphoid stroma were found in the cyst wall. Based on these findings, we concluded that only the cystic component of micronodular thymoma with lymphoid stroma had been removed, and that the residual lesion grew locally over the next 10 years before being completely resected by reoperation. CONCLUSION: We experienced an unusual case of micronodular thymoma with lymphoid stroma, which is a rare subtype of thymoma. Greater care should be taken to exclude a thymoma with a cystic lesion, even if a thymic cyst is strongly suspected on computed tomography and magnetic resonance imaging.

A new approach to left sleeve pneumonectomy: complete VATS left pneumonectomy followed by right thoracotomy for carinal resection and reconstruction.

BACKGROUND: Left sleeve pneumonectomy is a challenging operation that requires individualized approaches. Here, we present a new minimally invasive combined thoracoscopic approach. CASE PRESENTATION: A 61-year-old woman was diagnosed with tracheobronchial adenoid cystic carcinoma. The tumor originated from the left main stem bronchus, and tumor with carinal involvement was observed. We judged that complete resection would be possible via left sleeve pneumonectomy. However, because tumor involvement with the esophagus and descending aorta was suspected, evaluation of resectability in advance was necessary. After confirmation via examination thoracoscopy of no involvement with the surrounding organs, complete VATS left pneumonectomy was performed and followed by right thoracotomy for carinal resection and reconstruction. CONCLUSIONS: When thoracoscopic surgery becomes mainstream, this minimally invasive combined thoracoscopic approach might be an optimal option for patients who require left sleeve pneumonectomy.

Stereotactic body radiotherapy for second primary lung cancer and intra-parenchymal lung metastasis in patients previously treated with surgery: evaluation of indications and predictors of decreased respiratory function.

BACKGROUND: The adaptation criteria for administration of stereotactic body radiotherapy (SBRT) to patients with lung cancer who previously underwent surgery and subsequently developed a second primary lung cancer (SPLC) or intra-parenchymal lung metastasis (IPLM) are controversial, unlike the criteria for repeat surgery. We aimed to evaluate the feasibility of SBRT for these patients. Factors associated with decreased respiratory function were also evaluated. MATERIAL AND METHODS: Sixty-nine patients with 89 lesions who underwent SBRT between 2008 and 2017 were analyzed. Of these, 29 were diagnosed with SPLC while the remaining 40 had IPLM. The distribution of histological types was as follows: squamous cell carcinoma (n = 13 lesions); adenocarcinoma (n = 25); non-small cell carcinoma (n = 1); unknown histological type (n = 49). The prescribed doses to the planning target volume (PTV) were 50 Gy in five fractions for 85 lesions and 60 Gy in 10 fractions for four lesions at PTV mean. RESULTS: Over a median follow-up period of 55 months, the 4-year overall survival and local control rates were 50.3% and 87.6%, respectively. Six patients experienced grade 2 radiation pneumonitis and one experienced grade 3. Two patients experienced grade 5 pulmonary fibrosis. Decreased respiratory function was observed in 10 patients (15.1%). On multivariate analysis, the presence of pulmonary disease before SBRT was the only statistically significant factor associated with decreased respiratory function. CONCLUSIONS: SBRT is safe and feasible in patients with SPLC or IPLM previously treated surgically. Pre-existing pulmonary disease was a predictive factor for decreased respiratory function.

[Outcome of Surgical Treatment of Locally Advanced Lung Cancer after Induction Chemoradiotherapy].

OBJECTIVE: The outcome of surgical treatment of non-small-cell lung cancer after induction chemoradiotherapy was investigated. SUBJECTS: The subjects were 74 patients with non-small-cell lung cancer who received induction chemoradiotherapy( ICRT) between 1998 and 2016. ICRT was administered to pT3 lung cancer invading the chest wall(20 patients), pT4 lung cancer invading the adjacent organ(22 patients), and cN2 lung cancer(32 patients). cN2 was confirmed by mediastinoscopy(13 patients) and endobronchial ultrasound-guided transbronchial needle aspiration(EBUS-TBNA)(19 patients). RESULTS: Sixty-eight and 6 patients were male and female, respectively, and the mean age was 59.6 years old. The histologic type was adenocarcinoma in 43 patients, squamous cell carcinoma in 24, adenosquamous carcinoma in 5, and others in 2. In chemotherapy, 2 or more anticancer drugs including platinum agent were administered. The radiation dosage was 36 Gy in 1 patient, 40 Gy in 43, 50 Gy in 28, and 60 Gy in 2. The effect of ICRT was complete response( CR) in 1 patient, partial response( PR) in 40, and stable disease (SD) in 33 (CR+PR:55.4%). The surgical procedure was lobectomy in 60 patients, pneumonectomy in 10, bilobectomy in 3, and segmentectomy in 1. Tracheobronchoplasty was performed in 9 patients, and combined resection of the vertebral body, left atrium, carina, superior vena cava, aorta, and brachiocephalic subclavian artery was performed in 7, 5, 4, 3, 3, and 3 patients, respectively. Regarding postoperative complications, empyema developed in 5 patients, acute respiratory distress syndrome(ARDS)in 3, pneumonia in 3, tracheobronchial dehiscence in 2, postoperative hemorrhage in 1, atrial fibrillation in 1, and others in 5. Postoperative complication rate was 27.0%, and operative death occurred due to postoperative hemorrhage in 1 patient. Complete resection was achieved in 69 patients(93.2%). Regarding the histological effect of ICRT, Ef.1/2/3 = 32/28/14(Ef.2-3:56.7%), and down stage was achieved in 24 patients (32.4%). The 5-year survival rate of all 74 patients was 51.0%, median survival time (MST)was 62.7 months, and the recurrence-free survival rate was 47.3%. Recurrence occurred in 28 patients (40.6%)with complete resection and the recurrence was distant metastasis in 20 of them. Regarding the outcome by the effect of ICRT, the 5-year survival rates of patients who achieved CR+PR/SD, Ef.2-3/Ef.0-1, and down stage/non-down stage were 66.0%/34.3%(p=0.009), 73.2%/20.1%(p=0.001), and 83.7%/44.0%(p=0.02), respectively, showing that the outcomes of patients who achieved CR/PR, Ef.2-3, and down stage were significantly favorable. CONCLUSION: The morbidity and mortality rates of patients who underwent surgery after ICRT were 27 and 1.4%, respectively. More than half of the patients achieved CR-PR and Ef.2-3, 1/3 of the cases were down staged, and the outcomes of these patients were significantly favorable. Surgery after ICRT may improve the treatment outcome of patients with locally advanced lung cancer.

[A Patient with Lung Adenocarcinoma, Lymphangitis Carcinomatosa, and Multiple Bone Metastases Who Achieved Long-Term Survival after Successful Treatment with Carboplatin, Paclitaxel, and Bevacizumab].

BACKGROUND: Lymphangitis carcinomatosa of the lung is intractable and associated with a poor prognosis. CASE: A 53-year-old woman was admitted to our hospital due to an uncomfortable feeling on deep inspiration. She was diagnosed with left lung adenocarcinoma with lymphangitis carcinomatosa and bone metastases to the frontal bone of the skull and thoracic vertebrae. The lung carcinoma was positive for an EGFR mutation. Because the patient's performance status (PS) was 0, carboplatin plus paclitaxel plus bevacizumab therapy was initiated and she received zoledronic acid and concurrent radiation therapy of 40 Gy for the metastasis to the thoracic vertebrae. After 2 courses of treatment, the respiratory symptoms had improved. After 6 courses of treatment, a chest CT indicated that the lymphangitis carcinomatosa had disappeared. The serum CEA level, which was 126.2 ng/mL (normal<5.0) before treatment, reduced to 5.0 ng/mL. She was administered 10 courses of bevacizumab as a maintenance therapy; however, the CEA level rose again to 11.7 ng/mL, the lung tumor volume increased, and the metastasis of the frontal bone deteriorated. As second-line chemotherapy, EGFR-TKI was started. However, after 11 months, because of grade 4 liver dysfunction, EGFR-TKI was stopped. She then received fourth-line chemotherapy in our outpatient hospital. This patient has survived 52 months since the initial diagnosis. CONCLUSION: Chemotherapy including bevacizumab facilitated long-term survival (52 months) of a patient with lung adenocarcinoma accompanied by lymphangitis carcinomatosa and multiple bone metastases.

Excision repair cross complementation group 1 polymorphisms predict overall survival after platinum-based chemotherapy for completely resected non-small-cell lung cancer.

BACKGROUND: It has been reported that the expression of excision repair cross-complementation group 1 (ERCC1) protein predicts the effect of platinum-based chemotherapy and overall survival in the several cancers. And there are some reports suggesting that the polymorphism of the ERCC1 may predict the effect of platinum-based chemotherapy and survival of the patients. We have already reported that the expression of ERCC1 protein predicts survival after platinum-based chemotherapy for 90 completely resected non-small-cell lung cancers (NSCLC). MATERIALS AND METHODS: We investigated the ERCC1 polymorphisms (C8092A and C118T) whether these factors influence for the prognosis of these 90 NSCLC patients treated with platinum-based chemotherapy. RESULTS: Two of the ERCC1 polymorphisms, C8092A and C118T, affected the prognosis of the NSCLC patients who received adjuvant and/or neoadjuvant platinum-based chemotherapy. The wild type, C/C of the codon 8092, was associated with better prognosis than C/A or A/A types (P=0.0154) and the wild type C/C of the codon 118 was associated with better prognosis than C/T or T/T types (P=0.0307). This effect was not seen in an independent group of 55 completely resected NSCLC patients who were treated with surgery alone. The combination of low expression of ERCC1 protein together with the C/C type codon 8092 and C/C type codon 118 polymorphism of the ERCC1 gene was associated with the best prognosis. CONCLUSIONS: Our data seem to suggest that the ERCC1 protein expression and polymorphism of ERCC1 may predict the survival of patients who are treated with platinum-based chemotherapy.

[Surgical treatment for recurrent and second primary lung cancer].

We analyzed 39 patients who underwent a 2nd resection for recurrent (solitary pulmonary metastasis) or 2nd primary lung cancer. Based on the pathological findings, 18 patients were diagnosed as recurrent lung cancer, and 21 patients were diagnosed as 2nd primary lung cancer. Overall 5-year survival was 69.4%. There are no difference between recurrent group and 2nd primary group. It is difficult to distinguish preoperatively between recurrent lung cancer and 2nd primary lung cancer, so we must be consider the 2nd resection as a curative resection for "2nd primary lung cancer".

[Surgical treatment for Pancoast tumors--significance of surgical approach and induction chemoradiotherapy].

We analyzed 46 patients with Pancoast tumor who underwent surgical resection. Anterior approach was employed for 16 patients and hook approach for 30 patients. Twenty-one patients received preoperative treatment; chemotherapy for 1 patient, radiotherapy for 11 patients, and chemoradiotherapy for 9 patients. Complete resection was achieved in 59% (27/46) of patients. The overall 5-year survival rate was 10.9%. Five-year survival was significantly higher in the patients received complete resection than the patients received incomplete resection (18.5 vs 0%, p=0.0016). The complete resection rate has improved in recent cases, and one of the reasons seems to be the adoption of preoperative chemoradiotherapy. But postoperative complications occurred more frequently in patients who received induction therapy than the others. Optimal selection of surgical approach and induction chemoradiotherapy for Pancoast tumors appear to provide improved complete resection rate and long term survival.

Adjuvant Chemotherapy Based on the In Vitro Histoculture Drug Response Assay for Non-small Cell Lung Cancer Improves Survival.

BACKGROUND: In this study, we analyzed the usefulness of adjuvant chemotherapy for non-small cell lung cancer based on the histoculture drug response assay (HDRA). METHODS: From September 2001 to December 2008, 65 patients with pathologic stage II or higher non-small cell lung cancer who underwent surgery received two-cycle HDRA-based adjuvant chemotherapy. Chemosensitivity to cisplatin, carboplatin, paclitaxel, docetaxel, gemcitabine, and irinotecan was examined by the HDRA. All patients were classified according to the number of administered HDRA-positive drugs: the prediction-sensitive group (PSG) (n = 31) comprised patients treated with two HDRA-positive drugs and the prediction-nonsensitive group (PNSG) (n = 34) comprised those treated with a combination of one HDRA-positive and one HDRA-negative drug or two HDRA-negative drugs. The clinical outcomes of the two groups were analyzed. RESULTS: The overall 5-year survival rate of the PSG was 82.4%. On the other hand, that of the PNSG was 40.1%. There were significant differences between the two groups (p = 0.03). The 5-year disease-free survival rate was more favorable in the PSG than in the PNSG (PSG: 56.5%, PNSG: 30.1%, p = 0.05). Multivariate analysis showed that chemotherapy based on the HDRA was a significant prognostic factor (p = 0.03). CONCLUSIONS: The prognosis of patients treated with two HDRA-positive drugs was significantly better than that of those treated with one HDRA-positive drug or HDRA-negative drugs. Adjuvant chemotherapy based on the in vitro HDRA may be useful to improve survival in patients who have undergone surgery.

CHRNA5 gene D398N polymorphism in Japanese lung adenocarcinoma.

BACKGROUND: Recently, to identify genetic factors that modify lung cancer risk, CHRNA5 non-synonymous variant amino acid position 398 (D398N) was identified. The site was a highly conserved in the second cellular loop of the nicotinic acetylcholine receptor subunit protein. MATERIALS AND METHODS: We have investigated CHRNA5 gene polymorphism status in 302 surgically treated lung adenocarcinoma cases from Nagoya City University Hospital. The presence or absence of CHRNA5 polymorphism was analyzed by direct sequences. EGFR mutations status was already investigated and reported. RESULTS: We detected nine cases (2.98%) of CHRNA5 polymorphism (D398N) in our cohort. Total EGFR mutations were present in 129 patients (42.7%). The polymorphism statuses were not correlated with gender (women; 2.1% versus men; 3.7%, P = 0.5119), smoking status (never smoker; 2.0% versus smoker; 4.0%, P = 0.3339), pathological stages (stage I; 2.6% versus stage II-IV; 3.8%, P = 0.7246), and EGFR mutation status of the lung adenocarcinomas (mutation; 2.3% versus wild type; 3.7%, P = 0.7373). In this analysis, CHRNA5 polymorphism (D398N) patients had significantly worse prognosis (5/9 were dead; mean survival = 27.1 mo) than the patients with CHRNA5 wild type (74/293 were dead; mean survival = 113.9 mo) (log-rank test; P = 0.0146). CONCLUSION: Although CHRNA5 polymorphism is rare from Japanese lung cancer, polymorphism status might be correlated with shorter survival.

Thymoma with dissemination: efficacy of macroscopic total resection of disseminated nodules.

BACKGROUND: Advanced thymomas with disseminated nodules are difficult to manage, and the treatment strategy remains undefined. METHODS: A total of 28 thymoma patients with pleural and/or pericardial disseminated nodules were treated at Nagoya City University Hospital. Among them, 21 patients underwent resection of thymoma and pleural disseminated nodules. These patients were reviewed in the present study. RESULTS: Preoperative steroid pulse therapy was performed in 14 patients. Macroscopic total resection of all tumors was achieved in 15 patients. Postoperative adjuvant radiotherapy was performed for the mediastinum in 20 patients and hemithoracic irradiation (HTR) in 11 patients. The overall survival rate of operated 21 patients was 73.1% at 5 years. The patients who underwent resection showed a better prognosis than the patients without resection (p = 0.0006). Relapse was diagnosed in 14 of 21 patients who underwent resection. Disease-free survival was 67.5% at 1 year, 39.8% at 3 years, and 13.3% at 5 years. HTR alone did not improve the disease-free survival. Among the patients who underwent total resection, relapse-free survival was better than in the patients with subtotal resection (p = 0.009). Achievement of a trimodality therapy with preoperative steroid pulse, total resection, and postoperative HTR was associated with prolonged relapse-free survival in the operated patients (p = 0.027, hazard ratio 6.452). CONCLUSIONS: Pursuing total resection for thymoma and disseminated nodules may be beneficial for stage IV thymoma. The combination of preoperative steroid pulse therapy, macroscopic total resection, and postoperative HTR may prolong the interval to relapse, but it did not lead to cure.

[A case of non-small cell lung cancer with EGFR mutation responding to S-1 after a therapy with gefitinib].

A 78-year-old man had underwent right upper lobectomy for lung adenocarcinoma in July 1998(pT1N0M0, pStage Ia). In January2003, computed tomography showed a tumor in right lower lobe of lung, which grew slowly. He was treated with UFT. In April 2004, computed tomographyshowed multiple nodules in both lung, which was considered of metastasis of lung cancer. The increase of the nodules were observed, and treatment with gefitinib was started. Insertion mutation at EGFR in exon 20 was seen from the primarylung cancer. Since tumor growth occurred despite gefitinib administration, we converted gefitinib into S-1 using 80 mg/day for 28 days, followed by 14 days rest. Chest computed tomographyshowed a partial response. No side effect was observed, and continued internal use of S-1 until January 2007 when it was impossible to continue, and meanwhile, the increase of the tumor was not seen.

MEK1 gene mutation in Japanese lung adenocarcinoma patients.

Recently, to identify potential somatic mutations in genes of the epidermal growth factor receptor (EGFR) signaling pathway, the MEK1 gene mutation at exon 2 was identified. The mutant form of MEK1 leads to the constitutive activity of extracellular signal-regulated kinase (ERK)-1/2. We investigated MEK1 gene mutation status in 241 surgically treated lung adenocarcinoma cases from Nagoya City University Hospital. The presence or absence of the MEK1 mutation was analyzed by direct sequencing. EGFR mutation status was previously investigated and reported. We detected only one case (0.4%) of the MEK1 mutation (K57N) in our cohort. Total EGFR mutations were present in 101 patients (41.9%). The MEK1 mutation was mutually exclusive with B-raf, K-ras and EGFR mutations. Thus, it is a rare mutation in Japanese lung cancer patients, and of limited value for lung adenocarcinoma.

EGFR R497K polymorphism is a favorable prognostic factor for advanced lung cancer.

INTRODUCTION: It has been reported that the R497K polymorphism of the epidermal growth factor receptor (EGFR) gene has attenuated functions in ligand binding, tyrosine kinase activation, and growth stimulation. On other hand, EGFR gene mutations at kinase domain in non-small cell lung cancer (NSCLC) have been examined for their ability to predict sensitivity to gefitinib or erlotinib. MATERIALS AND METHODS: We investigated the EGFR mutations and/or R497K polymorphism statuses in 225 surgically treated NSCLC cases. 192 adenocarcinoma cases were included. The presence or absence of EGFR polymorphism of exon 13 was analyzed by PCR-RFLP method. RESULTS: EGFR mutations at kinase domain were found from 95 of 225 lung cancer patients. In 86.2% of patients, homo- or heterozygous Lys497 allele was present. No correlation existed between R497K EGFR genotype and clinico-pathological features, such as gender, smoking status, and pathological subtypes. CONCLUSIONS: EGFR mutation status was not correlated with R497KEGFR genotype of lung cancers. In node-negative patients, R497KEGFR genotype was not correlated with disease outcome. In node-positive patients, however, R497K EGFR was significantly associated with better overall survival. This association was attributable to neo-adjuvant or adjuvant chemotherapy. In 46 total gefitinib treated NSCLC patients, the prognosis was not different between the EGFR wild type (GG) patients and AG+AA patients. R497KEGFR polymorphism might be associated with favorable prognosis of advanced lung cancers and correlated with chemosensitivity.

Epidermal growth factor receptor gene amplification in surgical resected Japanese lung cancer.

To evaluate the epidermal growth factor receptor (EGFR) protein expression and increased copy number as predictors of clinical outcome in patients with non-small-cell lung cancer (NSCLC), we have performed fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). We investigated the EGFR increased copy number and EGFR protein expression statuses in 109 surgically treated NSCLC cases. The presence or absence of EGFR mutations of kinase domains was analyzed by genotyping analysis and sequences, and already reported. EGFR increased copy number was defined as Cappuzzo et al. criteria. FISH positive was found from 36/109 (33.0%) lung cancer patients, including 30 high polysomy cases and 6 gene amplification cases. FISH-positive cases were significantly correlated with worse prognosis (log-rank test p=0.0097). Within EGFR-mutant patients (n=55), FISH-positive cases were also correlated with poor prognosis (p=0.0255). FISH-negative tumors were found to be more frequently well-differentiated histology. Smoking status (never smoker vs. smoker, p=0.1510), and gender (p=0.5248) did not correlated with FISH positive. EGFR IHC results were correlated with FISH results (p=0.004), but not correlated with prognosis (p=0.2815). Although EGFR FISH-positive rate did not correlated with EGFR mutation (p=0.1973), EGFR polysomy or amplification cases were correlated with EGFR mutations (p=0.0023). In conclusion, the EGFR FISH-positive rate in Japanese patients with NSCLC was similar to rates in Western populations, unlike the higher frequencies of EGFR mutation in East Asians. A high EGFR gene copy number might have shorter survival in NSCLC.

Met gene copy number predicts the prognosis for completely resected non-small cell lung cancer.

The Met oncogene encodes the tyrosine kinase receptor for hepatocyte growth factor (HGF). Uncontrolled activation of Met is oncogenic and has been implicated in the growth, invasion and metastasis in a variety of tumors. Several distinct mechanisms including amplification, translocation or mutation of Met may underlie uncontrolled Met activation. In several solid tumors, amplification and mutation of Met were reported to be associated with tumorigenesis, invasion and metastasis. The present study evaluated the amplification and mutation of Met in a large number of non-small cell lung cancer (NSCLC). Among 213 NSCLC patients, increased Met copy number was identified in 12 patients (5.6%) and associated with a worse prognosis (P = 0.0414). The mutation of Met in 534 NSCLC patients was also evaluated. In these patients there were no previously reported mutations within the juxtamembrane (JM) domain (R988C, T1010I, S1058P and G1085X). However, a somatic exon 14 deleting splice variant in 3 (1.7%) of 178 NSCLC samples was identified for which sequencing was performed. Met amplification and mutation were rare in Japanese NSCLC. However, the results support a critical role of Met gene dose in NSCLC, suggesting that Met may be a specific molecular therapeutic target in selected NSCLC patients with increased Met copy number.

Fibroblast growth factor receptor 4 mutation and polymorphism in Japanese lung cancer.

We investigated the FGFR4 mutation status at the kinase domain and FGFR4 single nucleotide polymorphism (SNP) at codon 388 in surgically treated non-small cell lung cancer (NSCLC) cases. The presence or absence of FGFR4 mutations of kinase domains was analyzed by direct sequences (n=147), and the presence of FGFR4 Arg388 allele was analyzed by genotyping assay using LightCycler hybridization probes (n=387). FGFR4 mutations were not present in our lung cancer patients. In 61.8% of patients, homo- or heterozygous Arg388 allele was present. No correlation existed between the FGFR4 genotype and clinicopathological features such as gender, smoking status and pathological subtypes. EGFR mutation status was not correlated with the FGFR4 genotype of lung cancers. In node-negative patients, the FGFR4 genotype was not correlated with disease outcome, while in the node-positive patients FGFR4 Arg388 was significantly associated with worse survival. This association was not attributed to patient response to adjuvant chemotherapy. Therefore, the role of FGFR4 polymorphism is a prognostic marker for advanced NSCLC in Japanese patients.

Thymic carcinoma with dissemination: a retrospective analysis of ten patients.

OBJECTIVE: Thymic carcinoma is a rare mediastinal neoplasm with frequent pleural or pericardial dissemination. We retrospectively studied ten such cases and analyzed factors that influenced the survival of the patients. METHODS: Ten thymic carcinoma patients with dissemination have been treated since 1987. The clinical and pathological data were retrospectively reviewed. RESULTS: Pretreatment tumor biopsy was performed and demonstrated squamous cell carcinomas in nine and small cell carcinoma in one. In six of ten patients pleural or pericardial dissemination was clinically evident (cT4). These patients were basically regarded as inoperable and treated with chemotherapy and/or radiotherapy. Four other patients were diagnosed as cT3 preoperatively but were found to have dissemination at the time of thoracotomy. They underwent total resection of the thymic tumor and all visible pleural dissemination but without pericardial dissemination. Radiotherapy was performed pre-or postoperatively with or without chemotherapy. The 5-year survival rate in all patients was 42.0%. The patients with Masaoka stage IVa showed significantly better prognosis than the patients with stage IVb (MST, 69.7 months vs. 14.5 months; 5-year survival rate, 64.3% vs. 0%) (P = 0.03). The patients with cT3 disease showed significantly better prognosis (P = 0.016) than the patients with cT4 disease (MST, 69.7 months vs. 14.5 months; 5-year survival rate, 100% vs. 16.7%). CONCLUSIONS: Among thymic carcinoma patients with pleural or pericardial dissemination, there seem to be some patients who show good prognosis. These candidates are patients who underwent subtotal resection with disseminations that were identified only at the operation and without hematogenous or lymphogenous metastasis.