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Background Acneiform rash as an adverse event often affects the treatment by EGFR-TKIs. Since minocycline has been suggested to reduce the rash, we assessed the efficacy and safety of prophylactic administration of minocycline simultaneously during erlotinib treatment. Methods Patients of ECOG performance status 0-2 with advanced NSCLC, who had not been treated with EGFR-TKIs and would receive erlotinib treatment were randomized 1:1 into either group A, with minocycline or group B, without minocycline. The patients assigned to group A were started on minocycline 100mg/day orally for 8 weeks with erlotinib. Primary end point was the frequency of grade ≥2 rash acneiform by independent assessment in first 8 weeks. We expected the prophylactic minocycline decreased the incidence of grade ≥2 skin rash from 50% to 30%. The planned sample size was 280 patients with a = 0.025 (one-sided) and b = 0.10. Results Patients accrual was started in March 2015 and ended in June 2018 because of slow accrual. Ninety-four patients were finally enrolled and 93 were full-analysis set. The median age of the patients was 71 years old (range 45 to 89),58 patients were female. EGFR mutation status positive/negative/unknown=78/13/2 patients. The frequency of grade ≥2 rash acneiformby independent assessment was 33.3% [95%C.I. 20.0-49.0%] in group A vs. 44.2% [95%C.I. 29.1-60.1%] in group B (p = 0.296). The frequency by physicians’ evaluation was 31.3% [95%C.I. 18.7-48.8%] and 45.5% [95%C.I. 30.4-61.2%] (p = 0.161). However, the frequency of grade ≥2 rash acneiform on day 15 by physicians’ evaluation was significantly decreased (4.4% [95%C.I. 5.3-14.8%] in group A vs. 25.0% [95%C.I. 13.2-40.3%] in group B (p = 0.005)). As for toxicity, the incidence of any grade skin-related toxicity as pruritus (39.6% vs. 63.6%) and pain of skin (14.6% vs. 25.0%) was less common in group A. Hence, anorexia (41.7% vs 20.5%), nausea (25.0% vs 4.5%), and dysgeusia (22.9% vs 15.9%) occurred more frequently. Conclusions Although the frequency of acneiform rash tended to decrease, prophylactic administration of minocycline is not recommended because of increasing gastrointestinal toxicity. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure T. Kozuki: Honoraria (self), Research grant / Funding (self): AstraZeneca; Honoraria (self), Research grant / Funding (self): Chugai Pharmaceutical Co.; Honoraria (self), Research grant / Funding (self): Eli-Lilly Japan; Honoraria (self): Taiho Pharmaceutical Co.; Honoraria (self): Ono Pharmaceutical Co.; Honoraria (self): Bristol-Myers Squibb; Honoraria (self), Research grant / Funding (self): MSD; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Kyowa-Hakko Kirin; Honoraria (self): Pfizer; Honoraria (self): Nippon-kayaku; Research grant / Funding (self): Merck Biopharma. M. Takenoyama: Honoraria (self), Research grant / Funding (self): Chugai Pharmaceutical. All other authors have declared no conflicts of interest.

Background The aim of this study was to clarify the outcomes of lung resection for lung cancer in patients with cardiac disease, especially coronary artery disease, in a large-scale multi-institutional cohort. Methods We retrospectively analyzed the data on 1,254 patients who underwent major lung resection for lung cancer and had been diagnosed with coronary stenosis, atrial fibrillation, or both, in 58 institutions in Japan between January 2009 and December 2011. The primary outcome was 90-day postoperative mortality or in-hospital death. Results Among the 1,254 patients, 902 (71.9%) and 452 patients (36.0%) were preoperatively diagnosed with coronary stenosis and atrial fibrillation, respectively, and 951 patients (75.8%) received antiplatelet therapy. Among the patients with coronary stents (n = 532; 42.4%), 204 (16.3%) received drug-eluting stents. The 90-mortality or in-hospital death rate was 2.6% (n = 32), including stent thrombosis (n = 1), thromboembolic events without stent thrombosis (n = 2), and bleeding events (n = 2). In the multivariate analyses, blood transfusion, history of cerebrovascular disease, amount of bleeding, and history of congestive heart failure were associated with a higher independent risk of 90-day mortality or in-hospital death (odds ratio, 9.400, 3.574, 2.827, and 2.945, respectively). Preoperative discontinuation of antiplatelet therapy was not associated with an independent risk of 90-day mortality or in-hospital death on univariate analysis. Conclusions Major lung resection for lung cancer in patients with coronary artery disease is feasible. Our study suggests that discontinuation of antiplatelet therapy may not increase postoperative complications in patients with coronary artery disease.

Purpose: p27kip1 belongs to the KIP/CIP family of cyclin-dependent kinase inhibitors and is considered to be a tumor suppressor. Involucrin has been known as a marker of differentiation of squamous cell carcinoma (SCC). The aim of this study was to evaluate the clinicopathologic significance of the expression of p27 and involucrin in esophageal SCC. Methods: Immunohistochemical expression of p27 and involucrin was examined in 70 specimens of esophageal SCC. The correlation of the expression of these proteins and clinicopathologic features was evaluated. Results: Cellular differentiation in esophageal SCC was significantly correlated with the expression of p27 and involucrin (p = 0.010 and p = 0.002, respectively). Among well, moderately and poorly differentiated SCCs, 45.8 ± 21.6, 20.0 ± 15.0 and 10.6 ± 9.1% of carcinoma cells expressed involucrin, respectively (p < 0.0001 for well vs. poorly, p < 0.0001 for well vs. moderately, and p = 0.042 for moderately vs. poorly). There existed a more powerful statistical difference regarding the histological grade between SCCs with the expression of both p27 and involucrin and tumors with other expression patterns (p = 0.0001). Conclusions: Expression of both p27 and involucrin can be a powerful biological marker of cellular differentiation of esophageal SCC.

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).

Background and Aims: The widespread use of high resolution computed tomography has increased the number of small peripheral lung cancers. This study reviewed the clinicopathological features of the patients with non-small cell lung cancer (NSCLC) with a tumor diameter of 1 cm or less, in order to explore the adequate management of such small sized lung cancers. Material and Methods: This study was a retrospective analysis of consecutive 58 patients (5.3% out of 1095 patients) who underwent a complete resection for a peripheral NSCLC with a diameter of 1.0 cm or less. The clinical features and outcomes were compared with 203 patients with NSCLC with a diameter between 1.1 and 2.0 cm. Results: The mean age was 64.5 years and there were 26 males and 32 females. Clinical stage was IA in 57 (98%) and IIIA in 1. Lobectomy was performed in 39 patients, segmentectomy in nine, and nonanatomic wedge resection in ten. Two patients, who underwent systemic lymph node dissection, had mediastinal lymph node metastasis and were diagnosed as pathological stage IIIA; however they did not relapse after surgery. One patient with pathological stage IA papillary adenocarcinoma died due to brain metastases. The five-year overall survival rate and disease free survival rate was 95.0% and 95.3%, respectively. Patients with NSCLC of 1.0 cm or less showed significantly better survival than those with tumors measuring 1.1–2.0 cm in size (p = 0.048). Discussion: The indications for avoiding systemic lymph node dissection for operable NSCLC should not be based on the size of the tumor. A small-sized lung cancer might be surgically treated before the tumor enlarges to more than 1.0 cm in size.

Objectives: This study investigated the clinical features of patients with complete resection of thymic carcinoma. Patients and Methods: The clinical records from 11 patients who underwent a complete resection of thymic carcinoma were retrospectively reviewed. Results: Twelve of 22 patients underwent a resection (a complete resection in 11 and an incomplete in 1). Six of the 11 patients with complete had confirmed recurrent tumors. The 5-year survival rate was 45.4%, and the median survival time was 50.6 months. The patients who underwent complete resection showed significantly better prognosis than cases with incomplete resection and inoperable cases ( p = 0.048). Three of the 6 patients had a recurrence within 1 year. Frequent sites of recurrence were the pleura, pericardium, and lung. Conclusions: A complete resection improved the prognosis of thymic carcinoma. Further prospective studies regarding postoperative adjuvant therapy are necessary to prevent local recurrence after a surgical resection for thymic carcinoma.

Catenins are cytoplasmic proteins that play a pivotal role in cell adhesion. Conflicting results regarding the significance of their expression in esophageal squamous cell carcinoma (ESCC) have been reported. The expression of α-, β- and γ-catenin was examined using immunohistochemical methods in 69 samples collected from patients with ESCC who were surgically treated without any preoperative induction therapy. Reduced α-, β- and γ-catenin expression was observed in 48 (69.7%), 36 (52.2%) and 44 (63.8%) ESCC samples, respectively. According to univariate analysis, ESCC patients exhibiting the reduced expression of β-catenin (P=0.028), γ-catenin (P=0.010), α- and γ-catenin combined (P=0.047) or β- and γ-catenin combined (P=0.046) had a significantly more unfavorable rate of survival. Multivariate analysis demonstrated that the reduced expression of γ-catenin (P=0.015) as well as lymph node metastasis (P=0.015) could serve as independent prognostic indicators of unfavorable prognosis in ESCC patients. Reduced immunohistochemical expression of γ-catenin may thus prove to be a powerfull and useful predictor of prognosis in patients with ESCC.

Somatically acquired mutations in the epidermal growth factor receptor (EGFR) gene in lung cancer are associated with significant clinical responses to gefitinib, a tyrosine kinase inhibitor (TKI) that targets EGFR. In our previous report, 42.2% of adenocarcinoma patients has EGFR mutations, and these mutations were more frequently found in women than in men, in well differentiated tumors than poorly differentiated tumors, and in patients who were never smokers than in patients who were current/former smokers. Retrospectively, we screened the EGFR gene of tumors in 37 NSCLC patients who had been treated with gefitinib. EGFR mutations were found in 22 patients. Gefitinib was effective (CR/PR) in 15 of 22 (68.2%) patients with mutations compared with none of 15 patients without mutations. Patients with EGFR mutations survived for a longer period than without the mutations after initiation of gefitinib treatment (p = 0.0005). Gefitinib was not effective in 3 patients with K-ras mutations. Three of 4 tumors obtained from patients with acquired resistant to gefitinib, had a secondary T790M mutation. No T790M mutation was detected in pretreatment tumors. Molecular targeted therapy using TKI indicates an effective therapy specifically in lung cancer patients with EGFR mutations, and analyses of mechanisms of resistance to TKI are necessary for establishment of tailor-made therapy.

To assess whether a satellite lesion in the primary-tumor lobe is intrapulmonary metastasis from primary cancer (pm 1) or they are double primary lung cancers, we examined the postoperative prognosis of patients with pm 1 and the p 53 genetic differentiation between a satellite lesion and a primary lesion. Of 772 consecutive patients with N0-2M0 non-small cell lung cancer who underwent surgical resections between 1979 and 2000, 31 patients had a satellite lesion in the primary-tumor lobe. The 5-year survival rate was 26.3% in the pm 1 (+) T 4 group (n = 37), 14.7% in the pm 1 (-) T 4 group (n = 43), and 32.5% in the T 3 group (n = 132), suggesting that pm 1 cases should be classified as T 3. We examined 16 of 37 patients with pm 1 for mutations of the p 53 gene occurring exons 5 through 8 by the fluorescence-based polymerase chain reaction single-strand conformation polymorphism. Seven of the 16 patients analyzed had at least one p 53 mutations in their tumors. The mutational status of the p 53 gene was discordant in 5 patients, suggesting they were double primary lung cancers. The mutational status including DNA sequencing of the p 53 gene was concordant in 2 patients, suggesting they were intrapulmonary metastases. It remains arguable in the TNM staging system whether a satellite lesion in the primary-tumor lobe is intrapulmonary metastasis from primary cancer or they are double primary lung cancers.

Adhesion molecules are involved in intracellular signaling in various physiological and pathological processes including metastasis and growth of tumor cells. Tumor cells interact with various host cells as well as with extracellular matrices through certain adhesion molecules such as integrins. We here propose that stimulation of beta1 integrin reduces intercellular adhesion molecule (ICAM)-1-mediated interaction of lung cancer cells with CTLs. This concept is based on the following findings: (a) engagement of beta1 integrins on certain lung cancer cells by a specific antibody or by ligand matrices such as fibronectin and collagen markedly reduced ICAM-1 expression on the cell surface and induced sICAM-1; (b) down-regulation of ICAM-1 by stimulation of beta1 integrins was abrogated by tyrosine kinase inhibitors or by transfection of dominant negative truncations of focal adhesion kinase (FAK); (c) engagement of beta1 integrins also reduced ICAM-1-dependent adhesion of lung cancer cells to T cells, a process completely inhibited by tyrosine kinase inhibitors and by transfection of dominant negative forms of FAK; and (d) stimulation of beta1 integrins prevented killing of lung cancer cells by autologous CTLs. In malignant tumors, cancer cells, including lung cancer cells, are surrounded by extracellular matrix proteins such as fibronectin and collagen. This suggests that the engagement of beta1 integrins by matrix proteins potentially occurs in cancer cells in vivo and that continuous stimulation via beta1 integrins reduces ICAM-1-expression, ICAM-1-mediated adhesion of cancer cells to CTLs and their killing by CTLs. Our results suggest that such processes can lead to the escape of lung cancer cells in vivo from immunological surveillance.

BACKGROUND—Although the preoperative prediction of pulmonary complications after lung major surgery has been reported in various papers, it still remains unclear. METHODS—Eighty nine patients with stage I-IIIA non-small cell lung cancer (NSCLC) who underwent a complete resection at our institute from 1994-8 were evaluated for the feasibility of making a preoperative prediction of pulmonary complications. All had either a predicted postoperative forced vital capacity (FVC) of >800 ml/m2 or forced expiratory volume in one second (FEV1) of >600 ml/m2. RESULTS—Postoperative complications occurred in 37 patients (41.2%) but no patients died during the 30 day period after the operation. Pulmonary complications occurred in 20 patients (22.5%). Univariate analysis indicated that the factors significantly related to pulmonary complications were FVC

We have retrospectively analyzed the postoperative prognostic factors for 116 patients with stage I adenocarcinoma, with special reference to pleural retraction and intra-tumoral air-bronchogram imaged by computed tomography, which may represent the biological features of pulmonary adenocarcinoma for the retraction of surrounding tissues due to central necrosis and air space-lining growth, respectively.The subgroups divided according to the presence of pleural retraction and/or intra-tumoral air-bronchogram on pre-operative CT were compared with respect to the postoperative disease-free survival (DFS) and other clinico-pathological factors.The rates of DFS at 5 years associated with 61 patients with pleural retraction and with 55 patients without pleural retraction were 64.4% and 91.3%, respectively (P = 0.0052), and those associated with 83 patients with air-bronchogram-positive tumors and with 33 patients with air-bronchogram-negative tumors were 81.8% and 64.8%, respectively (P = 0.0040). The DFS at 5 years associated with T1 (73 patients) and T2 (43 patients) were 83.6% and 64.3%, respectively (P = 0.0153). The Cox proportional hazards model analysis revealed that the presence of pleural retraction and the absence of air-bronchogram were independent factors for poor prognosis with relative risks of 7.8 and 5.1, respectively. Pathological T factor was also a significant prognostic factor with a relative risk of 3.2. Seventeen patients with pleural retraction-positive and air-bronchogram-negative tumors showed the high recurrence rate of 47.5% and a poor prognosis with DFS at 5 years of 35.1%.These results suggested that, in stage I adenocarcinoma, the degree of malignant potential may be well figured by radiological imaging, with a significant affect on susceptibility of recurrence following complete resection.

We report the successful surgical treatment of chronic expanding hematoma in the chest. Four patients who had previously undergone artificial pneumothorax, thoracoplasty or tumor extirpation more than 30 years earlier recently became aware of a slowly growing mass. Chronic expanding hematoma which developed into very large masses over a long period of time were thus successfully resected. These patients are now all in good health with no recurrence after the operation. It is important to monitor such patients' laboratory data for hemostasis including the platelet cell counts, the % prothrombin time and the D-dimer, both before and immediately after operation, and the intraoperative bleeding volume.

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).

The effect of local injections with streptococcal preparation OK432 on the therapeutical potential of tumor-draining lymph node (LN) cells was investigated in mice. Peritumoral injections with OK432 on days 2, 4, 6, 8 and 10 showed no effect on the in vivo growth of s.c. inoculated B16F10 melanoma. The B16F10-draining OK432-treated LN cells, however, showed a high level of anti-B16F10 cytolytic activity after an in vitro culture first with both anti-CD3 monoclonal antibody (MAb) and activated B cell blasts, and subsequently with interleukin (IL)-2 without in vitro restimulation. Such in vitro expanded LN cells showed a remarkable antitumor effect against pulmonary metastasis of B16F10 melanoma, even without the concurrent administration of IL-2. In addition, the therapeutical protocol was also found to be moderately effective against poorly immunogenic MCA fibrosarcoma, and the in vivo antitumor effect was specific to the tumor from which the LNs were harvested. Interestingly, 2 kinds of comparative analyses of the cytokines revealed that the B16F10-bearing state induced the draining LN cells to develop a Th2-type response. However, the OK432 treatment was able to effectively augment their Th1-type response. Collectively, our results suggest that peritumoral injections with OK432 significantly increased the therapeutical potential of the tumor-draining LN cells by augmenting their Th1-type response.

Effect of a local injection with a streptococcal preparation OK432 on the in vitro generation of anti-tumor cytotoxic T lymphocytes (CTLs) from tumor-draining lymph nodes (LN) was investigated. A peritumoral injection with OK432 on days 2, 4, 6 and 8 significantly increased both the total cell number and the proportion of B cells in the draining LN cells on day 10 after a subcutaneous inoculation with B16 melanoma. In an in vitro proliferative assay, OK432 showed a stimulatory effect on both normal splenic T and B cells. In a cytolytic assay, the OK432-injected B16-draining LN cells showed a higher level of anti-B16 CTL activity than the B16-draining LN cells after in vitro restimulation. This augmenting effect of OK432 was dependent on the B cells. Moreover, nonadherent cells from the OK432-injected B16-draining LN cells showed a low but significantly higher level of anti-B16 CTL activity than those from the B 16-draining LN cells after in vitro restimulation, whereas this augmenting effect of OK432 was abolished by the in vitro addition of anti-interleukin (IL)-12 monoclonal antibody. Collectively, these findings suggest that the augmenting effect of a local injection with OK432 on the potential of tumor-draining LN cells to turn into anti-tumor CTLs after in vitro restimulation was at least in part due to IL-12 derived from the OK432-stimulated B cells.

We examined the possibility that Th1 type CD4+ T cells may be an effector against three kinds of syngeneic tumors such as highly immunogenic B16 melanoma (B16) and two poorly immunogenic lines of MCA fibrosarcoma (MCA) and 3LL carcinoma (3LL). In a proliferation assay, the Th1 type CD4+ T cell clone (MH2) recognized the purified protein derivatives (PPD) derived from Mycobacterium tuberculosis. In a tumor-neutralizing assay, MH2 showed anti-tumor activity against both B16 and MCA. In a model of pulmonary metastasis, MH2 also showed anti-tumor activity against both B16 and 3LL. In an assay of cytolysis, MH2 showed a moderate level of tumor necrosis factor-dependent cytolytic activity only against MCA. In a cytostasis assay, MH2 showed a high level of interferon gamma-dependent cytostatic activity against the three tumors in the presence of macrophages. The anti-tumor activity of MH2 against B16 and 3LL was suggested to be, at least in part, attributable to the augmented natural killer activity. Taken together, these findings suggest that we may potentially be able to utilize Th1 type CD4+ T cells as an effector for immunotherapy against poorly immunogenic tumors.

7562 Background: Carboplatin plus paclitaxel and carboplatin plus gemcitabine chemotherapy have shown a good response and an improved survival against advanced NSCLC. This phase II trial assessed the feasibility, safety and efficacy of a bi-weekly schedule for adjuvant chemotherapy. Methods: Patients with completely resected stage IB-IIIB NSCLC were randomized to either carboplatin (AUC3) plus paclitaxel (90mg/m2) (arm A) or carboplatin (AUC3) plus gemcitabine (1000 mg/m2) (arm B), q2w for 8 cycles within 8 weeks after surgery. The main inclusion criteria were no prior chemotherapy or radiotherapy, ECOG PS 0–1, an age of less than 80 years, and an adequate organ function. The primary endpoint was compliance, and secondary endpoints were the disease free survival (DFS) and toxicity. The patients were stratified by gender, histology (adenoca vs. non-adenoca) and disease stage. Results: Between 07/2005 and 06/2007, 76 patients were randomized and 75 were eligible (including 48 males, 27 females; median age 66 years) for intent-to-treat analysis (39 in arm A, 36 in arm B). The histologic types included adenocarcinoma (n=51), squamous cell carcinoma (n=18), large cell carcinoma (n=5), and adenosquamous cell carcinoma (n=1). The pathological stages were IB/IIA/IIB/IIIA/IIIB: 22/10/13/29/1. Twenty-one of 39 pts (54%) in arm A and 25 of 36 pts (69%) in arm B completed 8 cycles, and 59% in arm A and 81% in arm B completed ≥6 cycles. Grade 3/4 hematologic toxicities (%) in arms A/B were respectively; neutropenia 36/53, anemia 0/17, thrombocytopenia 3/0, nausea 3/3. No treatment related deaths were observed. Up to 12/2008, 11 of 39 pts in arm A and 13 of 36 pts in arm B had recurrent disease, but no significant difference was observed. Conclusions: This adjuvant bi- weekly scheduled chemotherapy in both arms resulted in a good compliance and feasible with acceptable levels of toxicity in completely resected NSCLC. No significant financial relationships to disclose.

18081 Background: Somatically acquired mutations in the EGFR gene in non-small cell lung cancer are associated with a significant clinical response to gefitinib, a tyrosine kinase inhibitor that targets EGFR, especially in patients with adenocarcinoma, females, and/or never/light smokers. In our retrospective study, cases with EGFR mutations (exon19del or L858R) showed a high sensitivity to gefitinib, and the patients with sensitive EGFR mutations also tended to have a more favorable prognosis than those with wild-type after gefitinib treatment (Uramoto, et al. Lung Cancer 2006;51:71). In the present study, we prospectively assessed the efficacy of gefitinib and the survival benefit for patients with EGFR mutations. Methods: Patients with either recurrent disease after undergoing surgery or advanced disease (IIIB or IV) of NSCLC which demonstrated EGFR mutations were eligible for this study. EGFR mutations in exons 19–21 were examined by our previously described screening method (Sugio, et al. Br J Cancer 2006;94:896) and confirmed by direct sequencing after informed consent was obtained from all patients. The patients with EGFR mutations were enrolled in this study after obtaining informed consent a second time, and they were thereafter treated with gefitinib. Results: Between 2005 and 2006, 16 patients (10 males/6 females, all adenocarcinoma) who had EGFR mutations were enrolled onto this study. Six pts had a deletion in exon 19, 8 pts had a missense mutation in exon 21 (L858R), 1 pt had both an exon 19 del and L858R, and 1 pts had an exon19 del and missense mutation in exon 20 (G796A). The overall response rate was 50%, and the disease control rate was 88%. In patients with exon19 del and L858R, the response rates were 83% and 25%, respectively. A case with a deletion in exon19 and a missense mutation in exon20 (G796A) showed resistance to gefitinib. The median progression-free survival time was 8.8 months, and the median survival time was 15.4 months. No life-threatening toxicity was observed. Conclusions: EGFR mutations in exons 19 or 21 are therefore considered to a good predictor of the efficacy of gefitinib, and the treatment with gefitinib was also found to achieve a prolonged survival. No significant financial relationships to disclose.

7703 Background: Somatically acquired mutations in the EGFR gene in non-small cell lung cancer are associated with a significant clinical response to a tyrosine kinase inhibitor (TKI). EGFR mutations occur predominantly in exon19 and/or exon21, namely, an in-frame deletion in exon19 or a missense mutation in exon21 (L858R), which have been found to be related to the sensitivity to TKI. However, most patients with such sensitive mutations in their tumor show progression during the TKI treatment. In such resistant tumors, a secondary threonine- to-methionine mutation at codon 790 (T790M) in exon20 has been reported to be related the resistance to either gefitinib or erlotinib. Methods: EGFR mutations in exons19–21 were examined by sequencing in 37 pretreatment tumors obtained from patients with NSCLC, who were treated by gefitinib. Of the 22 cases having sensitive EGFR mutations (19del or L858R), 15 showed CR/PR and 7 showed SD/PD. Of the 15 patients with CR/PR, 4 tumor samples (2 lung, 1 liver, and 1 pleural effusion) that became refractory to gefitinib, were obtained. In pretreatment tumor samples from 4 patients, an in-frame deletion of exon19 was observed in 3 tumors and a L858R mutation of exon21 was in 1 tumor. We next examined whether a secondary mutation occurred in a tumor with acquired resistance to gefitinib in 4 patients by the sequencing of exons 19–21, with informed consent. Results: Three of 4 tumor samples had a secondary T790M mutation, which was not detected in the pretreatment tumor samples. These 3 samples also had an in-frame deletion in exon19. There were no other novel secondary mutations in exons 19,20,21. In 7 cases showing resistance to gefitinib (SD/PD) in spite of the existence of sensitive mutations, 1 tumor demonstrated the co-existence of a missense mutation (G796A) in exon20. In vitro, a stable clone of cells bearing the G796A mutation was approximately 50,000-fold less sensitive to gefitinib in comparison to the cells carrying exon19 deletion. Conclusions: The T790M mutation is common in patients with acquired resistance to gefitinb. Our results suggest that screening tumor samples for a range of EGFR mutations may therefore improve our ability to identify the patients most likely to benefit from treatment with TKI. No significant financial relationships to disclose.