Search

A 75‐year‐old woman underwent thoracoscopic right upper lobectomy for lung cancer. A histopathological examination showed adenocarcinoma, pT1aN0M0 stage IA1. At six months after surgery, chest computed tomography (CT) revealed pericardial nodules that had not been detected before pulmonary resection. Postoperative CT performed two months later revealed that the nodules were growing and F18 fluorodeoxyglucose‐positron emission tomography showed a maximum standardized uptake of 9.87. Blood tests revealed no elevated tumor markers, with the exception of a mildly elevated interleukin‐2. Based on the above results, thoracoscopic biopsy was performed due to the suspected recurrence of lung cancer or malignant lymphoma. The histopathological examination of the nodule revealed immunoglobulin G4 (IgG4)‐related inflammatory pseudotumor. The serum IgG4 levels were elevated (358 mg/dL, normal: 4.5–117.0 mg/dL). No additional treatment was required because all nodules were observed to have disappeared naturally on a follow‐up CT scan performed two months after the surgical biopsy. The patient has been followed‐up for two years without recurrence. Key points Significant findings of the study We report a case of pericardial immunoglobulin G4‐related inflammatory pseudotumor that appeared after right upper lobectomy for lung cancer, and which naturally disappeared without any treatment. What this study adds There was an immunoglobulin G4‐related inflammatory pseudotumor which appeared as multiple nodules in the pericardial space, and this should be kept in mind when considering the differential diagnosis of intrapericardial nodules., We report a case of pericardial immunoglobulin G4‐related inflammatory pseudotumor that appeared after right upper lobectomy for lung cancer, and which naturally disappeared without any treatment.

Several authors have previously reported that patients with pulmonary combined large cell neuroendocrine cancer ( LCNEC) have a poor prognosis and there is no consensus on the treatment strategy for combined LCNEC as well as LCNEC. Here, we report the case of a long‐term survivor with pulmonary combined LCNEC. The patient was a 60‐year‐old man who underwent thoracoscopic right lower lobectomy. The final histopathology and staging of the tumor showed LCNEC combined with squamous cell carcinoma and T2aN0M0 stage IB. Multimodality treatments including chemotherapy, radiotherapy and surgery for several recurrences were performed after the pulmonary surgery. After immune checkpoint inhibitor (ICI) therapy with nivolumab, all the metastatic lesions shrunk and a partial response was maintained at five years after the first surgery. In our case, ICI after multimodality therapy combining cytotoxic anticancer drugs and radiotherapy was effective in LCNEC with metachronous multiple metastases. Key points Significant findings of the study Immune checkpoint inhibitor after multimodality therapy combining cytotoxic anticancer drugs and radiotherapy was effective in LCNEC with metachronous multiple metastases. The patient survived over five‐years after the first surgery. What this study adds Immune checkpoint inhibitor may be effective in some LCNEC patients.

BACKGROUND: To investigate the usefulness of (18)F-fluorodeoxy glucose-positron emission tomography ((18)F-FDG PET) for the preoperative imaging diagnosis of malignant grade in thymic epithelial tumors (TETs) and the correlation between the maximum standardized uptake value (SUVmax) and tumor size in TETs. METHODS: We retrospectively investigated 51 patients with TETs performed (18)F-FDG PET. The SUVmax was compared between thymic carcinomas and thymomas. We also evaluated the difference in the SUVmax limited to small TETs. In addition, the correlation between the SUVmax and the tumor size was evaluated. RESULTS: The mean SUVmax of thymic carcinomas (n=12) and thymomas (n=39) was 5.71±2.6 and 3.08±1.4, respectively. The SUVmax of thymic carcinomas was significantly higher than that of thymomas (P

Although there is a rough unified recommendation for the management of chest drainage tubes after major lung resection for lung cancer (1,2), there is no firm guideline. Therefore, in actuality, each general thoracic surgeon manages patients’ chest tubes based on their experience and the results of small-scale studies (3-5).

Background Mutations of the epidermal growth factor receptor (EGFR) gene at kinase domain have been reported in non-small-cell lung cancer (NSCLC), and some common somatic mutations in EGFR have been examined for their ability to predict sensitivity to gefitinib or erlotinib. However, EGFR mutations at exon 20 have been reported to predict resistance to gefitinib therapy. Materials and methods We investigated the EGFR mutations and/or polymorphism statuses at kinase domain in 303 surgically treated non-small cell lung cancer (NSCLC) cases. One hundred ninety-four adenocarcinoma cases were included. The presence or absence of EGFR polymorphism of kinase domains was analyzed by direct sequences. We have also investigated EGFR polymorphism status at exon 20 for 23 NSCLC patients who had undergone surgery followed by treatment with gefitinib at the National Hospital Organization, Kinki-chuo Chest Medical Center. Results EGFR mutations at kinase domain were found in 75 of 303 lung cancer patients. During sequencing of EGFR tyrosine kinase domain in tumors, 86 EGFR polymorphism (G2607A) cases were identified at exon 20. G2067A polymorphism was significantly higher in nonadenocarcinomas (37.4%) than in adenocarcinoma (25.3%, P = 0.0415). The polymorphism status did not correlate with gender, smoking (never smoker versus smoker), and EGFR mutations. In 46 total gefitinib treated NSCLC patients, there was a tendency toward better prognosis in EGFR wild type (GG) patients than AG + AA patients. EGFR polymorphism in Japanese lung cancers seemed to be less frequent than Caucasian lung cancers. Conclusions EGFR-tyrosine kinase polymorphism might be associated with clinicopathological background of lung cancers.

Mutations of the epidermal growth factor receptor (EGFR) gene at kinase domain have been reported in non-small-cell lung cancer (NSCLC). However, EGFR mutations status at C-terminal domain has not been reported in detail.We investigated the EGFR mutation and polymorphism statuses at C-terminal domain in 398 surgically treated NSCLC cases. Two hundred and sixty-eight adenocarcinoma cases were included. The presence or absence of EGFR mutation and polymorphism was analyzed by direct sequences.A novel EGFR somatic mutation at exon 25 (G3034, D1012H) was found from 1 of 398 lung cancer patients. During sequencing of EGFR C-terminal domain in NSCLC, 194 EGFR polymorphism (C2982T) cases were identified at exon 25. The polymorphism statuses were not correlated with gender, smoking status (never smoker vs. smoker), pathological subtypes and EGFR mutations. The EGFR polymorphism ratio was significantly higher in younger NSCLC (or =60, 56.8%) than in older NSCLC (60, 45.6%, P = 0.0467). The EGFR polymorphism ratio was significantly higher in lymph node positive NSCLC (57.4%) than in lymph node negative NSCLC (44%, P = 0.0168). In 46 total gefitinib treated NSCLC patients, exon 25 polymorphism was not correlated with prognosis.EGFR mutation at C-terminal in lung cancers seemed to be extremely rare, however, this D1012H mutation might be a role in EGFR function. EGFR polymorphism at exon 25 might be correlated with progression of NSCLC.

ErbB3 is a member of the epidermal growth factor receptor (EGFR) family of tyrosine kinase. A previous report has suggested that overexpression of ErbB3 protein was associated with lung cancer recurrence. Other reports suggested that high ErbB3 protein expression was associated with shorter survival in advanced non-small-cell lung carcinomas (NSCLC). The relationship between the erbB3 mRNA expression and EGFR mutation has not been reported. In this study, we have investigated the erbB3 mRNA levels in reference to clinicopathologic data and EGFR mutation status in Japanese lung cancer specimens.This study included 192 surgically removed NSCLC cases operated at Nagoya City University Hospital. The erbB3 mRNA levels were quantified by real-time polymerase chain reaction using LightCycler (Roche Molecular Biochemicals, Mannheim, Germany).The erbB3/glyceraldehydes-3-phosphatate dehydrogenase levels were significantly higher in female than in male (P0.0001), higher in nonsmoker than in smoker (P = 0.0007), higher in adenocarcinoma than in other types of lung cancers (P0.0001), and higher in well-differentiated than in less-differentiated subtypes (P = 0.0304). The erbB3/glyceraldehydes-3-phosphatate dehydrogenase levels were significantly higher in patients with EGFR gene mutation than in patients without mutation (P = 0.0124).The present study suggests that increased expression of erbB3 may play an additional role in NSCLC especially in female, nonsmoker, adenocarcinoma, and with EGFR gene mutation. Further studies on large sample sizes would help to determine if erbB3 expression is a clinically useful tool to further define patients who will benefit from EGFR TKIs.

To evaluate the epidermal growth factor receptor (EGFR) protein expression, gene mutations and amplification as predictors of clinical outcome in patients with non-small-cell lung cancer (NSCLC) receiving gefitinib, we have performed fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). We investigated the EGFR amplification and EGFR protein expression statuses in 27 surgically treated non-small-cell lung cancer (NSCLC) cases. These patients experienced relapse after surgery and received gefitinib 250 mg/day. The presence or absence of EGFR mutations of kinase domains was analyzed by genotyping analysis and sequences, and already reported. EGFR mutations were found from 15/27 lung cancer patients. EGFR mutation status was significantly correlated with better prognosis (log-rank test P=0.0023). Smoking status (never smoker vs. smoker, P=0.0032), and pathological subtypes (adenocarcinoma vs. non-adenocarcinoma, P=0.0011), but not EGFR amplification (P=0.1278), were correlated with survival of lung cancers. EGFR IHC results were correlated with FISH results (P=0.0125), but not correlated with prognosis (P=0.7921). Thus, the EGFR gene amplification or protein expression is not a predictor of gefitinib efficacy in Japanese patients with NSCLC. We have also evaluated the EGFR mutation status and clinico-pathological features for 27 NSCLC patients who had undergone surgery followed by treatment with gefitinib at the National Hospital Organization, Kinki-chuo Chest Medical Center. The EGFR mutation status, especially exon19 mutation was correlated with good response to gefitinib than exon 21 point mutation.

Much evidence has accumulated that the epidermal growth factor receptor (EGFR) and its family members are strongly implicated in the development and progression of lung cancers. Recently, erbB4 kinase domain mutations were reported in Korean patients with lung cancer. We hypothesized that erbB4 mutations correlate with clinicopathologic features of lung cancers.The presence or absence of erbB4 kinase domain mutations was analyzed by reverse-transcription polymerase chain reaction amplification and direct sequencing in 105 surgically treated non-small-cell lung cancer cases from Nagoya City University Hospital. Sixty-three adenocarcinoma cases were included. The EGFR mutation status for these 105 samples were already reported. We have investigated erbB4 expression status by immunohistochemistry in 40 non-small cell lung cancer cases.ErbB4 mutation was not found in 105 patients with lung cancer. The EGFR mutation status was significantly correlated with sex (women, 74.2% vs. men, 9.5%; P0.0001), smoking status (never-smokers, 68.8% vs. smokers, 11%; P0.0001), pathologic subtype (adenocarcinoma, 44.4% vs. non-adenocarcinoma, 4.8%; P0.0001), and differentiation status of the lung cancer (well-differentiated, 47.4% vs. others, 14.8%; P = 0.0004). We detected ErbB4 protein positivity in 20 samples. The ErbB4 protein status was not significantly correlated with sex (women, 28.6% vs. men, 54.5%; P = 0.4075), smoking status (never-smokers, 69.4% vs. smokers, 16.9%; P0.0001), pathologic subtype (adenocarcinoma, 46.2% vs. nonadenocarcinoma, 51.9%; P0.9999), or differentiation status of the lung cancer (well-differentiated, 54.5% vs. others, 48.3%; P0.9999).Thus, erbB4 mutations are rare in Japanese people with lung cancer and of limited value for molecular-targeted therapy.

目的．癌性胸膜炎は癌終末期の病態であるが，癌性胸水を完全に制御できればPSが保たれた癌の終末期状態となり，患者の享受できるメリットは少なくない．対象と方法．対象は9例の癌性胸水患者である．胸膜癒着術の成否は癒着剤（タルク）が万遍なく胸膜に散布されるか否かに依存する．そこで，われわれは胸腔鏡下に完全に癌性胸水を排除した後，任意の肋間から血管留置針を胸腔穿刺した．50 mlの注射器に5～10 gのタルクを入れておき，留置した針から胸腔内に空気とともに散布した．この操作を複数箇所から行うことで胸腔全体にタルクを散布できた．つづいて，ドレナージチューブを肋骨横隔膜洞と肺尖にそれぞれ1本づつ胸腔鏡下に確実に留置し，十分な陰圧をかけた．術後は7日間の持続吸引の後，ドレナージチューブを抜管した．全例で胸水の完全制御に成功している．しかしながら9例中1例は術後50日目に退院することなく死亡した．結論．本法は，分離肺換気麻酔下の胸腔鏡操作を必要とするが，確実に胸水を制御することが可能であった．本法は癌性胸水が確認されたら，なるべく早期に施行するべきであると考える．

Purpose Human MOB1 ( hMOB1 ) is a recently isolated gene that is a human homologue of the Schizosaccharomyces mitotic checkpoint gene MOB1 . The loss of checkpoint control in mammalian cells results in genomic instability, leading to the amplification, rearrangement, or loss of chromosomes, events associated with tumor progression. We hypothesized that hMOB1 might be expressed in non–small-cell lung cancer (NSCLC). Patients and Methods We attempted to determine the influence of hMOB1 expression on clinicopathologic features in patients with NSCLC who had undergone surgery. Expression of hMOB1 messenger RNA (mRNA) was evaluated by reverse transcription-polymerase chain reaction in 60 NSCLCs and adjacent histologic normal lung samples using LightCycler®. Results Human MOB1/glyseraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA expression was significantly decreased in the tumor of lung cancer tissue (3.347 ± 4.306) compared with normal lung tissue (4.833 ± 4.306; P = 0.0437), although 22 of 60 lung cancer tissue samples had > 1 tumor-normal ratio of MOB1/GAPDH mRNA expression. There was no relationship between hMOB1 gene expression and age, sex, pathologic stages, or pN status. However, decreased hMOB1/GAPDH expression was especially seen in pT1 lung cancer (tumor-normal ratio; 0.318 ± 0.328) when compared with pT4 lung cancer (1.915 ± 1.895; P = 0.0362). Conclusion The decreased expression of hMOB1 mRNA might be the early phase phenomenon for tumor invasion from NSCLC. Alternatively, loss of mitotic checkpoint might play a role in oncogenesis for lung cancer.

ObjectiveThe presence of epidermal growth factor receptor (EGFR) mutations has been reported to predict the response to gefitinib in pulmonary adenocarcinoma patients. A retrospective analysis was conducted to identify the correlation between computed tomographic findings of the nodules and EGFR status.Patients and MethodsComputed tomographic findings of 38 patients with peripheral pulmonary adenocarcinoma with EGFR mutations were reviewed and compared with those of 42 peripheral pulmonary adenocarcinoma patients with wild-type EGFR.ResultsMutations were found significantly more frequently among women (28 of 45 women versus 10 of 35 men) and among non-smokers (31 of 47 non-smokers and 7 of 33 smokers). The L858R mutation was found in 18 cases. Several types of deletion mutants in exon 19 were found in 18 cases. The nodules with EGFR mutations (2.5 ± 1.0 cm) were significantly smaller in diameter than those in the wild-type group (3.1 ± 1.9 cm). Ground glass opacity (GGO) was more often observed in the mutation group (28 of 38) than in the wild-type group (24 of 42), but the difference was not statistically significant. When mutations were analyzed with reference to both the tumor size and GGO ratio, patients with a tumor ≤3 cm and a GGO ratio ≥50% often had EGFR mutations, and most (10 of 12) were expressed in female patients. No male adenocarcinoma patients with a tumor larger than 4.0 cm had EGFR mutations.ConclusionsEGFR mutations were found most frequently in small peripheral adenocarcinomas with a GGO ratio ≥50%, especially among women. These factors may be useful in deciding therapeutic strategies for adenocarcinomas when resection or biopsy is not feasible.

Background: Epidermal growth factor receptor (EGFR) gene mutations have been reported to correlate with the sensitivity to the tyrosine kinase inhibitor treatment for advanced lung cancers. Since several reports have shown that invasive thymoma overexpress the EGFR protein, we examinedtheEGFRexpressionandmutationstatusesinthymomaandthymiccarcinomatissues. Methods: EGFR mutation statuses from 99 thymic epithelial tumor samples were evaluated by a rapid and sensitive TaqMan assay using Applied Biosysytems 7500 real-time PCR system. Probes were designed according to the 13 different EGFR mutations reported previously in lung cancers. A total of 38 thymoma samples were directly sequenced for the EGFR gene. Protein expressions were evaluated for 56 thymic epithelial tumors by immunohistochemistry. Results: EGFR gene mutations were not detected in any of the thymoma and thymic cancer samples using TaqMan PCR assay. Of the 38 samples 3 showed a heterozygous silent mutation without changes in the protein, a G to A transition at the nucleotide 2361 in exon 18. EGFR expression was significantly higher in invasive thymomas (stages III–IV, 15/19 were positive) than in early stage thymomas (stages I–II, 7/33 were positive) (P < 0.0001). All four carcinomas and all seven B3 thymomas showed EGFR positive staining. Conclusions: Although EGFR mutation at the tyrosine kinase domain is unlikely to be a therapeutictargetforthymoma,theinformationaboutEGFRexpressionwouldcontributetothefurther identification of the therapeutic target for advanced thymomas.

症例は66歳,女性.他院で腹腔鏡下胆嚢摘出術,総胆管切開・Cチューブドレナージ術を施行された. 7年半後,発熱,上腹部激痛,嘔気を主訴に当院初診となった.精査したところ,金属クリップを核とした総胆管結石を1個認めたため,開腹総胆管切開・Tチューブドレナージ術を施行した.摘出した結石は18×11mmのビリルピンカルシウム石で,内部中央に金属クリップを認めた.術中, 2個あるべき胆嚢動脈断端のクリップは1個しか認めず,結石の原因と考えられた.術後経過は良好で現在無再発経過観察中である.クリップを核とした総胆管結石は本邦で27例が報告されている.今回の症例では,術中所見から胆嚢動脈断端のクリップが総胆管内に引き込まれた可能性が推察された.

BACKGROUND Glucocorticoid was used in thymomas. The purpose of the study was to evaluate the efficacy of intravenous high-dose glucocorticoid (steroid pulse) therapy in patients with previously untreated advanced thymoma. Causes were also sought for a possible underlying mechanism of the effect of steroid on thymoma. METHODS Seventeen patients with invasive thymoma who had not received previous chemotherapy or radiation therapy were enrolled in the study. All cases were treated with 2 courses of glucocorticoid therapy before surgery. Tumor response was assessed by computed tomography (CT) scan 1 week after the steroid pulse therapy. Lymphocytes associated with thymoma were analyzed for their CD4/CD8 phenotype and glucocorticoid receptor (GR). TdT-mediated dUTP-biotin nick-end labeling (TUNEL) staining was used to analyze the apoptotic lymphocytes and epithelial cells. RESULTS The overall response rate to the steroid pulse therapy was 47.1% (8 of 17). The reduction in tumor size was most prominent in type B1 thymomas; there were significant differences between type AB and type B1 thymomas (P = .0234) and type B1 and type B3 thymomas (P = .0068). The reduction in tumor size was accompanied with a marked reduction in the CD4+8+ double-positive immature thymocytes that expressed higher levels of glucocorticoid receptor. Apoptotic changes were observed in both neoplastic epithelial cell and lymphocyte components after glucocorticoid therapy. CONCLUSIONS The efficiency of preoperative steroid pulse therapy in type B1 thymoma was most prominent, which is probably related to the specific effect on GR-rich CD4+8+ double-positive immature lymphocytes, which are abundant in this type of thymoma. Cancer 2006. © 2006 American Cancer Society.

目的. 第一肺癌切除術後に発生した第二肺癌切除術後の予後や合併症を知ることを目的とした. 対象と方法. 第一肺癌根治術後に発生した第二肺癌に対して, 過去10年間に当科で手術を施行した10例について検討した. 結果. 第一肺癌から第二肺癌出現までの期間は平均7年9ヶ月であった. 初回手術は全例で肺葉切除術以上が施行され, 第二手術は部分切除術1例, 区域切除術3例, 残存肺全摘術1例, 対側肺葉切除術が5例であった. 左上葉切除術後に右肺下葉切除術が施行された症例が, 術後右心不全, 肺水腫を併発し, 術後1ヶ月呼吸不全で死亡した. 結論. 両側肺葉切除術は術後の心肺合併症を引き起こす可能性があり, 術後には心肺機能不全に対する十分な注意が長期的に必要である.

Much evidence has accumulated that the epidermal growth factor receptor (EGFR) and its family members are strongly implicated in the development and progression of lung cancers. Somatic mutations of the EGFR gene were found in about 25–40% of Japanese lung cancer patients. More recently, erbB2 mutations are found in about 4% of European-derived lung cancer patients. We have investigated EGFR and erbB2 mutation status in 95 surgically treated nonsmall cell lung cancer (NSCLC) cases from Nagoya City University Hospital. Seventy-five adenocarcinoma cases were included. The presence or absence of EGFR and ernB2 mutations of kinase domains were analyzed by reverse transcription polymerase chain reaction (RT-PCR) amplifications and direct sequences. We have also investigated erbB2 mutation status in 27 surgically treated NSCLC cases followed by treatment with gefitinib from Kinki-chuo Chest Medical Center. EGFR mutations (CTGfiCGG; L858R) were found from 14 of 95 lung cancer patients. We also detected the deletion 1a-type mutations from 9 patients and deletion 4-type mutations from 6 patients in exon 19. In exon 20, 4 mutations including 2 novel mutations were found. Total EGFR mutations were present in 35 patients (36.8%). These mutation statuses were significantly correlated with gender (women 73.3% vs. men 20%, p < 0.0001), smoking status (never smoker 69.4% vs. smoker 16.9%, p < 0.0001), pathologic subtypes (adenocarcinoma 45.1% vs. nonadenocarcinoma 12.5%, p 5 0.0089) and differentiation status of the lung cancers (well 51% vs. moderately or poorly 18.4%, p 5 0.0021). On the other hand, erbB2 mutation was only found from 1 of 95 patients, at exon 20. This patient was female and a never smoker with adenocarcinoma. This 12 nucleotide insertion mutation (2324–2325 ins ATACGTGATGGC) was located in the exon 20 at kinase domain (775–776 ins YVMA). There was no erbB2 mutation in 27 gefitinib-treated NSCLC patients. In total, we have found only 1 erbB2 mutation from 122 (0.8%) Japanese NSCLC patients. There was a significantly higher erbB2 positive (21/31) ratio in EGFR mutant patients (13/25, 52.0%) compared to EGFR wild-type patients (10/ 62, 16.1%; p 5 0.0247). The NSCLC specimen with erbB2 mutation showed 11 immunoreactivity. The EGFR mutation status might correlate with the clinicopathologic features related to good response to gefitinib, such as gender, smoking history and pathologic subtypes of lung cancers. However, erbB2 mutation is rare from Japanese lung cancer and is of limited value for molecular target therapy. ' 2005 Wiley-Liss, Inc.

Thymic carcinoids are classified into three categories: (1) nonsecretory tumors, (2) hormonal secretory tumors, and (3) tumors associated with multiple endocrine neoplasia type 1. We report a rare case with adrenocorticotropic hormone secreting thymic carcinoid with multiple endocrine neoplasia type 1. Radiologic examination showed an anterior mediastinal mass and a parathyroid tumor. Blood analysis revealed high levels of parathyroid hormone and adrenocorticotropic hormone. Urine cortisol and 17-hydroxycorticoids levels were also elevated. Extended thymectomy was performed. Subsequently adjuvant radiation therapy and parathyroid tumor resection were performed. A germline mutation of exon 7 in the multiple endocrine neoplasia type 1 gene was detected and a somatic mutation of exon 9 was demonstrated in the thymic tumor.

Mutations of the epidermal growth factor receptor (EGFR) gene have been reported in non-small cell lung cancer (NSCLC), especially in female, never smoker patients with adenocarcinoma. Some common somatic mutations in EGFR, including deletion mutations in exon 19 and leucine to arginine substitution at amino acid position 858 (L858R) in exon 21, have been examined for their ability to predict sensitivity to gefitinib or erlotinib. On the other hand, previous report has shown that the insertion mutation at exon 20 is related to gefitinib resistance. We investigated the exon 20 EGFR mutation statuses in 322 surgically treated non-small cell lung cancer cases. Two hundred and five adenocarcinoma cases were included. The presence or absence of EGFR mutations of kinase domains was analyzed by direct sequences. EGFR insertion mutations at exon 20 were found from 7 of 322 (2.17%) lung cancer patients. We also detected the 18 deletion type mutations in exon 19, and 25 L858R type mutations in exon 21. There was a tendency towards higher exon 20 insertion ratio in never smoker (never smoker 4.4% versus smoker 1.3%, p=0.0996) and female (female 4.5% versus male 1.3%, p=0.0917). Two exon 20 insertion cases were treated with gefitinib and failed to response. EGFR insertion mutation in exon 20 could not be ignored from Japanese lung cancers.

Overexpression of the epidermal growth factor receptor (EGFR) is caused by EGFR gene amplification and is sometimes associated with expression of a variant EGFR (deletion exon 2-7 or EGFRvIII). EGFRvIII mutation has oncogenic potential and is investigated as a potential therapeutic target. We genotyped the EGFRvIII mutation status in 252 surgically treated lung cancer cases. The presence or absence of EGFRvIII mutation was analyzed by real-time quantitative polymerase chain reaction (PCR) with mutation specific sensor and anchor probes. EGFR copy number was evaluated with PCR-based assay. EGFR mutation status at kinase domain has been examined and reported. EGFRvIII mutation was found on 8 of 252 patients. All patients were male, smokers, and 7 had squamous cell carcinoma. The mutation status was significantly correlated with pathological subtypes (squamous cell carcinoma vs. adenocarcinoma, p=0.0114). Sixty EGFR mutations at kinase domain exclusively existed with EGFRvIII mutations. EGFR gene copy number was significantly higher in EGFRvIII mutant (4.711+/-4.968) than in non-EGFRvIII mutant (2.284+/-1.224) (p=0.0001). EGFRvIII gene mutation might be one of the mechanisms of increased EGFR copy number. Further studies are needed to confirm the mechanisms of EGFRvIII mutations for possible anti-EGFR therapy for lung cancer.

Several studies have suggested that epidermal growth factor receptor (EGFR) gene mutation, EGFR gene amplification, and some other biomarkers may be predictors of gefitinib sensitivity. We analyzed EGFR mutation and EGFR copy number in 22 gefitinib-treated non-small cell lung cancer (NSCLC) cases and their relation to the survival of patients. We also studied 143 gefitinib-naïve Japanese NSCLC cases. The erbB2 copy number was also studied in 59 gefitinib-naïve NSCLC cases. In gefitinib-treated patients, the presence of EGFR mutation was associated with a higher response rate to gefitinib and a longer overall survival, but the increased EGFR gene copy number was not. In gefitinib-naïve cases, EGFR mutation but not EGFR gene copy number was significantly correlated with gender, pathological subtypes, and smoking status. The erbB2 copy number was not significantly correlated with the EGFR mutation or EGFR copy number in 59 cases. In conclusion, EGFR mutation was a better predictor of clinical outcome in gefitinib-treated patients than the EGFR gene copy number.

Human kallikrein 11 (hK11) is a putative serine protease of the human kallikrein gene family. A recently developed method for measuring hK11 suggested that the hK11 level was an indicator of favorable prognosis in patients with ovarian cancer. We have investigated hK11 messenger RNA (mRNA) levels in lung cancer.This study included 64 lung cancer cases. The hK11 mRNA levels were quantified by real-time reverse-transcriptase polymerase chain reaction using LightCycler.The hK11 mRNA levels were lower in tumor tissues from lung cancer (1.88 +/- 6.314) compared with adjacent nonmalignant lung tissues (8.271 +/- 9.002; n = 45; P = 0.0001). No significant difference was found among sex, age, clinical stages, tumor status, and lymph node metastasis. The hK11 mRNA levels were lower in moderately or poorly differentiated adenocarcinoma lung cancer (0.452 +/- 1.614) compared with well-differentiated adenocarcinoma lung cancer (1.728 +/- 2.829; P = 0.0281). The group with low hK11/gylceraldehyde 3-phosphate dehydrogenase levels (0.6) had a significantly worse prognosis compared with the group with high hK11/gylceraldehyde 3-phosphate dehydrogenase levels (0.6; log-rank test, P = 0.0131; Breslow-Gehan-Wilcoxon test, P = 0.0172).Cox proportional hazard regression model (multivariate analysis) indicated that pathologic stages (P = 0.0443) and low hK11 expression levels (P = 0.0469) were the prognostic factors of lung cancers. However, additional studies and a longer follow-up are needed to confirm the impact of hK11 on the biologic behavior of the tumor.

We have investigated 26 adenosquamous lung cancer tissues and found that four EGFR mutations were mainly in female and non-smoker lung cancer. However, EGFR mutation at kinase domain was exclusive with K-ras mutation. However, smoking and gender status could affect the occurrence of EGFR mutation. There was no difference in EGFR mutation status if analysis was performed in never smoker female subgroup.

Somatic mutations of the PIK3CA (phosphatidylinostitol 3-kinase catalytic subunit) gene have been found in human cancer patients. Previous reports suggested that about 4% of lung cancers harbored PIK3CA gene mutations. However, the clinico-pathological background for PIK3CA gene mutations has not yet been investigated in lung cancer. We have genotyped the PIK3CA gene in Japanese lung cancer patients. The study included 235 lung cancer cases surgically removed in Nagoya City University Hospital. The two PIK3CA mutation hot spots (exon 9 and exon 20) were analyzed by real time polymerase chain reaction (PCR)-based assay. The data were confirmed by direct sequencing. In exon 9, somatic mutation was found in eight patients (3.4%). The mutation included three E542K (G1624A), three E545K (G1633A), one E542Q (G1624C), and one Q546K (C1636A). However, in exon 20, there was no mutation in our lung cancer patients. PIK3CA mutations were not correlated with gender (women versus men, p=0.4162), age (or =60 versus60, p=0.8027), or smoking status of the lung cancers (never versus smoker, p=0.5666). PIK3CA mutation incidence was significantly lower in adenocarcinoma (2/135, 1.5%) than in squamous cell carcinoma (5/77, 6.5%, p=0.0495). Among eight patients with a PIK3CA mutation, three patients also harbored an EGFR somatic mutation. PIK3CA gene mutations were rare in lung cancer; rarer in adenocarcinoma. Further functional analyses of the PIK3CA mutations are warranted to study if they could be the target of therapy for the lung cancer.

Somatic mutations of the epidermal growth factor receptor (EGFR) gene were found in about 25-40% of Japanese lung cancer patients. These mutations are associated with clinical and radiographic responses to EGFR tyrosine kinase inhibitors. Most common mutation are arginine for leucine substitution at amino acid 858 (L858R) and exon 19 deletions, especially deletion type 1 mutation. We investigated these EGFR mutation statuses in 575 surgically treated non-small cell lung cancer (NSCLC) cases. Three-hundred and sixty-two adenocarcinoma cases were included. The presence or absence of EGFR mutations of kinase domains was analyzed by genotyping analysis (TaqMan assay; n=386, and LightCycler assay; n=98) and sequences (n=91). EGFR mutations (CTG; CGG; L858R) were found from 63 of 575 lung cancer patients. We also detected the deletion 1a type mutations (2235-2249 del GGAATTAAGAGAAGC) from 39 patients and deletion 1b type mutations (2236-2250 del GAATTAAGAGAAGCA) from 15 patients in exon 19. These mutation statuses were significantly correlated with gender, smoking status (never smoker versus smoker), and pathological subtypes (adenocarcinoma versus non-adenocarcinoma). L858R mutation (p

Background The presence of epidermal growth factor receptor (EGFR) mutations in gefitinib-naive lung cancer patients has been reported to be higher in females, in non-smokers, in Japanese, and in adenocarcinoma patients, especially in bronchioloalveolar carcinoma (BAC). To further investigate the prevalence of EGFR mutations in relation to pathological factors, we evaluated EGFR mutations in series of Japanese adenocarcinoma patients who had never been treated with gefitinib. Methods In the previous studies, we examined mutation status in the tyrosine kinase domain of EGFR, exon18 through exon21, in 112 primary lung adenocarcinoma samples. Using these data, adenocarcinomas were histologically classified according to the presence or absence of bronchioloalveolar components. Results Among 112 patients, 48 had adenocarcinoma with BAC components. Those with adenocarcinomas with BAC components had higher frequency of EGFR mutation (28/48, 58%) than those with non-BAC adenocarcinoma (24/64, 37%, P = 0.036). Male patients had the same trend; 12/23 (52%) male patients with adenocarcinoma with BAC components and 10/47 (21%) of those with non-BAC adenocarcinoma had EGFR mutation (P = 0.0135) but there was no correlation between the EGFR mutation status and with/without BAC components in 42 female patients (P = 0.30). Among 11 male non-smokers, patients with adenocarcinoma with BAC components had a tendency to have EGFR mutation more frequently than those with non-BAC adenocarcinoma (P = 0.061). In clear contrast, the frequency of EGFR mutation did not differ significantly between male smoker patients with adenocarcinoma with BAC components and those with non-BAC. Among patients with adenocarcinoma with BAC components, those with adenocarcinoma with EGFR gene mutation had a significantly better 5 year survival than those with adenocarcinoma with wild-type (85.7 versus 46.0%, P = 0.0017). Conclusions Adenocarcinomas with BAC components in male non-smokers seem to predict the presence of EGFR mutation. Half of female adenocarcinoma patients with EGFR mutation exhibit adenocarcinomas with non-BAC suggesting a different behavior from those in males. The prognosis of patients with adenocarcinoma with BAC components with EGFR gene mutation is predicted to be better than that of patients with adenocarcinoma with BAC components with wild-type EGFR gene.

Background Recently, somatic mutations of the epidermal growth factor receptor ( EGFR ) gene and Braf gene were found in patients with lung cancer. These mutations might be correlated with a clinical response to molecular target therapy. Although a few Caucasian lung cancer patients harbored BRAF mutations, there have been no reports about the BRAF mutation in Japanese patients with lung cancer. Materials and methods We investigated BRAF mutations in Japanese lung cancer patients. The study included 129 surgically removed lung cancer cases from Nagoya City University Hospital. Braf , EGFR , and erbB2 mutations also were analyzed by reverse transcript polymerase chain reaction (RT-PCR) and direct sequencing. Results In exon 15, one BRAF mutation (1796 thymine to adenine; V599E) was found in nonsmoking woman with well-differentiated adenocarcinoma. We detected the 43 EGFR mutations, including 19 at exon 19 and 20 at exon 21 from the 129 patients analyzed (33.3%). We also detected one erbB2 mutation from 76 patients analyzed. All these mutations existed exclusively. Conclusions V599E BRAF mutation was uncommon in Japanese lung cancer. All three genes mutations were predominantly found in female nonsmoking subjects with adenocarcinomas. However, completely exclusive mutation status would help us to choose custom-made molecular target therapy for the lung cancer.

Summary Epidermal growth factor receptor ( EGFR ) gene mutations are frequently detected in lung cancer, especially in adenocarcinoma, in females, and non-smoking patients. EGFR mutations are closely associated with clinical response to EGFR tyrosine kinase inhibitor. Bronchioloalveolar carcinoma (BAC) appearance is a good predictor of response to this agent. Noguchi et al. subdivided small peripheral adenocarcinoma of the lung into two groups. One group was characterized with tumor cell growth replacing the normal alveolar cells with varying degree of fibrosis (types A–C), and the other shows non-replacing and destructive growth (types D–F). Using probes for the 13 mutations which have been previously described, we have genotyped the EGFR gene status in surgically resected atypical adenomatous hyperplasias (AAH) and small peripheral adenocarcinomas up to 2cm in diameter using TaqMan PCR assay. In 95 small-sized adenocarcinomas, the EGFR mutations were detected in 37 patients (38.9%), and no mutations were found in five AAHs. In small peripheral adenocarcinomas, EGFR mutations were found 47.1% of types A, B, or C adenocarcinomas; it was less frequent (16%) in Noguchi's types D, E or F adenocarcinomas. These results suggest that type D, F adenocarcinomas are not derived from the less malignant types A–C adenocarcinomas; rather, they have arisen de novo by distinct mechanisms. Although types A and B adenocarcinomas are almost 100% cured by surgery, some type C adenocarcinoma show lymph node metastasis and relapse. EGFR mutation analysis may help identify patients who will respond to treatment with tyrosine kinase inhibitors, e.g., gefitinib.

Purpose: Recently, somatic mutations of the epidermal growth factor receptor (EGFR) gene were found in ∼25% of Japanese lung cancer patients. These EGFR mutations are reported to be correlated with clinical response to gefitinib therapy. However, DNA sequencing using the PCR methods described to date is time-consuming and requires significant quantities of DNA; thus, this existing approach is not suitable for a routine pretherapeutic screening program. Experimental Design: We have genotyped EGFR mutation status in Japanese lung cancer patients, including 102 surgically treated lung cancer cases from Nagoya City University Hospital and 16 gefitinib-treated lung cancer cases from Kinki-chuo Chest Medical Center. The presence or absence of three common EGFR mutations were analyzed by real-time quantitative PCR with mutation-specific sensor and anchor probes. Results: In exon 21, EGFR mutations (CTG → CGG; L858R) were found from 8 of 102 patients from Nagoya and 1 of 16 from Kinki. We also detected the deletion mutations in exon 19 from 7 of 102 patients from Nagoya (all were deletion type 1a) and 4 of 16 patients from Kinki (one was type 1a and three were type 1b). In exon 18, one example of G719S mutation was found from both Nagoya and Kinki. The L858R mutation was significantly correlated with gender (women versus men, P < 0.0001), Brinkman index (600 ≤ versus 600>, P = 0.001), pathologic subtypes (adenocarcinoma versus nonadenocarcinoma, P = 0.007), and differentiation status of the lung cancers (well versus moderately or poorly, P = 0.0439), whereas the deletion mutants were not. EGFR gene status, including the type of EGFR somatic mutation, was correlated with sensitivity to gefitinib therapy. For example, some of our gefitinib-responsive patients had L858R or deletion type 1a mutations. On the other hand, one of our gefitinib-resistant patients had a G719S mutation. Conclusions: Using the LightCycler PCR assay, the EGFR L858R mutation status might correlate with gender, pathologic subtypes, and gefitinib sensitivity of lung cancers. However, further genotyping studies are needed to confirm the mechanisms of EGFR mutations for the sensitivity or resistance of gefitinib therapy for the lung cancer.