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Volume 49 (2009)
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Volume 49, Issue 6
Displaying 1-24 of 24 articles from this issue
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Review Article
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Miki Sugiura, Yukihiro Yoshida, Jun Nakajima, Kazuhiro Kakimi, Hiromi ...2009 Volume 49 Issue 6 Pages 823-830
Published: 2009
Released on J-STAGE: December 09, 2009
JOURNAL OPEN ACCESSLung cancer is the leading cause of cancer death in Japan and still requires more effective treatments. The potential of cancer vaccines is promising, although there are no satisfactory protocols available for lung cancer at present. However, encouraging evidence of clinical benefits from cancer vaccines is beginning to accumulate in several lung cancer trials. Here, we review recent advances in lung cancer vaccine trials, especially 5 phase III cancer vaccine trials including MAGE-A3, EGF, MUC-1, Belagenpumatucel-L, and MVA-MUC1-IL-2. In addition, we will focus on several phase I or II studies that take into account new strategies to overcome immune suppressive microenvironment and suggest future directions of lung cancer vaccines.
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Original Article
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Yukihiro Sugimoto, Hiroshi Semba, Shinji Fujii, Tomoki Tanaka, Eri Sat ...2009 Volume 49 Issue 6 Pages 831-835
Published: 2009
Released on J-STAGE: December 09, 2009
JOURNAL OPEN ACCESSBackground. Gefitinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) and has a response rate of 18.4% for recurrent non-small cell lung cancer (NSCLC) which has already been treated. There are few reports of effectiveness of retreatment after progressive disease (PD). Materials and Methods. We gave gefitinib to patients with recurrent NSCLC which had already been treated and in whom no response disappeared after initial good response. We attempted to treat with gefitinib twice or more in these cases of progressive disease from July 2002 to July 2006. We retrospectively examined 24 cases (3 men and 21 women) interms of performance status (PS), the tumor markers, and the antitumor response. Results. The subjects were between 54 and 84 years of age (median: 62 years old). They were all non-smokers and were stage IIIB and IV adenocarcinoma. From the 1st line to the 5th line, partial response (PR) was obtained in 12/3/0/0/0, stable disease (SD) in 11/18/8/3/1, while PD was seen in 0/3/1/2/0 respectively. Improvement, unchanged and deterioration of PS were seen in 12.5-29.2%/40.0-87.5%/0% respectively. The tumor markers tended to improve during the 1st and the 2nd line treatment, but tended to deteriorate from the 3rd line and thereafter. We conducted EGFR mutation analysis, and exon 19/exon 20/non-mutation was 4/4/3 respectively. The response rate to the 1st line treatment was 50%/50%/33%. Disease control rate was 100% regardless of EGFR mutation. Conclusion. These results suggested that gefitinib is most effective in the 1st and the 2nd line treatment. We want to expect prospective study from now on. We need to consider carefully the appropriate subjects and the timing of readministration of gefitinib in the clinical setting.
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Kikuo Nakano, Takeshi Masuda, Takashi Yoshida, Kazuhide Fukuhara2009 Volume 49 Issue 6 Pages 836-843
Published: 2009
Released on J-STAGE: December 09, 2009
JOURNAL OPEN ACCESSObjective. To clarify issues when terminating chemotherapy and shifting to palliative care for patients with recurrent non-small cell lung cancer (NSCLC) in the terminal stage. Methods. We conducted a retrospective review of patients who had had the first line of chemotherapy from January, 2002 to September, 2007, continued to have had the second or more lines of chemotherapy regimens, and had died by April, 2008. We carefully examined the patients' backgrounds, administration schedule of chemotherapy and the response to it, and the timing of having terminated chemotherapy and having been referred to palliative or hospice care. Results. Patients were 49 men and 12 women with a median age of 64 years old. A total of 25 patients (41%) had chemotherapy within 30 days of their death. Patients received platinum-based therapy in the first-line (66%), and gefitinib therapy in all lines. The response rate decreased in each subsequent line of chemotherapy, and the response rate and the median overall survival period because of the last treatment (between the second and sixth lines) were 10% and 3 months respectively. The poor performance status (56%), and complications and/or toxicity (32%) were the causes for termination of chemotherapy in the last month of life. Comparing patients who had chemotherapy within 30 days of their death and those who did not, the former had a shorter period from referral to a palliative care department to death (an average of 22.4 days versus 61.9 days), and they had significantly lower proportion of death in hospices (P=0.0373). Conclusion. Shifting to palliative or hospice care is delayed when chemotherapy is given to patients with non-small cell lung cancer just before death, because it has strong toxicity and minimum efficacy.
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Case Report
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Hidehito Matsuoka, Takeshi Hatta, Takeyuki Kushima2009 Volume 49 Issue 6 Pages 844-846
Published: 2009
Released on J-STAGE: December 09, 2009
JOURNAL OPEN ACCESSBackground. Large cell lung cancer is seldom complicated with chronic myelogenous leukemia (CML). Case. A 59-year-old CML man who had received chemotherapy for 3 years with 400 mg imatinib mesylate per day presented because a 50×45 mm tumor shadow was found in the right upper lobe on a chest X-ray film. Chest computed tomography showed right hilar lymphadenopathy and severe emphysematous change. Spirometry revealed mild obstructive change. The mass was diagnosed as primary lung cancer by bronchofiberscopy. A right upper lobectomy with ND2a lymph node dissection was performed without stopping imatinib mesylate intake. The postoperative diagnosis was T2N2M0, p-stage IIIA large cell cancer with single tracheobronchial lymph node metastasis. Moderate edema was observed on the face and upper limbs on the second postoperative day, but twice daily dose of 20 mg furosemide improved the edema within 2 days. Insertion of a cricothyroidotomy needle (Trahelper®) enabled removal massive sputum. The patient had no other complications and was discharged on the 20th postoperative day. Conclusion. Imatinib mesylate is highly effective in most patients with CML. Patients who respond well to imatinib mesylate are likely to live substantially longer than those who are not treated with previous therapies. Therefore imatinib mesylate is indicated in certain cases of malignant diseases including lung cancer. However caution is needed because imatinib mesylate may develop some unexpected complications such as large cell lung cancer in the postoperative period and there are few data about combination use of imatinib mesylate and other cytotoxic agents.
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Yoshihiro Kanemitsu, Masahito Emura, Takaya Nakamura, Shigeki Sakai, Y ...2009 Volume 49 Issue 6 Pages 847-851
Published: 2009
Released on J-STAGE: December 09, 2009
JOURNAL OPEN ACCESSBackground. Clear cell carcinoma of the lung (CCCL) is a tumor predominantly consisting of clear cytoplasm. The incidence of CCCL is from 0.3 to 3.4 percent of all types of primary lung cancer. Case. A 66-year-old man was with hemodialysis for chronic renal failure presented with left hemiplegia and admitted to our hospital. Brain CT showed multiple masses and chest X-ray showed a mass in the apex of the left lung. Resection of the brain tumor was performed to improve his activities of daily living (ADL) and to make a diagnosis. Hematoxylin and eosin stain showed clear cytoplasm in the metastatic brain tumor cells with partial appearance of cluster of differentiation 10 (CD 10), which frequently develops with renal cancer immunohistochemically. We suspected brain metastasis of renal cell carcinoma from histological and immunohistochemical findings, although no mass was radiologically detected in the kidneys. The mass of the lung continued to enlarge in spite of interferon therapy, and as a result of the histologic study of the specimen obtained from CT-guided percutaneous biopsy, we regarded the tumor as CCCL. He died on the 102nd day. Autopsy revealed that the lung tumor was the largest of all the tumors, but no abnormalities were found in the kidneys. Pathologically the lung and metastasic tumors were mainly composed of cancer cells with clear cytoplasm and we diagnosed it as a large cell variant of CCCL without any signs of differentiation such as formation of cancer pearls, intercellular bridging or glandular configuration. Conclusion. We reported a large cell variant of CCCL, based on the autopsy-proven findings.
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Kyoko Kudo, Miiru Izumi, Koichi Takayama, Satoru Fukuyama, Kentaro Tan ...2009 Volume 49 Issue 6 Pages 852-856
Published: 2009
Released on J-STAGE: December 09, 2009
JOURNAL OPEN ACCESSBackground. Paraneoplastic brainstem encephalitis and subacute sensory neuropathy are included in paraneoplastic neurological syndrome (PNS) and are rarely accompanied by small cell lung cancer. PNS is often difficult to diagnose or to treat them. Case. A 71 year-old man presented with syncope, diplopia, blepharoptosis and dysphagia and was admitted to our hospital. Brain MRI was normal. Chest CT showed mediastinal lymphadenopathy. The lymph node biopsy yielded a diagnosis of small cell lung cancer (cT4N2M0, stage IIIB). And as for the neurological symptoms, the presence of a serum anti-Hu antibody supported the diagnosis of paraneoplastic brainstem encephalitis and subacute sensory neuropathy. Platinum-based chemotherapy resulted in partial response but the neurological symptoms deteriorated. Conclusion. We reported a case of paraneoplastic brainstem encephalitis and subacute sensory neuropathy accompanied by small cell lung cancer. There are various types of paraneoplastic neurological syndrome, and further studies for the treatment of each neurological symptom are required.
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Shingen Nakamura, Noriaki Horiuchi2009 Volume 49 Issue 6 Pages 857-862
Published: 2009
Released on J-STAGE: December 09, 2009
JOURNAL OPEN ACCESSBackground. Drug-induced hypersensitivity syndrome (DIHS) is a drug reaction characterized by fever and multiple organ failure. It is rarely induced by drugs for neuropathic pain. Case. A 74-year-old woman presented with pain in the right side of the chest and was admitted to our hospital in November 2006. She had no history of smoking. After extensive examinations, adenocarcinoma in the right lung with systemic bone metastases (stage IV) was diagnosed. We gave her combination systemic chemotherapy consisting of carboplatin and paclitaxel, but since she could not tolerate it, we switched to treatment with gefitinib, which obtained partial response. Around the time when the chemotherapy regimen was changed, electric-shock-like pain in the lower legs developed. Therefore, we administered carbamazepine and mexiletine consecutively which showed immediate effects relieving the pain. Six weeks after starting gefitinib therapy, the patient developed fever, systemic rash, diarrhea, liver dysfunction, and atypical lymphocytosis. We sequentially discontinued the drugs including gefitinib, that were suspected to be responsible for these complications and administered steroids instead. However the skin rash persisted. Eight weeks after starting gefitinib therapy, the patient developed cytomegalovirus-induced interstitial pneumonia as the complication, and we diagnosed atypical DIHS due to carbamazepine or mexiletine. Gefitinib was not able to be administered again, and she died of lung cancer in July, 2007. Conclusion. The possibility of DIHS should be considered while administering drugs for neuropathic pain to patients with lung cancer, keeping in mind that DIHS can mimic the side effects of gefitinib.
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Kazuhiko Kataoka, Toshiya Fujiwara, Motoki Matsuura, Noritomo Seno2009 Volume 49 Issue 6 Pages 863-867
Published: 2009
Released on J-STAGE: December 09, 2009
JOURNAL OPEN ACCESSBackground. There are few reports of empyema occurring during postoperative adjuvant chemotherapy of the lung cancer. Case. A 74-year-old man was referred to our hospital because of an abnormal shadow on the chest CT. Right upper lobectomy with ND2a lymph node dissection was performed and the pathological diagnosis was primary adenocarcinoma (pT4N0M0, p0d0E0pm1, stage IIIB). Postoperative adjuvant chemotherapy with carboplatin and weekly paclitaxel was performed. On the 14th day of the 4th course, he developed high fever and was admitted. Chest X-ray and CT showed a large amount of pleural effusion in the right side. Chest tube drainage was performed, and the culture of pleural effusion revealed empyema caused by methicillin-resistant Staphylococcus aureus. Despite the continuous irrigation and the administration of vancomycin, CT on the 7th day of the admission showed pleural effusion in the posterior and supradiaphragmatic spaces. Thoracoscopic debridement of the empyema space under minithoracotomy was performed and 3 double-lumen drainage tubes were inserted on the 10th day after admission. We continued intrathoracic lavage and changed medication from vancomycin to linezolid. The drainage tubes were sequentially removed when the culture of the effusion turned negative. The patient was discharged on the 47th day after the operation. He has shown neither the original disease nor recurrence of the empyema for 22 months. Conclusion. There is a possibility of developing empyema during postoperative adjuvant chemotherapy of the lung cancer due to immunosuppression. When the empyema is not improved by conservative therapy, early thoracoscopic debridement must be performed.
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Teruhisa Takuwa, Masaki Hashimoto, Yoshitomo Okumura, Nobuyuki Kondo, ...2009 Volume 49 Issue 6 Pages 868-871
Published: 2009
Released on J-STAGE: December 09, 2009
JOURNAL OPEN ACCESSBackground. Coincidence of a primary lung cancer and pulmonary metastases from other malignancies should be kept in mind at the time of pulmonary resection. Case. Chest CT revealed a small pulmonary nodule (5 mm) in the right upper lobe and swelling of the interlobar lymph node (20 mm) in a 71-year-old man. He underwent resection of the right upper and middle lobes with lymph node dissection. As expected, pathological diagnosis of the lung nodule and the lymph node revealed adenocarcinoma. In addition to the above lesions, multiple microscopic pulmonary metastases of thyroid cancer were found at the time of postoperative detailed histological investigation. No primary thyroid lesion was detected by postoperative examination. Conclusion. Through pathological examination revealed an otherwise undetectable coincident second malignancy.
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Kimitoshi Nawa, Yasushi Nomoto, Koumei Kinoshita, Sukeyuki Nakamura, N ...2009 Volume 49 Issue 6 Pages 872-876
Published: 2009
Released on J-STAGE: December 09, 2009
JOURNAL OPEN ACCESSBackground. Intramedullary metastasis of lung cancer is rare, and no treatment has been established. Case. A 70-year-old man was given a diagnosis of at the end of March 2008, primary lung cancer in the right lower lobe (cT2N0M0, stage IB) and was waiting to undergo surgery. The patient reported neck pain and numbness in the left upper extremity, and after being admitted in early April, urination disorders and complete paralysis of bilateral upper and lower extremities quickly advanced. Cervical magnetic resonance imaging revealed a low signal intensity lesion in C4 indicating metastasis on T1-weighted imaging and a low signal intensity lesion inside the spine on T2-weighted imaging. Symptoms rapidly exacerbated, and 2 days after the diagnosis, the patient died of respiratory failure. Autopsy confirmed a poorly differentiated adenocarcinoma. As the histological findings were the same in the cervical vertebra, cervical spinal cord and lung, metastasis from the lung was suspected. However, the cervical vertebral tumor was not connected to the cervical spinal tumor, and no direct invasion was seen. Conclusion. Intramedullary metastasis of lung cancer has poor prognosis, and no general consensus has been reached regarding its therapy. To establish therapy in the future, accumulation of data from more patients is needed.
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Yukihiro Minagawa, Hideaki Komatsu, Hidenori Itabashi, Osamu Shimooki, ...2009 Volume 49 Issue 6 Pages 877-880
Published: 2009
Released on J-STAGE: December 09, 2009
JOURNAL OPEN ACCESSBackground. Lung cancer is prone to distant metastasis at an early stage. However, metastasis to the gastrointestinal tract appears relatively rare, although the rates of metastasis within the lungs, to lymph nodes and pleura are high. Case. An 85-year-old man with bloody sputum was admitted to the pulmonology department of our institution. Sputum cytology indicated a diagnosis of adenocarcinoma. He exhibited vomiting and was further examined due to symptoms of ileus. The target sign was observed on computed tomography (CT) and an emergency surgery was performed for suspected intussusception. Intussuscepted portions of the small intestine observed at 90 cm and 160 cm from the ligament of Treitz were resected. A tumor detected at 240 cm from the ligament was also resected. On a histologic examination, identical histology of the 3 lesions indicated a small intestinal metastasis of the lung adenocarcinoma. The patient died from the malignancy on postoperative day 101. Conclusion. We report a case of intussusception due to metastasis of lung cancer to the small intestine. In lung cancer patients exhibiting symptoms of ileus, intussusception due to small intestinal metastasis should be considered, and examination, diagnosis and surgical treatment should be performed forthwith.
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Jun Miyagi, Morikazu Akamine, Hidenori Kawasaki, Tsutomu Kawabata, Sei ...2009 Volume 49 Issue 6 Pages 881-884
Published: 2009
Released on J-STAGE: December 09, 2009
JOURNAL OPEN ACCESSBackground. Lung hamartoma with lung cancer has sometimes been reported. Case. Chest computed tomography (CT) in a 70-year-old woman was revealed a 2.0×1.5 cm nodule in the right S3. It was considered to be a lung hamartoma. Periodical CT examination was conducted, and 24 months later, a lesion with ground-glass opacity (GGO) was found in the same lobe as the lung hamartoma. The tumor was resected using video-assisted thoracic surgery (VATS). The post-operative pathologic diagnosis was bronchioloalveolar carcinoma of the lung. After the operation, the patient made a favorable recovery, and has maintained in good condition without recurrence for 5 years to date. Conclusion. The relationship between lung hamartoma and lung carcinoma is not clear. We consider that periodical CT examination contributes to identifying such tumors.
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Itaru Nagahiro2009 Volume 49 Issue 6 Pages 885-889
Published: 2009
Released on J-STAGE: December 09, 2009
JOURNAL OPEN ACCESSBackground. Cardiac tamponade due to malignant pericardial effusion of squamous cell carcinoma of an unknown primary site and its long-term survival is extremely rare. Case. A 51-year-old woman with fatigue and leg edema was referred to our hospital and given a diagnosis of cardiac tamponade in December, 2004, and pericardial drainage revealed bloody effusion. Cytologic diagnosis revealed class V squamous cell carcinoma. We searched carefully for the primary lesion but no lesion was detected. Only high accumulation of fluorodeoxyglucose (FDG) in the posterior pleural surface of the right lung was observed in positron emission tomography (PET) scan, however, retrospective review of a chest CT scan was not able to detect any abnormality in the region. She received 4 courses of chemotherapy of cisplatin and vinorelbine, thereafter, the pericardial effusion has never accumulated and the accumulation of FDG in the right lung has completely disappeared. She is doing well without any sign of recurrence in March, 2009 and she has totally returned to the previous job. Conclusions. This case might be a lung cancer or pleural cancer that could not be detected by CT scan. Cisplatin-based chemotherapy might have contributed to the long-term survival.
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Koh Uyama, Shoji Sakiyama, Hisashi Matsuoka, Hiroaki Toba, Hiromitsu T ...2009 Volume 49 Issue 6 Pages 890-893
Published: 2009
Released on J-STAGE: December 09, 2009
JOURNAL OPEN ACCESSBackground. Although some adenocarcinomas grow slower than other histological types of lung cancer, a lung cancer with a more than 10-year clinical history is rare. Case. A 48-year-old woman was admitted to our hospital because of a liver tumor detected by a medical check up. Chest CT before the liver surgery showed another abnormal lung shadow and she consulted us after the surgery. The same pulmonary lesion was detected on a chest CT about 10 years previously. Video-assisted thoracoscopic surgery (VATS) was first scheduled for a partial resection. Diagnosis of the frozen section showed lung cancer, which led us to perform additional resection of the right middle lobe and a lymph node dissection (ND2a). Histologically, it was diagnosed as mucinous adenocarcinoma and the final pathological stage was pT1N0M0 stage IA. Conclusion. We encountered an adenocarcinoma of the lung which had a clinical history of about 10 years before resection. It is necessary to remember the possibility of a very slow-growing lung cancer when we find an abnormal shadow of the lung that grows gradually over time.
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The 23rd Lung Cancer Workshop
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Hirotaka Osada2009 Volume 49 Issue 6 Pages 894-901
Published: 2009
Released on J-STAGE: December 09, 2009
JOURNAL OPEN ACCESSObjective. MicroRNAs (miRNAs) are small non-coding RNAs, thought to be involved in physiologic and developmental processes by negatively regulating expression of target genes. We assessed alterations of expressions of miRNAs in lung cancers. Methods. We examined the expression of miRNAs using Northern blot and quantitative RT-PCR. We also studied the functions of miRNAs using miRNA expression constructs and antisense oligonucleotides. Results. We found reduced expression of the let-7 family in lung cancers and significantly shorter survival after potentially curative resection in cases with reduced let-7 expression. We also found marked overexpression of the miR-17-92 cluster in lung cancers. Introduction of the expression construct of the miR-17-92 cluster enhanced lung cancer cell growth, whereas inhibition of two members of miR-17-92 cluster, miR-17-5p and miR-20a, with antisense oligonucleotides induced apoptosis selectively in lung cancer cells overexpressing miR-17-92. Conclusion. Our studies suggest that reduced expression of the let-7 family and marked overexpression of the miR-17-92 cluster may play roles in the development of lung cancers. These findings contribute towards better understanding of the anti-oncogenic roles of the let-7 family and oncogenic roles of miR-17-92, which might ultimately lead to future translation into clinical applications.
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Kiyoshi Yanagisawa, Shuta Tomida, Takashi Takahashi2009 Volume 49 Issue 6 Pages 902-909
Published: 2009
Released on J-STAGE: December 09, 2009
JOURNAL OPEN ACCESSWhile widespread metastasis is the major cause of human lung cancer-related deaths, its underlying mechanism remains largely unclear. Our genome-wide comparison of the expression profiles of a highly metastatic lung cancer cell line, NCI-H460-LNM35 (LNM35), and its parental clone NCI-H460-N15 (N15), resulted in the identification of a cancer metastasis signature composed of 45 genes. Through gene ontology analysis, our study also provided insights into how this 45-gene metastasis signature may contribute to the acquisition of metastatic potential. Furthermore, we were able to show that enforced expression of the DLX4 homeobox gene, which was identified as a gene with significant down-regulation in LNM35 as well as with significant association with favorable prognosis for lung cancer patients, markedly inhibited in vitro motility and invasion as well as in vivo metastasis via both hematogenous and lymphogenous routes. We further identified a novel gene, uncharacterized gene, which is associated with lung cancer metastasis. We confirmed upregulation of its gene expression in a significant fraction of human lung adenocarcinomas cases as well as lung cancer cell lines. Taken together, these findings indicate that our combined transcriptome analysis is an efficient approach to searching for genes possessing both clinical usefulness in terms of prognostic prediction in human cancer cases and clear functional relevance for studying cancer biology in relation to metastasis.
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Yoshinori Murakami2009 Volume 49 Issue 6 Pages 910-916
Published: 2009
Released on J-STAGE: December 09, 2009
JOURNAL OPEN ACCESSPurpose. Aberration of a novel tumor suppressor gene, CADM1(cell adhesion molecule 1)/TSLC1(tumor suppressor in lung cancer 1), and its pathological significance in multistage carcinogenesis of non-small cell lung cancer (NSCLC) were investigated. Methods. Methylation of the gene promoter was analyzed by bi-sulfite sequencing or bi-sulfite single-strand conformation polymorphism (SSCP) methods. Functions of CADM1 protein were examined by immunohistochemistry, immunoblotting and immunoprecipitation assays using specific antibodies against CADM1. Specific proteins that interact with CADM1 were identified by yeast 2-hybrid screening. Expression of CADM1 protein was induced in cells by introducing a plasmid containing a full-length CADM1, while CADM1 expression was suppressed by siRNA specific to CADM1 mRNA. Results. We show that CADM1 acts as an epithelial cell adhesion molecule, associates with 4.1B/DAL-1 as well as MPP3 proteins, and participates in formation of an epithelia-like cell structure. In human NSCLC, promoter methylations of the CADM1 and the 4.1B genes are observed in 45 (44%) and 59 (57%) out of 103 tumors, respectively. These methylations are preferentially detected in advanced NSCLC and correlate with poor prognosis. Conclusion. A novel molecular cascade that contains a cell adhesion molecule, CADM1, and an actin-binding protein, 4.1B, as its main components, is critically involved in tumor suppression in human non-small cell lung cancer.
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Yataro Daigo, Yusuke Nakamura2009 Volume 49 Issue 6 Pages 917-927
Published: 2009
Released on J-STAGE: December 09, 2009
JOURNAL OPEN ACCESSProgress in omics science including genomics and proteomics has enabled us to obtain comprehensive gene- and protein-expression profiles of cancers. We performed gene expression profile analysis of 101 archived lung cancers using an originally developed cDNA microarray system. Through a subsequent systematic approach using a tissue microarray containing 900 archived lung cancers, coupled with siRNA experiments, and high throughput enzyme-linked immunosorbent assay techniques covering serum samples from 500 lung cancer patients, as well as serum glycoproteomics that allows the high-throughput recognition of cancer-associated aberrant glycosylations, we have identified a set of oncoantigens and elucidated new cancer pathways that can be regarded as potential targets for the development of cancer biomarkers as well as being useful in the development of small molecule drugs, antibody drugs, peptide/siRNA-based drugs, and cancer vaccines. We here describe our effort to clarify the molecular mechanisms of lung carcinogenesis and to develop new diagnostic and therapeutic techniques based on genome-wide gene/protein expression profiles.
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Koichi Hagiwara2009 Volume 49 Issue 6 Pages 928-933
Published: 2009
Released on J-STAGE: December 09, 2009
JOURNAL OPEN ACCESSPurpose. Increasing number of studies have reported that information on the epidermal growth factor receptor (EGFR) mutation is useful when choosing the regimen for treating non-small cell lung cancers. Currently several methods are used to investigate EGFR mutation. The characteristics of these methods need to be clarified. Method. Summarize the characteristics of the direct sequencing method, the peptide nucleic acid-locked nucleic acid (PNA-LNA) PCR clamp method, the Scorpion amplification refractory mutation system (ARMS) method, the mutant-enriched PCR method, the cycleave method, the high-resolution mutation analysis method and the smart amplification process (SMAP) method using information from the literature. Results. For surgically excised specimens consisting mostly of cancer cells, direct sequencing is a good choice to test the mutation. The cancer cell content of the cytological specimens is often much less. When the presence of the cancer cells is confirmed by a pathological examination, the content of cancer cells is usually more than 1%, and high sensitivity detection methods are able to detect mutations. Conclusion. A high sensitivity detection method should be used to detect EGFR mutations from the cytological specimens. A quality management system for the mutation detection tests needs to be established.
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Kenji Sugio2009 Volume 49 Issue 6 Pages 934-938
Published: 2009
Released on J-STAGE: December 09, 2009
JOURNAL OPEN ACCESSSomatic mutations of the epidermal growth factor receptor (EGFR) gene in lung adenocarcinoma were significantly associated with response to EGFR-tyrosine kinase inhibitors (TKI) such as gefitinib and erlotinib. Various kinds of biomarker which show sensitivity or resistance to EGFR-TKI have also been reported. Increased copy numbers of the EGFR gene predicts sensitivity of TKI, in addition to EGFR mutations. Tumors with K-ras mutation rarely show response to EGFR-TKI, which indicates mutation as a resistance marker. Amplification of the MET gene is another mechanism of acquired resistance to EGFR-TKI. Establishment of the biomarker for EGFR-TKI is important to select patients with good response to EGFR-TKI. In addition, the monitoring of acquired resistance mutation in the tumor during EGFR-TKI treatment provides useful genetic information in developing molecular targeting agents.
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Seiji Yano2009 Volume 49 Issue 6 Pages 939-943
Published: 2009
Released on J-STAGE: December 09, 2009
JOURNAL OPEN ACCESSLung cancer with epidermal growth factor receptor (EGFR)-activating mutations (EGFRmu) responds favorably to the EGFR tyrosine kinase inhibitors (EGFR-TKIs), gefitinib or erlotinib. However, 25-30% of patients with EGFRmu show intrinsic resistance, and even responders invariably acquire resistance to EGFR-TKIs. Two mechanisms, second-site T790M point mutation in EGFR and MET amplification, which contribute to acquired resistance to EGFR-TKIs have been reported. T790M secondary mutation and MET amplification are found in approximately 50% and 20%, respectively, of patients acquiring resistance to EGFR-TKIs. However, the mechanisms of intrinsic resistance and the other 30% of cases of acquired resistance are still unknown. We recently reported hepatocyte growth factor (HGF) induced resistance as the third mechanism of EGFR-TKI resistance. HGF, produced by either cancer cells or host fibroblasts, induced resistance by restoring PI3K/Akt pathway via MET, independently of ErbB3. In addition, inhibitors of HGF-MET successfully overcame HGF-induced resistance to EGFR-TKIs, indicating the importance of HGF-MET signaling as a considerable target for more successful treatment with EGFR-TKIs.
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Seiji Niho2009 Volume 49 Issue 6 Pages 944-949
Published: 2009
Released on J-STAGE: December 09, 2009
JOURNAL OPEN ACCESSObjective. Two randomized trials (INTEREST and V15-32) were conducted to compare gefitinib with docetaxel on overall survival in patients with pretreated advanced non-small cell lung cancer (NSCLC) with the aim of demonstrating non-inferiority. Methods. Patients with advanced NSCLC who failed 1 or 2 chemotherapy regimens including platinum were randomized to gefitinib (250 mg/day) or docetaxel (75 mg/m2 in INTEREST, 60 mg/m2 in V15-32, every 3 weeks). Results. We registered 1466 and 489 eligible patients in INTEREST and V15-32, respectively. Non-inferiority in overall survival was achieved (hazard ratio (HR) 1.020; 96% confidence interval (CI) 0.905, 1.150) according to a predefined criterion (upper CI limit for HR<1.154) in INTEREST. On the other hand, non-inferiority was not achieved (HR 1.12; 95.24% CI 0.89, 1.40) according to a predefined criterion (upper CI limit for HR<1.25) in V15-32. Gefitinib significantly improved overall response rate in V15-32 (22.5% vs 12.8%; p=0.009). Incidence of interstitial lung disease was 5.7% (n=14) and 2.9% (n=7), respectively in V15-32. Conclusion. Non-inferiority in overall survival between gefitinib and docetaxel was demonstrated in INTEREST.
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Miyako Satouchi2009 Volume 49 Issue 6 Pages 950-956
Published: 2009
Released on J-STAGE: December 09, 2009
JOURNAL OPEN ACCESSGefitinib (Iressa®) and Erlotinib (Tarceva®) are epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) that deliver antitumor effects on non-small cell lung cancer (NSCLC) when used alone. Gefitinib was approved for clinical use in July 2002, resulting in an accumulation of data on its efficacy and safety. Erlotinib was approved in December 2007, effectively allowing the use of two EGFR-TKIs in Japan. Although the approved dose of Gefitinib was roughly one-third of the maximum tolerated dose (MTD), Erlotinib's approved dose is the same as its MTD. A simple comparison of outcomes from domestic Phase II studies on the two drugs apparently does not indicate any significant differences in response or survival. Moreover, there exists no clear evidence on how these two drugs, which have similar mechanisms of action as well as common elements in terms of predictive factors of efficacy, toxicity, and resistance mechanism, can be selectively used, i.e., 'Are there any clinical differences in the populations that respond to the drugs, the efficacy or toxicity?' and 'Can one of the drugs be effective on patients who fail to respond or develop resistance to the other?'. The aim of this paper is to examine the selective use of Gefitinib and Erlotinib through past findings.
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Nobuyuki Yamamoto, Takehito Shukuya2009 Volume 49 Issue 6 Pages 957-961
Published: 2009
Released on J-STAGE: December 09, 2009
JOURNAL OPEN ACCESSSeveral clinical trials have shown that epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are effective for EGFR mutation-positive advanced lung cancer, and a phase III study to prove survival benefit is ongoing. EGFR antibody and irreversible EGFR-TKIs are representative EGFR-targeted agents, but not reversible EGFR-TKI. Concerning EGFR antibodies, studies to evaluate cetuximab, matuzumab and nimotuzumab are ongoing. A phase III study of chemotherapy with or without cetuximab has shown promising results in EGFR-positive non-small cell lung cancer (NSCLC) patients. Concerning irreversible EGFR-TKIs, phase II and III studies of HKI-272, BIBW-2992, PF-299804 are being conducted for second line or more advanced treatment of NSCLC. We hope that development of these drugs will be effective in the treatment of lung cancer.
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