Naohiro Nose

Association Between Estrogen Receptor-{beta} Expression and Epidermal Growth Factor Receptor Mutation in the Postoperative Prognosis of Adenocarcinoma of the Lung

PURPOSE Adenocarcinoma of the lung unrelated to a smoking habit occurs more frequently in women than men, thus suggesting an association between female hormones and development of these tumors. The aim of this study was to elucidate the correlation between expression of estrogen receptor (ER) and clinicopathologic factors, including a mutation in the tyrosine kinase domain of epidermal growth factor receptor (EGFR), and prognosis in adenocarcinoma of the lung. PATIENTS AND METHODS This study evaluated 447 resected primary lung adenocarcinoma specimens. The expression of ERalpha and ERbeta was evaluated with an immunohistochemical method. The EGFR mutation was evaluated with polymerase chain reaction. RESULTS A strong cytoplasmic expression of ERalpha and nuclear expression of ERbeta were detected in 49.4% and 48.5% of all patients, respectively. A strong nuclear expression of ERbeta was independently associated with the EGFR mutations (odds ratio = 2.947; 95% CI, 1.97 to 4.57; P < .001) and good differentiation (odds ratio = 1.84; 95% CI, 1.21 to 2.80; P = .004) and was correlated with an increasing disease-free survival in patients with EGFR mutations (hazard ratio = 2.18; 95% CI, 1.18 to 4.06; P = .014). However, no prognostic significance was identified in patients without EGFR mutations. No clinicopathologic and/or prognostic significance of a strong expression of cytoplasmic ERalpha was found. CONCLUSION A strong nuclear expression of ERbeta correlates with EGFR mutations, and its favorable prognostic significance was influenced by the EGFR mutations in adenocarcinoma of the lung.

Acquired resistance to gefitinib: the contribution of mechanisms other than the T790M, MET, and HGF status.

BACKGROUND Some types of somatic mutation of the epidermal growth factor receptor (EGFR) gene in non-small cell lung cancer (NSCLC) are associated with a significant clinical response to a tyrosine kinase inhibitor (TKI). However, most of the patients with this type of sensitive mutations in their tumor show acquired resistance during the TKI treatment. METHODS The mutations in exons 19-21 of the EGFR gene were examined in both the pre-treatment and the post-treatment gefitinib resistant tumors in 10 patients with lung adenocarcinoma. Eight patients were recurrent cases after surgery, and two patients were non-surgical cases whose tumor specimens were obtained from the metastatic lymph node and endobronchially invading tumor. RESULTS In 10 patients, 5 patients had a deletion in exon 19 and another 5 did L858R mutation in exon 21 of EGFR in gefitinib pre-treatment tumors. The mutation status did not change in the gefitinib-resistant tumors. In 7 of 10 patients, the gefitinib-resistant tumors had a secondary T790M mutation, which was not detected in the gefitinib pre-treatment tumors. In one patient, only one of the 4 gefitinib-resistant tumors showed the T790M mutation. Neither other novel secondary mutations of EGFR nor the K-ras were observed in their gefitinib-resistant tumors. Neither MET gene amplification nor HGF were observed in their gefitinib-resistant tumors without T790M mutation. CONCLUSIONS The T790M mutation in the EGFR is relatively common in the patients with acquired resistance to gefitinib. However, mechanisms other than T790M, MET, and HGF status are involved in resistance to gefitinib.

Expression of estrogen receptor beta predicts a clinical response and longer progression-free survival after treatment with EGFR-TKI for adenocarcinoma of the lung.

PURPOSE Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (EGFR-TKI) demonstrates a dramatic clinical response for the lung adenocarcinoma patients harboring a somatic mutation of EGFR. Such EGFR mutations are frequently found in adenocarcinoma with a strong expression of estrogen receptor (ER) beta, which has been shown to correlate with a favorable prognosis for the patients with EGFR mutations. The aim of this study is to elucidate the correlation between expression of ER beta and the therapeutic effect of EGFR-TKI in adenocarcinoma of the lung. PATIENTS AND METHODS Forty-three patients who were treated with EGFR-TKI for adenocarcinoma of the lung were evaluated. The expression of ER beta and the EGFR mutation were evaluated by immunohistochemistry and the polymerase chain reaction, respectively. Patients divided into two groups by the nuclear expression of ER beta. The clinical response and survival data were compared between the two groups. RESULT Strong (S) and weak (W) expression of ER beta was observed in 21 and 22 patients, respectively. EGFR mutations were detected in 30 (69.8%) cases. The S group had more frequent EGFR mutations than the W group (85.7%, 54.5%, p=0.045). The S group had better response rate (p=0.006) and longer progression-free survival (PFS; p=0.001) than the W group. Even in a limited analysis in the patients with EGFR mutations, the S group had tended to have a better response rate (77.8%, 41.7%, p=0.063), and significant longer PFS (p=0.012) than the W group. CONCLUSION A strong expression of ER beta predicts a good clinical outcome for patients with adenocarcinoma of the lung after treatment with EGFR-TKI. This suggests that the expression status of ER beta can be a candidate surrogate marker for EGFR-TKI treatment of patients with adenocarcinoma of the lung. Further investigation will be necessary to identify biomarkers using a larger cohort of patients in a prospective study.

Expression of cytochrome P450 in non-small cell lung cancer.

Lung cancer accounts for most of cancer-related deaths in both men and women. Lung cancer is also associated with cigarette smoking that exposes the individual to carcinogenic chemicals. Normally, CYP enzymes (cytochrome P450s) metabolize carcinogens to inactive derivatives, however, occasionally the action of CYP enzymes leads to development of more potent carcinogens. In addition to the metabolism of carcinogenic compounds, CYP enzymes are also involved in the activation and/or inactivation of agents, which are used in the treatment of lung cancer. Therefore, the local level of CYP enzymes in lung cancer and surrounding tissues could be an important determinant in the efficacy of anticancer drugs. Furthermore, the expression of CYP19 (aromatase), estrogen synthesis P450, was found in more than 80 percent of non-small cell lung cancers. Lung cancer was also found to frequently express CYP24A1 that converts 1 alpha, 25-dihydroxyvitamin D3 to its inactive 24-hydroxylated derivatives. The understanding of the local expression of CYP enzymes in tumor tissues is important in the development of better treatment for lung cancer and a standardized treatment, tailor-made, for individual patients.

Leiomyoma originating from the extrapleural tissue of the chest wall

We describe a rare case of leiomyoma of the chest wall in a 55-year-old female. Computed tomography showed a well-circumscribed neoplasm with a diameter of 2 cm in the right chest wall. The tumor was excised with video-assisted thoracic surgery. Histopathology confirmed that the tumor was leiomyoma arising from the microvascular smooth muscle in the chest wall. We present the immunohistochemical profiles of the tumor in detail, critically reviewing the previously reported cases.

Pulmonary dirofilariasis in a 59-year-old man

We present a case of a human pulmonary dirofilariasis in a 59-year-old man. At the medical examination, a chest computed tomography (CT) revealed a mass, measuring 18 × 15 mm in diameter, with an irregular margin on the bottom of the right lower lobe. We could not neglect the possibility of a primary lung cancer, and therefore, a lung partial resection was performed under video-assisted thoracoscopic surgery. The intra-operative pathological findings revealed inflammatory granuloma with coagulation necrosis and no malignant cells. The permanent pathological examination showed occlusion of the peripheral pulmonary artery by worms and formation of a necrotic mass surrounded by reactive inflammation and hemorrhage. Human pulmonary dirofilariasis is an extremely rare zoonotic infection, and sometimes it is difficult to distinguish it from a primary lung cancer on radiographic findings.

Gefitinib and a ventriculo-peritoneal shunt to manage carcinomatous meningitis from non-small-cell lung cancer: Report of two cases

The prognosis of patients with carcinomatous meningitis from non-small-cell lung cancer (NSCLC) remains poor, and the available treatment options for the lung cancer do not relieve the severe symptoms of this sequela. We report the successful treatment of two cases of carcinomatous meningitis caused by NSCLC, using gefitinib and a ventriculo-peritoneal (V-P) shunt. The first patient was a 43-year-old woman with pT1N0M0 adenocarcinoma. Multiple brain and vertebral metastases were found 13 months after surgery. She had undergone gamma-knife radiosurgery for the brain metastases, radiotherapy for the vertebral metastases, and two regimens of systemic chemotherapy, before carcinomatous meningitis was diagnosed. She was given gefitinib, and then a V-P shunt was placed. She continued to take gefitinib and was free of subjected symptoms for 5 months until she died. The second patient was a 64-year-old woman with cT4N0M0 adenocarcinoma. After local chemotherapy using cisplatin and OK-432 for carcinomatosis pleuritis and two regimens of systemic chemotherapy, carcinomatous meningitis was detected. A V-P shunt was placed, and she was sequentially given gefitinib. At her 15-month follow-up, she was free of symptoms of carcinomatous meningitis. No adverse effects or shunt problems were detected in either patient. This therapeutic modality may liberate carcinomatous meningitis patients with severe symptoms from hospitalization and improve their quality of life.

The diagnosis of primary cardiac lymphoma was facilitated by computed tomographic coronary angiography

Primary cardiac lymphoma (PCL) is a rare entity that leads to fatal symptoms such as serious arrhythmia. The present case was an 80-year-old female with severe dyspnea caused by 30 bpm bradycardia. Computed tomography revealed a tumor invading to the right inferior myocardium. A computed tomographic coronary angiography (CTCA) study revealed the right coronary artery penetrating the tumor with no invasion by the surrounding tumor. Because a percutaneous biopsy was unsuccessful, video-assisted thoracic surgery (VATS) was performed. The final pathological diagnosis was diffuse large B cell lymphoma. Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) chemotherapy reduced the size of the tumor, and the symptoms thereafter improved. An observation of the coronary artery penetrating the tumor without tumor invasion may be a characteristic finding of PCL. CTCA is useful to detect this finding. When a percutaneous biopsy is unavailable, VATS should be considered as a minimally invasive procedure to obtain a reliable diagnosis of PCL.

Detection of EGFR and K-ras mutations for diagnosis of multiple lung adenocarcinomas.

The incidence of multiple primary lung adenocarcinoma (MPLA) is increasing, and it is important to distinguish MPLA from intrapulmonary metastasis (IPM) in order to determine the therapeutic strategy. However, there is no reliable method to differentiate between the two. The purpose of this study was to distinguish MPLA from IPM based on the gene status of EGFR and K-ras and the morphological Noguchi classification system. Sixty-eight tumors from 34 cases of clinical MPLA were evaluated. Of them, 11 cases (32.4%) were diagnosed as biological MPLA (bMPLA) by EGFR/K-ras mutation analyses, and 12 cases (35.3%) by morphological analysis. In all, 23 of the 34 cases (67.6%) were diagnosed as bMPLA. The remaining 11 cases were diagnosed as biological IPM (bIPM). The 5-year survival rates of bMPLA and bIPM were 90.9% and 63.6%, respectively (p=0.04). These findings suggest that the combination method including gene mutation and morphological analysis can guide treatment decisions and that there is a need for systemic chemotherapy, and surveillance monitoring.

A case of spontaneous hemopneumothorax in which the condition worsened after chest drainage

Abstract A 45-year-old woman was referred to our hospital with sudden chest pain. She came on foot with normal vital signs. Computed tomography (CT) revealed right mild pneumothorax with niveau level. We suspected spontaneous hemopneumothorax (SHP) and inserted a thoracic drain. After 800 ml of blood and air was evacuated immediately, the outflow from the drain stopped. However, despite the outflow of blood from the drainage tube having stopped, she developed hemorrhage shock 2 h after drainage. Contrast-enhanced CT revealed extra-vascular signs at the top of the right pleural cavity. Emergency video-assisted thoracic surgery (VATS) was performed. We identified the chest drain as being obstructed by blood clot. Continuous bleeding from a small aberrant vessel at the top of the thoracic cavity was identified, and we stanched it easily by clipping. The present experience suggests that routine enhanced CT and aggressive emergent VATS should be performed in cases of SHP.