Ei Yamaki

Mechanisms of Resistance to EGFR TKIs and Development of a New Generation of Drugs in Non-Small-Cell Lung Cancer

Gefitinib and erlotinib, which are epidermal growth factor receptor- (EGFR-) specific tyrosine kinase inhibitors (TKIs), are widely used as molecularly targeted drugs for non-small-cell lung cancer (NSCLC). Currently, the search for EGFR gene mutations is becoming essential for the treatment of NSCLC since these have been identified as predictive factors for drug sensitivity. On the other hand, in almost all patients responsive to EGFR-TKIs, acquired resistance is a major clinical problem. Mechanisms of acquired resistance reported in the past few years include secondary mutation of the EGFR gene, amplification of the MET gene, and overexpression of HGF; novel pharmaceutical agents are currently being developed to overcome resistance. This review focuses on these mechanisms of acquired resistance to EGFR-TKIs and discusses how they can be overcome.

FBXW7 Mediates Chemotherapeutic Sensitivity and Prognosis in NSCLCs

Non–small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide. To improve the prognosis of patients with NSCLCs, new and validated therapeutic targets are critically needed. In this study, we focused on F-box and WD repeat domain containing-7 (FBXW7), an E3 ubiquitin ligase, that regulates the degradation of MCL1, Myc, cyclin E, and TOP2A. Importantly, loss of FBXW7 was associated with increased sensitivity of tumors to a class I–specific histone deacetylase (HDAC) inhibitor, MS-275. Immunohistochemical analysis revealed increased expression of FBXW7 targets, MCL1 and TOP2A, in NSCLC tumors with low expression of FBXW7. Moreover, clinical specimens exhibiting low FBXW7 expression presented with more progressive cancer and significantly shorter cancer-specific survival than patients with high FBXW7 expression. Mechanistic study of NSCLC cell lines with silenced FBXW7 revealed enhanced MS-275 sensitivity and taxol resistance. Interestingly, taxol resistance was eliminated by MS-275 treatment, suggesting the potential of HDAC inhibitors for the treatment of aggressive taxol-resistant NSCLCs that lack FBXW7. Implications: FBXW7 status impacts chemosensitivity and is a prognostic marker in NSCLCs. Visual Overview: http://mcr.aacrjournals.org/content/early/2013/12/19/1541-7786.MCR-13-0341/F1.large.jpg. Mol Cancer Res; 12(1); 32–37. ©2013 AACR.

Laparoscopic Appendectomy for Appendiceal Endometriosis Presenting as Acute Appendicitis: Report of a Case

Endometriosis is a relatively common disorder in women of reproductive age; however, appendiceal endometriosis is rare. Thus, a definitive diagnosis is likely to be established only by histology of the appendix. We report a case of endometriosis of the appendix in a 42-year-old woman who presented with symptoms of acute appendicitis. We treated the patient by performing laparoscopic appendectomy, which resulted in a good outcome.

SIRT6 expression is associated with poor prognosis and chemosensitivity in patients with non‐small cell lung cancer

Despite advances in the development of various therapeutic agents, non‐small cell lung cancer (NSCLC) is associated with a poor prognosis. To improve the prognosis of patients with NSCLC, new therapeutic targets for overcoming drug resistance are required. The process of autophagy is required to support the tumorigenesis and drug resistance of cancer cells. We investigated the clinical significance of SIRT6, a member of the NAD+‐dependent deacetylase family, which regulates a variety of cancer‐related processes, including autophagy.

Immunohistochemical analysis of phosphorylated epidermal growth factor receptor might provide a surrogate marker of EGFR mutation

PURPOSE Overexpression of EGFR is found in several malignancies including lung cancers. Recently, EGFR mutation has been shown to correlate with responsiveness to tyrosine kinase inhibitors (TKI). Although antibodies against phophorylated EGFR have been used in vitro, phosphorylated EGFR has yet not been examined well in resected non-small cell lung cancers (NSCLCs). EXPERIMENTAL DESIGN We studied the immunohistochemistry of anti-EGFR and phosphorylated EGFR in 97 resected NSCLCs, examined the relationship with EGFR mutation, and performed quantitative RT-PCR of the EGFR gene in the TaqMan assay. RESULT EGFR mutation was seen in 27% of 97 NSCLCs and 37% of 70 adenocarcinomas. EGFR was stained in 60% of 97 NSCLCs. Phosphorylation of tyrosine 845 (pY845) and 1068 (pY1068) was positive in 49% and 48%, respectively. The observed correlation with EGFR mutation and pY845 or pY1068 was statistically significant (P=0.0001 for pY845, P<0.0001 for pY1068, chi square test), although phospho-EGFR status was not associated with a particular mutation type. pY1068-positive tumors also correlated with female, light smoker, and adenocarcinoma histology, but not with mRNA expression. Moreover, patients with pY1068-positive tumors showed prolonged survival (P=0.0093, log-rank test). CONCLUSION It is possible that immunohistochemistry of phosphorylated EGFR can substitute for EGFR mutation analysis. Further investigation is necessary to determine whether phospho-EGFR immunohistochemistry predicts response to TKIs and survival benefit.

Primary mediastinal atypical meningioma: Report of a case and literature review

Meningiomas are common neoplasms arising from the central nervous system meninges. On the other hand, primary ectopic meningiomas are extremely rare and usually limited to the head and neck region or to the paravertebral soft tissues. Their occurrence in the mediastinum is even rarer. Until now, only 4 cases of primary mediastinal meningioma have been reported in the literature searched on Medline. Because of its rarity and intriguing pathogenesis, we report here a case of primary mediastinal meningioma that was treated by surgical resection. The clinical features, treatment, pathological findings, and prognosis are analyzed, and the literature on ectopic meningioma is reviewed.

Successful resection of a glomus tumor of the trachea

Extracutaneous glomus tumors are uncommon, and their occurrence in the trachea is rare. We present a case of a surgically resected glomus tumor of the trachea in a 56-year-old woman who presented with worsening dyspnea and cough. Bronchoscopy and computed tomography showed a polypoid tumor arising from the posterior membrane of the lower trachea just above the carina; the tracheal lumen was approximately 80% occluded. The patient underwent successful tracheal sleeve resection with primary reconstruction. The histological characteristics and immunohistochemical profile were typical for this tumor. The clinicopathological features of this unusual neoplasm are discussed, and the literature is reviewed.

Pulmonary metastasis from breast cancer with an 18-year disease-free interval: implication of the role of surgery.

The appearance of pulmonary metastasis more than 15 years after primary treatment for breast cancer is rare. We herein report the case of a breast cancer patient with solitary pulmonary metastasis, after an 18-year disease-free period, treated with resection. A 66-year-old Japanese woman was found to exhibit an abnormal shadow on a chest X-ray. She had undergone a left mastectomy for breast cancer 18 years previously. The nodule was suspected to be either metastatic or primary lung cancer, and thus thoracoscopic surgery was performed. The histologic diagnosis was metastasis from breast cancer. Pulmonary resection in breast cancer recurrence is an important diagnostic tool that allows for a differential diagnosis with primary lung cancer. The clinical implication of surgery for a solitary pulmonary metastasis from breast cancer is discussed in this report.

Surgical resection and reconstruction for a giant cell tumor of the anterior rib

Giant cell tumors (GCTs) are rare neoplasms, most commonly arising in the metaphysis/epiphysis of long bones. They consist of multinucleated giant cells with surrounding spindle-shaped mononuclear stromal cells. GCTs rarely appear in the ribs. We report a case of a GCT originating from the anterior arc of the fourth rib in a 31-year-old man who presented with a progressively growing thoracic mass in the left anterior chest wall. Thoracotomy involving en bloc resection of the chest wall and tumor and a reconstruction of the chest wall were performed.

Thoracoscopic resection of a mesenchymal cystic hamartoma of the lung

Mesenchymal cystic hamartomas are uncommon tumors originating from nodules of primitive mesenchymal cells, and their occurrence in the lung is extremely rare. We present a case of surgically resected mesenchymal cystic hamartoma of the lung in a 49-yearold woman who presented without any symptoms. Chest computed tomography showed a solitary cystic lesion in the right lower lobe. The patient underwent preoperative marking by 0.2 ml lipiodol 4 days before surgery. Thoracoscopic partial resection of the right lower lobe was performed. The histological picture and immunohistochemical profile were compatible with this tumor.