逆転写反応および特異的DNA増幅反応法を用いた胃癌の内視鏡的生検組織におけるc-erbB-2mRNAの特異的検出

取得学位 : 博士（医学）, 学位授与番号 : 医博甲第1115号, 学位授与年月日：平成6年3月25日,学位授与年：199

Overexpression and gene amplification of both ERBB2 and EGFR in an esophageal squamous cell carcinoma revealed by fluorescence in situ hybridization, multiplex ligation-dependent probe amplification and immunohistochemistry

EGFR and ERBB2 belong to the EGFR gene family. In esophageal squamous cell carcinomas (SCCs), amplification of EGFR or ERBB2 is usually mutually exclusive. EGFR amplification occurs in approximately 15% of SCCs, ERBB2 occurs in less than 5%. Here, we report the co-amplification of EGFR and ERBB2 in an ulcerative and infiltrating-type SCC that measured approximately 4.2 × 2.7 × 1.2cm with a superficial lesion occurring in the thoracic esophagus of a 72-year-old man. Multiplex ligation-dependent probe amplification using representative tumor sections showed gain of CCND1 and coincident amplification of ERBB2 or EGFR or neither. Immunohistochemistry and fluorescence in situ hybridization revealed that the tumor comprised three cancer-cell populations: well-differentiated SCC with high-level ERBB2 amplification and ERBB2 overexpression, more infiltrative poorly-differentiated SCC with high-level EGFR amplification and EGFR overexpression, and poorly-differentiated SCC lacking any ERBB2 or EGFR abnormality. These three populations each had low-level CCND1 amplification and nuclear cyclin D1 overexpression. This histological topology and gene amplification combinations suggested that genetic instability first produced CCND1 amplification, and then ERBB2 or EGFR gene amplification occurred. It is further speculated that during cancer progression and clonal selection indecisive predominance of either clone caused the rare co-amplification of ERBB2 and EGFR in a single chimeric tumor. © 2015 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.発行後1年より全文公

Gene amplification of ERBB2 and EGFR in adenocarcinoma in situ and intramucosal adenocarcinoma of Barrett\u27s esophagus

金沢大学医薬保健研究域医学系We examined 11 cases of carcinoma arising from Barrett\u27s esophagus consisting of two adenocarcinomas in situ (ACIS), two intramucosal adenocarcinomas, and seven overt invasive adenocarcinomas. Overexpression of p53 (implying a mutation of the p53 gene), ERBB2, and EGFR was measured by immunohistochemistry, and gene amplification of ERBB2 and EGFR was measured by fluorescence in situ hybridization (FISH). In all cases of ACIS and the intramucosal adenocarcinomas, almost all cancer cells overexpressed p53, however the populations overexpressing ERBB2 and EGFR varied in different cases: in one ACIS, ERBB2 was coexpressed in all the cancer cells, in the other ACIS and one intramucosal adenocarcinoma, ERBB2 was overexpressed in about 50% and only 10% of the p53-positive cells respectively. EGFR was co-expressed in 20% in the other intramucosal adenocarcinoma. Protein overexpression of ERBB2 or EGFR corresponded to the amplification of their respective genes on a cell by cell basis. These gene amplifications, however, were not found in the seven invasive adenocarcinomas. Thus we speculate that the gene amplification occurred late in the dysplasia-carcinoma sequence probably after the mutation of p53. Furthermore, new clonal expansion accompanied by tumor invasion might have extinguished the originally amplified genes in these tumors. © 2010 Japanese Society of Pathology and Blackwell Publishing Asia Pty Ltd

Results of video-assisted thoracoscopic surgery for esophageal cancer during the induction period

金沢大学医学部附属病院胃腸外科Objective. The attainment of proficiency in thoracoscopic radical esophagectomy for thoracic esophageal cancer requires much experience. We aimed to master this procedure safely with our regular surgical team members under the direction of an experienced surgeon. We evaluated the efficacy of instruction during the induction period and the significance of our results. Methods. We compared the results of 12 thoracic esophageal cancer patients who underwent thoracoscopic radical esophagectomy in our institution (group A) to those of the initial 17 patients who underwent the same operation at the director\u27s institution (group B). Results. We were able to perform complete thoracoscopic radical esophagectomies without any direction after experiencing 10 cases that were performed under adequate direction. The number of dissected lymph nodes and the duration of the procedure were similar in the two groups: 34 (22-53) vs. 26 (9-55) nodes, P = 0.23; and 327.5 (230-455) vs. 315 (190-515) min, P = 0.947, respectively. The amount of thoracic blood loss was significantly less in group A than in group B: 185 (110-380) g vs. 440 (110-2360) g, P = 0.0035. Postoperative pneumonia and atelectasis were observed in 25.0% of group A patients and in 17.6% of group B patients. The incidence of recurrent nerve palsy was 30.7% in group A and 11.7% in group B, but there was no statistically significant difference (P = 0.19). The morbidity rates in group A and group B were 41.6% and 29.4%, respectively (P = 0.694). Conclusion. Thoracoscopic radical esophagectomy can be mastered relatively quickly and safely under the direction of an experienced surgeon and a regular surgical team. © 2008 The Japanese Association for Thoracic Surgery

Potential of extravasated platelet aggregation as a surrogate marker for overall survival in patients with advanced gastric cancer treated with preoperative docetaxel, cisplatin and S-1: a retrospective observational study

Background: The theory of extravasated platelet aggregation in cancer lesions was recently introduced. We investigated the association of platelet aggregation in gastric cancer stroma with clinicopathological features, chemotherapeutic response, pathological response, and survival. Methods: The study comprised 78 patients with advanced gastric cancer who had undergone gastrectomy with or without combination of docetaxel, cisplatin and S-1 (DCS) as preoperative chemotherapy between 2005 and 2014. The patients were divided into two groups: patients who had received preoperative DCS therapy forming the p-DCS group and patients who had not received preoperative DCS therapy forming the control group. The 39 patients in the control group had received gastrectomy and postoperative chemotherapy of S-1 alone. Platelet aggregation in biopsy specimens before preoperative DCS therapy in the p-DCS group and at the time of diagnosis in the control group were evaluated using CD42b immunohistochemical staining. Results: Twenty-four patients in the p-DCS group and 19 in the control group were found to have platelet aggregation in their cancer stroma. Patients with histologically confirmed platelet aggregation had significantly higher rates of chemoresistance (58.3%) than those without platelet aggregation (20.0%) (P = 0.019). According to multivariate analysis, CD42b expression (odds ratio: 5.102, 95% confidence interval: 1.039-25.00, P = 0.045) was correlated with chemoresistance. CD42b expression and histological non-responder status were both significantly correlated with poor overall survival (OS) (P = 0.012, P = 0.016); however, RECIST was not correlated with OS. In the control group, CD42b expression was also significantly correlated with poor overall survival (OS) (P = 0.033). In the p-DCS group, according to multivariate analysis, male sex (hazard ratio: 0.281, 95% confidence interval: 0.093-0.846, P = 0.024) was correlated with good prognosis and CD42b expression (hazard ratio: 4.406, 95% confidence interval: 1.325-14.65, P = 0.016) with poor prognosis. Conclusions: This study suggests that platelets in gastric cancer stroma may create a favorable microenvironment for chemoresistance. CD42b immunohistochemical staining of biopsy specimens is a promising candidate for being a prognostic marker in patients with gastric cancer. © 2017 The Author(s)

Learning of thoracoscopic radical esophagectomy: How can the learning curve be made short and flat?

金沢大学附属病院胃腸外科Attainment of proficiency in video-assisted thoracoscopic radical esophagectomy (VATS) for thoracic esophageal cancer requires much experience. We have mastered this procedure safely under the direction of an experienced surgeon. After adoption of the procedure, the educated surgeon directed induction of this surgical procedure at another institution. We evaluated the efficacy of instruction during the induction period by comparing the results at the two institutions in which VATS had been newly induced. We defined the induction period as the time from the beginning of VATS to the time when the last instruction was carried out. From January 2003 to December 2007, 53 patients were candidates for VATS at Kanazawa University (institution 1). Of these, 46 patients underwent curative VATS by a single operator. We divided this period into three parts: the induction period of VATS, post-induction period, and proficient period when the educated surgeon of institution 1 directed the procedure at Maebashi Red Cross Hospital (institution 2). At institution 1, 12 VATS were scheduled, and nine procedures (75%) (group A) including eight instructions were completed during the induction period (from January 2003 to August 2004). Thereafter, VATS was performed without instruction. In the post-induction period, nine VATS were scheduled, and eight procedures (88.8%) (group B) were completed from September 2004 to August 2005. Subsequently, 32 VATS were scheduled, and 29 procedures (90.6%) (group C) were completed during the proficient period (from September 2005 to December 2007). The surgeon at Maebashi Red Cross Hospital (institution 2) started to perform VATS under the direction of the surgeon who had been educated at institution 1 from September 2005. VATS was completed in 13 (76.4%) (group D) of 17 cases by a single surgeon including seven instructions during the induction period at institution 2 from September 2005 to December 2007. No lethal complication occurred during the induction period at both institutions. We compared the results of VATS among four groups from the two institutions. There were no differences in the background and clinicopathological features among the four groups. The number of dissected lymph nodes and amount of thoracic blood loss were similar in the four groups (35 [22-52] vs 41 [26-53] vs 32 [17-69] vs 29 [17-42] nodes, P = 0.139, and 170 [90-380] vs 275 [130-550] vs 220 [10-660] vs 210 [75-543] g, P = 0.373, respectively). There was no difference in the duration of the thoracic procedure during the induction period at the two institutions. However, the duration of the procedure was significantly shorter in the proficient period of institution 1 (group C: 266 [195-555] minutes) than in the induction period of both institutions (group A: 350 [280-448] minutes [P = 0.005] and group D: 345 [270-420] mL [P = 0.002]). There were no surgery-related deaths in any of the groups. The incidence of postoperative complications did not differ among the four groups. Thoracoscopic radical esophagectomy can be mastered quickly and safely with a flat learning curve under the direction of an experienced surgeon. The educated surgeon can instruct surgeons at another institution on how to perform thoracoscopic esophagectomy. The operation time of thoracoscopic surgery is shortened by experience. © 2010 Copyright the Authors. Journal compilation © 2010, Wiley Periodicals, Inc. and the International Society for Diseases of the Esophagus

Serum cytokeratin 18 as a biomarker for gastric cancer

Cytokeratin 18 (CK18) fragments are released into circulation during epithelial cell death. M30 (reflects caspase-cleaved CK18 fragment) and M65 (reflects total CK18 fragment) enzyme-linked immunosorbent assay (ELISA) detect circulating CK18 fragments released during caspase-dependent or total cell death, respectively; thus, CK18 has the potential of being a biomarker for epithelial cancers. In the present study, we investigated the serum levels of M30 and M65 in patients with gastric cancer, determined correlation of these levels with clinical features, and evaluated the usefulness of these enzymes as diagnostic and prognostic markers. We enrolled 54 gastric cancer patients and 12 healthy volunteers in this study. We measured the serum levels of M30 and M65 by quantitative ELISA. The levels of M30 and M65 in gastric cancer patients were significantly higher than those in healthy volunteers (P = 0.001, P < 0.001). The enzyme levels were elevated with the progress of gastric cancer. The sensitivity and specificity of M30 as a diagnostic marker were 67.5 and 90.9 %, respectively, and those of M65 were 70.1 and 90.9 %, respectively. The serum levels of M30 and M65 in patient with early gastric cancer were elevated in 38.1 and 66.7 %, respectively. Further, increased serum level of M65 is an independent indicator of poor prognosis (P = 0.036). The serum levels of M30 and M65 may be useful biomarkers for gastric cancer as diagnostic markers that can reflect the extent of cancer. Moreover, M65 levels can be used as a prognostic indicator. © 2012 Springer-Verlag