Takeyuki Wada

Alternative splicing of CD44 mRNA by ESRP1 enhances lung colonization of metastatic cancer cell

In cancer metastasis, various environmental stressors attack the disseminating cells. The successful colonization of cancer cells in secondary sites therefore requires the ability of the cells to avoid the consequences of such exposure to the stressors. Here we show that orthotopic transplantation of a CD44 variant isoform-expressing (CD44v(+)) subpopulation of 4T1 breast cancer cells, but not that of a CD44v(-) subpopulation, in mice results in efficient lung metastasis accompanied by expansion of stem-like cancer cells. Such metastasis is dependent on the activity of the cystine transporter xCT, and the stability of this protein is controlled by CD44v. We find that epithelial splicing regulatory protein 1 regulates the expression of CD44v, and knockdown of epithelial splicing regulatory protein 1 in CD44v(+) cells results in an isoform switch from CD44v to CD44 standard (CD44s), leading to reduced cell surface expression of xCT and suppression of lung colonization. The epithelial splicing regulatory protein 1-CD44v-xCT axis is thus a potential therapeutic target for the prevention of metastasis.

Functional role of CD44v‐xCT system in the development of spasmolytic polypeptide‐expressing metaplasia

Cancer development is often preceded by the appearance of preneoplastic lesions. In gastric carcinogenesis, chronic inflammation and histopathologic progression of the stomach epithelium lead to the development of metaplasia and eventually adenocarcinoma. The cell surface protein CD44, especially its variant isoforms (CD44v), has been implicated in metaplasia–carcinoma sequence progression in the stomach. We recently found that CD44v interacts with and stabilizes xCT, a subunit of the cystine transporter system xc(–), in cancer cells and thereby increases cystine uptake and confers resistance to various types of cellular stress in vivo. The functional relevance of CD44v and xCT in the development of preneoplastic lesions, however, has remained unknown. We have now examined the role of the CD44v‐xCT system in the development of spasmolytic polypeptide‐expressing metaplasia (SPEM) in mouse models of gastric carcinogenesis. CD44v was found to be expressed de novo in SPEM, and CD44v+ metaplastic cells manifested upregulation of xCT expression compared with CD44v− cells. Genetic ablation of CD44 or treatment with sulfasalazine, an inhibitor of xCT‐dependent cystine transport, suppressed the development of SPEM and subsequent gastric tumor growth. Therapy targeted to CD44v‐xCT could thus prove effective for prevention or attenuation of the CD44v‐dependent development of preneoplastic lesions and cancer.

Laparoscopic resection of an epidermoid cyst originating from an intrapancreatic accessory spleen: Report of a case

A 67-year-old man underwent an investigation of epigastric pain and weight loss. Preoperative imaging findings suggested the presence of a tumor, which developed as an epidermoid cyst and originated from an intrapancreatic accessory spleen; however, the possibility of malignancy could not be ruled out. We therefore performed a laparoscopic-assisted distal pancreatectomy with a splenectomy for both diagnostic and treatment purposes. Five laparoscopic ports were created. After the spleen and pancreatic tail were dissected from the retroperitoneum laparoscopically, they were pulled out through a 7-cm left subcostal incision and resected with an endoscopic linear stapler. The operative time was 227 min and the blood loss was 400 ml. The postoperative course was uneventful. The final pathological diagnosis was in agreement with the preoperative diagnosis. This case demonstrates that the minimally invasive approach of laparoscopic surgery can be used safely and successfully for difficult-to-diagnose pancreatic tumors. This is the first report describing a laparoscopic resection of an epidermoid cyst originating from an intrapancreatic accessory spleen.

Laparoscopic-assisted limited liver resection: Technique, indications and results

BACKGROUND/PURPOSE The purpose of this work was to evaluate the short-term results of laparoscopic-assisted limited liver resection. METHODS We analyzed the clinical outcome in 17 patients (mean age 70 +/- 8 years) who had undergone laparoscopic-assisted limited liver resection from March 2006 to December 2008. Preoperative diagnoses were HCC in 13 patients and metastasis of colon cancer in 4. The operation consisted of laparoscopic mobilization of the target liver lobe, followed by open liver resection through a 7- to 10-cm extraction site. RESULTS Mean tumor size was 3.0 +/- 1.1 cm (range 1.2-5 cm). The mean operative time was 362 +/- 85 min. The mean blood loss was 451 +/- 413 ml, and no blood transfusion was required in any patient. There were no intraoperative complications, and conversion to laparotomy was needed in one case. Postoperative complications developed in 4 cases (4 infections, 24%), all of which were improved by conservative management. However, there was no postoperative mortality. None of the patients had any peritoneal carcinomatosis or port-site or resection site recurrence during a mean follow-up of 18 +/- 9.6 months. According to the analysis of the tumor location, the criterion for an adequate tumor location in the right lobe for this operation was set with the tumor at a distance of more than 5 cm from the inferior vena cava and the root of the hepatic vein (5 cm rule). CONCLUSION Laparoscopic-assisted limited liver resection is feasible and well tolerated. Accumulation of more data may be needed for evaluation of long-term outcome.

A male case of an undifferentiated carcinoma with osteoclast-like giant cells originating in an indeterminate mucin-producing cystic neoplasm of the pancreas. A case report and review of the literature

We report a rare male case of an undifferentiated carcinoma with osteoclast-like giant cells originating in an indeterminate mucin-producing cystic neoplasm of the pancreas. A 59-year-old Japanese man with diabetes visited our hospital, complaining of fullness in the upper abdomen. A laboratory analysis revealed anemia (Hemoglobin; 9.7 g/dl) and elevated C-reactive protein (3.01 mg/dl). Carbohydrate antigen 19-9 was 274 U/ml and Carcinoembryonic antigen was 29.6 ng/ml. A computed tomography scan of the abdomen revealed a 14-cm cystic mass in the upper left quadrant of the abdomen that appeared to originate from the pancreatic tail. The patient underwent distal pancreatectomy/splenectomy/total gastrectomy/cholecystectomy. The mass consisted of a multilocular cystic lesion. Microscopically, the cyst was lined by cuboidal or columnar epithelium, including mucinous epithelium. Sarcomatous mononuclear cells and multinucleated osteoclast-like giant cells were found in the stroma. Ovarian-type stroma was not seen. We made a diagnosis of osteoclast-like giant cell tumor originating in an indeterminate mucin-producing cystic neoplasm of the pancreas. All surgical margins were negative, however, two peripancreatic lymph nodes were positive. The patient recovered uneventfully. Two months after the operation, multiple metastases occurred in the liver. He died 4 months after the operation.

Clinical utility of preoperative evaluation of bronchial arteries by three-dimensional computed tomographic angiography for esophageal cancer surgery

An identification of bronchial arteries (BAs) is critical in esophageal cancer surgery to avoid tracheobronchial ischemia and unexpected massive bleeding during surgical procedure particularly in thoracoscopic video-assisted esophagectomy. We describe the efficacy of three-dimensional computed tomographic angiography (3D-CTA) of BAs for preoperative evaluation in esophageal cancer surgery. Sixty-four patients with esophageal cancer who preoperatively underwent multidetector computed tomography examination were included in this study. We evaluated the number, origin, and intraoperative preservation rate of BAs, and we compared the number of thoracic paratracheal lymph nodes harvested between two groups comprising patients who either underwent preoperative 3D-CTA of BAs (3D-CTA group) or did not (non-3D-CTA group). The right and left BAs were preoperatively identified in 62 patients (97%) and 55 patients (86%), respectively, using 3D-CTA. In 34 patients (53%), the right BA originated as a common trunk with the right intercostal artery. In 48 patients (75%), the left BA originated from the descending aorta as a single or double branch. Some anomalies such as the right BA originated from the left subclavian artery were observed. In all patients, either the right or the left BA was preserved. The number of harvested lymph nodes in left side of paratrachea was significantly increased in 3D-CTA group, than those in non-3D-CTA group. 3D-CTA clearly revealed BA anatomy, contributing to BA preservation and safe and precise lymphadenectomy in esophageal cancer surgery. 3D-CTA of BAs is useful for preoperative evaluation in esophageal cancer surgery.

Ink4a/Arf-Dependent Loss of Parietal Cells Induced by Oxidative Stress Promotes CD44-Dependent Gastric Tumorigenesis.

Loss of parietal cells initiates the development of spasmolytic polypeptide–expressing metaplasia (SPEM), a precancerous lesion in stomach. CD44 variant (CD44v) that enhances the ability to defend against reactive oxygen species (ROS) in epithelial cells is expressed de novo in SPEM of K19-Wnt1/C2mE mice, a transgenic model of gastric tumorigenesis, and is required for the efficient development of SPEM and gastric tumor in these animals. The role of ROS and its downstream signaling in CD44-dependent gastric tumorigenesis has remained unknown, however. With the use of the K19-Wnt1/C2mE mouse, we now show that parietal cells in the inflamed stomach are highly sensitive to oxidative stress and manifest activation of p38MAPK signaling by ROS. Oral treatment with the antioxidant ascorbic acid or genetic ablation of the Ink4a/Arf locus, a major downstream target of ROS-p38MAPK signaling, inhibited parietal cell loss and the subsequent gastric tumorigenesis. Our results indicate that signaling activated by oxidative stress in parietal cells plays a key role in CD44-dependent gastric tumorigenesis. Cancer Prev Res; 8(6); 492–501. ©2015 AACR.

Successful Management of Anastomotic Leakage and Lung Fistula After Esophagectomy

We report the successful management of a case of anastomotic leakage with a lung fistula as a complication of esophagectomy by use of a double elementary diet tube.

Abstract 65: Ink4a/Arf locus drives gastric tumorigenesis through induction of parietal cell loss

Background: Cancer development is often preceded by the appearance of preneoplastic lesions. In gastric carcinogenesis, chronic inflammation and histopathologic progression of the stomach epithelium lead to the development of metaplasia and eventually adenocarcinoma. Spasmolytic polypeptide-expressing metaplasia (SPEM) is one of the preneoplastic lesions in the stomach and is triggered by the loss of parietal cells that secrete gastric acid. The Ink4a/Arf locus encodes two structurally unrelated tumor suppressor proteins, p16(INK4a) and p19(ARF) in mice. However, little is known regarding the role of these proteins encoded by the INK4a/ARF locus in gastric tumorigenesis.Methods: To evaluate the functional role of Ink4a/Arf locus, we crossed mouse gastric cancer modelK19-Wnt1/C2mE mice with Ink4a/Arf (-/-) mouse and generated Ink4a/Arf (-/-) K19-Wnt1/C2mE mice and evaluated the effect of deletion of Ink4a/Arf locus on the parietal cell loss and formation of SPEM and gastric tumor. Results: In K19-Wnt1/C2mE mice, accumulation of reactive oxygen species (ROS) and the increase of p19 expression were observed in gastric epithelium along with the parietal cells loss leading to SPEM development. However, the parietal cells loss followed by formation of SPEM and gastric tumor were drastically suppressed in Ink4a/Arf (-/-) K19-Wnt1/C2mE mice. Furthermore, treatment of tamoxifen, an inducer of parietal cells loss, in Ink4a/Arf (-/-) mice revealed that deletion of Ink4a/Arf locus suppresses parietal cells loss in mice. Conclusion: These results suggest that activation of p19(ARF) tumor suppressor protein by ROS accumulation paradoxically play a key role in the parietal cells loss leading to gastric tumorigenesis. Citation Format: Ryo Seishima, Takeyuki Wada, Hirotoshi Hasegawa, Yoshiyuki Ishii, Koji Okabayashi, Masashi Tsuruta, Yuko Kitagawa, Hideyuki Saya, Osamu Nagano. Ink4a/Arf locus drives gastric tumorigenesis through induction of parietal cell loss. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 65. doi:10.1158/1538-7445.AM2014-65

Intractable esophago-mediastinal fistula as a rare complication following thoracoabdominal aortic replacement

Although occurring infrequently, esophago-mediastinal fistula is potentially life-threatening. We report a rare case of intractable esophago-mediastinal fistula following thoracoabdominal aortic replacement. A 62-year-old male patient with aortic dissection underwent thoracoabdominal aortic replacement. He suddenly developed septic shock with esophageal perforation on the 6th postoperative day. Conservative therapy was employed, and he was discharged from the hospital. However, he suffered another attack of septic shock resulting from an esophago-mediastinal fistula. Gastrointestinal endoscopy revealed a suture thread beside an esophageal fistula. The patient consequently underwent esophagectomy. After removal of the esophagus, we found a suture thread with pledgets in the mediastinum and removed it. He recovered successfully thereafter. Esophago-mediastinal fistula associated with pledgets is a rare complication of thoracoabdominal aortic replacement. We believe that radical surgery can be an effective treatment. A review of the current literature did not reveal any similar cases. In this report, we discuss the clinical course of such a rare case.