Yukinori Yamagata

CDX1 confers intestinal phenotype on gastric epithelial cells via induction of stemness-associated reprogramming factors SALL4 and KLF5

Intestinal metaplasia of the stomach, a mucosal change characterized by the conversion of gastric epithelium into an intestinal phenotype, is a precancerous lesion from which intestinal-type gastric adenocarcinoma arises. Chronic infection with Helicobacter pylori is a major cause of gastric intestinal metaplasia, and aberrant induction by H. pylori of the intestine-specific caudal-related homeobox (CDX) transcription factors, CDX1 and CDX2, plays a key role in this metaplastic change. As such, a critical issue arises as to how these factors govern the cell- and tissue-type switching. In this study, we explored genes directly activated by CDX1 in gastric epithelial cells and identified stemness-associated reprogramming factors SALL4 and KLF5. Indeed, SALL4 and KLF5 were aberrantly expressed in the CDX1+ intestinal metaplasia of the stomach in both humans and mice. In cultured gastric epithelial cells, sustained expression of CDX1 gave rise to the induction of early intestinal-stemness markers, followed by the expression of intestinal-differentiation markers. Furthermore, the induction of these markers was suppressed by inhibiting either SALL4 or KLF5 expression, indicating that CDX1-induced SALL4 and KLF5 converted gastric epithelial cells into tissue stem-like progenitor cells, which then transdifferentiated into intestinal epithelial cells. Our study places the stemness-related reprogramming factors as critical components of CDX1-directed transcriptional circuitries that promote intestinal metaplasia. Requirement of a transit through dedifferentiated stem/progenitor-like cells, which share properties in common with cancer stem cells, may underlie predisposition of intestinal metaplasia to neoplastic transformation.

Tests for Serum Levels of Trefoil Factor Family Proteins Can Improve Gastric Cancer Screening

BACKGROUND & AIMS Improving methods for early detection of gastric cancer could reduce mortality. Measurements of serum pepsinogen levels have been used for screening in Japan without satisfactory levels of sensitivity or specificity. Trefoil factor family (TFF) proteins (TFF1, TFF2, and TFF3) are small and stable molecules secreted by the mammalian gastrointestinal tract. Foveolar hyperplasia, spasmolytic polypeptide (TFF2)-expressing metaplasia, and intestinal metaplasia are histologic changes observed in patients with atrophic gastritis; they express TFF1, TFF2, and TFF3, respectively. We investigated whether serum levels of TFF can be used as markers for gastric cancer screening. METHODS Serum was collected from 183 patients with gastric cancer and 280 healthy individuals without cancer. Serum levels of anti-Helicobacter pylori immunoglobulin G, pepsinogen I, pepsinogen II, TFF1, TFF2, and TFF3 were measured by enzyme-linked immunosorbent assay and associated with gastric cancer. RESULTS Using a cutoff of 3.6 ng/mL, the level of TFF3 was significantly increased in serum samples from patients with cancer (odds ratio, 18.1; 95% confidence interval, 11.2-29.2); using this test, patients with cancer were identified with 80.9% sensitivity and 81.0% specificity. The test for TFF3 had a significantly higher odds ratio than that for pepsinogen. A test for the combination of TFF3 and pepsinogen had better results than the test for only pepsinogen. CONCLUSIONS Serum levels of TFF3 are a better marker of gastric cancer than pepsinogen; a test for the combined levels of serum pepsinogen and TFF3 could improve gastric cancer screening.

Short-term outcomes of robotic radical esophagectomy for esophageal cancer by a nontransthoracic approach compared with conventional transthoracic surgery.

Summary Transthoracic esophagectomy (TTE) is believed to have advantages for mediastinal lymphadenectomy in the treatment of resectable esophageal cancer despite its association with a greater incidence of pulmonary complications and postoperative mortality. Transhiatal esophagectomy is regarded as less invasive, though insufficient in terms of lymph node dissection. With the aim of achieving lymph dissection equivalent to that of TTE, we have developed a nontransthoracic esophagectomy (NTTE) procedure combining a video‐assisted cervical approach for the upper mediastinum and a robot‐assisted transhiatal approach for the middle and lower mediastinum. We prospectively studied 22 accumulated cases of NTTE and verified feasibility by analyzing perioperative and histopathological outcomes. We compared this groups short‐term outcomes with outcomes of 139 equivalent esophageal cancer cases operated on at our institution by conventional TTE (TTE group). In the NTTE group, there were no procedure‐related events and no midway conversions to the conventional surgery; the mean operation time was longer (median, 524 vs. 428 minutes); estimated blood loss did not differ significantly between the two groups (median, 385 mL vs. 490 mL); in the NTTE group, the postoperative hospital stay was shorter (median, 18 days vs. 24 days). No postoperative pneumonia occurred in the NTTE group. The frequencies of other major postoperative complications did not differ significantly, nor were there differences in the numbers of harvested mediastinal lymph nodes (median, 30 vs. 29) or in other histopathology findings. NTTE offers a new radical procedure for resection of esophageal cancer combining a cervical video‐assisted approach and a transhiatal robotic approach. Although further accumulation of surgical cases is needed to corroborate these results, NTTE promises better prevention of pulmonary complications in the management of esophageal cancer.

Robotic-assisted totally transhiatal lymphadenectomy in the middle mediastinum for esophageal cancer

Robotic-assisted esophagectomy has been introduced as a minimally invasive esophagectomy; however, transhiatal esophagectomy with extended lymphadenectomy in the middle retromediastinal field has never been reported so far. We have developed a totally transhiatal robotic manipulation which enables middle retromediastinal lymph dissection. With this method, transthoracic approach, which is associated with risk of lung injury and loss of ventilatory function, can be avoided in radical esophageal cancer surgery. The robotic arms and camera entered the mediastinum passing the hiatus, and the dissection was performed along the medial aspect of the mediastinal pleura, the pericardia, and the aorta. The devices were able to reach the middle mediastinum, and lymph nodes on the bilateral main bronchi and the carina were retrieved by robotic manipulation. We present here our first experience of laparoscopic transhiatal lymphadenectomy of the middle mediastinal field, including a video, which could not have been possible without robotic-assisted surgery.

Rapid and sensitive detection of early esophageal squamous cell carcinoma with fluorescence probe targeting dipeptidylpeptidase IV

Early detection of esophageal squamous cell carcinoma (ESCC) is an important prognosticator, but is difficult to achieve by conventional endoscopy. Conventional lugol chromoendoscopy and equipment-based image-enhanced endoscopy, such as narrow-band imaging (NBI), have various practical limitations. Since fluorescence-based visualization is considered a promising approach, we aimed to develop an activatable fluorescence probe to visualize ESCCs. First, based on the fact that various aminopeptidase activities are elevated in cancer, we screened freshly resected specimens from patients with a series of aminopeptidase-activatable fluorescence probes. The results indicated that dipeptidylpeptidase IV (DPP-IV) is specifically activated in ESCCs, and would be a suitable molecular target for detection of esophageal cancer. Therefore, we designed, synthesized and characterized a series of DPP-IV-activatable fluorescence probes. When the selected probe was topically sprayed onto endoscopic submucosal dissection (ESD) or surgical specimens, tumors were visualized within 5 min, and when the probe was sprayed on biopsy samples, the sensitivity, specificity and accuracy reached 96.9%, 85.7% and 90.5%. We believe that DPP-IV-targeted activatable fluorescence probes are practically translatable as convenient tools for clinical application to enable rapid and accurate diagnosis of early esophageal cancer during endoscopic or surgical procedures.

A two-stage operation for thoracic esophageal cancer: esophagectomy and subsequent reconstruction by a free jejunal flap

When the stomach is unavailable for esophageal reconstruction due to previous gastrectomy or synchronous gastric cancer, a pedicled jejunum or colon, with or without vascular supercharge, has been the alternative. However, these reconstructions are not free from severe complications, such as necrosis. We have introduced a new surgical technique for delayed esophageal reconstruction using a free jejunal flap. We used this technique in 11 patients. Four weeks after subtotal esophagectomy, reconstruction using free jejunal flaps was performed. A free jejunum was placed at the pre-sternum, and the internal thoracic artery and vein were usually used as the recipient vessels. There were no cases of flap necrosis and no hospital deaths. Anastomotic leakage occurred in two cases. Both leakages were cured by conservative treatment. Delayed esophageal reconstruction using a free jejunal flap can be considered to be a safe procedure when the stomach is unavailable as an esophageal substitute.

Columnar metaplasia in a surgical mouse model of gastro-esophageal reflux disease is not derived from bone marrow-derived cell

The incidence of esophageal adenocarcinoma has increased in the last 25 years. Columnar metaplasia in Barretts mucosa is assumed to be a precancerous lesion for esophageal adenocarcinoma. However, the induction process of Barretts mucosa is still unknown. To analyze the induction of esophageal columnar metaplasia, we established a mouse gastro‐esophageal reflux disease (GERD) model with associated development of columnar metaplasia in the esophagus. C57BL/6 mice received side‐to‐side anastomosis of the esophagogastric junction with the jejunum, and mice were killed 10, 20, and 40 weeks after operation. To analyze the contribution of bone marrow‐derived cells to columnar metaplasia in this surgical GERD model, some mice were transplanted with GFP‐marked bone marrow after the operation. Seventy‐three percent of the mice (16/22) showed thickened mucosa in esophagus and 41% of mice (9/22) developed columnar metaplasia 40 weeks after the operation with a mortality rate of 4%. Bone marrow‐derived cells were not detected in columnar metaplastic epithelia. However, scattered epithelial cells in the thickened squamous epithelia in regions of esophagitis did show bone marrow derivation. The results demonstrate that reflux induced by esophago‐jejunostomy in mice leads to the development of columnar metaplasia in the esophagus. However, bone marrow‐derived cells do not contribute directly to columnar metaplasia in this mouse model.

Preclinical study of transcervical upper mediastinal dissection for esophageal malignancy by robot-assisted surgery.

Robotic surgical systems are potentially applicable to transcervical mediastinal lymph dissection for esophageal malignancy.

Evaluation of 18F-FDG uptake for detecting lymph node metastasis of gastric cancer: a prospective pilot study for one-to-one comparison of radiation dose and pathological findings.

BackgroundGastric cancer exhibits various degrees of fluorine F-18 fluorodeoxyglucose (18F-FDG) uptake on positron emission tomography/computed tomography (PET/CT). We evaluated the relationship between 18F-FDG uptake and the presence/absence of metastasis in individual lymph nodes (LN) on a one-to-one basis.MethodsWe analyzed 21 patients with gastric cancer. We injected 18F-FDG intravenously in the morning, and gastrectomy with LN dissection was performed in the afternoon of the same day. Radiation doses were measured at each LN using a well-type counter, and we then compared 18F-FDG uptake, the shortest diameter, and pathological examination results for each LN.ResultsIn our study, 906 LNs were analyzed, including 115 metastatic LNs. Metastatic LNs showed significantly higher 18F-FDG uptake (P < 0.0001), and were significantly enlarged (P < 0.0001). The receiver operating characteristics (ROC) curve had a larger area under the curve (0.71) for 18F-FDG uptake than for the shortest LN diameter (0.60). Considering histology, the ROC curve for intestinal type adenocarcinoma had a larger area under the curve than that for diffuse type (0.75 vs 0.61).ConclusionsF-FDG uptake is potentially a more useful variable than LN diameter for discriminating between LN with and without metastasis, especially in intestinal type gastric cancer cases.

Solitary fibrous tumor of the greater omentum, mimicking gastrointestinal stromal tumor of the small intestine: a case report.

Solitary fibrous tumor (SFT) is one of the mesenchymal tumors, which rarely arises in the abdominal space. We report a very rare case of abdominal SFT, mimicking another mesenchymal tumor. A 52-year-old Japanese man was referred to our hospital for further evaluation and treatment of gallbladder polyp. Contrast-enhanced computed tomography (CT) showed an enhanced nodule within the gallbladder, and incidentally, also showed a well-circumscribed mass adjacent to the small intestine. The mass was depicted as slightly high density in plain CT, and with contrast-enhancement, the mass was partially stained in early phase and the stained area spread heterogeneously in delayed phase. Magnetic resonance imaging showed that the abdominal mass was depicted as slightly high intensity on T2-weighted imaging and low intensity on T1-weighted imaging. With double-balloon endoscopy and capsule endoscopy, we did not find any tumor inside the small intestine. These visual findings lead us to diagnose it as gastrointestinal stromal tumor of the small intestine with extraluminal growth. We planned to resect both the gallbladder polyp and the intraperitoneal tumor at the same time for pathologic diagnosis and treatment. When the operation was performed, we found a milk-white lobulated tumor on the greater omentum and the tumor was entirely resected. Microscopically, the gallbladder polyp was diagnosed as tubular adenoma, and the omental tumor was diagnosed as SFT. It is important to bear in mind that omental SFTs sometimes mimic other mesenchymal tumors and should be included in the differential diagnosis of abdominal tumor not revealed by endoscopy.