Susumu Aikou

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.

Non-exposed endoscopic wall-inversion surgery as a novel partial gastrectomy technique

In gastric full-thickness resection employing both endoscopy and laparoscopy, intraabdominal contamination or even possibly tumor seeding is unavoidable as a result of iatrogenic perforation and the resultant spread of gastric juice. To minimize contamination and resected tissue volume, we developed a new technique without perforation termed non-exposed endoscopic wall-inversion surgery (NEWS), and present here the preliminary results. In a clinical observation cohort study, NEWS was attempted in six patients with gastric SMT to investigate the procedure, mortality, and morbidity. NEWS consists of several steps: marking around a tumor on the mucosal as well as the serosal surface, submucosal injection of sodium hyaluronate with indigo carmine dye, circumferential seromuscular dissection with suture closure under laparoscopy, and circumferential mucosubmucosal incision under gastric endoscopy. The resected specimen is then retrieved perorally. Perforation occurred as a result of misidentification and technical inadequacy in the first three patients. After modification of the devices, the entire procedure was successfully achieved in the latter three. There were no complications in any of our six cases. NEWS allows en bloc full-thickness resection, theoretically avoiding contamination and tumor dissemination into the peritoneal cavity.

Efficacy Evaluation of Subtotal and Total Gastrectomies in Robotic Surgery for Gastric Cancer Compared with that in Open and Laparoscopic Resections: A Meta-Analysis

Purposes Robotic gastrectomy (RG), as an innovation of minimally invasive surgical method, is developing rapidly for gastric cancer. But there is still no consensus on its comparative merit in either subtotal or total gastrectomy compared with laparoscopic and open resections. Methods Literature searches of PubMed, Embase and Cochrane Library were performed. We combined the data of four studies for RG versus open gastrectomy (OG), and 11 studies for robotic RG versus laparoscopic gastrectomy (LG). Moreover, subgroup analyses of subtotal and total gastrectomies were performed in both RG vs. OG and RG vs. LG. Results Totally 12 studies involving 8493 patients met the criteria. RG, similar with LG, significantly reduced the intraoperative blood loss than OG. But the duration of surgery is longer in RG than in both OG and LG. The number of lymph nodes retrieved in RG was close to that in OG and LG (WMD = −0.78 and 95% CI, −2.15−0.59; WMD = 0.63 and 95% CI, −2.24−3.51). And RG did not increase morbidity and mortality in comparison with OG and LG (OR = 0.92 and 95% CI, 0.69−1.23; OR = 0.72 and 95% CI, 0.25−2.06) and (OR = 1.06 and 95% CI, 0.84−1.34; OR = 1.55 and 95% CI, 0.49−4.94). Moreover, subgroup analysis of subtotal and total gastrectomies in both RG vs. OG and RG vs. LG revealed that the scope of surgical dissection was not a positive factor to influence the comparative results of RG vs. OG or LG in surgery time, blood loss, hospital stay, lymph node harvest, morbidity, and mortality. Conclusions This meta-analysis highlights that robotic gastrectomy may be a technically feasible alternative for gastric cancer because of its affirmative role in both subtotal and total gastrectomies compared with laparoscopic and open resections.

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.

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.

Feasibility of laparoscopic gastrectomy for elderly gastric cancer patients: meta-analysis of non-randomized controlled studies

The aim of this meta-analysis was to determine the feasibility of laparoscopic gastrectomy (LG) for elderly gastric cancer patients by comparing laparoscopic and conventional open gastrectomies (OG). Comprehensive search of the PubMed, EMBASE, and Cochrane Library databases revealed nine non-randomized controlled studies that compared LG and OG in elderly gastric cancer patients We then analyzed dichotomous or continuous parameters using odds ratios (ORs) or weighted mean differences (WMDs). Overall survival was estimated using hazard ratios (HRs) with a fixed effects or random effects model. We observed that the age distribution was similar between the LG and OG patient groups (WMD -0.22 95% CI, -1.26-0.82). LG patients experienced less blood loss (WMD -119.14 95% CI, -204.17--34.11) and had shorter hospital stays (WMD -3.48 95% CI, -5.41--1.56), but endured longer operation times (WMD 10.87 95% CI, 2.50-19.24). Postoperatively, LG patients exhibited lower incidences of postoperative morbidities (OR 0.59 95% CI, 0.43-0.79), surgery related morbidities (OR 0.58 95% CI, 0.41-0.81) and systemic morbidities (OR 0.56 95% CI, 0.38-0.82). We observed no differences between the LG and OG patient groups regarding anastomotic leakage (OR 0.69 95% CI, 0.34-1.41), mental disease (OR 0.72 95% CI, 0.37-1.41) and long term effects (HR 0.98 95% CI, 0.74-1.32). We therefore conclude that laparoscopic gastrectomy might be technically feasible for elderly gastric cancer patients.The aim of this meta-analysis was to determine the feasibility of laparoscopic gastrectomy (LG) for elderly gastric cancer patients by comparing laparoscopic and conventional open gastrectomies (OG). Comprehensive search of the PubMed, EMBASE, and Cochrane Library databases revealed nine non-randomized controlled studies that compared LG and OG in elderly gastric cancer patients We then analyzed dichotomous or continuous parameters using odds ratios (ORs) or weighted mean differences (WMDs). Overall survival was estimated using hazard ratios (HRs) with a fixed effects or random effects model. We observed that the age distribution was similar between the LG and OG patient groups (WMD -0.22 95% CI, -1.26−0.82). LG patients experienced less blood loss (WMD -119.14 95% CI, -204.17−-34.11) and had shorter hospital stays (WMD -3.48 95% CI, -5.41−-1.56), but endured longer operation times (WMD 10.87 95% CI, 2.50−19.24). Postoperatively, LG patients exhibited lower incidences of postoperative morbidities (OR 0.59 95% CI, 0.43−0.79), surgery related morbidities (OR 0.58 95% CI, 0.41−0.81) and systemic morbidities (OR 0.56 95% CI, 0.38−0.82). We observed no differences between the LG and OG patient groups regarding anastomotic leakage (OR 0.69 95% CI, 0.34−1.41), mental disease (OR 0.72 95% CI, 0.37−1.41) and long term effects (HR 0.98 95% CI, 0.74−1.32). We therefore conclude that laparoscopic gastrectomy might be technically feasible for elderly gastric cancer patients.

Alterations in gastric mucosal lineages before or after acute oxyntic atrophy in gastrin receptor and H2 histamine receptor-deficient mice.

Spasmolytic polypeptide (SP/TFF2)-expressing metaplasia (SPEM) is induced by oxyntic atrophy and is known as a precancerous or paracancerous lesion. We seek to determine whether the gastrin receptor or H2 histamine receptor influence the development of SPEM. DMP-777 was administered to gastrin receptor and/or H2 receptor-deficient mice and wild-type mice. Gastric mucosal lineage changes were analyzed. The mucosa from double knockout mice and H2 receptor knockout mice contained elevated numbers of dual TFF2 and intrinsic factor immunoreactive cells even before DMP-777 treatment. All genotypes of mice showed SPEM after 7-day treatment. In all types of knockout mice, the number of TFF2 immunoreactive cells remained elevated after cessation of treatment. The H2 receptor and gastrin receptor do not affect emergence of SPEM. However, it is suggested that the absence of H2 receptor signaling causes a delay in the maturation of chief cells from mucous neck cells.

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.