MET4 expression predicts poor prognosis of gastric cancers with Helicobacter pylori infection.

The role of HGF/SF-MET signaling is important in cancer progression, but its relation with Helicobacter pylori-positive gastric cancers remains to be elucidated. In total, 201 patients with primary gastric carcinoma who underwent curative or debulking resection without preoperative chemotherapy were studied. MET4 and anti-HGF/SF mAbs were used for immunohistochemical analysis. Survival of gastric cancer patients was estimated by Kaplan-Meier method and compared with log-rank. Cox proportional hazards models were fit to determine the independent association of MET-staining status with outcome. The effect of live H. pylori bacteria on cell signaling and biological behaviors was evaluated using gastric cancer cell lines. MET4-positive gastric cancers showed poorer prognosis than MET4-negative cases (overall survival, P = 0.02; relapse-free survival, P = 0.06). Positive staining for MET4 was also a statistically significant factor to predict poor prognosis in H. pylori-positive cases (overall survival, P < 0.01; relapse-free survival, P = 0.01) but not in H. pylori-negative cases. Gastric cancers positively stained with both HGF/SF and MET4 showed a tendency of the worst prognosis. Stimulation of MET-positive gastric cancer cells with live H. pylori bacteria directly upregulated MET phosphorylation and activated MET downstream signals such as p44/42MAPK and Akt, conferring cell proliferation and anti-apoptotic activity. In conclusion, positive staining for MET4 was useful for predicting poor prognosis of gastric cancers with H. pylori infection. Helicobacter pylori stimulated MET-positive gastric cancers and activated downstream signaling, thereby promoting cancer proliferation and anti-apoptotic activity. These results support the importance of H. pylori elimination from gastric epithelial surface in clinical therapy.

Systemic inflammatory response syndrome as a predictor of anastomotic leakage after esophagectomy.

PURPOSE: Esophageal anastomotic leakage is still a major cause of morbidity and mortality after esophagectomy. We conducted this study to elucidate how anastomotic leakage affects the systemic inflammatory response syndrome (SIRS) criteria. METHODS: The subjects of this retrospective study were 61 patients who underwent esophagectomy. We evaluated their preoperative status, the surgical procedures, and postoperative systemic response, including white blood cell count, heart rate, respiratory rate, body temperature, and laboratory data up to postoperative day (POD) 4. RESULTS: Anastomotic leakage developed in nine patients (14.8%) and was found on POD 7 on average. These patients had a significantly longer hospital stay than those without leakage. Although no difference was observed in postoperative changes of any of the SIRS criteria, the postoperative incidence of SIRS was significantly higher in the patients with anastomotic leakage on POD 4. The number of positive criteria for SIRS was also significantly higher in patients with anastomotic leakage than in those without leakage on PODs 3 and 4. CONCLUSIONS: The SIRS scoring system is valuable for evaluating the severity of systemic inflammatory response caused by anastomosis leakage, and may serve as an indicator for prompt management.

One-step nucleic acid amplification (OSNA) for the application of sentinel node concept in gastric cancer.

PURPOSE: This study was designed to apply safely the sentinel node navigation surgery (SNNS) to the malignancies, an accurate and prompt intraoperative diagnosis of SN is essential, and micrometastasis has been frequently missed by conventional frozen sections. Recently, a novel molecular-based rapid diagnosis for the lymph node (LN) metastases has been developed using (OSNA) in breast cancer, which takes approximately 30 min to obtain a final result. We evaluated the efficacy of OSNA in terms of the intraoperative diagnosis of LN metastasis in patients with gastric cancer. METHODS: A total of 162 LNs dissected from 32 patients with gastric cancer was included in this study; 45 LNs were pathologically diagnosed as metastatic LNs and 117 LNs were negative. The LNs were bisected; halves were examined with H&E stain, and the opposite halves were subjected to OSNA analyses of CK19 mRNA. The CK19 mRNA expression was examined in the positive or negative metastatic LNs, and the correlation between the tumor volume and CK19 mRNA expression in the metastatic LNs was examined. RESULTS: The CK19 mRNA expressions in the positive metastatic LNs were significantly higher than those of negative LNs. When 250 copies/µl was set as a cutoff value, the concordance rate was 94.4%, the sensitivity was 88.9%, and the specificity was 96.6%. The OSNA expression was significantly correlated with the estimated tumor volumes in the metastatic LNs. CONCLUSIONS: The OSNA method is feasible and acceptable for detecting LN metastases in patients with gastric cancer. This should be applied for the intraoperative diagnosis in the SN-navigation surgery in gastric cancer.

Computed tomography lymphography for the detection of sentinel nodes in patients with gastric carcinoma.

The sentinel node (SN) concept has been found to be feasible in gastric cancer. However, the lymphatic network of gastric cancer may be more complex, and it may be difficult to visualize all the SN distributed in unexpected areas by conventional modalities. In this study, we evaluate the feasibility and efficacy of CT lymphography for the detection of SN in gastric cancer. A total 24 patients with early gastric cancer were enrolled in the study. Three modalities (CT lymphography, dye and radioisotope [RI] methods) were used for the detection of SN. The images of CT lymphography were obtained at 10 min after injection of contrast agents. The SN were successfully identified by CT lymphography in 83.3% of patients; detection rates by the dye and RI methods were 95% and 100%, respectively. Most patients, in whom SN were successfully detected by CT lymphography, had positive results at 5 min after injection of the contrast material. The SN stations detected by CT lymphography were consistent with or included those detected by dye and/or RI methods. In conclusion, CT lymphography for the detection of SN in gastric cancer is feasible and has several advantages. However, based on this initial experience, CT lymphography had a relatively low detection rate compared with conventional methods, and further efforts will be necessary to improve the detection rate and widen the clinical application of CT lymphography for the detection of SN in gastric cancer.

Prognostic significance of the number of lymph nodes examined in colon cancer surgery: clinical application beyond simple measurement.

OBJECTIVE: To identify an optimal cutoff value for the number of lymph node examined (NLNE) to distinguish the prognoses in patients following a curative resection for advanced colon cancer, to clarify the mechanism of the difference, and to suggest the integration of NLNE to colon cancer staging. PATIENTS AND METHODS: A total of 859 patients who had undergone surgical treatment for localized colon cancer from 1980 to 2000 were reviewed. This was a cohort from a single institution with mean NLNE of 20.7 and more than 12 NLNE in 77% of the patients. The optimal breakpoint for NLNE was calculated by a receiver operating characteristic curve (ROC) analysis. The patients were stratified into groups based on various parameters and underwent univariate and multivariate analyses with respect to survival. RESULTS: The ROC analysis identified NLNE as a significant prognostic factor with cutoff value of 18 for node-negative and 20 for node-positive patients. A multivariate analysis with these cutoff values identified NLNE as a significant prognostic factor independent of tumor depth and the number of lymph nodes involved. The 5-year cause-specific survival of stage IIB patients was 96.5% with 18 or more NLNE and 67.5% with NLNE less than 18 (P[r]=0.0067). Similarly, a cutoff value of 20 NLNE for node-positive patients separated the 5-year cause-specific survival of stage IIIB patients into 79.3% with 20 or more NLNE and 63.3% with less than 20 NLNE (P=0.0052). CONCLUSIONS: The clinical significance of NLNE is not limited to being a benchmark for quality care, but has a definite benefit as a prognostic indicator across the stages. Patients could be stratified more efficiently by the integration of NLNE to TNM staging.

Roles of inflammatory cytokines in the progression of gastric cancer: friends or foes?

Increasing evidence is being reported regarding the hypothesis that several proinflammatory and anti-inflammatory cytokines may promote tumor progression and affect the host antitumor response. However, the manner in which a local cytokine network operates in tumor development remains unclear. We reviewed the literature to examine the consequences of novel insights into inflammatory cytokines associated with gastric cancer progression. The Medline and EMBASE databases were searched for publications regarding the role of inflammatory cytokines in the development of gastric cancer. A number of studies have suggested that several proinflammatory and anti-inflammatory cytokines promote tumor progression through the direct activation of nuclear factor-κB (NF-κB) and the upregulation of angiogenesis and adhesion molecules. Furthermore, these processes suppress host antitumor immunity, leading to tumor progression and metastasis. In patients with advanced gastric cancer, most cytokines that enhance or suppress host antitumor immunity appear to have elevated serum and local expression levels. The net cytokine environment fluctuates at various stages of tumor development. In conclusion, a more detailed understanding of the differential roles of malignant cell-derived and hostderived cytokines at different stages of the malignant process could, consequently, open new avenues for the manipulation of cytokine expression and function in cancer immunotherapy for gastric cancer.

Minimally invasive surgery for resection of duodenal carcinoid tumors: endoscopic full-thickness resection under laparoscopic observation.

BACKGROUND: Carcinoid tumors of the duodenum are rare, and the most effective treatment for duodenal carcinoid tumors remains debatable. Because carcinoid tumors of the gastrointestinal tract tend to spread to the submucosal layer even during the early stages of the disease, the possibility of tumor seeding in the vertical margin of the tumor cannot be eliminated by conventional endoscopic mucosal resection (EMR). In addition, because the duodenal wall is thinner than the gastric wall, EMR performed for duodenal lesions may be associated with a high risk of accidental perforation. In this article, we introduce a minimally invasive endoscopic full-thickness resection technique after laparoscopic repair for the local resection of duodenal carcinoid tumors. METHODS: Under general anesthesia, after the duodenum was mobilized laparoscopically, the duodenal serosa at the site of the lesion was suctioned under laparoscopic observation, and full-thickness resection of the duodenum was performed using a cap-fitted endoscope, i.e., EMR-c, without injecting hypertonic saline-epinephrine. The sample was retrieved endoscopically after resection. After confirming that the full-thickness resection of the duodenal wall with enough surgical margins was achieved and that there was no active bleeding, the wound was sutured by the laparoscopic hand-suturing technique. RESULTS: We have performed this surgical procedure in two cases of duodenal carcinoid tumor. The mean operation time was 116 +/- 14 minutes, and the estimated blood loss was 2.5 +/- 0.5 ml. The postoperative courses were uneventful in both cases. CONCLUSIONS: The technique of endoscopic full-thickness resection of gastrointestinal tract under laparoscopic observation is a safe, simple, and can be radical surgical procedure for a small duodenal carcinoid tumor. This surgical procedure may be applicable in the case of other gastrointestinal tumors.

Gastric tube reconstruction by laparoscopy-assisted surgery attenuates postoperative systemic inflammatory response after esophagectomy for esophageal cancer.

BACKGROUND: Conventional open procedures have been supplanted in part by less invasive approaches, such as laparoscopic surgery developed for treating gastrointestinal malignancies. However, it is unclear whether laparoscopy-assisted gastric tube reconstruction (LAGT) can attenuate the postoperative systemic inflammatory response after esophagectomy for esophageal cancer. METHODS: We investigated the postoperative clinical course of the systemic inflammatory response syndrome (SIRS) in patients who underwent an esophagectomy for esophageal cancer by LAGT (LAGT group) and gastric tube reconstruction by conventional open surgery (Open group). RESULTS: Compared with the Open group, the LAGT group had a significantly shorter operative time (539.6 min vs. 639.8 min), shorter duration of postoperative mechanical ventilation (1.1 days vs. 2.8 days), and shorter length of stay in the intensive care unit (2.1 days vs. 4.4 days). The LAGT group also had a significantly shorter SIRS duration (1.4 days vs. 2.7 days), a significantly lower incidence of SIRS, and a smaller number of positive SIRS criteria. Throughout the investigation period, the postoperative white blood cell count was lower in the LAGT group than in the Open group. Additionally, in the LAGT group, the heart rate was lower on each postoperative day (POD), and the respiratory rate was significantly lower on postoperative days (PODs) 1 and 4. There was no difference in postoperative oxygenation, morbidity, and mortality between the groups. The C-reactive protein level on PODs 3 and 4 was significantly lower in the LAGT group than in the Open group. CONCLUSIONS: Laparoscopy-assisted gastric tube reconstruction significantly attenuates postoperative SIRS, and it is therefore a potentially less invasive surgical procedure.

Has the accuracy of preoperative diagnosis improved in cases of early-stage gastric cancer?

BACKGROUND: Adequate preoperative evaluation for gastric cancer staging is essential to develop an individualized treatment strategy involving surgery with reduced lymphadenectomy and laparoscopic gastrectomy. METHODS: A total of 509 gastric cancer patients with clinical Stage IA or IB disease were divided into two groups: 304 patients were admitted in 2000 or earlier (Group A), and 205 patients were admitted in 2001, when multidetector computed tomography (MD-CT) was available, or later (Group B). We evaluated the accuracy of the preoperative diagnoses of tumor depth, lymph node involvement, and tumor stage. RESULTS: With respect to tumor depth, 94.5 and 52.8% of patients were staged correctly in cT1 and cT2 patients, respectively. Among both cT1 and cT2 patients, the underestimated rates were lower in Group B than in Group A. For nodal metastasis, 83.2 and 30.0% of patients were staged correctly in cN0 and cN1 patients, respectively. Among the cN0 patients, 82.1 and 84.7% of Group A and Group B patients, respectively, were staged correctly. Among the cN1 patients, none of the patients in Group B was underestimated, while 9.7% of Group A patients were underestimated. There was a significant increase in the percentage of correctly staged patients and a decrease in the percentage of underestimated patients in Group B in comparison to Group A in both cStage IA and cStage IB patients. CONCLUSIONS: Remarkable advances have been observed in the accuracy of preoperative staging in the early stage of gastric cancer. However, it is necessary to continue to develop accurate preoperative and intraoperative diagnostic systems.

Isolated gastric metastasis from renal cell carcinoma 19 years after radical nephrectomy.

Metastatic tumors in the stomach are rare. We report a case of solitary gastric metastasis from renal cell carcinoma (RCC) 19 years after radical excision of the primary tumor. During evaluation for anemia with melena, a small elevated tumor with ulceration was detected in the gastric fundus of this patient. The tumor was diagnosed as RCC based on endoscopic biopsy findings. There was no evidence of any other metastatic lesion, and a wedge resection of the stomach was performed. No additional metastasis or recurrence has been detected in the patient 12 months after discharge. This case confirms the existence of a very slow growing type of RCC with the potential for late solitary metastases and describes the surgical resectability.

Limited gastrectomy with dissection of sentinel node stations for early gastric cancer with negative sentinel node biopsy.

OBJECTIVE: To evaluate the early results of sentinel node (SN)-navigated limited surgery for early gastric cancer. SUMMARY BACKGROUND DATA: False-negative results of SN biopsy cannot be ignored in gastric cancer surgery. Previous studies suggest that dissection of lymph node stations where SNs belong (SN stations) may minimize the possibility of leaving metastasis behind in SN-navigated surgery. METHODS: Patients with T1N0M0 gastric cancer <4 cm were informed about the SN-navigated limited surgery from 2003 to 2008. SNs were identified using radioisotope and dye methods. When the SN biopsy by frozen section was negative, limited gastrectomy with dissection of SN stations was performed. Patients with SN stations limited to either the lesser or greater curvature underwent a wedge resection unless it would cause a strong deformity of the stomach. A sleeve gastrectomy was performed in other cases. RESULTS: Six of the 60 enrolled patients chose a standard gastrectomy. Sixteen patients were excluded after laparotomy due to a T2-T3 tumor or tumor location. Three patients with positive SN biopsy underwent D2 gastrectomy, and 35 with negative SN biopsy underwent limited gastrectomy with dissection of SN stations; wedge resection in 8 and sleeve gastrectomy in 27. There were no operative mortalities or morbidities. All patients undergoing the limited surgery had no lymph node metastasis by postoperative pathology, and survived without any recurrence. The average area of the resected stomach for limited surgery was significantly smaller than that for standard procedures (92 +/- 50 vs. 189 +/- 64 cm, P < 0.001). CONCLUSIONS: SN-navigated limited gastrectomy with dissection of SN stations for T1N0M0 gastric cancer was considered safe and acceptable although long-term follow-up is mandatory.

Impact of postoperative infection on long-term survival after potentially curative resection for gastric cancer.

We focused on the impact of postoperative infection on long-term survival after potentially curative resection for gastric cancer. Postoperative surgical and medical complications have been implicated as a negative predictor of long-term outcome in various malignancies. However, there have been no published reports assessing the impact of complications arising from postoperative infection on survival in gastric cancer. We studied a population of 1,332 patients who underwent curative resection for gastric cancer. These patients were divided into two groups based on the occurrence (141 patients, 10.6%) or absence (1,191 patients, 89.4%) of postoperative complications due to infection. We investigated the demographic and clinicopathological features of each patient with and without postoperative complications from infection, and thereby the impact of postoperative infection on long-term survival. Patients with postoperative infection had significantly higher frequency of males, upper side tumor location, and total gastrectomy as a surgical procedure, more advanced stage of gastric cancer, and greater age compared with those without postoperative infection. Patients with complications due to postoperative infection had significantly more unfavorable outcome compared with those patients without postoperative infection. Multivariate analysis demonstrated that age, preoperative comorbidity, blood transfusion, tumor depth, nodal involvement, and postoperative infection correlated with overall survival. We conclude that postoperative complications from infection are a predictor of adverse clinical outcome in patients with gastric cancer. However, further immunological study and prospective trials are necessary to confirm the biological significance of these findings.

Helicobacter pylori augments growth of gastric cancers via the lipopolysaccharide-toll-like receptor 4 pathway whereas its lipopolysaccharide attenuates antitumor activities of human mononuclear cells.

PURPOSE: Helicobacter pylori is reportedly involved in the development of gastric cancer. We investigated the mechanisms by which H. pylori affects gastric cancer growth and antitumor immunities in the host, focusing on H. pylori-derived lipopolysaccharide (LPS). EXPERIMENTAL DESIGN: H. pylori and four gastric cancer cell lines (MKN28, MKN45, NUGC3, and KATOIII) were used. We examined the effect of H. pylori or its LPS stimulation on cancer growth and the involvement of the H. pylori LPS-toll-like receptor 4 (TLR4) pathway. We also examined the cytotoxicities of H. pylori/LPS-stimulated human mononuclear cells (MNC) against gastric cancer cells and the effect of H. pylori LPS stimulation on cytokine production by MNC. RESULTS: H. pylori, as well as its LPS, augmented the growth of gastric cancers, all of which expressed TLR4. Neutralization of TLR4 almost completely abrogated the H. pylori-induced proliferative activity of cancer cells. Escherichia coli LPS also augmented cancer growth via the LPS-TLR4 pathway. However, only H. pylori-derived LPS attenuated the cytotoxicity of MNC against gastric cancer cells. Stimulation with H. pylori/LPS also down-regulated perforin production in cancer cell-cocultured CD56+ natural killer cells. H. pylori LPS induced neither interleukin-12 nor IFN-gamma production by MNC, although E. coli LPS did induce production of both significantly. Nevertheless, interleukin-12 stimulation restored the IFN-gamma-producing capacity of H. pylori LPS-stimulated MNC. CONCLUSION: H. pylori augmented the growth of gastric cancers via the LPS-TLR4 pathway, whereas it attenuated the antitumor activity and IFN-gamma-mediated cellular immunity of MNC. H. pylori infection might thereby promote proliferation and progression of gastric cancers.

[Progress in sentinel node navigation surgery for gastric cancer].

Sentinel lymph nodes (SLNs) are identified by injecting lymphatic tracer dye or radioisotope-labeled particles, or both, around a gastric tumor into the submucosa endoscopically or into the subserosa from the exterior of the stomach. Many reports have suggested the feasibility of the SLN concept in T1 gastric cancer. We consider it reasonable to convert from D1+alpha/beta dissection to D2 dissection when an SLN biopsy is positive and have used this strategy since 2000. Although false-negative SLN biopsy results cannot be avoided, previous studies suggested that the dissection of lymph node stations where SLNs occur (SLN stations) may minimize the possibility of leaving metastases, even micrometastases, behind in cases of a negative SLN biopsy. Since 2003, we have performed limited gastrectomy with dissection of SLN stations when the SLN biopsy was negative. A sleeve gastrectomy was sometimes needed due to the distribution of SLN stations or the location of the tumor. It is preferable to conclude the surgery with endoscopic submucosal dissection in cases of negative SLN biopsy, which is performed laparoscopically. For this final goal, it is mandatory to standardize the method of SLN identification and to increase the sensitivity of intraoperative diagnosis of lymph node metastases.

A case of a long-term survival achieved by surgical treatment and chemotherapy for late recurrence of AFP-producing gastric cancer.

BACKGROUND: Alpha-fetoprotein-producing gastric cancer (AFP-GC) is a relatively rare disease, with a dismal prognosis. CASE PRESENTATION: We report the case of a patient with long-term survival after surgery for the recurrence of AFP-GC. A 71-year-old man was diagnosed with gastric cancer and underwent distal gastrectomy with D2 lymphadenectomy (pT3N2M0). Pathological examination of the resected specimen revealed AFP-GC. Fifteen years after the gastrectomy, the patient experienced anorexia and was admitted with a mass located at the mesentery of the small intestine. Following a diagnosis of gastrointestinal stromal tumor of the mesentery, a tumor resection with partial small intestine was performed. The final histopathological diagnosis was AFP-GC's recurrence in the small-bowel mesentery. Two months later, multiple liver metastases were identified, and serum AFP level was found to be extremely high (17,447 ng/mL). Chemotherapy with S-1+CDDP (SP) was initiated for liver metastasis. However, owing to anorexia and fatigue, SP therapy was discontinued following the patient's request at the end of two courses. A CT scan at 1 month after the discontinuation of chemotherapy did not reveal liver metastasis, and serum AFP level decreased to the normal range. He is alive at present with no re-recurrence and no elevation of serum AFP level at 7 years after the second surgery without any chemotherapy. CONCLUSION: Even if recurrence of AFP-GC is diagnosed, radical resection and chemotherapy are effective, as noted in the present case.

Long-term outcome following sentinel node navigation surgery for cT1 gastric cancer.

Sentinel node navigation surgery (SNNS) has become a standard procedure for early-stage melanoma and breast cancer. However, very few studies have evaluated the long-term clinical outcomes following SNNS for gastric cancer. The present study analyzed 51 patients with cT1 gastric cancer who underwent SNNS at our hospital. Sentinel nodes (SNs) were identified using the dual tracer method. Patients underwent limited gastrectomy with SN station dissection when the SNs were reported as pathologically negative during surgery. When SNs were pathologically positive, standard gastrectomy with D2 lymphadenectomy was performed. Out of the 51 cases, 42 cases (82%) were pathologically diagnosed as SN-negative using a frozen section. The surgical procedures included segmental gastrectomy (n=33) and local resection (n=9). A total of 9 patients (18%) had lymph node metastasis in SNs. The mean observation period was 3,125±167 days, and the 5-year overall survival rate was 98%. There was no recurrence, and body weight loss was minimal following the SNNS. Remnant gastric cancer developed in 4 (8%) of the 50 patients except total gastrectomy. Thus, SNNS was a useful procedure for cT1 gastric cancer from the long-term clinical outcomes, though metachronous gastric cancer should paid further attention to.

Gastric cancer cells exploit CD4+ cell-derived CCL5 for their growth and prevention of CD8+ cell-involved tumor elimination.

The level of serum CCL5, a C-C chemokine, is reportedly correlated with tumor progression in several cancers. We herein investigated the mechanisms by which CCL5 might contribute to tumor progression in gastric cancer. Serum CCL5 levels significantly correlated with tumor progression and prognosis in patients with gastric cancer. Immunohistochemistry showed that tumor-infiltrating lymphocytes expressed CCL5, while the tumor cells expressed the CCL5 receptors. Fluorescent double staining showed that tumor-infiltrating CD4+ cells rather than CD8+ cells preferentially expressed CCL5. Using gastric cancer cell lines (MKN45, KATO III), we examined CCL5 production by coculturing whole peripheral blood mononuclear cells (PBMCs), CD4+ cells, or CD8+ cells, with tumor cells. CD4+ cells cocultured with tumor cells remarkably enhanced CCL5 production in a direct cell-cell contact manner over other cocultured PBMCs, including CD8+ cells. Gastric cancer cell lines expressed CCL5 receptors and augmented their proliferation in response to CCL5 stimulation. Furthermore, we examined the effect of CCL5-treated cancer cells on the cocultured PBMCs, focusing on the CD4+/CD8+ proportion and apoptosis. Coculture of CCL5-treated gastric cancer cells with PBMCs resulted in a significant decrease in the proportion of CD8+ cells but not CD4+ cells, suggesting Fas-FasL-mediated apoptosis in CD8+ cells. In immunodeficient mice coinjected with KATO III and PBMCs, neutralization of CCL5 significantly suppressed tumor progression, resulting in a favorable outcome. In conclusion, gastric cancer cells might thus induce CD4+ T cells to secrete CCL5 and exploit it for their progression, as well as to aid in the prevention of CD8+ T cell-involved tumor elimination.

A tissue-engineered stomach shows presence of proton pump and G-cells in a rat model, resulting in improved anemia following total gastrectomy.

Despite advances in surgical reconstruction, total gastrectomy still is accompanied by various complications, especially chronic ones, such as pernicious anemia, resulting in refractory malnutrition. As an alternative approach, we have proposed a tissue-engineered stomach as a replacement of the native stomach. This study aimed to assess the secretory functions of a tissue-engineered stomach in a rat model and the nutritional status of the recipients over an extended time period. Stomach epithelial organoid units were isolated from neonatal rats and seeded onto biodegradable polymers. These constructs were implanted into the omenta of adult recipient rats. After 3 weeks, cyst-like structures had formed, henceforth referred to as tissue-engineered stomachs. The recipient stomachs were resected and replaced by their tissue-engineered counterparts. At 24 weeks after implantation, the secretory function of the tissue-engineered stomach was evaluated using immunohistochemical staining. The hemoglobin levels and nutritional status of the recipients were compared with a control group that had undergone a simple Roux-en-Y reconstruction following total gastrectomy. Recipient rats tolerated the tissue-engineered stomachs well. X-ray examination using barium as contrast showed no bowel stenosis. Staining for proton pump alpha-subunit and gastrin demonstrated the existence of parietal cells and G-cells in the neogastric mucosa, respectively, suggesting secretory functions. The treatment group showed significantly higher hemoglobin levels than the control group, although no differences in the body weight change, total protein, or cholesterol levels were observed between the two groups. A tissue-engineered stomach has the potential to function as a food reservoir following total gastrectomy. It is conjectured that replacement with a tissue-engineered stomach might restore the proton pump parietal cells and G-cells, and thereby improve anemia after a total gastrectomy in a rat model.

Analysis of sentinel node involvement in gastric cancer.

BACKGROUND & AIMS: Sentinel node navigation surgery (SNNS) is performed for patients with early gastric cancer. Because sentinel nodes (SNs) to gastric cancer exist but they have not been well-described, we attempted to validate the SN concept at the micrometastasis level. METHODS: For 53 patients who underwent curative gastrectomy for T1/T2 (<4 cm) N0 gastric cancer, SNNS was performed with radioactive tin colloid and/or indocyanine green, and subsequent modified D1 lymphadenectomies were added. Whole formalin-fixed paraffin-embedded tissues of all resected lymph nodes from these patients were cut into 5-mum thick serial step sections at 85-mum intervals, and occult metastases were examined immunohistochemically. RESULTS: Metastases were detected in 3 (1.5%) of 204 SNs and 3 (0.33%) of 901 non-SNs in pN0 cases and in 18 (46%) of 39 SNs and 3 (1.9%) of 158 non-SNs in pN1 cases. On a patient basis, metastases were detected in 4 (9%) of 46 pN0 patients, 2 (4%) each in SNs and non-SNs, and in 7 pN1 patients, of whom 7 and 4 had SN and non-SN metastases, respectively. The sensitivity, false-negative rate, and accuracy of SN identification by SNNS were 82%, 18%, and 96%, respectively, at the occult metastasis level. However, on the basis of the concept of the sentinel lymphatic station (SLS), which represents all lymphatic stations to which SNs belong, metastases were always limited to the lymph nodes in SLS in the 11 cases with metastases. Non-SN metastases occurred in 3 (60%) of 5 patients with SN metastases >2.0 mm in diameter but not in 4 patients with SN metastases

ADAM23, a possible tumor suppressor gene, is frequently silenced in gastric cancers by homozygous deletion or aberrant promoter hypermethylation.

Array-based comparative genomic hybridization (CGH-array) has a powerful potential for high-throughput identification of genetic aberrations in cell genomes. We identified a homozygous loss of ADAM23 (2q33.3) in the course of a program to screen a panel of gastric cancer (GC) cell lines (1/32, 3.1%) for genomic copy-number aberrations using our custom-made CGH-array. Infrequent homozygous deletion of ADAM23 was also seen in primary gastric tumors (1/39, 2.6%). ADAM23 mRNA was expressed in normal stomach tissue, but not in the majority of GC cell lines without homozygous deletion of this gene. Expression of ADAM23 mRNA was restored to gene-silenced GC cells after treatment with 5-aza 2'-deoxycytidine. The methylation status of the ADAM23 CpG island, which showed promoter activity, correlated inversely with its expression. Methylation of this CpG island was observed both in GC cell lines and in primary GC tissues; in primary tumors with a hypermethylated CpG island, expression of ADAM23 was lower than in adjacent noncancerous tissues. Moreover, restoration of ADAM23 in GC cells reduced their numbers in colony-formation assays. These results suggest that genetic or epigenetic silencing by hypermethylation of the ADAM23 CpG-rich promoter region leads to loss of ADAM23 function, which may be a factor in gastric carcinogenesis.