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Background/aim Targeting of the human epidermal growth factor receptor 2 (HER2) is suggested to be beneficial for esophageal squamous cell carcinoma (ESCC) patients with HER2 amplification. In this study, we evaluated the effects of combination chemotherapy with HER2-targeted drug trastuzumab in ESCC cells and examined the underlying mechanism contributing to these effects. Materials and methods HER2 expression was verified, and the efficacy of chemotherapy with and without trastuzumab was investigated in vitro and in vivo. Results The combination of trastuzumab and a combined-modality therapy stimulated the PI3K/Akt pathway in ESCC cells overexpressing HER2. Trastuzumab treatment resulted in the intranuclear accumulation of FOXO3A in ESCC xenografts overexpressing HER2. The combination of trastuzumab and a combined-modality therapy enhanced antitumor effects in HER2-overexpressing ESCC xenografts. Conclusion FOXO3A plays an important role in mediating the effects of trastuzumab, and combination chemotherapy may be a promising treatment for patients with HER2-overexpressing ESCC.

In patients with early stage gastric cancer in the middle third of the stomach, pylorus-preserving gastrectomy (PPG) can be an option as function-preserving surgery, although its oncologic safety is not definitively defined. This issues may be overcome using the sentinel node (SN) concept. The aim of this study was to investigate the effectiveness of the SN concept in early gastric cancer patients who are candidates for PPG. One hundred fifty-six patients with middle-third location of cT1N0 gastric cancer (single lesion

Radiotherapy (RT) or chemoradiotherapy (CRT) is a potentially curative, non-surgical treatment option for esophageal cancer, although the rate of local failure within the esophagus remains relatively high. Salvage esophagectomy is not regarded as a common treatment for esophageal cancer, since it is a high-risk surgery with a relatively high surgical mortality rate. Salvage endoscopic resection (ER) for local failure is used for treatment when esophageal cancer is localized and superficial. To evaluate to usefulness of salvage ER, the present study reviewed the clinicopathological records and follow-up data of 37 patients that underwent salvage ER for esophageal cancer, following initial treatment with RT or CRT. Salvage ER was conducted on a total of 78 lesions observed in the 37 patients. Since a thick epithelium and lack of normal vessels on the surface of the mucosa are characteristics of esophageal mucosa following RT or CRT, almost all the lesions were detected using iodine dyeing, and not by narrow band imaging. The growth rate of the detected lesions was relatively high, and early treatment was required. No particular complications occurred during the endoscopic treatment. A total of 11 patients survived for >5 years subsequent to initial endoscopic treatment. Only 4 patients succumbed to esophageal cancer. In conclusion, the present study demonstrated that salvage ER following CRT or RT for esophageal cancer is a minimally invasive, safe, adaptive and curative method for superficial lesions without distant metastases in patients with esophageal cancer with local failure following CRT or RT.

Background The objectives were to investigate the accuracy of sentinel lymph node (SLN) biopsy, detect the predictors for undetected or false-negative cases, evaluate the indications for SLN-navigated gastrectomy, and characterize the problems of SLN mapping in gastric cancer. The SLN concept may be applicable to early gastric cancer, particularly clinical T1N0M0 or T2N0M0 with tumor diameter ≤4 cm. Methods A total of 385 consecutive patients diagnosed with cT1N0M0 or cT2aN0M0 operable gastric cancer from April 1999 to December 2007 underwent radical gastrectomy with SLN mapping. SLNs were identified using radio-guided and dye-guided methods. Predictors for undetected or false-negative cases on SLN mapping were examined by multivariate regression analysis. Results The detection rate of hot and/or blue nodes was 96.6% (372 of 385). The accuracy of metastatic status based on SLNs was 98.9% (368 of 372) for all cases in whom SLNs could be detected. Furthermore, the accuracy of metastatic status based on SLNs was 99.1% (344 of 347) in cT1 gastric cancer and 96.0% (24 of 25) in cT2 gastric cancer. Pathologically, the tumors invaded to the muscularis propria or deeper in three of four false-negative cases. All but one case had metastatic lymph nodes within the sentinel basins. In terms of 5-y recurrence free survival, positive SLN cases (SLN(+)) had a worse prognosis than negative SLN cases (SLN(−); P = 0.008). Moreover, SLN(+) and non-SLN(−) cases (SLN(+)/non-SLN(−)) had a similar prognosis as SLN(+) and non-SLN(+) cases (SLN(+)/non-SLN(+)) (P = 0.511). On multivariate regression analysis, undetected or false-negative cases were significantly associated with the time period. Conclusions The present results appeared to validate the SLN concept for untreated cT1 gastric cancer with tumor diameter ≤4 cm. SLN mapping may provide an effective method of staging the lymph node status of patients undergoing minimized gastrectomy. Sentinel basin dissection guards against the possibility of leaving positive lymph nodes. Stabilization of the procedure and experience with SLN mapping in gastric cancer might decrease undetected or false-negative cases.

Xanthogranulomas are known to develop in the gallbladder and kidney. Xanthogranuloma of the stomach is a rare disease, and to the best of our knowledge, only a few cases have been reported to date. The present patient was a 64-year-old man who underwent a wide resection of the stomach following a Billroth-I reconstruction for a gastric ulcer ~40 years prior to the current presentation. Due to tarry stools, a gastrointestinal endoscopy was performed, leading to identification of an ulcerated gastric lesion located at the previous suture line at the lesser curvature of the remnant stomach. This lesion was elevated, appearing to indicate a submucosal tumor. Positron emission tomography revealed uptake of fluorodeoxyglucose radiotracer by the tumor. Although not indicated by the biopsy specimens, a malignant tumor of the remnant stomach was suspected, in the form of a malignant gastrointestinal tumor or remnant gastric cancer. Curative resection of the tumor was successfully performed. Histological examination of the resected specimens revealed xanthogranulomatous inflammation consisting of foamy histiocytes and plasma cells, however, no cancer cells were observed. The tumor was diagnosed as xanthogranulomatous gastritis that mimicked a malignant tumor of the remnant stomach. The present study therefore indicates that inflammatory tumors should be considered in the differential diagnosis of malignant tumors.

Sentinel node (SN) mapping using dye and radioisotope (RI) tracer has been reported to be feasible in cases of early gastric cancer. Because accurate diagnosis of micrometastasis is sometimes difficult in the limited time available during surgery, a faster and simpler method of improving the intraoperative diagnostic precision of lymph node metastasis is needed. The amount of tracer deposited in an SN can be determined from its radioactivity; however, the significance of the RI count has not been fully discussed. We investigated the clinical impact of the RI count when used as an adjunct to conventional lymph node dissection when diagnosing lymphatic metastasis in cases of early gastric cancer. From 2008 to 2009, patients with clinically diagnosed T1N0M0 gastric cancers who underwent gastrectomy and SN mapping were enrolled. SNs were examined by intraoperative and postoperative pathology. The RI count was measured for each SN with a handheld gamma probe; the correlation between nodal metastasis and the RI count was assessed. A total of 308 SNs were harvested from 72 patients. Patients with SN metastasis had significantly higher total RI counts than those without SN metastasis (p = 0.007). Among cases with SN metastasis, RI counts were also significantly elevated in metastasis-positive nodes, stations, and basins. In these cases, the most of SNs having the highest RI count in each case had metastasis including isolated tumor cells. In early gastric cancer patients, a high RI count from an SN was correlated with lymph node metastasis. Therefore, RI counting may aid efficient pathological diagnosis and focused lymph node dissection.

Drug resistance to chemotherapy is a major issue in esophageal cancer management. Drug resistance may be mediated by genetic changes in the tumor; therefore, the identification of gene mutations may lead to better therapeutic outcomes. We used a novel method involving transposons to screen and identify drug-resistant genes. Transposons are DNA sequences that move from one location on the gene to another. A modified piggyBac transposon was designed as an insertion mutagen, and a cytomegalovirus (CMV) promoter sequence was added to induce strong transcription. When the transposon is inserted to the upstream of a certain gene, the gene will be overexpressed while when intserted down or intragenically, it will be downregulated. After establishing a transposon-tagged cell library, we treated cell lines derived from esophageal squamous cell carcinomas (ESCC) [Tohoku esophagus (TE)] with cisplatin (CDDP). We performed splinkerette PCR and TOPO cloning on the resistant colonies. Bacterial colonies were sequenced, and next-generation sequencing was used to identify the overexpressed/downregulated sequences as candidate genes for CDDP resistance. We established 4 cell lines of transposon-tagged cells, TE4, 5, 9 and 15. We treated the two relatively viable cell lines, TE4 and TE15, with CDDP. We identified 37 candidate genes from 8 resistant colonies. Eight genes were overexpressed whilst 29 were downregulated. Among these genes was Janus kinase 2 (JAK2) that is implicated in the progression of myeloproliferative neoplasms. We identified 37 candidate genes responsible for CDDP resistance in the two cell lines derived from ESCC cells. The method is inexpensive, relatively simple, and capable of introducing activating and de-activating mutations in the genome, allowing for drug-resistant genes to be identified.

Esophagectomy for esophageal cancer is one of the most invasive operative procedures. Surgical stress induces the release of proinflammatory cytokines, and overproduction induces a systemic inflammatory response syndrome, which may lead to acute lung injury and multiple organ dysfunction syndrome. In addition, surgical stress may cause immunosuppression, which may affect not only perioperative mortality but also long-term survival. Between 2006 and 2013, levels of perioperative serum cytokines were evaluated in 90 patients who underwent esophagectomy for esophageal carcinoma. The serum interleukin (IL)-6, IL-8, and IL-10 levels were measured by enzyme-linked immunosorbent assays. We reviewed and assessed medical records, including cytokine profiles, and determined the factors affecting postoperative serum cytokine levels. These cytokine levels peaked on postoperative day 1 and decreased gradually. Of the clinicopathologic factors, a thoracoscopic approach was a significant factor in attenuating IL-6 and IL-8 levels on postoperative day 1 in multivariate analysis, and a longer operative time was a significant factor in increasing these levels. During postoperative days 3–7, the thoracoscopic approach and early enteral nutrition were significant factors in attenuating serum cytokine changes in multivariate analysis, and postoperative infectious complications were significant factors in increasing these levels. The thoracoscopic approach and early enteral nutrition could attenuate the cytokine change after esophagectomy, and a longer operative time and postoperative infectious complication could increase it. We should undertake strategies to minimize the surgical stress to reduce potential short-term and long-term consequences for patients.

The purpose of this study was to establish the clinicopathological significance of circulating tumor cells (CTCs) in patients with advanced or recurrent esophageal cancer who received either chemotherapy or chemoradiotherapy. CTCs from 38 patients with advanced or recurrent esophageal cancer were quantified using the CellSearch system before and approximately 3–5 weeks after the initiation of a new line of chemotherapy or chemoradiotherapy. The correlation between CTC counts and clinicopathological variables was examined. Of the 38 patients, 15 (39 %) had recurrent esophageal cancer, and 23 patients (61 %) had primary advanced esophageal cancer. The mean age was 63 years (range 43–87 years). One patient (2.6 %) had a complete response to treatment, 16 (42.1 %) had a partial response, 12 (31.6 %) showed stable disease, and nine (23.7 %) showed signs of progressive disease. The overall survival of patients with ≥2 CTCs was significantly shorter than that of patients with

Brain metastasis from esophageal carcinoma is uncommon. The aims of this study were to assess the frequency of brain metastasis from esophageal carcinoma, describe treatment modalities and their outcomes, and determine predictors of survival. Between 2004 and 2012, 680 patients with esophageal carcinoma were registered at Keio University Hospital, Tokyo, Japan. Of these patients, 16 (2.3 %) were diagnosed with brain metastasis. We reviewed their medical records and performed statistical analyses. The median survival after diagnosis of brain metastasis was 5.0 months (95 % CI 1.2–8.7 months). The only statistically significant baseline characteristic that predicted worse survival from brain metastasis was the onset form of brain metastasis (p = 0.01). At the onset of brain metastasis, the median survival from brain metastasis was 13.0 months (95 % CI 0.0–31.0 months) in patients without extracranial metastasis and 2.0 months (95 % CI 0.0–4.3 months) in patients with extracranial metastasis (p = 0.01). Approximately 2 % patients with esophageal carcinoma were diagnosed with brain metastasis. The prognosis of brain metastasis is extremely poor, but long-term survival may be expected with intensive treatment for brain metastasis when the first metastatic site is the brain.

Esophagogastric junction carcinoma incidence is increasing worldwide. However, surgical strategies for this cancer remain controversial. This study aimed to clarify the optimal surgical strategy for esophagogastric junction carcinoma. We retrospectively reviewed a database of 68 consecutive patients with esophagogastric junction carcinoma [Japanese classification of gastric carcinoma (Nishi’s definition): adenocarcinoma, N = 53; squamous cell carcinoma, N = 15] who underwent curative surgical resection at Keio University Hospital between January 2000 and September 2008. In both adenocarcinoma and squamous cell carcinoma, most lymph node metastases were located in the lesser curvature area. Mediastinal lymph node metastasis was observed in 4 patients (7.5 %) with adenocarcinoma and 7 patients (46.7 %) with squamous cell carcinoma. No patient presented with lymph node metastases in the pyloric region. The therapeutic value of extended lymph node dissection was 0, except for lymph node station numbers 1, 2, 3, 4sa, 7, and 110. Extended lymph node dissection in the lesser curvature area showed a high therapeutic value. The para-aortic lymph node was the most frequent nodal recurrence site. All patients with tumor centers located below the esophagogastric junction (N = 37) did not develop mediastinal lymph node metastasis or recurrence. Proximal gastrectomy through a transhiatal approach may be the optimal surgical strategy for esophagogastric carcinoma. Mediastinal lymph node dissection through a thoracic approach seems unnecessary, particularly when the tumor center is located below the esophagogastric junction. To confirm the necessity of para-aortic nodal dissection, further studies are required.

Background The renin-angiotensin system (RAS) affects inflammatory responses during sepsis. Nonproteolytic activation of prorenin by the (pro)renin receptor has recently been shown to stimulate the tissue RAS. In the present study, the effect of (pro)renin receptor blocker (PRRB) pretreatment on sepsis in a rat cecal ligation and puncture (CLP) model was investigated. Materials and methods Male Sprague-Dawley rats underwent CLP and were randomly divided into two groups: PRRB-treated group and control peptide–treated group. Survival was analyzed for 7 d after CLP. The serum concentrations of cytokines and high-mobility group box chromosomal protein 1 (HMGB1) were measured at three time points (0, 3, and 6 h after CLP). Hematoxylin-eosin staining and immunohistochemical staining for nonproteolytically activated prorenin and HMGB1 were performed on the cecum to assess pathologic changes found 6 h after CLP. Results Treatment with PRRB improved the survival rate of the post-CLP septic rats (P = 0.023). PRRB also significantly reduced serum tumor necrosis factor-α, interleukin-1β, and HMGB1 levels 6 h after CLP. In CLP rats that were treated with control peptide, the expression of activated prorenin was elevated in peritoneal foam cells. Moreover, expression of HMGB1 was increased in peritoneal inflammatory cells. In contrast, both were markedly suppressed in CLP rats that were treated with PRRB. Conclusions PRRB significantly improved the survival rate of rats with clinically relevant sepsis, possibly by attenuating a sepsis-induced systemic inflammatory response. We propose that overactivation of the RAS by activation of prorenin in foam cells may be a significant contributor to sepsis.

We investigated clinical and treatment-related factors as predictors of symptomatic pericardial effusion in esophageal cancer patients after concurrent chemoradiation therapy.We reviewed 214 consecutive primary esophageal cancer patients treated with concurrent chemoradiation therapy between 2001 and 2010 in our institute. Pericardial effusion was detected on follow-up computed tomography. Symptomatic effusion was defined as effusion ≥grade 3 according to Common Terminology Criteria for Adverse Events v4.0 criteria. Percent volume irradiated with 5 to 65 Gy (V5-V65) and mean dose to the pericardium were evaluated employing dose-volume histograms. To evaluate dosimetry for patients treated with two-dimensional planning in the earlier period (2001-2005), computed tomography data at diagnosis were transferred to a treatment planning system to reconstruct three-dimensional plans without modification. Optimal dosimetric thresholds for symptomatic pericardial effusion were calculated by receiver operating characteristic curves. Associating clinical and treatment-related risk factors for symptomatic pericardial effusion were detected by univariate and multivariate analyses.The median follow-up was 29 (range, 6-121) months for eligible 167 patients. Symptomatic pericardial effusion was observed in 14 (8.4%) patients. Dosimetric analyses revealed average values of V30 to V45 for the pericardium and mean pericardial doses were significantly higher in patients with symptomatic pericardial effusion than in those with asymptomatic pericardial effusion (P.05). Pericardial V5 to V55 and mean pericardial doses were significantly higher in patients with symptomatic pericardial effusion than in those without pericardial effusion (P.001). Mean pericardial doses of 36.5 Gy and V45 of 58% were selected as optimal cutoff values for predicting symptomatic pericardial effusion. Multivariate analysis identified mean pericardial dose as the strongest risk factor for symptomatic pericardial effusion.Dose-volume thresholds for the pericardium facilitate predicting symptomatic pericardial effusion. Mean pericardial dose was selected based not only on the optimal dose-volume threshold but also on the most significant risk factor for symptomatic pericardial effusion.

CXCL-8, known as proinflammatory cytokine interleukin (IL)-8, and its receptor, CXCR-2, are expressed in various cancer cells. CXCL-8/CXCR-2 network is believed to be involved in angiogenesis, growth, and invasion of tumor cells. To date, the clinical significance of CXCL-8/CXCR-2 network in esophageal squamous cell carcinoma (ESCC) remains unclear. Here, we investigated the role of CXCL- 8/CXCR-2 network in ESCC.The subjects included 78 patients with primary ESCC. We examined CXCL-8 and CXCR-2 expression in surgically resected specimens using immunohistochemistry. The association between CXCL-8/CXCR-2 expression and level of preoperative serum cytokines, C-reactive protein (CRP), coagulation factors, clinicopathologic background factors, and survival of ESCC patients was assessed.Thirty-seven (47%) and 36 (46%) patients were positive for CXCL-8 and CXCR-2 expression, respectively. Both CXCL-8 and CXCR-2 were expressed in 26 patients (33%). We compared the results of these 26 patients [CXCL-8(+)/CXCR-2(+) group] with those of the other group (n = 52). The depth of invasion (pT factor; P.001), lymph node metastasis (pN factor; P = .001), pathologic stage (P .001), lymphatic invasion (P = .010), and venous invasion (P = .001) were significantly more advanced in the CXCL-8(+)/CXCR-2(+) group compared with the other group. Preoperative IL-6, IL-8, CRP, fibrin/fibrinogen degradation product, and fibrinogen levels in the CXCL-8(+)/CXCR-2(+) group were also significantly higher than those in the other group (P = .046, .009, .029, .010, and.001, respectively). The CXCL-8(+)/CXCR-2(+) group also showed a significantly lower recurrence-free survival (RFS; P.001) and disease-specific survival (P = .008). As per Cox's hazards model, CXCL-8/CXCR-2 expression (hazard ratio, 2.89; P = .008) was independent predictive factor for RFS.Increased expression of both CXCL-8 and CXCR-2 correlated with tumor progression, metastasis, higher preoperative levels of proinflammatory cytokines, CRP, activation of exogenous coagulation factors, and poor prognosis in ESCC patients. These results indicate that overexpression of both CXCL-8 and CXCR-2 may be a useful marker for predicting the outcome in ESCC patients, and more important, has potential in becoming a critical diagnostic marker for selection of appropriate treatments.

Overexpression of human epidermal growth factor receptor (EGFR) has been detected in various tumors and is associated with poor outcomes. Combination treatment regimens with EGFR-targeting and cytotoxic agents are a potential therapeutic option for rhabdomyosarcoma (RMS) with EGFR amplification. We investigated the effects of combination treatment with actinomycin D and the EGFR-targeting agent cetuximab in 4 RMS cell lines. All 4 RMS cell lines expressed wild-type K-ras, and 2 of the 4 overexpressed EGFR, as determined by flow cytometry, real-time PCR and direct sequencing. Combination of cetuximab and actinomycin D was highly effective, synergistically inhibiting cell growth with a combination index of less than 1. Moreover, combination treatment with these two reagents increased the rate of apoptosis in EGFR-positive cells. Cetuximab has antitumor activity in EGFR-amplified RMS cells when combined with antitumor reagents, indicating that cetuximab is a potential therapeutic reagent for RMS with EGFR amplification.

At present, no suitable GIST model exists for the analysis of drug resistance or metastasis using established human gastrointestinal stromal tumor (GIST) cell lines or xenografts even though the molecular mechanisms of drug resistance, progression and metastasis require clarification. The aim of this study was to establish and characterize human GIST cell lines and xenografts that can be used for evaluating drug resistance or various new molecularly targeted therapies. GIST tissues from patients were cultured and implanted under the skin of NOG (NOD/Shi-scid, IL-2Rrnu) mice. Two new cell lines (GK1C and GK3C) and three xenografts (GK1X, GK2X and GK3X) were generated from these clinical samples. The established GIST cell lines and xenografts were investigated for tumorigenesis and imatinib sensitivity. These cell lines and xenografts showed characteristic GIST morphology and exhibited KIT expression profiles similar to those of the patient samples. In addition, these GIST cell lines and xenografts were sensitive to imatinib. In conclusion, new human GIST cell lines and xenografts were established and maintained through repeated passages. These models will enable further study of combination therapies and the mechanisms of resistance, and allow testing of novel targeted monotherapies and combination therapies.

Gastric cancer is the second leading cause of death from malignant disease worldwide and most frequently discovered in advanced stages. Because curative surgery is regarded as the only option for cure, early detection of resectable gastric cancer is extremely important for good patient outcomes. Therefore, noninvasive diagnostic modalities such as evolutionary endoscopy and positron emission tomography are utilized as screening tools for gastric cancer. To date, early gastric cancer is being treated using minimally invasive methods such as endoscopic treatment and laparoscopic surgery, while in advanced cancer it is necessary to consider multimodality treatment including chemotherapy, radiotherapy, and surgery. Because of the results of large clinical trials, surgery with extended lymphadenectomy could not be recommended as a standard therapy for advanced gastric cancer. Recent clinical trials had shown survival benefits of adjuvant chemotherapy after curative resection compared with surgery alone. In addition, recent advances of molecular targeted agents would play an important role as one of the modalities for advanced gastric cancer. In this review, we summarize the current status of diagnostic technology and treatment for gastric cancer.

Background The chemokine CXCL12 and its corresponding receptor CXCR4 are key players in the development of several cancers. Therefore, we hypothesized that there is a functional causality between CXCL12 expression and tumor progression in patients with esophageal squamous cell carcinoma (ESCC). Methods We performed an immunohistochemical analysis in 79 consecutive patients with ESCC. We performed in vitro and in vivo cell proliferation assays using ESCC cell lines and a newly established transfectant stably overexpressing CXCL12. Results Immunohistochemistry revealed positive CXCR4 and CXCL12 expression in 48 (61 %) and 62 (78 %) patients, respectively. Additionally, the expression levels did not significantly correlate with any clinicopathological factors. The MIB-1 proliferation index was markedly higher in ESCC with a positive expression of CXCR4 or CXCL12. Positive CXCL12 expression was significantly correlated with lower recurrence-free survival (RFS, p = 0.02). Cox’s hazard models revealed CXCL12 expression as an independent predictive factor for recurrence. In vitro, CXCL12 exposure or overexpression enhanced ESCC proliferation; and AMD3100, a specific inhibitor of CXCR4, equally decreased proliferation irrespective of CXCL12 exposure or overexpression. In the mouse model, AMD3100 significantly decreased ESCC tumor size (p = 0.03). Conclusions CXCL12 stimulates ESCC proliferation, and its expression levels are related to lower RFS in patients with ESCC. Our findings indicate that positive CXCL12 expression may be a useful marker for predicting the outcome in patients with ESCC and is a potentially new therapeutic target for ESCC.

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.

Background: Laparoscopic wedge resection is accepted as a curative treatment for small- and mediumsized gastroin-testinal stromal tumors (GISTs) of the stomach. Conventional methods involving surgical staplers require relatively large lateral margins, which may cause deformity and postoperative dysfunction of the gastric remnant. In this study, we introduce a novel technique called laparoscopic submucosal dissection (LSD) in which the defects of the stomach are minimized and a microscopic negative margin is secured. Methods: The normal seromuscular layer of the gastric wall was dissected with a 5 mm lateral margin. Then, the submucosal tissue was divided carefully using a monopolar electrosurgical device with a curved spatula tip. Results: The operation time was 170 min, and the amount of bleeding was very small. We confirmed an intact pseudo-capsule and marginal subserosal or submucosal tissue of the tumor by histological analysis. The postoperative course was uneventful with no complications. Endoscopy showed minimal deformity of the gastric remnant. Conclusions: We think that LSD is a curative and less invasive treatment for GIST of the stomach. Further investigations are necessary to evaluate the oncological and functional outcomes of this procedure.

Overexpression of human epidermal growth factor receptor (EGFR) has been detected in gastric cancer (GC) and is associated with poor outcomes. Combination treatment regimens with EGFR-targeting agents and cytotoxic agents are considered to be a potential therapeutic option for EGFR-overexpressing GC. Herein, we have investigated the effects of combination treatment with the oral fluoropyrimidine S-1 and the EGFR-targeting agent cetuximab in GC cells with or without EGFR overexpression. EGFR expression was determined by FACS and quantitative PCR in GC cells. Experimental 5-fluorouracil (5FU) was used instead of S-1 for in vitro experiments. The efficacy of 5FU or cetuximab monotherapy or combination 5FU/cetuximab therapy was examined in vitro and in vivo. Clinical specimens were examined for EGFR by immunohistochemistry (IHC). EGFR expression score was defined as strong membrane and cytoplasmic staining in at least 50–75% of cells. The combination of 5FU and cetuximab synergistically inhibited cell proliferation and exhibited an enhanced proapoptotic effect in GC cells with EGFR overexpression. Cetuximab also induced down-regulation of phosphorylation of EGFR and AKT, leading to diminished signaling. The antitumor effect of the combination of S-1 and cetuximab in vivo was also greater than that of either drug alone. Our preclinical findings thus indicate that the combination of S-1 and EGFR-targeting therapy is a promising treatment option for GC with EGFR overexpression.

Described is a novel real-time multiplex reverse transcription-polymerase chain reaction (RT-PCR) assay suitable for intraoperative detection of micrometastasis (MM) in sentinel nodes (SNs) dissected from patients with clinical N0 (cN0) gastric carcinoma.One hundred three patients with gastric cancer, who were preoperatively diagnosed with cN0 and clinical T1 or T2, were enrolled. The patients underwent SN mapping followed by standard radical gastrectomy with lymph node dissection. In addition to all SNs, non-SNs (NSNs) within the SN lymphatic basin and NSN from a different lymphatic basin were randomly sampled. All SNs and NSNs were examined by routine histologic diagnosis and RT-PCR for the expression of cytokeratin (CK) 19, CK20, and carcinoembryonic antigen (CEA).The RT-PCR assay and histologic examination were performed in 512 SNs and 299 NSNs from 103 patients. Pathologic l lymph node metastasis was revealed in 13 (12.6%) of 103 patients. All metastatic lymph nodes were identified within SNs. SNs of these 13 patients had positive findings on RT-PCR. Twenty-eight (27.2%) of 103 patients had negative histopathology but positive findings on RT-PCR. In 7 patients (6.8%), SNs were negative but NSNs were positive on RT-PCR. RT-PCR-positive NSNs were present in the same station as corresponding SNs in 3 of these 7 patients and in the same basin as SNs in 4 patients.The real-time multiplex RT-PCR assay is a useful tool for the detection of MM in SNs and NSNs in patients with gastric cancer.

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.

Laparoscopic antireflux surgery (LARS) is a feasible treatment for gastroesophageal reflux disease (GERD) patients, but it is unclear who will benefit from the surgery. This study investigated patients' GERDspecific quality of life (GsQOL) and analyzed the factors leading to the performance of successful LARS.Twenty-six (57.8%) of 45 consecutive patients who underwent LARS for GERD during the last decade were enrolled. All patients were evaluated by 24-h pH monitoring, esophageal manometry, esophagogastro-duodenoscopy and physical examinations. GsQOL was assessed by a visual analog scale, and the difference between the pre- and postoperative scores was defined as the visual analog scale improvement score (VASIS). The patients were classified into three groups based on the VASIS, and their clinical factors and surgical outcomes were compared.The high VASIS group patients (70 VASIS; Excellent group) patients were significantly younger and obese in comparison to low the VASIS group (30 VASIS; Poor group) consisting of older nonobese patients (P0.05). A multiple regression analysis revealed that age60 years and body mass index (BMI)25 kg/m(2) were significant factors that affected postoperative GsQOL. No other clinical or surgical factors had any influence on the postoperative GsQOL.These results suggest that age and BMI can be predictive factors for the performance of successful LARS.

Sivelestat sodium hydrate is a selective inhibitor of neutrophil elastase, which is effective in acute lung injury associated with systemic inflammatory response syndrome. However, the effectiveness of sivelestat in sepsis has not been fully examined. In the present study, the effect of sivelestat on severe sepsis in a rat cecal ligation and puncture (CLP) model was investigated. Adult male Sprague-Dawley rats underwent CLP and were randomly divided into two groups: sivelestat-treated group and saline-treated controls. The serum concentrations of several inflammatory mediators were measured. Hematoxylin-eosin staining, and immunohistochemical staining for high-mobility group box chromosomal protein 1 (HMGB1), IL-8, and CD68 were performed on the lungs to assess pathological changes found 12 h after the CLP procedure. Treatment with sivelestat significantly improved the survival rate of the post-CLP septic animals (P = 0.030). Sivelestat also induced a significant reduction in serum IL-1beta (P = 0.038) and IL-10 (P = 0.008) levels in these CLP rats. Serum HMGB1 levels had no significant difference between the sivelestat-treated and the control group. The lungs from sivelestat-treated rats exhibited less severe pathological changes and decreased the numbers of HMGB1, IL-8, and CD68-positive cells (P < 0.001). Sivelestat significantly improved survival rate of rats with clinically relevant sepsis, possibly by attenuating sepsis-induced systemic inflammatory response and lung injury. This may explain the implicated health benefits of sivelestat in reducing morbidity and mortality from sepsis.

A low curability of ulcers infected with Candida has been reported in the literature. The aim of the study reported here was to investigate experimentally whether Candida infection affects the healing of ulcers. Candida albicans (the Candida group) or saline (the control group) was administered intragastrically into rats with a cysteamine-induced duodenal ulcer. The duodenal lesions, vascular endothelial growth factor A (VEGF-A) and proliferating cell nuclear antigen (PCNA) were assessed. On Day 7 post-administration, 70.4% rats of the Candida group had a duodenal ulcer compared with 33.3% in the control group (P < 0.05). The duodenal ulcer in the Candida group was significantly larger and deeper than that in the control group. The number of VEGF-A- and PCNA-positive cells was smaller and the area of VEGF-A expression was lower in the Candida group. Using a rat model, we have demonstrated that Candida infection can delay the wound healing process of duodenal ulcers by means of a low expression of VEGF-A and PCNA.

Since the 1990s, the minimalization of surgical invasiveness to reduce postoperative complications has become a major topic in the field of gastrointestinal surgery, including esophageal surgery. Initial challenges in the field of esophageal surgery were reported in 1993. Although the initial reports of thoracoscopic esophagectomy failed to show the lower incidence of postoperative complication compared with conventional open surgery, recent reports that cleared the initial learning phase are indicating relatively lower morbidity in endoscopic surgery. The magnified view by endoscope enables us to perform precise dissection of lymph nodes and to reduce total blood loss. Thus, endoscopic esophageal surgery has been introduced as a novel surgical approach for relatively early stage esophageal cancer. Although recent reports suggest several clinical benefits of this procedure compared with conventional open surgery, a large-scale randomized controlled trial to prove these potential benefits is essential.

In June 2000, we started performing mechanical-stapled anastomosis (MSA) for Billroth-I reconstruction (B-I) in distal gastrectomy. Thus, we performed a retrospective study to compare the clinical outcome of MSA and conventional hand-sutured anastomosis (HA).We evaluated 103 patients who underwent a B-I reconstruction. The data we collected included operative time, operative blood loss, time until oral intake, postoperative hospital stay, and anastomotic and general complications. We also examined the remnant stomach by endoscopy and classified it according to the Residue, Gastritis, Bile (RGB) criteria.The operative time was significantly shorter with MSA than with HA, but there were no other significant differences between the two groups. The RGB classification showed that there was more residual stomach content after MSA than after HA. The incidence of gastritis and bile reflux was not significantly different between the two procedures.The operative time for B-I reconstruction with distal gastrectomy was significantly shorter with MSA than with HA. While there were no significant disadvantages in the incidence of complications associated with MSA compared with HA, MSA resulted in more residue in the remnant stomach. The findings of this study showed the advantages and disadvantages of MSA, and suggest that MSA and HA are equivalent as anastomotic procedures in B-I reconstruction.

The sentinel node (SN) concept is safely applied and validated in early gastric cancer. Gastric lymph nodes are divided into five basins with the main gastric arteries, and the anterosuperior lymph nodes with the common hepatic artery (No. 8a) are classified in the right gastric artery (r-GA) basin. Although No. 8a are considered to have lymphatic flow from the r-GA basin, there might be additional multiple lymphatic flows into No. 8a. The aim of this study is to analyze the lymphatic flows to No. 8a and to investigate the clinical significance of No. 8a as a sentinel node (SN No. 8a). Four hundred and twenty-nine patients with cT1N0 or cT2N0 gastric cancer underwent SN mapping. We used technetium-99 tin colloid solution and blue dye as a tracer. We detected SN No. 8a in 35 (8.2 %) patients. In these patients, we detected SN No. 8a with SNs that belonged to the left gastric artery (l-GA) basin (66 %), right gastroepiploic artery (r-GEA) basin (54 %), and right gastric artery (r-GA) basin (46 %). In addition, celiac artery lymph nodes were detected as SNs significantly more frequently. Function-preserving surgery was performed significantly less often in patients with SN No. 8a (p =0.018). We found that SN No. 8a seemed to have lymphatic flow not only from the r-GA basin, but also from the l-GA basin or r-GEA basin. When SN No. 8a are detected, we should be careful to perform function-preserving surgery, even in SN-negative cases.

Background Esophagectomy is one of the most invasive surgical treatments for digestive tract cancer, and the blood levels of inflammatory cytokines such as interleukin-1, interleukin-6, and interleukin-8 are increased for several hours after surgery or in patients experiencing postoperative complications. CXCR2, an interleukin-8 receptor, is reportedly expressed in several carcinomas, and interleukin-8 signaling promotes cancer cell proliferation. The impact of postoperative complications following esophagectomy on long-term survival is controversial. In this study, we demonstrate the significance of CXCR2 expression and validate the effects of CXCR2 expression and postoperative complications on long-term prognosis of esophageal squamous cell carcinoma using resected specimens. Methods Eighty-two specimens were sectioned from archived, paraffin-embedded tumor tissues obtained from patients with esophageal squamous cell carcinoma who underwent esophagectomy and extended lymphadenectomy for complete resection of cancer in our institute between 1997 and 2002. Immunohistochemistry was performed using a polyclonal antibody to CXCR2, and the correlation of stainability with clinicopathological factors and long-term survival was examined. Results CXCR2 was expressed in 33 of 82 (40.2 %) specimens. In the CXCR2-positive group, the recurrence-free survival and overall survival rates of patients who developed postoperative complications were both significantly lower than those for patients who did not develop any complications. In contrast, in the CXCR2-negative group, there was no significant difference in long-term prognosis between patients with and without complications. CXCR2 positivity combined with postoperative complications was an independent risk factor for subsequent tumor recurrence, showing the highest hazard ratio. Conclusions Our results suggest that the patients with CXCR2-positive esophageal cancer who develop postoperative complications have a poor prognosis and should be carefully followed. Trial registration This study was approved by Keio University School of Medicine Ethics Committee with a trial registration number of 2011-241.

Background Removal of the primary lesion with a clear operative margin is the standard treatment for gastrointestinal stromal tumor (GIST) of the stomach. However, there are few reports on the operative indications for relatively small GIST. Methods Clinicopathologic features and survival data of all 60 patients with GIST of the stomach treated at Keio University Hospital from 1993 to 2004 were analyzed. Laparoscopic wedge resection was used as the primary procedure for tumors between 2 to 5 cm. Tumors larger than 5 cm were resected by laparotomy or laparoscopy-assisted operation. Results Thirty-five lesions (58.3%) were resected by laparoscopic wedge resection, 3 by laparoscopic operation with a small skin incision and 22 by conventional open procedures. The mean size of the tumors was 42.5 mm, with a range of 18 to 150 mm and a median value of 35.5 mm. All operative margins were clear, but 1 patient had liver metastases at the time of resection of the primary lesion. The median follow-up period was 53 months and the 5-year disease-free survival rate (DFS) was 96.1%. No local recurrence or distant metastasis was encountered in patients with tumors smaller than 4 cm. A statistically significant correlation was observed between tumor size and mitotic count in this cohort ( P = .010). Tumors from the intermediate- (n = 14) and high-risk (n = 10) groups as classified by the Risk Assessment Classification showed significantly worse DFS than the low-risk and very low risk group (n = 35) (89.9% vs 100% in 5-year DFS, P = .045). Even among tumors smaller than 3 cm, 2 of 14 cases (14.3%) were classified into the intermediate-risk group. Conclusions Although a prospective randomized trial remains to be performed, this study provides additional evidence suggesting that the early removal of GIST, at 5 cm or less in size, provides better DFS than later removal of the tumor at a larger size.

The minimalization of therapeutic invasiveness in order to preserve quality of life (QOL) is a major topic in the management of early gastric cancer. After laparoscopic surgery for gastric cancer was introduced by Kitano et al. in 1991, an enthusiasm to develop laparoscopic procedures has grown steadily. In the initial phase, early gastric cancer limited to the mucosal layer with no risk of lymph node metastasis was treated by laparoscopic wedge resection or intragastric mucosal resection. Since technical and instrumental advances in endoscopic treatment were achieved by gastroenterologists, these cases can be managed by intraluminal endoscopic approaches. The attention of surgeons then shifted to more radical procedures such as laparoscopic gastrectomy with lymph node dissection, which is comparable to open surgery and can be indicated even in advanced cancer. Although this paradigm shift has already been realized in the field of colorectal surgery, we must pay attention to the particular biological nature of gastric cancer in terms of the potential of peritoneal dissemination. While early-phase recovery after surgery has been improved by laparoscopic surgery, preservation of late-phase QOL by function-preserving surgery is also essential in this regard; therefore, the sentinel node (SN) concept has been a much-discussed topic in gastric cancer surgery to approach this aspect. Recently, the validity of the SN concept has been demonstrated by a number of single institutional studies, and prospective multicenter trials are currently ongoing. Theoretically, various types of function-preserving surgery could be applied in cases of early gastric cancer with negative SNs as less invasive surgery to improve long-term QOL. Although we still have to solve several remaining issues in the treatment of gastric cancers, a confluence of these two major streams, laparoscopic surgery and sentinel node navigation surgery, would enable us to apply a novel individualized minimally invasive approach, both in terms of degree of incisional access and extent of function preservation.

We report a case of advanced gastric cancer exhibiting the features of a submucosal tumor (SMT) of the gastric body. The patient was a 50-year-old male in whom a gastric SMT was detected during a mass screening examination. Upper gastrointestinal endoscopy revealed a protuberant tumor, 2 cm in diameter, covered with normal-appearing mucosa. Examination of an endoscopic biopsy specimen of the tumor revealed chronic gastritis with regenerative and erosive changes. An endoscopic ultrasound examination demonstrated a hypoechoic mass in the third layer of the gastric wall. The clinical diagnosis was gastric SMT, and the patient's course was monitored. Twenty-six months after the initial visit to our hospital, an endosonograph-guided biopsy revealed Group III (borderline lesion). Three months after the biopsy, the size of the SMT had increased slightly. Laparoscopic wedge resection of the tumor was performed to make a pathologic diagnosis and we were able to make a diagnosis of gastric lymphoepithelioma-like carcinoma intraoperatively. Gastrectomy with lymph node dissection was followed as curative surgery. Laparoscopic total excision biopsy is a useful technique in patients with a gastric SMT whose diagnosis has not been confirmed pathologically.

The precise mechanisms that cause gastroesophageal reflux after distal gastrectomy remain unclear. We analyzed the endoscopic findings of the cardia and the position of the remnant stomach, which are related to gastroesophageal reflux. We retrospectively examined the records of 45 patients with Billroth I (B-I) and 39 patients with Roux-en-Y (R-Y) procedure for gastric cancer. Esophagitis was evaluated by the Los Angeles (LA) classification. The endoscopic findings of hiatus hernia were classified according to the criteria of the Keio Cancer Detection Center form (K-form). The valvular appearance of the cardia was classified according to V-grades. The height of the remnant stomach was measured on computed tomography scans. The postoperative findings of esophagitis in the B-I group were significantly worse than the preoperative findings, but no significant change was observed in the R-Y group. The postoperative V-grades and K-forrn findings in the B-I group were worse than their preoperative findings. In the R-Y group, however, there was no significant change in the V-grades or K-form findings. In addition, the height of the remnant stomach was significantly higher in the B-I group than in the R-Y group. This study suggested that an aggravated cardia is associated with the B-I procedure and that the position of the remnant stomach may therefore play an important role in the occurrence of postoperative reflux esophagitis. In contrast, the R-Y operation was shown to preserve the cardia and the position of the remnant stomach better. As a result, R-Y might help prevent not only duodenogastric reflux but also gastroesophageal reflux.

Background: Squamous cell papilloma of the esophagus is considered to be a rare condition; however, the number of cases with this condition reported in recent years has increased, perhaps due to advances in endoscopic diagnosis. Methods: We reviewed the clinicopathological features of 26 lesions of squamous cell papilloma of the esophagus in 24 cases seen at our hospital from 1994 to 2003. There were nine men and 15 women, with a mean age of 60.5 years (range, 31–82 years). Six patients had a history of malignant disease in the past. With regard to the presence of other lesions in the esophagus, six patients had hiatal hernia and four had gastroesophageal reflux disease. Results: Two patients each had two lesions of squamous cell papilloma. There were seven lesions in which inflammatory cell infiltration was found on hisotological examination, of which four had underlying hiatal hernia; five lesions were found to have mild dysplasia on histological examination of which three had gastroesophageal reflux disease. The median duration of follow up of the cases was 8 months (range, 1–101 months). During the follow-up period, none of the lesions showed any dramatic change of appearance or malignant transformation. Conclusion: In principle, while it may be sufficient to keep patients with squamous cell papilloma of the esophagus under simple follow up, the patients must be investigated to rule out malignancy of other organs, and the small probability of malignant transformation of the tumor must always be borne in mind.

Gastric hamartomatous polyps are rare and difficult to diagnose. We report the case of a 43-year-old woman admitted to our hospital after an upper gastrointestinal series revealed a submucosal tumor. Upper gastrointestinal endoscopy showed a submucosal tumor (SMT), which was eroded with a depression on its surface, in the upper corpus. Endoscopic ultrasonography showed a heterogeneous tumor in the third layer. A laparoscopic wedge resection of the stomach allowed us to perform complete resection of the tumor, which measured 2.8 cm in diameter. The pathological diagnosis was a gastric hamartomatous inverted polyp. The postoperative course was uneventful. Only 27 cases of gastric hamartomatous polyps have been reported in Japan. Hamartomatous inverted polyps without a stalk are classified as the "SMT type" because the tumor is inverted into the submucosal layer, whereas polyps with a stalk are classified as the "polyp type." All of the polyps in past reports were resected endoscopically; however, laparoscopic wedge resection may be indicated for SMT-type hamartomatous inverted polyps larger than 2.0 cm in diameter.

To identify chemoresistance-related genes of gastric cancer, we utilized cDNA microarray technology. Thirty-five gastric cancer specimens surgically resected at our institute between 1998 and 1999 were studied for quantification of expression of 6300 genes by means of oligonucleotide microarray methods, and the results were evaluated in comparison with the chemoresistance of the specimens, which was determined by MTT (tetrazolium-based 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Inhibition rates (IR) were determined for cisplatin (DDP), 5-fluorouracil (5-FU), mitomycin C or doxorubicin. IR of 60% or more was regarded as sensitive to each agent, and IR of less than 40% was defined as resistant. Clustering was successfully completed for DDP, resulting in selection of 23 candidates as DDP-resistance-related genes, including vascular permeability factor, 2 membrane transporting subunits, and retinoblastoma-binding protein-1. In addition, further selection of DDP-resistance-related genes was performed according to these criteria: 1) Expression of the gene can be detected in more than 70% of resistant tumors. 2) Expression can be detected in less than 30% of sensitive tumors. 3) Expression in tumors is more than twice that of normal mucosa in more than 50% of specimens. Then, metallothionein-IG and heparin-binding epidermal growth factor-like growth factor (HB-EGF) were identified as candidate DDP-resistance-related genes. When known DDP-resistance-related genes were analyzed according to the MTT assay result, families of glutathione-S-transferase and cyclooxygenase-2 genes were also evaluated as resistance-related genes. For 5-FU resistance, dihydropyrimidine dehydrogenase and HB-EGF-like growth factor genes were also suggested to be resistance-related genes. The present study demonstrated that oligonucleotide microarrays can provide information regarding chemoresistance factors in cancer.

Marimastat is a broad-spectrum matrix metalloproteinase (MMP) inhibitor that inhibits almost all major MMPs, key enzymes in gastric cancer invasion and metastasis. We investigated the ability of marimastat to inhibit tumor angiogenesis in the severe combined immuno-deficient (SCID) mouse/human gastric cancer model of peritoneal dissemination. A human stomach adenocarcinoma cell line, TMK-1, was injected intraperitoneally into SCID mice. On the 7th day after tumor inoculation, the administration of marimastat (27 mg/kg/day) was initiated and the treatment was continued for 2 weeks using subcutaneously-inoculating mini-osmotic pumps. On the 21st day, the mice were killed and the disseminated nodules were evaluated. Total weights, numbers, and the microvascular density of the disseminating nodules were significantly lower in mice treated with marimastat compared to the control group. Film in situ zymography demonstrated that net gelatinolytic activity in the tissues was weaker in treated-group nodules than in control-group nodules. Thus, our results suggested that marimastat inhibited peritoneal dissemination of human gastric cancer cells through inhibition of tumor angiogenesis, possibly involving the down-regulation of gelatinases, in SCID mice injected with human gastric cancer cells.

腹腔鏡下手術(LS)は, 1987年フランスの産婦人科医師Mouretが婦人科のLSの際に胆嚢を摘出したのが初めである. LSの利点として, 1)疼痛が軽微, 2)術後腸蠕動回復が早く早期に経口摂取が可能, 3)早期退院・早期社会復帰が可能, 4)創が小さく美容的,などがある. LSの技術・器具の進歩により今や開腹で行われる手術術式のほとんどは技術的にLSで施行可能である.一方でLSの施設間の技術格差は未だ大きい.熟練した内視鏡外科医のもとではLSは標準術式としての安全性・簡便性が確保されてきたものの,全ての外科医に普及した技術とは未だ言えない. LSの課題としては,まず,標準術式化を目指して,術式の適応選択基準の確立とより簡便かつ安全な手術技術の開発が望まれる.またLSを初めとした手術の縮小化には, sentinel lymph node navigationなど,より高度の補助診断技術の開発も重要であり.放射線科・内科技術の発展も期待される.

Remnant gastric cancer (RGC) is one of the less prevalent gastric cancers. The purpose of this study was to explore the clinicopathological characteristics and results of the operation of RGC following distal gastrectomy. In particular, we examined factors related to prognosis. Between January 1970 and December 2012, 122 patients with RGC following distal gastrectomy underwent further surgery and were analyzed retrospectively. Initial gastric diseases included benign (49 patients, 40.2 %) and malignant diseases (73 patients, 59.8 %). Reconstructions by initial surgery included Billroth I (80 patients, 65.6 %) and Billroth II (42 patients, 34.4 %). Tumors were located at anastomotic (44 patients, 36.1 %) and nonanastomotic sites (78 patients, 63.9 %). There were 59 patients (48.4 %) classified with pathological (p) stage I, 19 as p stage II (15.6 %), 22 as p stage III (18.0 %), and 22 (18.0 %) as p stage IV. A total of 100 patients (82.0 %) underwent curative resection, and 22 underwent noncurative resection. The number of cases of postoperative morbidity, 90-day mortality, and adjuvant chemotherapy were 23 (18.9 %), 3 (2.5 %), and 20 (16.4 %), respectively. Univariate and multivariate analyses were performed to identify the prognostic factors of RGC. Multivariate analysis revealed historical periods, pathological venous invasion, curative resection, and postoperative morbidity to be independent prognostic factors. The prognosis of patients with RGC can be improved by aggressively performing curative resection without causing complications.

157 Background: The aim of this phase I study is to confirm the dose of cisplatin as adjuvant combination chemotherapy with S-1 in gastric cancer patients in an outpatient setting. Methods: The first course was initiated with S-1 monotherapy on days 1-28. From the second to sixth course, S-1 was administered on days 1-28 and cisplatin was added on days 1, 15, and 29. Dose level of cisplatin was escalated as follows: 20 mg/m2 (level 1); 25 mg/m2 (level 2); 30 mg/m2 (level 3). Results: Between Sep. 2010 and Feb. 2014, 13 patients were entered into this study. The median age was 65 years. All patients had a performance status of 0. Final stages were: Stage IIIA, 4; Stage IIIB, 8; and Stage IIIC, 1. The first three patients enrolled at level 1 and none of the three patients experienced Dose-limiting toxicity (DLT). However, one patient at level 2 could not complete administration of cisplatin. Therefore, an additional three patients were entered into level 2. Since these patients did not experience any severe adverse events, level 2 was completed. The first patient enrolled at level 3 had experienced leukocytopenia and elevated bilirubin. These toxicities did not resolve to the level of the starting criteria for the next course within 21 days. In the next patient, the third course could not be started within 21 days because of fatigue and anorexia. Based on these results, the Maximum Tolerated Dose and Recommended Dose were confirmed as level 3 and level 2, respectively. The DLT was >21-day delay of starting the next course. Three patients at level 1 completed combination adjuvant chemotherapy between the second and sixth course based on the protocol. During these treatments, no grade >2 hematological or non-hematological toxicities were experienced. At level 2, two out of six patients completed 5 courses of combination chemotherapy without experiencing severe adverse events. Three out of six patients at level 2 had received 4 courses of combination chemotherapy. Conclusions: Although further clinical trials are recommended to evaluate efficacy, this combination S-1 plus cisplatin regimen is expected to become a standard adjuvant treatment for gastric cancer in the outpatient setting. Clinical trial information: 601995.

症例は53歳女性で,腹痛,血便を主訴に来院した.注腸造影検査で盲腸に腫瘍を認めた.大腸内視鏡,腹部CT検査の結果,終末回腸に生じた腺癌が先進部となった回腸結腸型腸重積症と診断した.開腹術を施行し,重積した腸管を用手的に整復後,回腸30cmを含む回盲部切除とリンパ節郭清を行った.回盲弁より12cm口側の回腸に8×4×1cmの側方発育型腫瘍を認め,病理組織所見は粘膜下層に浸潤する高分化腺癌であった.早期小腸癌の最近の本邦報告12例を集計し検討を加えた.

The cyclin D1 protein is one of the cell cycle regulators required for cell cycle progression through G1 phase to S phase. The cyclin D1-cyclin-dependent kinase (CDK) system is thought to control the cell cycle through mediating extracellular signals from mitogens, such as epidermal growth factor (EGF). In this study, we attempted to examine the therapeutic effect of cyclin D1 antisense oligonucleotides (AS/D1) on cell proliferation and apoptosis of the gastric cancer cell line MKN-74, in the presence and absence of EGF-stimulation. Evaluation of cell survival and DNA synthesis revealed that enhanced cell growth following EGF-stimulation was completely inhibited by a 24 h pre-incubation with 100 nM AD/D1. This inhibition was down to 19.3% compared with maximal DNA synthesis after stimulation with 3 nM EGF alone. Western blotting demonstrated that while EGF-stimulation led to cyclin D1 over-expression, AS/D1 inhibited cyclin D1 protein expression. We also demonstrated the induction of apoptosis in MKN-74 cells by AS/D1. In conclusion, EGF-stimulated MKN-74 cell proliferation was inhibited by AS/D1, which could overcome EGF-induced cyclin D1 over-expression. AS/D1 also affected cell survival by inducing apoptosis through cell cycle arrest following cyclin D1 depletion. Thus, AS/D1 may be a candidate for use as a novel cancer therapy specifically targeted against the over-expression of cyclin D1 enhanced by EGF in malignant cells.