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Background: Recently, various type of surgical treatment such as endoscopic mucosal resection, laparoscopic gastrectomy has been performed in early gastric cancer. When the indication of such treatments is decided, it is important to diagnose the lymph node metastasis as correct as possible. The development of sensitive immunohistochemical techniques relying on specific monoclonal antibodies has made possible the detection of lymph node micrometastasis. The purpose of this study was to analyze the distribution of lymph node metastasis including micrometastasis in early gastric cancer. Patients and methods: A total 324 patients with early gastric cancer were enrolled in this study between 1973 and 1998. Of these, 178 patients had mucosal cancer and 146 submucosal cancer. Lymph node metastasis was found in 32 patients by routine histological examination. Immunohistochemical examination using anti-cytokeratin antibody was performed in 57 patients with submucosal cancer between 1990 and 1998. The tumor location was divided into 7 regions, namely, upper and lesser curvature (UlLess), upper and great curvature (UlGre), middle lesser curvature (MlLess), middle greater curvature (MlGre), lower and lesser curvature (LlLess), lower and greater curvature (LlLess) and esophageal invasion (E). Results: Lymph node metastasis was found in 2% (2/178) of mucosal cancer and 20% (30/146) of submucosal cancer. Significant difference was found in tumor size and tumor depth between node positive and node negative patients. In patients with tumor at E and UlLess, MlLess and MlGre, lymph node metastasis was distributed along the left gastric artery. The patients with LlLess tumor had lymph node metastasis along left and right gastric artery, and right gastro-epiploic artery. In UGre tumor, lymph node metastasis was found in right gastro-epiploic artery. The incidence of micrometastasis was detected by immunohistochemistry was 9 of 47 in node negative patients and 7 of 10 in node positive patients by histology. The distribution of lymph node micrometastasis was similar to the area distributed as above. Conclusion: Lymph node metastasis in early gastric cancer was distributed according to the lymphatic pathway of tumor location. Since lymph node micrometastasis was found in even early gastric cancer, especially in submucosal cancer, histologic examination of lymph node during operation is recommended for minimally invasive surgery.

NeitherLA nor OA inducedapoptosis. 00 stimulatedapoptosis almost as muchas FO at 48h and, to a lesserdegree,at 72h (see table).Regarding cell differentiation, both OA and 00 at 30 and 2oop.M inducedS-I and DPPIV Conclusions: While both 00 and OA were able to inducedifferentiation, only 00 clearly stimulated apoptosis suggesting that other components, other than OA, could be accountable for this effect

胸部食道癌の適切なリンパ節郭清範囲を知るために, 44例にリンホシンチグラフィーを行い食道のリンパ流を検討し, さらに, 両側頸部・上縦隔郭清50例の転移状況と対比した. 胸部上・中部食道癌で頸部, 上・中縦隔, 胃上部リンパ節群, 下部食道癌で下縦隔, 胃上部, 腹腔動脈周囲リンパ節群に高い転移率を認めた. 頸部リンパ節ではNo.104とNo.101の下方, 上縦隔ではNo.106右, 左が転移率, RI uptakeともに高い. 上・中部食道から頸部に至る直結型リンパ流のため, 両側頸部郭清は対側の上縦隔郭清と同じ意義を有し, 下部食道からは, 大動脈周囲リンパ節といえども豊富なリンパ流を認めており, これらの部位の検索と郭清を今後積極的に検討すべきである.

診断学の進歩と積極的リンパ節郭清の実施に伴い, 食道表在癌とくに, m癌とリンパ節転移を伴うsm癌の頻度が最近の5年間に急増した. m癌, リンパ節転移の無いsm癌, 転移陽性sm癌の病理組織学的所見の差異を中心に検討した結果, m癌はsm癌に比べ腫瘍の厚みと粘膜面からの高低差が小さく, リンパ管侵襲陽性の頻度は転移陽性sm癌で他の2群よりも有意に高かった. sm癌の2群では腫瘍長径・厚み, sm浸潤の長さ・割合・深さ, 浸潤増殖様式, 周囲のdysplasiaなどいずれも転移陽性群で大きい値や浸潤の強い傾向を示した. 肉眼的に隆起・陥凹が強く, 混合型や多発・壁内転移を示すものにリンパ節転移陽性のsm癌が高頻度に存在した. 転移陽性sm癌の生存率は不良であったが, 従来の成績よりも改善傾向がみられた.

Background Esophageal squamous cell carcinoma is an aggressive gastrointestinal tract cancer. To date, the presence of circulating tumor cells (CTC) has been reported as a prognostic factor in peripheral blood from patients with gastrointestinal cancers. Methods The CellSearch system was used to isolate and enumerate CTCs. A total of 90 patients with esophageal squamous cell carcinoma who received chemotherapy or chemoradiotherapy were enrolled. Peripheral blood specimens were collected before and after treatments. Results At baseline analysis, CTCs were detected in 25 patients (27.8 %). Overall survival was significantly shorter in patients with than without CTCs. Follow-up blood specimens were obtained from 71 patients. Partial response, stable disease, and progressive disease after treatment were seen in 32, 12, and 27 patients, respectively. CTC positivity after treatment in the progressive disease group (40.7 %) was significantly higher than that of the partial response group (6.3 %). Patients with a change in CTC status from positive to negative had a good prognosis as well as patients without baseline CTCs. Conclusions Evaluation of CTCs may be a promising indicator for predicting tumor prognosis and the clinical efficacy of chemotherapy or chemoradiation therapy in patients with esophageal squamous cell carcinoma. Electronic supplementary material The online version of this article (doi:10.1245/s10434-015-4392-8) contains supplementary material, which is available to authorized users.

Background The expression of the receptor for advanced glycation end products (RAGE) has an impact on the mechanisms giving rise to characteristic features of various cancer cells. The purpose of this study was to elucidate the clinicopathological relevance of the level of RAGE expression in patients with hepatocellular carcinoma (HCC) and to explore the effect of RAGE expression on the characteristic features of HCC. Methods The expression of RAGE was assessed in paired cancer and noncancerous tissues with HCC, using reverse-transcription polymerase chain reaction (RT-PCR), and immunohistochemistry. The quantitative RT-PCR data were analyzed in association with the clinicopathological factors of the patients with HCC. In in vitro experiments, the survival of RAGE-transfected Cos7 and mock-transfected Cos7 cells was compared under hypoxic conditions. In addition, after reducing RAGE levels in RAGE-transfected Cos7 cells by siRNA, similar experiments were performed. Results The expression of RAGE mRNA was lower in normal liver than in hepatitis and highest in HCC. Furthermore, in HCC, it was high in well- and moderately differentiated tumors but declined as tumors dedifferentiated to poorly differentiated HCC. Furthermore, HCC lines resistant to hypoxia were found to have higher levels of RAGE expression, and RAGE transfectant also showed significantly prolonged survival under hypoxia. Conclusions Our results suggest that HCC during the early stage of tumorigenesis with less blood supply may acquire resistance to stringent hypoxic milieu by hypoxia-induced RAGE expression.

Background & Aims Esophageal squamous cell carcinoma (ESCC) is the predominant form of esophageal cancer in Japan. Smoking and drinking alcohol are environmental risk factors for ESCC, whereas single nucleotide polymorphisms in ADH1B and ALDH2 , which increase harmful intermediates produced by drinking alcohol, are genetic risk factors. We conducted a large-scale genomic analysis of ESCCs from patients in Japan to determine the mutational landscape of this cancer. Methods We performed whole-exome sequence analysis of tumor and nontumor esophageal tissues collected from 144 patients with ESCC who underwent surgery at 5 hospitals in Japan. We also performed single-nucleotide polymorphism array-based copy number profile and germline genotype analyses of polymorphisms in ADH1B and ALDH2 . Polymorphisms in CYP2A6, which increase harmful effects of smoking, were analyzed. Functions of TET2 mutants were evaluated in KYSE410 and HEK293FT cells. Results A high proportion of mutations in the 144 tumor samples were C to T substitution in CpG dinucleotides (called the CpG signature) and C to G/T substitutions with a flanking 5′ thymine (called the APOBEC signature). Based on mutational signatures, patients were assigned to 3 groups, which associated with environmental (drinking and smoking) and genetic (polymorphisms in ALDH2 and CYP2A6 ) factors. Many tumors contained mutations in genes that regulate the cell cycle ( TP53, CCND1, CDKN2A , FBXW7 ); epigenetic processes ( MLL2, EP300, CREBBP , TET2 ); and the NOTCH ( NOTCH1 , NOTCH3 ), WNT ( FAT1 , YAP1 , AJUBA ) and receptor-tyrosine kinase−phosphoinositide 3-kinase signaling pathways ( PIK3CA , EGFR , ERBB2 ). Mutations in EP300 and TET2 correlated with shorter survival times, and mutations in ZNF750 associated with an increased number of mutations of the APOBEC signature. Expression of mutant forms of TET2 did not increase cellular levels of 5-hydroxymethylcytosine in HEK293FT cells, whereas knockdown of TET2 increased the invasive activity of KYSE410 ESCC cells. Computational analyses associated the mutations in NFE2L2 we identified with transcriptional activation of its target genes. Conclusions We associated environmental and genetic factors with base substitution patterns of somatic mutations and provide a registry of genes and pathways that are disrupted in ESCCs. These findings might be used to design specific treatments for patients with esophageal squamous cancers.

Purpose Capecitabine plus cisplatin (XP) is a standard therapy for metastatic gastric cancer (mGC). However, while results from previous phase III trials suggested that the cisplatin dosage should be reduced in Japanese patients, no clinical data exist to support this. Here, we conducted a multicenter study to evaluate the efficacy and safety of modified XP (mXP) in Japanese patients with mGC. Methods Patients with previously untreated mGC received mXP (cisplatin 60 mg/m2 on day 1 plus capecitabine 1000 mg/m2 twice daily on days 1–14) every 3 weeks. The primary endpoint was the Response Evaluation Criteria in Solid Tumors-confirmed overall response rate (ORR). A sample size of 40 was planned for a threshold ORR of 30% and an expected value of 50%, with a one-sided α of 0.05 and a beta of approximately 0.2. Results Forty-two patients were enrolled. One patient did not fulfill the eligibility criteria; therefore, a total of 41 patients were assessed. The results were as follows: complete response in 2 patients, partial response in 16, stable disease in 14, progressive disease in 8, and no evaluation in 1. The confirmed ORR was 43.9% (95% confidence interval 28.7–59.1%). The median progression-free survival and median overall survival were 4.6 and 11.3 months, respectively. The most common grade 3 or 4 adverse events were neutropenia (37.5%), anemia (24.4%), anorexia (24.4%), and nausea (12.2%). Conclusions First-line chemotherapy with mXP in Japanese patients with mGC did not reach its primary objective. However, it did show a promising response rate and an acceptable tolerability profile.

Background The aim of this study was to investigate the maintenance of volume as a spacer by comparing vascular supply and apoptosis in an implanted autologous-free dermal fat graft (FDFG) and free fat graft (FFG). An autologous FDFG is a material used in plastic surgery and oncoplastic breast surgery that is ideal for immediate volume replacement after partial mastectomy because of its easy availability and minimal invasion of the donor site; however, immunohistochemical findings and survival procedures have not yet been reported. Methods An experimental protocol using a unique animal model was designed for the present study. The expression of vascular endothelial growth factor (VEGF) was measured in FDFGs and FFGs implanted onto the pectoral major muscle of Wistar rats. Thirty Wistar rats were divided into two groups and postoperatively 1, 2, 4, 8, and 16 weeks (POW1, 2, 4, 8, 16). Six samples from three rats in each group were used as control samples (POW0). Results The thickness of the implanted FDFG was not significantly different from the control sample at POW1, 2, 4, 8, and 16 between FDFG and FFG group; however, the thickness at POW8 and 16 was significantly lesser in the FFG group than in the control samples. The average proportion of fatty tissue to whole tissue ranged from 34.2 to 48.6 % in the FDFG group and from 57.2 to 76.7 % in the FFG group during the observation period; however, there was no significant difference in the proportion of fatty tissue between these two groups. There were no significant differences between the average number of VEGF-positive cells in the FDFG group and the FFG group at POW1, 2, 4, 8, and 16. The average number of TUNEL-positive cells in the early period at POW1 was significantly lower in the FDFG group than in the FFG group. Conclusions This rat model was useful for investigating the mechanisms of angiogenesis, apoptosis, structure maintenance, and fibromatous changes. From the present experimental study, we believe that FDFG is one of the most convenient materials currently available to repair small defects at the time of BCS even in the clinical field.

Background Advanced gastric cancer in the lower third of the stomach often results in stricture of the gastric cavity and digestive symptoms. Gastrojejunostomy has been suggested to improve such symptoms, and the advent of new anticancer agents for gastric cancer has improved the response rate of the disease, which makes it possible to perform R0 gastrectomy in part of patients with stage IV gastric cancer. We experienced a rare case in which a patient with stage IV gastric cancer and cancerous pyloric stenosis was treated with R0 surgery after undergoing a gastrojejunal bypass procedure and multidisciplinary treatment. There have not been any previous reports about cases in which a previous gastrojejunostomy was utilized as a reconstruction route during distal gastrectomy in a patient with gastric cancer that had been treated with chemotherapy and/or CRT. Case presentation An 80-year-old female with advanced gastric cancer and pyloric stenosis was admitted to Kagoshima University Hospital. As peritoneal washing cytology produced a positive result, laparoscopic gastrojejunostomy (modified Devine procedure) was performed to improve food passage, and S-1 (100 mg/body, days 1–14) plus paclitaxel (120 mg/body, days 1 and 15) was administered. Although the tumor was temporarily reduced in size, an abdominal computed tomography scan obtained after four courses of chemotherapy showed progressive disease. Thus, chemoradiotherapy (56 Gy, S-1: 60 mg/body, CDDP: 5 mg/body, days 1–5) was indicated. Marked tumor shrinkage and negative peritoneal washing cytological results were achieved. Curative gastrectomy with D2 lymphadenectomy was performed. We carried out distal gastrectomy and lymph node dissection, and the gastrojejunostomy produced as a gastric bypass in the previous operation was preserved. The patient has not suffered a tumor relapse in 4 years since the surgery. Conclusions We surgeons increase a chance to perform R0 gastrectomy for stage IV gastric cancer following intensive chemotherapy and/or CRT. We should choose proper position of gastrojejunostomy in producing alimentary bypass for stage IV gastric cancer patients to facilitate curative surgery.

Background While recent research has shown that expression of ZEB-1 in a variety of tumors has a crucial impact on patient survival, there is little information regarding ZEB-1 expression in hepatocellular carcinoma (HCC). This study investigated the co-expression of ZEB-1 and E-cadherin in HCC by immunohistochemistry and evaluated its association with clinical factors, including patient prognosis. Methods A total of 108 patients with primary HCC treated by curative hepatectomy were enrolled. ZEB-1 expression was immunohistochemically categorized as positive if at least 1% cancer cells exhibited nuclear staining. E-cadherin expression was divided into preserved and reduced expression groups and correlations between ZEB-1 and E-cadherin expression and clinical factors were then evaluated. Results With respect to ZEB-1 expression, 23 patients were classified into the positive group and 85 into the negative group. Reduced E-cadherin expression was seen in 44 patients and preserved expression in the remaining 64 patients. ZEB-1 positivity was significantly associated with reduced expression of E-cadherin (p = 0.027). Moreover, significant associations were found between ZEB-1 expression and venous invasion and TNM stage. ZEB-1 positivity was associated with poorer prognosis (p = 0.025). Reduced E-cadherin expression was significantly associated with intrahepatic metastasis and poorer prognosis (p = 0.047). In particular, patients with both ZEB-1 positivity and reduced E-cadherin expression had a poorer prognosis (p = 0.005). Regardless of E-cadherin status, ZEB-1 was not a significant prognostic factor by multivariate analysis. There was no statistical difference in overall survival when E-cadherin expression was reduced in the ZEB-1 positive group (p = 0.24). Conclusions Positive ZEB-1 expression and loss of E-cadherin expression are correlated with poor prognosis in HCC patients and malignancy of ZEB-1 positive tumors involves EMT.

Background We reported our experience of adenocarcinoma of sigmoid colon neovagina. Case presentation A 67-year-old female with a history of neovagina construction for Rokitansky syndrome complained of vaginal bleeding. She had a mucinous adenocarcinoma at the anterior aspect of the neovagina. Her original surgery, using sigmoid colon to construct the artificial vagina, was 40 years ago Conclusions This patient’s case may contribute to our understanding of carcinogenesis in the colon.

Background Perioperative staging laparoscopy is a useful tool for the detection of occult peritoneal metastases in gastrointestinal cancers. This retrospective study aimed to determine the clinical value of staging laparoscopy for advanced or recurrent gastric cancer. Methods A total of 178 patients with advanced or recurred gastric cancer who underwent perioperative staging laparoscopy were enrolled. In the absence of peritoneal deposits (P1) and positive peritoneal cytology (CY1), gastrectomy with lymph node dissection was indicated with curative intent. If P1 or CY1 was detected intraoperatively, patients received intensive chemotherapy and laparoscopic surgical intervention. Results Curative gastrectomy was performed in 104 patients after confirmation of P0 and CY0 status. P1 or CY1 was detected for the first time in 23 (15%) patients. A total of 13 patients were converted from gastrectomy to intensive chemotherapy after detection of P1 or CY1. Additional laparoscopic interventions included insertion of intraperitoneal reservoir port in 54 patients, insertion of a metallic stent in five, ileostomy for colon stricture in six, jejunostomy in 19, and gastrojejunostomy in 16. Of eight patients treated with intensive chemotherapy who underwent R0 gastrectomy after second-look laparoscopy, five are currently free from recurrence of gastric cancer for 25.5 months. Conclusions Occult peritoneal dissemination was detected in about 14% in patients with tumors deeper than T2. Moreover, additional laparoscopic interventions can be utilized for P1 or CY1 patients. The excellent surgical outcomes of R0 gastrectomy after chemotherapy and second-look laparoscopy indicate that confirmation of P0 and CY0 status by staging laparoscopy is of value to determine treatment strategy in patients with advanced gastric cancer. Electronic supplementary material The online version of this article (doi:10.1186/1477-7819-12-350) contains supplementary material, which is available to authorized users.

Background Since a phase I clinical trial using three HLA-A24-binding peptides from TTK protein kinase (TTK), lymphocyte antigen-6 complex locus K (LY6K), and insulin-like growth factor-II mRNA binding protein-3 (IMP3) had been shown to be promising for esophageal squamous cell carcinoma (ESCC), we further performed a multicenter, non-randomized phase II clinical trial. Patients and methods Sixty ESCC patients were enrolled to evaluate OS, PFS, immunological response employing ELISPOT and pentamer assays. Each of the three peptides was administered with IFA weekly. All patients received the vaccination without knowing an HLA-A type, and the HLA types were key-opened at the analysis point. Hence, the endpoints were set to evaluate differences between HLA-A*2402-positive (24(+)) and -negative (24(−)) groups. Results The OS in the 24 (+) group (n = 35) tended to be better than that in the 24(−) group (n = 25) (MST 4.6 vs. 2.6 month, respectively, p = 0.121), although the difference was not statistically significant. However, the PFS in the 24(+) group was significantly better than that in the 24(−) group (p = 0.032). In the 24(+) group, ELISPOT assay indicated that the LY6K-, TTK-, and IMP3-specific CTL responses were observed after the vaccination in 63%, 45%, and 60% of the 24(+) group, respectively. The patients having LY6K-, TTK-, and IMP3-specific CTL responses revealed the better OS than those not having CTL induction, respectively. The patients showing the CTL induction for multiple peptides have better clinical responses. Conclusions The immune response induced by the vaccination could make the prognosis better for advanced ESCC patients. Trial registration ClinicalTrials.gov, number NCT00995358