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Pedicled jejunal flap and colon graft interposition are choices for esophageal reconstruction in patients with a history of gastrectomy or those who have undergone synchronous esophagogastrectomy. However, the optimal conduit in this situation is still being debated. We reviewed the literature concerning esophageal reconstruction using a conduit other than the stomach. Approximately 10 % of esophagectomized patients undergo esophageal reconstruction using pedicled jejunum or colon interposition in Japan. The jejunal graft and colon graft are selected evenly, although the percentage of jejunal graft use is gradually increasing. Microvascular supercharge was performed in most of the reports of pedicled jejunal graft reconstruction, whereas vascular enhancement was not popularly used in the reports of colon graft interposition. Although the incidences of graft loss and anastomotic leakage were comparable between grafts, mortality rates seem to be higher in patients who undergo colon graft reconstruction than in those who undergo reconstruction with a jejunal graft. Prospective comparisons of short-term outcomes as well as long-term quality of life are needed to identify the best method of reconstruction.

Esophagectomy for patients with esophageal cancer remains a high-risk surgery. We introduced a multidisciplinary perioperative management team in the Cancer Institute Hospital (PeriCan) to improve short-term outcomes after esophagectomy. To clarify the effect of PeriCan, we compared short-term outcomes between patients who underwent esophagectomy 1 year before the introduction of PeriCan and those who underwent esophagectomy 1 year after the introduction. One hundred and thirteen patients who underwent esophagectomy between October 2012 and September 2013 were included in the “Before PeriCan” group, while 105 patients who underwent esophagectomy between October 2013 and September 2014 were included in the “PeriCan” group. The incidence of postoperative complications significantly decreased from 73 to 49 % (P = 0.0003) with the introduction of PeriCan. In particular, the incidence of postoperative pneumonia significantly decreased from 43 to 13 % (P

Minimally invasive esophagectomy (MIE) is being increasingly performed worldwide. When performing MIE, we sometimes experienced difficulties due to a narrow upper mediastinum or a middle to lower thoracic esophagus hidden by the projection of the vertebral body. However, there were no reports regarding the influence of anatomical factors on the difficulty of performing MIE. The aim of this study was to evaluate whether anatomical factors could be related to the difficulty of the thoracic procedure in MIE.We investigated 87 consecutive patients undergoing MIE for primary esophageal cancer between 2013 and 2015 and created novel indices to assess the upper mediastinal narrowness and vertebral body projection at middle thoracic part on preoperative computed tomography images. We assessed clinicopathological and anatomical factors and determined the factors influencing the thoracic procedural difficulty in MIE. The thoracic procedure duration was selected as the variable representing technical difficulty.The mean thoracic procedure duration was 280.2 ± 52.5 min. There were no significant correlations between the indices and patient factors such as age, sex, and body mass index. Meanwhile, there was a significant correlation between the upper mediastinal narrowness and the vertebral body projection (p 0.01). Of the clinicopathological and anatomical factors, blood loss during the thoracic procedure, thoracic duct resection, and vertebral body projection independently were related to the prolonged thoracic procedure duration in multiple linear regression analysis (p = 0.01, 0.03, and0.01, respectively). The other factors including upper mediastinal narrowness were not statistically significant.This is the first study to reveal the influence of anatomical factors on the difficulty of the thoracic procedure in MIE. The vertebral body projection at middle thoracic part appears to be a useful tool for predicting the thoracic procedural difficulty in MIE preoperatively.

Excessive visceral fat may promote cancer development and progression because of metabolic derangements. The purpose of this study was to clarify the impact of abdominal fat distribution on patient prognosis after esophagectomy for esophageal squamous cell carcinoma (ESCC). Computed tomography volumetry was performed in 150 patients who underwent curative esophagectomy for ESCC between 2012 and 2013. Visceral fat area (VFA) and subcutaneous fat area (SFA) at umbilicus level were measured, and the VFA/SFA ratio was calculated in each patient. Prognoses of the patients were compared between groups classified according to VFA/SFA ratio. Both relapse-free survival and overall survival of the low VFA/SFA group were significantly better than those of the high VFA/SFA group (log-rank test p = 0.005, p = 0.01). Univariate analysis also found that low VFA/SFA ratio significantly predicted an increase in relapse-free and overall survival. In multivariate analysis, low VFA/SFA ratio was an independent factor for relapse-free survival [p = 0.042, hazard ratio (HR) 0.12, 95 % confidence interval (CI) 0.01–0.93]. In addition, low VFA/SFA ratio tended to be a significant variable that predicted better overall survival (p = 0.057, HR 0.14, 95 % CI 0.01–1.05). Low VFA/SFA ratio was significantly associated with better prognosis in patients who undergo curative esophagectomy for ESCC. Abdominal fat distribution may influence the biological features of ESCC.

Esophageal and head and neck (HN) cancers often occur synchronously, this study aimed to clarify the benefits and disadvantages of synchronous and staged operations for double HN/esophagus cancers. We retrospectively reviewed 43 patients with synchronous double cancer of HN and esophagus treated between July 2005 and July 2014, of whom 33 patients underwent synchronous operation (SYN) and 10 underwent staged operations (STG). We compared the short-term outcomes between the groups. Operation time was longer, amount of blood loss was larger, and hospital stay was longer in the SYN group than in each single surgery of the STG group. Incidence of postoperative complications did not differ between the groups. Tracheal necrosis was observed only in the SYN group. One patient died because of postoperative bleeding in the SYN group, whereas no mortality was seen in the STG group. Both the peripheral white blood cell counts and serum CRP levels during postoperative period were significantly higher in the SYN group than each single surgery of STG group. The staged surgery strategy for patients with synchronous esophagus/HN cancers can attenuate surgical stress and thus may increase safety.

Esophageal and head and neck (H&N) cancers often occur synchronously, this study aimed to clarify the benefits and disadvantages of synchronous and staged operations for double H&N/esophagus cancers. We retrospectively reviewed 43 patients with synchronous double cancer of H&N and esophagus treated between July 2005 and July 2014, of whom 33 patients underwent synchronous operation (SYN) and 10 underwent staged operations (STG). We compared the short-term outcomes between the groups. Operation time was longer, amount of blood loss was larger, and hospital stay was longer in the SYN group than in each single surgery of the STG group. Incidence of postoperative complications did not differ between the groups. Tracheal necrosis was observed only in the SYN group. One patient died because of postoperative bleeding in the SYN group, whereas no mortality was seen in the STG group. Both the peripheral white blood cell counts and serum CRP levels during postoperative period were significantly higher in the SYN group than each single surgery of STG group. The staged surgery strategy for patients with synchronous esophagus/H&N cancers can attenuate surgical stress and thus may increase safety.

Obesity is considered to influence the difficulty of surgery. However, whether mediastinal adiposity influences the difficulty of the thoracic procedure in minimally invasive esophagectomy (MIE) remains unclear. Computed tomography volumetry was performed in 142 patients who underwent MIE between 2012 and 2014. We measured abdominal visceral fat area (AVFA) at the umbilicus level and mediastinal fat area (MFA) at the tracheal carina level. The influence of MFA on the difficulty of the thoracic procedure was assessed using the thoracic procedure duration as a parameter, and the effect of MFA on morbidity after MIE was assessed. MFA was significantly smaller than AVFA (p

Here we report a case of primary glomus tumor of the esophagus, which is extremely rare, and review the corresponding literature. A 69-year-old man underwent screening endoscopy during a medical checkup and a submucosal tumor was incidentally found in the midthoracic esophagus. Endoscopic ultrasonography revealed that the tumor originated from the muscle layer of the esophagus. Computed tomography and 18F-fluorodeoxyglucose positron emission tomography revealed neither lymphadenopathy nor distant metastasis. Endoscopic ultrasonography-guided fine needle aspiration biopsy indicated epithelioid mesenchymal tumor. Immunohistochemically, the tumor cells were positive for alpha smooth muscle actin, and focally positive for Discovered on GIST1 but negative for c-kit and protein kinase C theta, suggesting that the lesion was a KIT-negative epithelioid gastrointestinal stromal tumor or glomus tumor. The tumor was successfully enucleated through right thoracotomy. Pathological examination confirmed that the tumor was a glomus tumor of the esophagus. The patient remains healthy without any recurrence to date one year after surgery.

When tracheal injury occurs during esophagectomy, it is a very serious and frequently fatal complication. We experienced a case of intractable tracheomediastinal fistula caused by tracheal injury during esophagectomy that was successfully repaired using a pedicle flap of the left pectoralis major muscle. A 55-year-old Japanese man who had congenital right aortic arch was referred to our hospital with a complaint of dysphagia. He had a type 2 carcinoma from the distal part of the cervical esophagus to the upper thoracic esophagus, 4.5 cm in length and attached to the membranous wall of the trachea. Subtotal esophagectomy was performed with left thoracotomy. The tumor adhered tightly to the membranous portion of the trachea, and the trachea was injured during removal of the tumor. The laceration was directly sutured and covered with a latissimus dorsi muscle flap. However, a tracheomediastinal fistula became enlarged and the left subclavian artery became exposed. Repair of the fistula was performed 31 days after the first operation: a permanent tracheotomy was made, laryngectomy was performed, and the fistula was filled with a pedicle flap of the pectoralis major muscle. The postoperative course was uneventful and the patient’s general condition improved. The use of a pectoralis major muscle flap was effective for repairing the tracheomediastinal fistula.

Intussusception is a rare cause of postoperative intestinal obstruction in adults. We experienced two cases of bowel obstruction due to the jejuno-jejunal intussusception after harvest of a free jejunum graft for reconstruction after cervical esophagectomy. Bowel obstruction occurred early in the postoperative course, and reoperations were needed in both cases. In both case, the anastomotic site was resected and re-anastomosed in a side-to-side fashion. Recurrence of intussusception has not been observed. In the literature, such a complication has been documented in two case series and a case report. The reported incidence of postoperative intussusception of the case series was 2.8% and 7.4%, respectively. The jejuno-jejunal anastomoses were performed with end-to-end fashion by two layered hand-sewn suture (Albert-Lembert method) in all cases reported. In order to prevent the occurrence of postoperative intussusception, we recommend to harvest a free jejunal graft as far from the Treitz ligament as possible and to avoid reconstruction by an Albert-Lembert end-to-end anastomosis.

The aim of this study was to identify good candidates for salvage esophagectomy after definitive chemoradiotherapy (dCRT), based on safety and survival. Sixty-three patients who underwent salvage esophagectomy, after dCRT, at the Cancer Institute Hospital, Tokyo, Japan, between 1988 and 2013, were retrospectively analyzed. Short-term outcomes were evaluated by reviewing postoperative complications, length of postoperative hospital stay, and mortality. Survival rates were calculated using the Kaplan–Meier method, and statistical significance was determined using the log-rank test. The Cox proportional hazards model was used for univariate and multivariate analyses of overall survival. Univariate logistic regression analysis was used to identify factors related to R0 resection. Postoperative complications occurred in 41 patients (65.1 %), and the mortality rate was 7.9 %. In-hospital deaths did not occur among patients with less advanced tumors prior to dCRT (cT1–2 and cN0), or among those who had previously achieved a complete response (CR); the 3- and 5-year overall survival rates were 29.8 % and 15.0 %, respectively. Univariate analysis revealed that residual disease, tumor depth, dCRT response, lymph node metastasis, and time to relapse were significant factors affecting overall survival. Multivariate analysis demonstrated that R0 resection and ypT0–2 tumors were significant, favorable prognostic factors in patients undergoing salvage esophagectomy. In addition, cT1–2 tumors, initially resectable tumors, ycT1–2 tumors, and relapse after CR were factors predicting R0 resection. Based on both short- and long-term outcomes, patients with pretreatment or preoperative T1–2 tumors and those with relapse after CR are good candidates for salvage esophagectomy.

Cytochrome p4501A1 gene (CYP1A1) and glutathione S-transferase mu gene (GSTM1) are involved in the metabolic activation or detoxification of environmental carcinogens including benzo[a]pyrene in tobacco smoke. Individuals with both Val/Val and C type of CYP1A1 (CYP1A1; Val/Val and CYP1A1; C) or homozygous null (-/-) genotype of GSTM1 gene (GSTM1; -/-) show increased susceptibility to lung cancer. The incidence of p53 gene mutations are related to the smoking index of the lung cancer patients. Therefore we determined genotypes of these enzymes and screened p53 gene mutations in 123 non-small cell lung cancer (NSCLC) patients. p53 gene mutations were found in 35% (43/123) of the patients. The incidence of p53 gene mutation CYP1A1; Val/Val (60.0%), CYP1A1; C (50.0%) tended to be higher than those of CYPIAI; Ile/Ile and Ile/Val (40.4%) or CYP1A1; A and B (40.5%). We conclude that the incidence of the p53 mutations does not seem to be significantly affected by only CYP1A1 or GSTM1 polymorphisms in lung cancer patients.

SUMMARY. Salvage esophagectomy is performed for esophageal cancer after definitive chemoradiotherapy. The clinical significance and safety of salvage surgery has not been well established. We reviewed 14 cases of salvage esophagectomy following definitive chemoradiotherapy from 1994 through 2005 and investigated complication rates and outcomes. Seven of 14 cases were completely resected with salvage surgery. Operation time and bleeding were greater in patients who experienced incomplete resection (R1/R2). Anastomosis leakage, pulmonary dysfunction and heart failure were recognized in four, two and one patients, respectively. The postoperative complications were more frequent (71.4%) in patients with incomplete resection (R1/R2) than in patients with complete resection (R0) (28.4%). Two patients with complete resection (R0) showed long-term survival. Salvage esophagectomy may be indicated when the tumor can be resected completely after definitive chemotherapy. However, all cases of T4 cancer cannot be resected completely, resulting in a high risk for complications and poor survival.

The clinical significance of isolated tumor cells (ITC) circulating in the blood of patients with colorectal cancer is unclear. In this study, we investigated the relationship between the presence of ITC that express carcinoembryonic antigen (CEA) and/or cytokeratin 20 (CK20) transcripts in the blood and the clinicopathological findings and prognosis using the quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) assay. We studied peripheral blood and tumor drainage blood from 167 patients with colorectal cancer. Quantitative real-time RT-PCR assay was able to detect one tumor cell in 3x10(6) peripheral blood mononuclear cells. Applying a cut-off value, CEA and/or CK20 (CEA/CK20) were detected in 10.2% (17/167) of the patients' preoperative peripheral blood samples and 34.1% (57/167) of the patients' tumor drainage blood samples. In the relationship between the CEA/CK20 of the blood and the clinicopathological factors, a significant correlation was demonstrated between the positivity of marker genes and the depth of invasion, venous invasion, lymph node metastasis, liver metastasis or stage. The disease-free and overall survival of patients with CEA/CK20-positive peripheral or tumor drainage blood was significantly shorter than that of marker gene-negative patients. CEA/CK20 transcripts in tumor drainage blood were independent factors for prognosis in disease-free survival and overall survival. These results suggest that detecting CEA/CK20 mRNA in tumor drainage blood by real-time RT-PCR has prognostic value in patients with colorectal cancer. Large scale and long-term clinical studies are needed to confirm the prognostic value of genetically detecting ITC in the peripheral blood.

Because the epithelial cell adhesion molecule (Ep-CAM) is expressed in almost all carcinomas and human leucocyte antigen (HLA)-A*2402 is the most common allele in many ethnic groups, including Japanese, the identificationof peptide sequences, which elicit HLA-A*2402-restricted Ep-CAM-specific cytotoxic T-lymphocyte (CTL) responses, would facilitate specific immunotherapy for various histological types of carcinomas. An epitope was identified through the following steps: (i) computer-based epitope prediction from the amino acid sequence of Ep-CAM, (ii) major histocompatibility complex (MHC) stabilization assay to determine the affinity of the predicted peptide with HLA-A*2402 molecules, (iii) stimulation of CDB + T cells with peptide-pulsed dendritic cells and (iv) testing the CTL specificity by means of enzyme-linked immunospot (ELISPOT) assays, CTL assays and MHC/peptide-tetramer staining. Peripheral CD8 + T cells of four of five healthy donors after three rounds of stimulation with the peptide Ep-CAM 1 7 3 - 1 8 1 (RYQLDPKFI) secreted interferon-γ in ELISPOT assays when exposed to the peptide. A CTL clone specific to the peptide efficiently lysed Ep-CAM-expressing cancer cell lines in an HLA-A*2402-restricted fashion. Endogenous processing and presentation of the peptide in a lung cancer cell line were confirmed by means of cold target inhibition assays. The CTL clone was also lyric to normal bronchial epithelial cells but to a lesser extent at low effector: target ratios. All these data suggest that the peptide-specific CTL responses may play some roles both in anti-cancer and autoimmune reactions. The peptide should prove useful to study anti-Ep-CAM CTL responses among population possessing HLA-A*2402.

A low expression level of cyclin-dependent kinase (Cdk) inhibitor p27 is associated with high aggressiveness and poor prognosis of various carcinomas. Human Cdk subunit 1 (Cks1), as well as S-phase kinase-associated protein 2 (Skp2), is an essential and specific factor in the p27 proteolysis by SCF(Skp2) ubiquitin ligase. The purpose of this study is to clarify the clinical significance of Cks1 expression and the relationship between Cks1 and p27 expression in gastric carcinomas.We measured Cks1 expression using quantitative reverse transcription-PCR in 76 human gastric carcinomas and p27 expression using immunohistochemistry in 28 cases. Moreover, we established Cks1- and/or Skp2-transfected gastric carcinoma cell lines and assessed the relationship between Cks1, Skp2, and p27 expression using quantitative reverse transcription-PCR and Western blot analysis.Cks1 high expression was correlated with poor prognosis (P0.05) and Cks1 expression was inversely correlated with the expression level of p27 protein in gastric carcinomas (P0.05). Using combined Skp2 data [T-a. Masuda, Cancer Res., 62: 3819-3825, 2002], 88.9% of the Cks1/Skp2 double-high cases expressed a low level of p27 protein and showed the poorest prognosis (P0.05). Western blot analysis showed that Cks1/Skp2-cotransfected cells expressed a much lower level of p27 protein than the controls.These findings indicate that Cks1, as well as Skp2, regulates the expression level of p27 protein in gastric carcinomas. Cks1 could play an important role in gastric carcinoma progression and would be a novel target for the treatment of gastric carcinomas as well as a strong prognostic marker.

14031 Background: Docetaxel (TXT) and S-1 are active agents against gastric cancer. A synergistic antitumor effect has been shown in a preclinical study (Takahashi et al., Oncology 2005), and our previous phase I trial demonstrated the safety and tolerability of the combination, and its potent activity. To prospectively evaluate toxicity and efficacy of S-1/ biweekly TXT, we conducted the current phase II study in patients with advanced and recurrent gastric cancer. Methods: Patients (pts) with advanced or recurrent gastric cancer, who have not received any chemotherapy except postoperative chemotherapy (not including S-1 or TXT), were eligible for the trial, and were treated with docetaxel 35 mg/m2 one hour iv infusion on day 1 and 15, and S-1 at a full dose of 80 mg/m2/day for two weeks every four weeks. Results: Thirty-five pts with measurable lesions (RECIST) (10 females, 25 males; performance status [PS] 0/1/2: 23/8/4, age 27–74, differentiated/undifferentiated adenocarcinoma: 19/16) have been enrolled. A total of 113 cycles were administered (median 3, range 1–6), and all pts were assessable for toxicity and efficacy. Grade 3–4 toxicities were: neutropenia in 20.0% (grade 4: 11.4%) of patients, leukocytopenia in 11.4% (grade 4: 0%), anemia in 5.7%, appetite loss in 8.6%, stomatitis in 8.6%, fever in 2.9%, and fatigue in 2.9%. All treatment related toxicities resolved, and no toxic death was reported. Thirteen partial responses (PR) were obtained, resulting in an overall response (OR) rate of 37.1% (95% CI: 0.22–0.55). Thirteen pts (37.5%) had stable disease, and 4 pts (12.5%) progressed. The tumor control rate was 74.3% (95% CI: 0.57–0.88). The median survival time (MST) and time to treatment failure (TTF) were 326 and 75 days, respectively. Conclusions: The combination of S-1/ biweekly TXT is active in advanced or recurrent gastric cancer, and can be given safely with proper management of adverse events even in outpatient clinic. S-1/ biweekly TXT is one of the most effective regimen to control metastatic gastric cancer with less toxicity. No significant financial relationships to disclose.

4034 Background: Growth factor receptor-mediated signal transduction has been recently implicated in conferring resistance to conventional chemotherapy on cancer cells. We have described a pathway that involves AKT/PI3K to mediate chemoresistance in gastric cancer patients. The phosphatase activity of PTEN is crucial in controlling the phosphatidylinositol-3 (PI-3) kinase signal transduction pathway and in the activation of the protein kinase B(PKB/Akt) proto-oncogene. This indicates that PTEN exerts its tumor-suppressor function by negatively regulating the anitapoptotic PI3-kinase/AKT signaling pathway. Methods: Primary gastric carcinoma tissues and corresponding normal mucosa were obtained from 119 gastric cancer patients who underwent surgery in the Department of Surgery II in Kyushu University Hospital from the years 1996 to 2000. Methylation of PTEN was studied with methylation-specific PCR and LOH (loss of heterozygosity) of PTEN was studied using a DNA sequencer with D10S796 and D10S1173 microsatellite marker in the same samples. AKT activation was investigated by immunostaining with a phosphorylation-specific antibody. The chemotherapeutic sensibilities of these patients were investigated using an MTT assay. Results: We found that methylation of PTEN was rarely recognized, However, the gastric cancer patients who had a higher AKT phosphorylation (activated AKT) appeared to have LOH of PTEN (p < 0.0008), and the prognosis of the patient who has LOH of PTEN was significantly poor. When the chemotherapeutic sensibilities of these patients were studied in an MTT assay, it was found that the activated AKT was associated with increased resistance to multiple chemotherapeutic agents, which included those currently used on gastric cancer patients (5-fluorouracil, adriamycin, mitomycin C, and cis-platinum). Conclusions: The results of this study indicate that AKT activation and LOH of PTEN plays an important role in conferring a broad-spectrum chemoresistance in gastric cancer patients. It also indicates that clinical trials for an appropriate chemotherapy combination with conventional drugs and a new generation of signal transduction inhibitors that inhibit the PTEN/AKT pathway should be considered in treating gastric cancer in the near future. No significant financial relationships to disclose.

4049 Background: Esophageal cancer tends to mainly occur in elderly patients. Although a radical operation is the most effective existing therapy, the associated operative morbidity is still high. As a result, the indications for an esophagectomy in elderly patients (especially for patients over 80 years of age) remain controversial. Methods: A total of 599 patients with thoracic esophageal cancer who underwent an esophagectomy by the transthoracic approach since 1986 were evaluated. They were divided into 3 groups depending on age, namely groups I ( 70%). Results: Postoperative complications occurred in 31 % of group I and 39 % of group II patients, and the incidence of pulmonary complication was 9 and 18 %, respectively (P < 0.01). In group III, the operative morbidity and mortality were 27 and 0 %, respectively, and pulmonary complications only occurred in one patient (7%). No significant difference was observed in the disease-free survival (DFS: 50, 46 and 58 % for 3yrs, 44, 40 and 33 % for 5 yrs), while the overall survival rates were worse in the older groups as a result of death due to causes other than recurrence (45, 34 and 34 % for 3yrs and 38, 26 and 9 % for 5 yrs in groups I, II and III, respectively. P < 0.01 group I v.s. II). Conclusions: An esophagectomy is considered to be a viable treatment alternative in patients over 80 years of age without increasing morbidity, when the indications for surgery are strictly determined. Furthermore, the DFS in these patients was similar to that observed in younger patients although the incidence of death due to causes other than cancer was found to be higher. An esophagectomy should therefore be considered as an effective treatment strategy even in elderly patients over 80 years of age. No significant financial relationships to disclose.