Incidence of Metachronous Remnant Gastric Cancer after Proximal Gastrectomy with the Double-flap Technique (rD-FLAP-rGC Study): A Multicenter, Retrospective Study.

BACKGROUND: Although proximal gastrectomy (PG) with the double-flap technique (DFT) is a function-preserving surgery that prevents esophagogastric reflux, there is a risk of developing metachronous remnant gastric cancer (MRGC). Moreover, details of MRGC and appropriate postoperative follow-up after PG with DFT are unclear. METHODS: We reviewed the medical records of 471 patients who underwent PG with DFT for cancer in a preceding, multicenter, retrospective study (rD-FLAP Study). We investigated the incidence of MRGC, frequency of follow-up endoscopy, and eradication of Helicobacter pylori (H. pylori) infection. RESULTS: MRGC was diagnosed in 42 (8.9%) of the 471 patients, and 56 lesions of MRGC were observed. The cumulative 5- and 10-year incidence rates were 5.7 and 11.4%, respectively. There was no clinicopathological difference at the time of primary PG between patients with and without MRGC. Curative resection for MRGC was performed for 49 (88%) lesions. All patients with a 1-year, follow-up, endoscopy interval were diagnosed with early-stage MRGC, and none of them died due to MRGC. Overall and disease-specific survival rates did not significantly differ between patients with and without MRGC. The incidence rate of MRGC in the eradicated group after PG was 10.8% and that in the uneradicated group was 19.6%, which was significantly higher than that in patients without H. pylori infection at primary PG (7.6%) (p = 0.049). CONCLUSIONS: The incidence rate of MRGC after PG with DFT was 8.9%. Early detection of MRGC with annual endoscopy provides survival benefits. Eradicating H. pylori infection can reduce the incidence of MRGC.

Technique of vessel-skeletonized parenchyma-sparing hepatectomy for the oncological treatment of bilobar colorectal liver metastases.

BACKGROUND: To aid in the oncological management of multiple bilobar colorectal liver metastases (CRLMs), we describe a new surgical procedure, VEssel-Skeletonized PArenchyma-sparing Hepatectomy (VESPAH). STUDY DESIGN: Of 152 patients with CRLMs treated with hepatectomy, 33 patients had multiple bilobar liver metastases (≥8 liver metastases); their surgical procedures and clinical outcomes were retrospectively summarized and compared between those who underwent VESPAH and those who underwent major hepatectomy (Major Hx). RESULTS: Of the 33 patients, 20 patients were resected by VESPAH (the VESPAH group) and 13 patients by major hepatectomy (Major Hx group). The median number of CRLMs was 13 (range, 8-53) in the VESPAH group and 10 (range, 8-41) in the Major Hx group (P=0.511). No operative mortality nor severe morbidity was observed in either group. The VESPAH group showed earlier recovery of remnant liver function after surgery than the Major Hx group; the incidence of grade B/C post hepatectomy liver failure was 5% in the VESPAH group and 38% in the Major Hx group, P=0.048). Intrahepatic tumor recurrence was confirmed in 14 (70%) and 7 (54%) patients in the VESPAH and Major Hx groups, respectively (P=0.416). There was no significant difference in median overall survival (OS) after hepatectomy between the two groups; the median OS was 47 months in the VESPAH group and 33 months in the Major Hx group (P=0.481). The VESPAH group showed the higher induction rate of adjuvant chemotherapy within 2 months after surgery (P=0.002) and total number of repeat hepatectomy for intrahepatic recurrence (P=0.060) than the Major Hx group. CONCLUSIONS: VESPAH enables us to clear surgical navigation by hepatic vessel skeletonization and may enhance patient tolerability of not only adjuvant chemotherapy but also repeat hepatectomies during the patients' lifetimes.

Preoperative prognostic nutritional index predicts postoperative infectious complications and oncological outcomes after hepatectomy in intrahepatic cholangiocarcinoma.

BACKGROUND: In the surgical treatment of intrahepatic cholangiocarcinoma (ICC), postoperative complications may be predictive of long-term survival. This study aimed to identify an immune-nutritional index (INI) that can be used for preoperative prediction of complications. PATIENTS AND METHODS: Multi-institutional data from 316 patients with ICC who had undergone surgical resection were retrospectively analysed, with a focus on various preoperative INIs. RESULTS: Severe complications (Clavien-Dindo grade III-V) were identified in 66 patients (20.8%), including Grade V complications in 7 patients (2.2%). Comparison of areas under the receiver operating characteristic curve (AUCs) among various INIs identified the prognostic nutritional index (PNI) as offering the highest predictive value for severe complications (AUC = 0.609, cut-off = 50, P = 0.008). Multivariate analysis revealed PNI <  50 (odds ratio [OR] = 2.22, P = 0.013), hilar lesion (OR = 2.46, P = 0.026), and long operation time (OR = 1.003, P = 0.029) as independent risk factors for severe complications. In comparing a high-PNI group (PNI ≥ 50, n = 142) and a low-PNI group (PNI <  50, n = 174), the low-PNI group showed higher rates of both major complications (27% vs. 13.4%; P = 0.003) and infectious complications (14.9% vs. 3.5%; P = 0.0021). Furthermore, median survival time and 1- and 5-year overall survival rates were 34.2 months and 77.4 and 33.8% in the low-PNI group, respectively, and 52.4 months and 89.3 and 47.5% in the high-PNI group, respectively (P = 0.0017). CONCLUSION: Preoperative PNI appears useful as an INI correlating with postoperative severe complications and as a prognostic indicator for ICC.

Laparoscopic Hepatectomy for the Patient with Hemophilia A with High Titer Factor VIII Inhibitor.

We present the first case of laparoscopic left lateral segmentectomy for hepatocellular carcinoma (HCC) in a patient with hemophilia A, acquired hepatitis C, and high-titer factor VIII inhibitor, which was confirmed by preoperative diagnosis. He underwent laparoscopic left lateral segmentectomy with the administration of recombinant activated factor VII. Surgery could be performed with reduced intraoperative hemorrhage. He experienced postoperative intra-abdominal wall hemorrhage, which was successfully managed with red cell concentrates transfusion and administration of recombinant activated factor VII. Laparoscopic hepatectomy can be applied for hemophilia patients with high titer inhibitors.

Shorter Survival of Patients with Upper-Third Gastric Cancer Preoperatively Diagnosed as Stage IA Compared with Those with Middle to Lower Lesions.

BACKGROUND: Although preoperatively diagnosed stage IA (cT1N0) gastric cancer includes pathologically advanced disease, patients with cT1N0 middle- to lower-third gastric cancer (MLTG) experience favorable outcomes even if they undergo gastrectomy with limited lymph node dissection; however, whether this is true for upper-third gastric cancer (UTG) patients is unknown. In this study, we examined the survival of patients with cT1N0 UTG compared with patients with MLTG. METHODS: We retrospectively reviewed the data for 1707 consecutive patients with cT1N0 gastric cancer who underwent gastrectomy between 2006 and 2013. Patients were divided into the UTG or MLTG groups, and clinicopathological characteristics and survival were compared between the groups. Factors affecting survival were identified using multivariate analysis. Survival was calculated according to pathological findings. RESULTS: The patient group included 334 UTG patients and 1373 MLTG patients. The 5-year overall survival (OS) of UTG patients was significantly shorter than that of MLTG patients, and UTG was identified as an independent prognostic factor of cT1N0 gastric cancer. Among UTG cases, the OS of pT2-4 or pN1-3 was significantly shorter than that of pT1 or pN0 disease. No significant differences were found between such diseases in MLTG. All relapses in UTG were distant metastases. CONCLUSIONS: cT1N0 UTG with pT2-4 or pN1-3 are prognostic indicators of shorter OS, although MLTG of either disease is associated with favorable prognosis. Thus, UTG is an independent prognostic factor in cT1N0 gastric cancer; however, limited dissection is acceptable for cT1N0 UTG because relapses occur at distant sites.

Risk factor of mediastinal lymph node metastasis of Siewert type I and II esophagogastric junction carcinomas.

BACKGROUND: Incidence of esophagogastric junction (EGJ) carcinoma has been increasing worldwide. Several studies revealed that the distance from the EGJ to the proximal edge of the primary tumor (esophageal invasion: EI) may be a significant indicator of metastasis in the mediastinal lymph nodes in patients with Siewert type II carcinomas. However, few studies have been conducted in patients with carcinomas located at Siewert type II sequentially to upper carcinomas (Siewert type I) for mediastinal metastasis regardless of histological types. METHODS: This was a single-center retrospective cohort study. EGJ carcinomas located at Siewert type I and II regions including both squamous cell carcinoma (SCC) and adenocarcinoma were analyzed in terms of lymph node metastasis patterns. RESULTS: We included 121 patients in this study. Thirty-three (27.3%) patients had SCC. In multivariate analysis, the distance of EI (> 20 mm) was an independent risk factor (OR 11.80, p = 0.005) for lower mediastinal lymph node metastasis. In terms of above the middle mediastinal metastasis, the distance of EI (> 30 m), histological type (SCC), and tumor size (> 40 mm) were risk factors in univariate analysis. Furthermore, EI was significant (OR 13.50, p = 0.026) in multivariate analysis. CONCLUSIONS: The distance of EI was the independent risk factor for mediastinal lymph node metastasis, especially > 20 mm related with a higher risk for mediastinal lymph node metastasis. Furthermore, EGJ carcinoma patients who have EI > 30 mm, large SCC carcinoma, and multiple lymph node metastasis might be considered the middle-upper mediastinal lymph node dissection by transthoracic approach.

Significant differences in T cell receptor repertoires in lung adenocarcinomas with and without epidermal growth factor receptor mutations.

Recent clinical trials of non-small cell lung cancer with immune checkpoint inhibitors revealed that patients with epidermal growth factor receptor (EGFR) mutations had more unfavorable outcomes compared with those with wild-type EGFR. However, the underlying mechanism for the link between EGFR mutations and immune resistance remains unclear. We performed T cell receptor (TCR) repertoire analysis of resected lung adenocarcinoma tissues with and without EGFR mutations to investigate the characteristics of TCR repertoires. We collected a total of 39 paired (normal and tumor) lung tissue samples (20 had EGFR mutations) and conducted TCR repertoire analysis as well as whole-exome sequencing (WES) and transcriptome analysis. The TCR diversity index in EGFR-mutant tumors was significantly higher than that in EGFR-wild-type tumors (median [range] 552 [162-1,135] vs 230 [30-764]; P < .01), suggesting higher T cell clonal expansion in EGFR-wild-type tumors than in EGFR-mutant tumors. In WES, EGFR-mutant tumors showed lower numbers of non-synonymous mutations and predicted neoantigens than EGFR-wild-type tumors (P < .01, P = .03, respectively). The number of non-synonymous mutations revealed a positive correlation with the sum of frequencies of the TCRß clonotypes of 1% or higher in tumors (r = .52, P = .04). The present study demonstrates significant differences in TCR repertoires and the number of predicted neoantigens between EGFR-mutant and wild-type lung tumors. Our findings provide important information for understanding the molecular mechanism behind EGFR-mutant patients showing unfavorable responses to immune checkpoint inhibitors.

The era of immunogenomics/immunopharmacogenomics.

Although germline alterations and somatic mutations in disease cells have been extensively analyzed, molecular changes in immune cells associated with disease conditions have not been characterized in depth. It is clear that our immune system has a critical role in various biological and pathological conditions, such as infectious diseases, autoimmune diseases, drug-induced skin and liver toxicity, food allergy, and rejection of transplanted organs. The recent development of cancer immunotherapies, particularly drugs modulating the immune checkpoint molecules, has clearly demonstrated the importance of host immune cells in cancer treatments. However, the molecular mechanisms by which these new therapies kill tumor cells are still not fully understood. In this regard, we have begun to explore the role of newly developed tools such as next-generation sequencing in the genetic characterization of both cancer cells and host immune cells, a field that is called immunogenomics/ immunopharmacogenomics. This new field has enormous potential to help us better understand changes in our immune system during the course of various disease conditions. Here we report the potential of deep sequencing of T-cell and B-cell receptors in capturing the molecular contribution of the immune system, which we believe plays critical roles in the pathogenesis of various human diseases.

Laparoscopic and luminal endoscopic cooperative surgery can be a standard treatment for submucosal tumors of the stomach: a retrospective multicenter study.

Background and study aims We have developed a combined laparoscopic and luminal endoscopic surgery technique for resection of gastric submucosal tumors (SMTs) that can be performed without excessive resection of the stomach. In a multicenter retrospective study we aimed to evaluate the feasibility and safety of laparoscopic and endoscopic cooperative surgery (LECS) for gastric SMT resection. Patients and methods Between October 2007 and December 2011, 126 patients with gastric SMTs underwent LECS at 8 institutions. Patient demographics, tumor histopathologic characteristics, and operative and follow-up data were reviewed. Results 16 tumors (12.7 %) were located in the upper third of the stomach, 88 (69.8 %) in the middle third, 5 (4.0 %) in the lower third, and 17 (13.5 %) at the esophagogastric junction. The mean (standard deviation [SD]) operation time for LECS was 190.2 (66.8) min, with a mean estimated blood loss of 15.1 (38.6) mL. In 2 cases (1.6 %), the procedure was converted to open surgery because of intra-abdominal adhesions or stenosis. Morbidity was found in 6 cases (4.8 %), including 2 leakage, 2 gastric stasis, 1 fever, and 1 cystitis. Histologically, a gastrointestinal stromal tumor (GIST) was found in 86 (68.3 %) cases. The median follow-up period was 54.7 months; no local or distant tumor recurrence was observed and all patients were alive. Conclusions LECS proved to be a safe and feasible procedure for the resection of gastric SMTs, with a reasonable operation time, low bleeding, and an acceptable complication rate in this multicenter study in Japan.

Feasibility of laparoscopic and endoscopic cooperative surgery for gastric submucosal tumors (with video).

BACKGROUND AND AIMS: Laparoscopic gastric resection is widely used for gastric submucosal tumors (SMTs). However, determining an appropriate resection line using only the laparoscopic approach is difficult. We developed a laparoscopic and endoscopic cooperative surgery (LECS) technique by combining laparoscopic gastric resection with endoscopic submucosal dissection, and we have used this procedure to resect gastric SMTs. In this study, the procedure is presented and its safety and feasibility for resecting gastric SMTs are evaluated. METHODS: This retrospective study included 100 patients who underwent LECS for SMTs at the Department of Gastroenterological Surgery, Cancer Institute, between June 2006 and November 2014. The demographics, tumor histopathologic characteristics, and operative and follow-up data were reviewed. RESULTS: Complete resection with negative surgical margins was achieved in all patients, and LECS was performed regardless of tumor location. The mean operation time was 174.3 minutes, with an estimated blood loss of 16.3 mL. In addition, the mean time until the initiation of oral intake was 1.4 days, and the mean postoperative hospital stay was 8.4 days. Moreover, no local or distant tumor recurrence was observed. The only severe adverse event was leakage, which was observed in 1 patient. CONCLUSIONS: LECS was performed with a reasonable operation time, low blood loss, and minimal adverse events. Therefore LECS is safe and feasible for resecting gastric SMTs.

Theoretical therapeutic impact of lymph node dissection on adenocarcinoma and squamous cell carcinoma of the esophagogastric junction.

BACKGROUNDS: The aim of this study was to evaluate the theoretical therapeutic impact of dissecting each lymph node station for adenocarcinoma and squamous cell carcinoma of the esophagogastric junction. METHODS: This multicenter study included 431 junctional cancer patients (381 adenocarcinomas and 50 squamous cell carcinomas) who fulfilled the following criteria: (1) the center of the tumor was located between 1 cm above and 2 cm below the esophagogastric junction, and (2) the tumor invaded the junction. The theoretical therapeutic impact of dissecting each lymph node station was evaluated based on the therapeutic value index calculated by multiplying the frequency of metastasis to each station and the 5-year survival rate of patients with metastasis to that station. RESULTS: The 5-year overall survival rates (95% confidence interval) were 60.4% (55.1-65.7) in the adenocarcinoma cases and 52.3% (35.6-69.0) in the squamous cell carcinoma cases. The nodal stations showing the first to fifth highest index were the paracardial and lesser curvature nodes (nos. 1, 2 and 3), nodes at the root of the left gastric artery (no. 7) and lower mediastinal lymph nodes, regardless of the histology. CONCLUSIONS: Nodal dissection achieved by proximal gastrectomy and lower esophagectomy should be the minimal requirement for junctional cancer regardless of the histology, considering the therapeutic value indices for the relevant lymph node stations.

Clinicopathological Characteristics and Prognostic Factors of Patients with Siewert Type II Esophagogastric Junction Carcinoma: A Retrospective Multicenter Study.

BACKGROUND: The incidence of esophagogastric junction (EGJ) carcinoma is increasing, but its optimal surgical management remains controversial. METHODS: We retrospectively reviewed the database of 400 patients with Siewert type II EGJ carcinoma who were treated surgically at 7 institutions between March 1986 and October 2010. We examined the clinicopathological characteristics, prognostic factors, and risk factors associated with each recurrence pattern. RESULTS: The 5-year overall survival rate of all patients with Siewert type II EGJ carcinoma was 58.4 %. Multivariate analysis showed that T and N stages were independent prognostic factors. We also found that the incidence of lower mediastinal lymph node metastasis (17.7 %) and para-aortic lymph node metastasis (16.1 %) was relatively high. In addition, the para-aortic lymph nodes (N = 39, 9.8 %) were the most frequent node recurrence site, followed by the mediastinal lymph nodes (N = 23, 5.8 %). Lung recurrence was more common than was peritoneal recurrence. Considering each type of recurrence, multivariate analysis showed that the differentiated type was associated with a higher risk of lung recurrence than was the undifferentiated type, and N stage (pN2-3) and positive venous invasion were independent risk factors for liver recurrence. CONCLUSIONS: This study is one of the largest retrospective studies to evaluate patients with Siewert type II EGJ carcinoma. Para-aortic and mediastinal lymph node metastasis and recurrence rates were relatively high. During the postoperative follow-up of patients with differentiated Siewert type II EGJ carcinoma, patients should be monitored for lung recurrence more closely than that for peritoneal recurrence.

Phase I pilot study of Wilms tumor gene 1 peptide-pulsed dendritic cell vaccination combined with gemcitabine in pancreatic cancer.

This study aimed to evaluate the feasibility of and immune response to Wilms tumor gene 1 (WT1) peptide-pulsed dendritic cell vaccination combined with gemcitabine (DCGEM) as a first-line therapy among patients with advanced pancreatic cancer. Ten HLA-A*2402 patients were treated with WT1 peptide-pulsed DC vaccination (1 × 10(7) cells) on days 8 and 22 and gemcitabine (1000 mg/m(2) ) on days 1, 8 and 15. Induction of a WT1-specific immune response was evaluated using the delayed-type hypersensitivity (DTH) skin test, interferon-γ enzyme-linked immunospot and HLA tetramer assays, along with assays for various immunological factors. DCGEM was well-tolerated, and the relative dose intensity of gemcitabine was 87%. Disease control associated with a low neutrophil/lymphocyte ratio was observed in all three patients with DTH positivity; it was also correlated with a low percentage of granulocytic myeloid derived suppressor cells in the pretreatment peripheral blood (P = 0.017). Patients with liver metastases and high levels of inflammatory markers such as C-reactive protein and interleukin-8 (IL-8) showed poor survival even though a WT1-specific immune response was induced in them. WT1 peptide-pulsed DCGEM is feasible and effective for inducing anti-tumor T-cell responses. Our results support future investigations for pancreatic cancer patients with non-liver metastases and favorable immunological conditions. This trial was registered with the University hospital Medical Information Network (UMIN) Clinical Trials Registry (http://www.umin.ac.jp/ctr/ number: UMIN-000004855).

Estimation of subepithelial lateral extent in submucosal early gastric cancer: retrospective histological analysis.

BACKGROUND: Endoscopic full-thickness resection (EFTR) is expected to make possible minimally invasive local resection of early gastric cancer (EGC). However, no consensus exists regarding how far an optimal safety margin should be set in determining the resection area by endoscopy. We aimed to investigate the optimal lateral margin of EGC which could be a candidate for EFTR by measuring the subepithelial extent (SE) of tumors. METHODS: In 60 surgically resected submucosal EGCs 4 cm or smaller, 595 prepared slides which showed lateral tumor borders both on the epithelial surface and on the subepithelial layer were assessed. The distance between the epithelial and the subepithelial tumor edge was measured under microscopic observation, followed by analyses of the relationship between the measured SE and the histological characteristics. RESULTS: The average and the median SE were 1.1 mm (standard deviation 1.8 mm) and 0.3 mm (range 0-12.3 mm), respectively. The 99th percentile was 8.8 mm. With regard to the histological type, the median SE was significantly greater in diffuse-type tumor than in intestinal-type tumor (0.9 mm vs 0 mm, p < 0.0001). With regard to the location of the subepithelilal tumor edge, the median SE was significantly greater in the submucosal layer than in the mucosal layer (2.6 mm vs 0.3 mm, p < 0.0001). CONCLUSIONS: In most lesions, the SE was less than 1 cm. A safety margin may be set at 1 cm in EFTR of submucosal EGC.

First case of non-exposed endoscopic wall-inversion surgery with sentinel node basin dissection for early gastric cancer.

INTRODUCTION: Non-exposed endoscopic wall-inversion surgery (NEWS) is a novel technique of endoscopic full-thickness resection without transluminal access mainly designed to treat gastric cancer. Here, we report a successful case of NEWS with sentinel node basin dissection (SNBD) for early gastric cancer (EGC) with the risk of lymph node metastasis. PATIENT AND METHODS: A 55-year-old female patient with a 2-cm, diffuse-type intramucosal EGC with ulceration was referred to our hospital for a less invasive gastrectomy based on sentinel node navigation surgery. After obtaining informed consent, NEWS with SNBD was applied. After placing mucosal markings, indocyanine green solution was injected endoscopically into the submucosa around the lesion to examine sentinel nodes (SNs). The SN basin (the area of the left gastric artery), including three stained SNs(#3), was dissected, and an intraoperative pathological diagnosis confirmed that no metastasis had occurred. Subsequently, NEWS was performed for the primary lesion. Serosal markings were placed laparoscopically, submucosal injection was added endoscopically, and circumferential sero-muscular incision and suturing were performed laparoscopically, with the lesion inverted toward the inside of the stomach. Finally, the circumferential mucosal incision was performed, and the lesion was retrieved perorally. RESULTS: The operation was finished in 270 min without complications. The patient was uneventfully discharged 10 days after the procedure. The final pathological diagnosis was coincident with the pre- and intraoperative assessment. CONCLUSIONS: We demonstrated the feasibility and safety of NEWS with SNBD with a favorable result. This surgical concept is expected to become a promising, minimally invasive, function-preserving surgery to cure cases of EGC that are possibly node-positive.

Laparoscopic endoscopic cooperative surgery.

Laparoscopic and endoscopic cooperative surgery (LECS) is a newly developed concept for tumor dissection of the gastrointestinal tract that was first investigated for local resection of gastric gastrointestinal stromal tumors (GIST). The first reported version of LECS for GIST has been named 'classical LECS' to distinguish it from other modified LECS procedures, such as inverted LECS, a combination of laparoscopic and endoscopic approaches to neoplasia with a non-exposure technique (CLEAN-NET), and non-exposed endoscopic wall-inversion surgery (NEWS). These modified LECS procedures were developed for dissection of malignant tumors which may seed tumor cells into the abdominal cavity. While these LECS-related procedures might prevent tumor seeding, their application is limited by several factors, such as tumor size, location and technical difficulty. Currently, classical LECS is a safe and useful procedure for gastric submucosal tumors without mucosal defects, independent of tumor location, such as proximity to the esophagogastric junction or pyloric ring. For future applications of LECS-related procedures for other malignant diseases with mucosal lesions such as GIST with mucosal defects and gastric cancer, some improvements in the techniques are needed.

EpCAM, a potential therapeutic target for esophageal squamous cell carcinoma.

BACKGROUND: Molecular-targeted drugs are not available for esophageal squamous cell carcinoma (ESCC), which has a poor prognosis. We investigated the clinicopathological significance of epithelial cell adhesion molecule (EpCAM) expression and the utility of EpCAM as a potential therapeutic target. METHODS: The relationship between EpCAM expression and clinicopathological factors was examined by immunohistochemistry in 74 patients with resectable ESCC. A total of ten ESCC cell lines were analyzed for EpCAM expression. The effects of EpCAM knockdown in TE4, TE10, and TE14 cells were examined with regard to cell proliferation and gene expression in vitro and tumor growth in vivo. The antitumor effect of catumaxomab in ESCC cell lines was examined. RESULTS: EpCAM overexpression was associated with poor survival in ESCC patients (P = 0.026). Multivariate Cox regression analysis showed that EpCAM overexpression was a significant and independent prognostic factor for surgically treated ESCC (P = 0.004). TE4 and TE10 cells showed high EpCAM expression, in contrast to TE14. EpCAM siRNA knockdown in TE4 and TE10 cells downregulated CCND1 and CCNE2 and suppressed cell proliferation. Low EpCAM expression reduced tumorigenesis; TE4 cells initiated tumorigenesis in seven of the ten mice injected, whereas shRNA knockdown resulted in smaller tumors in two of ten mice at 6 weeks after transplantation. Concentration- and time-dependent antitumor effects of catumaxomab were observed in TE4 and TE10 cells. CONCLUSIONS: EpCAM overexpression is an independent prognostic factor for surgically treated ESCC. EpCAM contributes to cell proliferation and tumorigenesis and may be a useful therapeutic target for ESCC.

Sentinel node mapping in adenocarcinoma of the esophagogastric junction.

BACKGROUND: The incidence of adenocarcinoma of the esophagogastric junction (AEG) is increasing, but the surgical strategy for AEG remains controversial. We hypothesized that sentinel node (SN) mapping for AEG could be validated to avoid unnecessary lymphadenectomy and permit minimally invasive surgery. We examined the feasibility of SN mapping for AEG. METHODS: We enrolled 15 patients with preoperatively diagnosed cT1 N0 M0 primary AEG (Siewert type I, N = 3; Siewert type II, N = 12) lesions measuring <4 cm in diameter. The dual tracer method employing radioactive colloid and blue dye was used to detect SNs. The distribution of SNs was compared with that of metastatic lymph nodes in 52 patients who were surgically treated without SN mapping. RESULTS: SNs were successfully identified in all the patients. Two patients with lymph node metastasis had positive SNs identified via an intraoperative pathological examination, and the diagnostic sensitivity and accuracy based on the SN status were both 100 %. For Siewert type II AEG, the SNs were not detected in the lower mediastinum by intraoperative gamma probing. Thus, all surgical procedures were performed via a transhiatal approach. No patient without SN metastasis experienced cancer recurrence during a 38-month median follow-up. The distribution of SNs was similar to that of lymph node metastasis in the patients who were surgically treated without SN mapping. CONCLUSIONS: We achieved 100 % SN detection. Our results suggested that SN mapping is feasible for AEG and highly sensitive and accurate in diagnosing lymph node metastasis. SN mapping may clarify the necessity of mediastinal lymph node dissection and individualize minimally invasive surgery.

Clinical implications and optimal extent of lymphadenectomy for intrahepatic cholangiocarcinoma: A multicenter analysis of the therapeutic index.

Aims: Lymph node metastases (LNM) are associated with lethal prognosis in intrahepatic cholangiocarcinoma (ICC). Lymphadenectomy is crucial for accurate staging and hopes of possible oncological treatment. However, the therapeutic implications and optimal extent of lymphadenectomy remain contentious. Methods: To clarify the prognostic value and optimal extent of lymphadenectomy, the therapeutic index (TI) for each lymph node was analyzed for 279 cases that had undergone lymphadenectomy in a multi-institutional database. Tumor localization was divided into hilar lesions (n = 130), right peripheral lesions (n = 60), and left peripheral lesions (n = 89). In addition, the lymph node station was classified as Level 1 (LV1: hepatoduodenal ligament node), Level 2 (LV2: postpancreatic or common hepatic artery nodes), or Level 3 (LV3: gastrocardiac, left gastric artery, or celiac artery nodes). Results: Lymph node metastases were confirmed in 109 patients (39%). Five-y survival rates were 45.3% for N0 disease, 27.1% for LV1-LNM, 22.9% for LV2-LNM, and 7.3% for LV3-LNM (P < 0.001). LV3-LNM were the most frequent and earliest recurrence outcome, including multisite recurrence, followed by LV2, LV1, and N0 disease. The 5-year TI (5year-TI) for lymphadenectomy was 7.2 for LV1, 5.5 for LV2, and 1.9 for LV3. Regarding tumor location, hilar lesions showed 5-year TI >5.0 in LV1 and LV2, whereas bilateral peripheral lesions showed 5-year TI > 5.0 in LV1. Conclusion: The implications and extent of lymphadenectomy for ICC appear to rely on tumor location. In the peripheral type, the benefit of lymphadenectomy would be limited and dissection beyond LV1 should be avoided, while in the hilar type, lymphadenectomy up to LV2 could be recommended.