Risk factors for esophageal iodine-unstained lesions and changing trends among Japanese alcohol-dependent men (2003-2018).

Globally, a decreasing incidence of male esophageal squamous cell carcinoma (ESCC) has been observed in recent decades. We evaluated the determinants of esophageal distinct iodine-unstained lesions (DIULs), high-cancer-risk lesions and ESCC, among 3858 Japanese alcohol-dependent men (40-79 years) who underwent chromoendoscopic screening between 2003 and 2018. The initial screening detected DIULs ≥ 5 mm in 541 patients (dysplasia in 319 and SCC in 129) and multiple DIULs in 640. The detection rates for DIULs and chronic atrophic gastritis (CAG), pack-years, and the mean corpuscular volume (MCV) decreased over the course of the study period, while the detection of hiatal hernia and/or columnar-lined esophagus (HH/CLE) and the carriers of inactive heterozygous aldehyde dehydrogenase-2 (ALDH2, rs671) increased. Multiple logistic regression analyses showed that an older age, larger number of pack-years, smaller body mass index, larger MCV, presence of a slow-metabolizing alcohol dehydrogenase-1B genotype (rs1229984), presence of an inactive heterozygous ALDH2 genotype, and more advanced degree of CAG increased the odds ratios (ORs) for DIULs, while the 2008-2013 and 2014-2018 screening periods had lower ORs for DIULs than the 2003-2007 screening period. The presence of HH/CLE decreased the OR for multiple DIULs and was associated with a more proximal location of ESCC. In conclusion, the detection of DIULs in an alcohol-dependent population decreased between 2003 and 2018. In addition to reported determinants of ESCC, CAG and HH/CLE were associated with the risk of DIULs. Enigmatically, however, the decline in the detection of DIULs was not adequately explained by these factors and warrants further research.

Association between macrocytosis and metachronous squamous cell carcinoma of the esophagus after endoscopic resection in men with early esophageal squamous cell carcinoma.

BACKGROUND: Macrocytosis is associated with an increased risk of squamous cell carcinoma (SCC) arising in the esophagus in men. The aim of this study was to evaluate the association between macrocytosis and metachronous SCC of the esophagus after endoscopic resection (ER) of early esophageal SCC in men. METHODS: The study group comprised 278 men with early esophageal SCC after ER. The main study variables were as follows: (1) cumulative incidence and total number of metachronous SCC of the esophagus according to the presence or absence of macrocytosis (mean corpuscular volume ≥ 106 fl) and (2) predictors of metachronous SCC of the esophagus as assessed with a multivariate Cox proportional-hazards model. RESULTS: The median follow-up was 50.3 months. Macrocytosis was associated with a higher 2-year cumulative incidence of metachronous SCC of the esophagus (without macrocytosis vs. with macrocytosis: 11.4% vs. 38.1%, p = 0.002). Macrocytosis was also associated with a higher total number of metachronous SCC of the esophagus per 100 person-years (without macrocytosis vs. with macrocytosis: 7.7 vs. 31.5 per 100 person-years, p < 0.0001). In addition, macrocytosis was a significant predictor of metachronous SCC of the esophagus on multivariate Cox proportional-hazards analysis (relative risk 2.23). CONCLUSION: Macrocytosis is a useful predictor of the risk of metachronous SCC of the esophagus after ER of early esophageal SCC in men.

Risk of lymph node metastasis in undifferentiated-type mucosal gastric carcinoma.

BACKGROUND: Endoscopic resection (ER) has come to be recognized as a standard treatment for early gastric cancer (EGC). While its adoption is expanding, ER remains restricted to cases of EGC without lymph node metastasis for the treatment of local resection. On the other hand, histopathological analyses of surgically resected specimens of EGC have revealed the presence of lymph node (LN) metastasis in some cases of mucosal gastric cancer (MGC) and undifferentiated MGC (UD-MGC) is considered to have higher risk of nodal metastases than differentiated MGC (D-MGC). To evaluate the risk factors for LN metastasis in MGC, we investigated the characteristics of UD-MGC associated with LN metastasis. METHODS: Among all UD-MGC patients who underwent surgery as initial treatment, between January 2000 and March 2016, we reviewed the clinicopathological data, including the preoperative endoscopic findings and histopathological findings in the resected specimens, of the 11 UD-MGC patients who were identified as having lymph node metastasis. Furthermore, in comparison with cases without lymph node metastasis, we examined the possibility of expansion of the indication for local treatment. RESULTS: In most of the cases of UD-MGC with LN metastasis, the lesions were relatively large (> 20 mm in diameter) and of the clearly depressed type with faded color and apparent border, and histopathology revealed a high percentage of cases with lymphatic invasion and a predominance of signet ring cell carcinomas. No cases with LN metastasis without depressed macroscopic type nor signet ring cell carcinoma component existed. A degree of invasion of lamina propria (LP) or muscularis mucosae (MM) had same relation to the risk of LN metastasis. CONCLUSIONS: In this study, none of the cases of undifferentiated-type mucosal cancer (UD-MGC) with LN metastasis satisfied the current adoption criteria for ER. We suggested significant risk factors for LN metastasis in UD-MGC cases as depressed tumor type, presence of a signet ring cell carcinoma component, presence of lymphatic tumor invasion, and a large tumor size. More detailed analyses of the endoscopic and histopathological findings may allow further risk classification for LN metastasis in cases of UD-MGC.

Soft palatal melanosis, a simple predictor for neoplasia in the upper aerodigestive tract in Japanese alcoholic men.

Soft palatal melanosis can be detected by visual inspection during routine physical examination or even personally in a mirror. The aim of this study was to evaluate the association between squamous cell neoplasia in the upper aerodigestive tract (UAT) and soft palatal melanosis. We reviewed digitized records of high-quality endoscopic images of the soft palate of 1786 Japanese alcoholic men who underwent endoscopic screening. Soft palatal melanosis was observed in 381 (21.3%) of the subjects (distinct, 6.3%). Older age, an inactive heterozygous aldehyde dehydrogenase-2 genotype, smoking, and a high mean corpuscular volume were positively associated with the presence of soft palatal melanosis. The age-adjusted odds ratio (95% confidence interval) for UAT neoplasia was 1.92 (1.40-2.64) in the group with melanosis and 2.51 (1.55-4.06) in the group with distinct melanosis, compared with the melanosis-free group. A multivariate analysis showed that the presence of soft palatal melanosis was independently associated with a high risk of UAT neoplasia. We calculated the individual number of risk factors out of four easily identifiable and significant factors: age ≥55 years, current/former alcohol flushing, mean corpuscular volume ≥106 fL, and distinct soft palatal melanosis. Compared with the risk-factor-free condition, the odds ratio (95% confidence interval) values of UAT neoplasia for one, two, three, and four risk factors were 1.49 (0.97-2.30), 3.14 (2.02-4.88), 4.80 (2.71-8.51), and 7.80 (2.17-28.1), respectively. The presence of soft palatal melanosis provides a simple new strategy for identifying heavy drinkers with a high risk for UAT neoplasia.

Alcohol Consumption and Multiple Dysplastic Lesions Increase Risk of Squamous Cell Carcinoma in the Esophagus, Head, and Neck.

BACKGROUND & AIMS: Some patients develop multiple squamous cell carcinomas (SCCs) in the upper aerodigestive tract, attributed to field cancerization; alcohol consumption has been associated with this process. We examined the association between multiple areas of dysplastic squamous epithelium with the development of SCC of the esophagus or head and neck cancer, as well as alcohol consumption and smoking. METHODS: We examined 331 patients with early stage esophageal SCC using Lugol chromoendoscopy to evaluate the dysplastic squamous epithelium in the esophagus. Patients then were assigned to 3 groups, based on the number of Lugol-voiding lesions: A, no lesion; B, 1-9 lesions; or C, 10 or more lesions. Participants completed lifestyle surveys on their history of drinking, smoking, and diet. All participants were evaluated by laryngopharyngoscopy before registration; only those without head and neck cancer were included, except for patients with superficial SCC limited to the subepithelial layer. Lesions detected in the esophagus and head and neck by surveillance were considered to be metachronous. The study end point was the cumulative incidence of metachronous SCCs in the esophagus and head and neck after endoscopic resection of esophageal SCC, according to the grade of Lugol-voiding lesions. At study entry, all patients were instructed to abstain from alcohol and smoking. RESULTS: Over the 2-year study period, metachronous SCCs of the esophagus were detected in 4% of patients in group A, in 9.4% of patients in group B, and in 24.7% of patients in group C (P < .0001 for patients in group A vs B or B vs C). Head and neck SCCs were detected in none of the patients in group A, in 1.7% of the patients in group B, and in 8.6% of the patients in group C (P = .016 for patients in group A vs C and P = .008 for patients in group B vs C). SCC of the esophagus or head and neck developed in 4.0% of patients in group A, in 10.0% of patients in group B, and in 31.4% of patients in group C (P < .0001 for group A vs B or A vs C). Alcohol abstinence decreased the risk of multiple SCCs of the esophagus (adjusted hazard ratio, 0.47, 95% confidence interval, 0.25-0.91; P = .025), whereas smoking abstinence did not. CONCLUSIONS: Multiple dysplastic lesions in the esophagus increase the risk of multiple SCCs. Alcohol abstinence reduces the risk of metachronous SCCs. Clinical Trials registry: UMIN000001676 and UMIN000005466.

Endoscopic findings of laryngopharyngeal and esophageal involvement in autoimmune bullous disease.

BACKGROUND AND AIM: Autoimmune bullous disease (ABD) is induced by autoantibodies against cell adhesion molecules, and blistering may occur on the mucous membranes of the eyes, nose, mouth, oral cavity, laryngopharynx, and esophagus. Endoscopic prevalence and features of ABD-associated esophageal lesions are not well known. We conducted the present study to assess the endoscopic prevalence of ABD-associated mucosal lesions. METHODS: Endoscopic prevalence of mucosal lesions, particularly laryngopharyngeal and esophageal lesions, was used as the primary endpoint to assess the significance of upper gastrointestinal endoscopy, and clinical and endoscopic features were secondary endpoints. RESULTS: Of 123 ABD patients, 50.4% had apparent oral or laryngopharyngeal lesions and 30.8% had laryngopharyngeal lesions. Esophageal lesions were detected through normal observation in 16.8% of affected patients, whereas 40.6% exhibited epidermolysis or blood blisters by mechanical inducement, regardless of esophageal mucosal lesion detection by normal observation. Additionally, 56.0% exhibited the Nikolsky sign with mechanical inducement. Of the 123 patients, 29.2% did not have exposed skin lesions. Of these patients, 77.7% had oral cavity or laryngopharyngeal lesions, 36.1% had esophageal lesions, and 58.3% exhibited the Nikolsky sign on esophageal mucosa. CONCLUSION: It is important to determine the endoscopic characteristics and findings of ABD. ABD can be suspected from endoscopic findings.

Pylorus-Preserving Surgery Based on the Sentinel Node Concept in Early Gastric Cancer.

BACKGROUND: 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. METHODS: One hundred fifty-six patients with middle-third location of cT1N0 gastric cancer (single lesion, <4 cm) underwent distal gastrectomy with SN mapping. As a tracer, technetium-99 tin colloid solution and blue dye were endoscopically injected into the submucosal layer surrounding the primary tumor. RESULTS: SN detection rate was 100 % (156 of 156), and the accuracy of the nodal evaluation of metastasis was 99 % (155 of 156). Suprapyloric lymph node (LN; LN No. 5) and infrapyloric LN (LN No. 6) were detected as SNs in 6 and 14 % of the patients, respectively. We also found two cases with metastasis to LN No. 5 or LN No. 6. DISCUSSION: When performing PPG, the possibility of LN metastasis, especially to LN No. 5 and LN No. 6, cannot be underestimated. SN mapping can play an important role to predict the possibility of metastasis to LN No. 5 and LN No. 6.

CXCL12 expression promotes esophageal squamous cell carcinoma proliferation and worsens the prognosis.

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.

Auxiliary diagnosis of lymph node metastasis in early gastric cancer using quantitative evaluation of sentinel node radioactivity.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Clinical significance of the anterosuperior lymph nodes along the common hepatic artery identified by sentinel node mapping in patients with gastric cancer.

BACKGROUND: 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). METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Incidence of and risk factors for venous thromboembolism during surgical treatment for esophageal cancer: a single-institution study.

PURPOSE: During the treatment of esophageal cancer with curative intent, patients sometimes experience deep vein thrombosis, pulmonary embolism or a central venous catheter-associated thrombus. In this study, we retrospectively reviewed our new-onset esophageal cancer patients and determined the incidence of venous thromboembolism (VTE), the location of the thrombus and the risk factors for VTE. METHODS: One hundred and fifty-three patients undergoing treatment with curative intent were reviewed as candidates. The existence of VTE was assessed from the neck to the pelvis with computed tomography at the initial visit, after neo-adjuvant chemotherapy and postoperatively. RESULTS: Twenty-one VTE events (13.7%) were observed, 16 of which (76.2%) were suggested to be associated with central venous catheterization. When both the pre-therapeutic plasma fibrinogen and C-reactive protein levels were high (≥350 mg/dL and ≥0.2 µg/mL, respectively), the risk of preoperative VTE and overall VTE were significantly higher than normal (p = 0.040, and p = 0.030, respectively). Adenocarcinoma histology and neck lymph node dissection were the independent risk factors that significantly increased the overall risk of VTE (p = 0.015, and p = 0.017, respectively). CONCLUSIONS: This study revealed that the pre-therapeutic plasma fibrinogen level, C-reactive protein level, adenocarcinoma histology and neck lymph node dissection are the risk factors for venous thromboembolism in patients with esophageal cancer undergoing treatment with curative intent.

Cumulative prognostic scores based on plasma fibrinogen and serum albumin levels in esophageal cancer patients treated with transthoracic esophagectomy: comparison with the Glasgow prognostic score.

PURPOSE: The purpose of this study was to establish a prognostic indicator based on preoperative plasma fibrinogen and serum albumin levels (FA score) in esophageal cancer patients and to compare the correlation with survival to that of the Glasgow prognostic score. METHODS: Patient characteristics, clinicopathological factors, and preoperative biochemical markers (fibrinogen, albumin, and C-reactive protein) were investigated in esophageal cancer patients who underwent transthoracic esophagectomy. Pretreatment fibrinogen and albumin levels were reviewed in patients who received neoadjuvant treatment. Patients with elevated fibrinogen and decreased albumin levels were allocated a score of 2, those with only one of these abnormalities were allocated a score of 1, and those with neither of these abnormalities were allocated a score of 0. The fibrinogen cut-off value was defined as 350 mg/dL according to our previous report, and the albumin cut-off value was defined as the lower quartile. RESULTS: Among 199 consecutive patients, the interquartile range of preoperative albumin was 3.8-4.3 g/dL and the cut-off value was 3.8 g/dL. Thus, 108 (54 %), 68 (34 %), and 23 (12 %) patients had an FA score of 0, 1, and 2. The patients with a high preoperative FA score showed considerably shorter disease-free survival (DFS) and overall survival (OS). Multivariate analysis showed that pretreatment stage and preoperative FA score were independently associated with postoperative DFS and OS. CONCLUSIONS: Preoperative FA score was significantly associated with postoperative survival in esophageal cancer patients, and the prognostic value is currently being validated in a prospective multicenter cohort study.

Attenuation of lipopolysaccharide-induced acute lung injury after (pro)renin receptor blockade.

PURPOSE/AIM: We performed a randomized, prospective animal study to investigate whether inhibiting the renin-angiotensin system with a (pro)renin receptor blocker (PRRB) prevents acute lung injury (ALI) in a rodent model. MATERIALS: We used Thirty-six male Sprague-Dawley rats. We administered lipopolysaccharide (LPS; 2 mg/kg) intratracheally with or without PRRB pretreatment (1 mg/kg/d). METHODS: We performed bronchoalveolar lavage (BAL) and lung removal at 4 h after LPS administration and measured levels of inflammatory cytokines, high mobility group box 1 (HMGB-1) protein, and total protein in bronchoalveolar lavage fluid (BALF). Myeloperoxidase (MPO) activity was detected in lung tissue homogenates using a sensitive ELISA. We performed hematoxylin and eosin staining and immunohistochemical staining for nonproteolytically activated prorenin in the left lung. RESULTS: The PRRB decreased leukocyte counts and total protein, tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-2, IL-6, and IL-10 levels in the BALF and MPO activity in lung tissue. The PRRB reduced interstitial edema, hemorrhage, and the neutrophil count in the lung tissues. Consistent with the reduction in lung tissue damage, immunohistochemical staining showed that the PRRB decreased the amount of nonproteolytically activated prorenin. CONCLUSIONS: The PRRB blocked LPS-induced inflammatory response in the lung and protected against ALI. Therefore, it is a potential therapeutic agent for preventing ALI.

Postoperative hyperbilirubinemia suggests the occurrence of complications after esophagectomy for esophageal cancer.

BACKGROUND: Serum bilirubin levels frequently increase after esophagectomy for esophageal cancer. Several studies have reported hyperbilirubinemia in patients with postoperative complications. We aimed to perform a detailed large-scale analysis to clarify this association. METHODS: We compared postoperative serum bilirubin levels of 200 patients with esophageal cancer who underwent esophagectomy, with and without postoperative complications, from January 2008 to July 2013 at Keio University Hospital, Tokyo, Japan. We also analyzed other risk factors for postoperative hyperbilirubinemia by univariate and multivariate analyses in an attempt to determine the mechanism of postoperative hyperbilirubinemia. RESULTS: Hyperbilirubinemia (total bilirubin >2.0 mg/dL) occurred in 71 patients (35.5 %). The mean total bilirubin peak level was 1.5 mg/dL in patients without complications, 2.0 mg/dL in those with at least one complication, 2.1 mg/dL in those with pneumonia, and 2.3 mg/dL in those with anastomotic leakage. Bilirubin levels were significantly higher in each complication group than in the non-complication group (p < 0.05 for all). Risk factors of postoperative hyperbilirubinemia by univariate analysis were the preoperative bilirubin level, video-assisted thoracoscopic surgery, three-field lymph node dissection, thoracic duct resection, prolonged surgical duration, severe complications (Clavien-Dindo grade ≥3), and severe anastomotic leakage (Clavien-Dindo grade ≥3). In contrast, the pT factor and postoperative enteral nutrition were negatively associated with postoperative hyperbilirubinemia. Risk factors by multivariate analysis were the preoperative bilirubin level, prolonged surgical duration, severe complications, and postoperative enteral nutrition. CONCLUSIONS: Although various factors impact postoperative hyperbilirubinemia, postoperative complications were most significantly associated with postoperative hyperbilirubinemia. Patients with postoperative hyperbilirubinemia after esophagectomy must be managed more carefully because unnoticed complications may be associated with hyperbilirubinemia.

CXCR2 expression and postoperative complications affect long-term survival in patients with esophageal cancer.

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.

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.

Suitability of sentinel node mapping as an index of metastasis in early gastric cancer following endoscopic resection.

BACKGROUND: When pathological diagnosis following endoscopic resection (ER) for early gastric cancer (EGC) suggests probable lymph node metastasis, additional surgery with lymphadenectomy should be performed. The sentinel node (SN) concept has yet to be applied to tumors following ER. The aim of this study was to evaluate the feasibility of SN navigation surgery for such tumors. METHODS: Forty patients diagnosed with EGC lesions <4 cm in diameter underwent gastrectomy with SN mapping following ER. A technetium-99 m tin colloid solution and a dye were injected into the submucosal layer around the post-ER scar in all four abdominal quadrants. We then compared the SN distribution and metastases among the patients who underwent ER and controls (n = 192). RESULTS: SNs were identifiable in all patients, and the mean number of SNs per case was 4.9. The location of the SN basin was similar in the patients who underwent ER and the controls. One patient (3 %) whose primary tumor had invaded the submucosal layer had a metastatic SN. The median time from ER to surgery was 73 days. No postoperative recurrence was observed in any patient over a median follow-up of 1,023 days. CONCLUSIONS: Our findings suggest that the SN basin is not greatly affected by ER. The SN concept could be suitable for tumors following ER, but conventional gastrectomy with lymphadenectomy involving the SN basin should be used at present.

CC-Chemokine receptor CCR7: a key molecule for lymph node metastasis in esophageal squamous cell carcinoma.

BACKGROUND: CC-chemokine receptor 7 (CCR7), a known lymph node homing receptor for immune cells, has been reported as a key molecule in lymph node metastasis. We hypothesized a clinicopathological correlation and functional causality between CCR7 expression and lymph node metastasis in patients with esophageal squamous cell carcinoma (ESCC). METHODS: We performed immunohistochemical analysis of 105 consecutive and 61 exclusive pathological T1 ESCC patients, followed by adhesion assay and in vivo experiment using a newly developed lymph node metastasis mouse model. The adhesive ability in response to CC-chemokine ligand 21/secondary lymphoid-tissue chemokine (CCL21/SLC) was assessed in the presence or absence of lymphatic endothelial cells and anti-CCR7 antibody. We established a heterotopic transplantation mouse model and analyzed lymph node metastasis by quantitative real-time RT-PCR. RESULTS: Positive CCR7 expression in immunohistochemistory was detected in 28 (27%) of 105 consecutive patients and 17 (28%) of 61 T1 patients, which significantly correlated with lymph node metastasis (p = 0.037 and p = 0.040, respectively) and poor five-year survival (p = 0.013 and p = 0.012, respectively). Adhesion assay revealed an enhanced adhesive ability of CCR7-expressing cells in response to CCL21/SLC, in particular, in the presence of lymphatic endothelial cells (p = 0.005). In the mouse model, lymph nodes from mice transplanted with CCR7-expressing cells showed significantly higher DNA levels at 5 weeks (p = 0.019), indicating a high metastatic potential of CCR7-expressing cells. CONCLUSION: These results demonstrated the significant clinicopathological relationship and functional causality between CCR7 expression and lymph node metastasis in ESCC patients.

Clinical utility of a novel hybrid position combining the left lateral decubitus and prone positions during thoracoscopic esophagectomy.

BACKGROUND: We developed a hybrid of the prone and left lateral decubitus positions for thoracoscopic esophagectomy (TE) in 2009. This study aimed to evaluate the feasibility of applying this novel TE position. METHODS: We retrospectively analyzed 78 patients who underwent TE at our institution between 2005 and 2010. Altogether, 33 patients underwent TE in the left lateral decubitus position (LD-TE) from 2005 to 2008, and 45 underwent TE in the hybrid position (hybrid-TE) from 2009 to 2010. Radical lymphadenectomy along the bilateral recurrent laryngeal nerves was performed in both groups. The thoracic duct was preserved in the LD-TE group and resected in the hybrid-TE group. In the LD-TE group, all thoracic procedures were performed with the patient in the left lateral decubitus position. In the hybrid-TE group, the upper mediastinal procedure was performed with the patient in the left lateral decubitus position, and procedures at the middle and lower mediastinum were performed with the patient in the prone position under CO2 pneumothorax. RESULTS: Hybrid-TE was associated with increased operating time. The number of harvested mediastinal nodes and the PaO2/FiO2 ratio on postoperative day 1 were both greater in this position. Although vocal cord palsy was observed more frequently in the hybrid-TE group, there was no significant difference in the rate of other complications or in-hospital mortality between the two groups. CONCLUSIONS: The novel hybrid position is believed feasible for use during TE. We believe that this position facilitates a more radical mediastinal lymphadenectomy with minimal intraoperative pulmonary damage.

Intra-abdominal desmoid tumor mimicking gastric cancer recurrence: a case report.

Intra-abdominal desmoid tumors are rare and most often occur in patients with a history of familial adenomatous polyposis, surgery, or pregnancy. We report a case of an intra-abdominal desmoid tumor mimicking the recurrence of gastric cancer. A 57-year-old male had undergone distal gastrectomy for advanced gastric cancer. Serum levels of carcinoembryonic antigen were found to be elevated 27 months after surgery. Computed tomography revealed a 15-mm mass in the mesentery of the transverse colon. In addition, radiotracer fluorodeoxyglucose uptake of the tumor was detected by positron emission tomography. The patient was diagnosed with gastric cancer recurrence, and chemotherapy consisting of cisplatin and S-1 was commenced. After five courses of chemotherapy, although no significant clinical response was seen, no new lesions were seen either. Thus, a curative resection of the recurrent tumor seemed possible, which was successfully performed. Histological examination of the resected specimen revealed spindle-shaped tumor cells with collagen fiber progression; no cancer cells were detected. The tumor was diagnosed as an intra-abdominal desmoid tumor. We report a rare case of an intra-abdominal desmoid tumor that mimicked a recurrent tumor arising from gastric cancer. In patients with history of surgery for intra-abdominal malignancies, it may be difficult to distinguish the recurrence of malignancy from desmoid tumors but the possibility of desmoid tumors must be considered in the differential diagnosis.