Engineering of an EPHA2-Targeted Monobody for the Detection of Colorectal Cancer.

BACKGROUND/AIM: Colorectal cancer (CRC) is the third most common cancer worldwide, and is second only to lung cancer with respect to cancer-related deaths. Noninvasive molecular imaging using established markers is a new emerging method to diagnose CRC. The human ephrin receptor family type-A 2 (hEPHA2) oncoprotein is overexpressed at the early, but not late, stages of CRC. Previously, we reported development of an E1 monobody that is specific for hEPHA2-expressing cancer cells both in vitro and in vivo. Herein, we investigated the ability of the E1 monobody to detect hEPHA2 expressing colorectal tumors in a mouse model, as well as in CRC tissue. MATERIALS AND METHODS: The expression of hEPHA2 on the surface of CRC cells was analyzed by western blotting and flow cytometry. The targeting efficacy of the E1 monobody for CRC cells was examined by flow cytometry, and immunofluorescence staining. E1 conjugated to the Renilla luciferase variant 8 (Rluc8) reporter protein was used for in vivo imaging in mice. Additionally, an enhanced green fluorescence protein (EGFP) conjugated E1 monobody was used to check the ability of the E1 monobody to target CRC tissue. RESULTS: The E1 monobody bound efficiently to hEPHA2-expressing CRC cell lines, and E1 conjugated to the Rluc8 reporter protein targeted tumor tissues in mice transplanted with HCT116 CRC tumor cells. Finally, E1-EGFP stained tumor tissues from human CRC patients, showing a pattern similar to that of an anti-hEPHA2 antibody. CONCLUSION: The E1 monobody has utility as an EPHA2 targeting agent for the detection of CRC.

Primary rectal mucosa-associated lymphoid tissue lymphoma treated with only endoscopic submucosal dissection: A case report.

BACKGROUND: Mucosa-associated lymphoid tissue (MALT) lymphoma is a distinct subtype of non-Hodgkin B cell lymphoma that mostly involves the gastrointestinal tract. The stomach is the most commonly affected site whereas colorectal involvement occurs very rarely. Given its rarity, the management and clinical outcome of colorectal MALT lymphoma are not well established yet. CASE SUMMARY: From the superficial capillary bed in the lower rectum. Endoscopic ultrasonography showed homogenous hypoechoic lesions in the deep mucosal layer. Endoscopic submucosal dissection (ESD) was done for accurate histologic diagnosis and treatment and both the rectal lesions were completely removed en bloc and subsequently diagnosed as primary rectal MALT lymphoma. Herein, we report a case of primary rectal MALT lymphoma in a 68-year-old woman that was treated by only ESD, and the 12-month follow-up revealed no tumour recurrence. CONCLUSION: These results of our case and previous reports suggest that endoscopic resection alone may be a feasible and safe treatment for primary colorectal MALT lymphoma and allows organ preservation.

A comparative study of magnifying endoscopy with narrow-band image and endocytoscopy in the diagnosis of gastric neoplasm: a pilot study.

BACKGROUND/AIMS: Endoscopic technologies have recently advanced to optimize the detection and diagnosis of gastric lesions. Endocytoscopy aids in the virtual realization of histology. Herein, we aimed to investigate gastric lesions using single-stain endocytoscopy and compare them using magnifying endoscopy with narrow-band imaging (ME-NBI) in terms of diagnostic yield in vivo. METHODS AND METHODS: In the present prospective study, we registered 24 patients with gastric neoplasms and retrospectively reviewed their images. Three endoscopists reviewed the images of gastric neoplasms using white light, ME-NBI, and endocytoscopy. The diagnostic yield of endocytoscopy in early gastric cancer (EGC) was assessed using histopathology as the gold standard. RESULTS: Endocytoscopy was performed in 24 patients with gastric neoplasms. Of these, 15 patients had adenocarcinomas, while nine patients had low-grade dysplasia. The sensitivity, specificity, and accuracy of endocytoscopy for EGC detection were reported as 80.0% [95% confidence interval (CI), 51.9-95.7], 66.7% (95% CI, 58.4-91.9), and 75.0% (95% CI, 53.3-90.2) by endoscopist A; 80.0% (95% CI, 51.9-95.7), 44.4% (95% CI, 13.7-78.8), and 66.7% (95% CI, 44.7-84.4) by endoscopist B; and 93.3% (95% CI, 68.1-99.8), 55.6% (95% CI, 21.2-86.3), and 79.2% (95% CI, 57.9-92.8) by endoscopist C; these findings were not inferior to NBI. The inter-observer agreement, κ statistic = 0.67 (95% CI, 0.43-0.90) was favorable. CONCLUSION: Endocytoscopy aid in the diagnosis of EGC because of its better sensitivity and accuracy compared to NBI or white-light imaging. However, further large-scale studies are required to confirm our findings.

The anticancer effect of PASylated calreticulin-targeting L-ASNase in solid tumor bearing mice with immunogenic cell death-inducing chemotherapy.

L-Asparaginase (L-ASNase), a bacterial enzyme that degrades asparagine, has been commonly used in combination with several chemical drugs to treat malignant hematopoietic cancers such as acute lymphoblastic leukemia (ALL). In contrast, the enzyme was known to inhibit the growth of solid tumor cells in vitro, but not to be effective in vivo. We previously reported that two novel monobodies (CRT3 and CRT4) bound specifically with calreticulin (CRT) exposed on tumor cells and tissues during immunogenic cell death (ICD). Here, we engineered L-ASNases conjugated with monobodies at the N-termini and PAS200 tags at the C-termini (CRT3LP and CRT4LP). These proteins were expected to possess four monobody and PAS200 tag moieties, which did not disrupt the L-ASNase conformation. These proteins were expressed 3.8-fold more highly in E. coli than those without PASylation. The purified proteins were highly soluble, with much greater apparent molecular weights than expected ones. Their affinity (Kd) against CRT was about 2 nM, 4-fold higher than that of monobodies. Their enzyme activity (∼6.5 IU/nmol) was similar to that of L-ASNase (∼7.2 IU/nmol), and their thermal stability was significantly increased at 55 °C. Their half-life times were > 9 h in mouse sera, about 5-fold longer than that of L-ASNase (∼1.8 h). Moreover, CRT3LP and CRT4LP bound specifically with CRT exposed on tumor cells in vitro, and additively suppressed the tumor growth in CT-26 and MC-38 tumor-bearing mice treated with ICD-inducing drugs (doxorubicin and mitoxantrone) but not with a non-ICD-inducing drug (gemcitabine). All data indicated that PASylated CRT-targeted L-ASNases enhanced the anticancer efficacy of ICD-inducing chemotherapy. Taken together, L-ASNase would be a potential anticancer drug for treating solid tumors.

Follicular pancreatitis: Case report and literature review.

RATIONALE: Follicular pancreatitis is a very rare type of focal chronic pancreatitis and is often mistaken for pancreatic neoplasms. It is histologically characterized by extensive lymphoid follicular formation with reactive germinal centers. PATIENT CONCERNS: A 50-year-old man was admitted to our hospital with 1-month history of epigastric pain. Contrast-enhanced computed tomography and magnetic resonance imaging revealed a 4.7 cm sized enhancing pancreatic head mass with anterior mesenteric soft tissue infiltration and superior mesenteric vein invasion. Endoscopic ultrasonography revealed an ill-defined hypoechoic mass in the head of the pancreas. DIAGNOSES: A laparoscopic surgical biopsy was performed. Hematoxylin-eosin staining showed the acini structure destruction within the pancreatic parenchyma and different-sized lymphoid follicles with reactive germinal centers around the duct. Immunohistochemical examination showed that cells were positive for the B-cell marker CD20, T-cell marker CD3, and slightly positive for IgG4. However, cells were negative for the B-cell marker Bcl-2. Follicular pancreatitis was confirmed based on the findings of histology and immunohistochemistry. INTERVENTIONS: The patient was regularly followed without any specific treatment. OUTCOMES: Follow-up computed tomography revealed no change in the lesion 1 year after diagnosis. LESSONS: To the best of our knowledge, this is the first case of follicular pancreatitis in Korea.

Over-expression of Anterior Gradient 3 Is Associated With Tumor Progression and Poor Survival in Gastric Cancer.

BACKGROUND/AIM: Anterior gradient (AGR) proteins, including AGR1, AGR2, and AGR3, which are members of the protein disulfide isomerase family, have been reported as biomarkers for various carcinogenesis processes. Although AGR2 and AGR1 have been demonstrated to be associated with gastric cancer (GC) progression and poor survival, the effect of AGR3 on the progression and prognosis of GC remains unknown. Therefore, our study aimed to examine the expression and prognostic significance of AGR3 in patients with GC. PATIENTS AND METHODS: We investigated 271 GC patients receiving curative surgery. Formalin-fixed and paraffin-embedded tissue blocks were obtained, and long-term survival analysis was performed. The expression of AGR3 in GC tissues was investigated by quantitative reverse transcription-polymerase chain reaction, western blotting, and immunohistochemistry. RESULTS: AGR3 was over-expressed in GC tissue compared with paired normal tissue at the mRNA and protein levels. AGR3 over-expression was significantly associated with larger tumor size, deeper tumor invasion, lymph node metastasis, and advanced tumor stage. The overall survival of patients with positive AGR3 expression was significantly lower than that of patients without positive AGR3 expression. Multivariate analysis demonstrated that AGR3 and age were independent prognostic factors associated with overall survival. CONCLUSION: Over-expression of AGR3 was significantly associated with tumor progression and poor survival of GC patients. Therefore, AGR3 may be a novel biomarker and prognostic factor for GC.

Clinical Outcome and Risk Factors of Chronic Radiation Proctitis Following Pelvic Radiation Therapy.

BACKGROUND/AIM: Pelvic radiation therapy (RT) is a common treatment for malignancies, including gynecological, genitourinary, and lower gastrointestinal tract cancers. However, chronic radiation proctitis (RP) is an unavoidable side effect, and its clinical presentation varies from asymptomatic to potentially life-threatening. This study evaluated the clinical characteristics and risk factors of chronic RP. PATIENTS AND METHODS: Patients with chronic RP (212) following RT for various pelvic cancers between January 2015 and December 2021 were enrolled. Clinical characteristics of RP were analyzed retrospectively. Severity was graded according to the Radiation Therapy Oncology Group (RTOG) modified rectal toxicity score and Vienna rectoscopy score (VRS), and risk factors were statistically analyzed. RESULTS: The most common pelvic cancer observed was cervical cancer. The patients received three-dimensional conformal RT (3D-CRT), intensity-modulated RT, or a combination of 3D-CRT and intracavitary RT (ICR). Rectal bleeding occurred in 70 (33.0%) patients. Previous abdominopelvic surgery and total radiation dose significantly correlated with the RTOG score and VRS. Previous abdominopelvic surgery, ICR, and total radiation dose were associated with chronic hemorrhagic RP. All patients with chronic hemorrhagic RP were treated with argon plasma coagulation (APC). 91.4% of cases required 1-3 APC sessions to resolve the bleeding, with a mean of 1.7 sessions. CONCLUSION: Our results showed that previous abdominopelvic surgery and total radiation dose were significant risk factors related to chronic RP, while total radiation dose was related to chronic hemorrhagic RP. We also showed that APC was effective and safe for chronic hemorrhagic RP.

CD47 mediates the progression of colorectal cancer by inducing tumor cell apoptosis and angiogenesis.

CD47 is an immunoregulatory protein that is found on the cell surface and plays significant roles in cellular functions such as proliferation, apoptosis, migration, and immune homeostasis. CD47 is overexpressed in various human cancers and is associated with tumor development, progression, and poor prognosis. In this study, we analyzed the expression of CD47 to determine whether it affected the oncogenic behavior of colorectal cancer (CRC) and investigated the prognostic value of CD47 expression in patients with CRC. We investigated 468 patients with CRC who underwent curative surgery and examined the expression of CD47 in tumor and lymph node tissues by performing RT-PCR and immunohistochemistry. Apoptosis, proliferation, angiogenesis, and lymphangiogenesis were determined via a TUNEL assay and immunohistochemical staining for Ki-67, CD34, and D2-40. CD47 expression was increased in human CRC tumors and metastatic lymph nodes compared with normal colorectal mucosa and non-metastatic lymph node tissues. CD47 expression was significantly associated with perineural invasion, lymphovascular invasion, cell differentiation, cancer stage, depth of invasion, lymph node metastasis, distant metastasis, and poor survival. The mean apoptotic index and microvessel density value of CD47-positive tumors were significantly higher than those of CD47-negative tumors. However, no significant difference was observed between CD47 expression and Ki-67 labeling index or lymphatic vessel density. These results indicate that CD47 mediated the progression of CRC by inducing tumor cell apoptosis and angiogenesis.

Engulfment and Cell Motility 1 (ELMO1) Regulates Tumor Cell Behavior and Predicts Prognosis in Colorectal Cancer.

BACKGROUND/AIM: Engulfment and cell motility 1 (ELMO1) plays a crucial role in the process of migration, chemotaxis, and metastasis of tumor cells. ELMO1 has been implicated in the pathogenesis of various cancers. However, the distinct function of ELMO1 in colorectal cancer (CRC) is unclear. We determined whether ELMO1 affects the oncogenic behavior of CRC cells and investigated its prognostic value in CRC patients. MATERIALS AND METHODS: We investigated the impact of ELMO1 on tumor cell behavior using small interference RNA (siRNA) in CRC cell lines, including SW480 and DLD1. The expression of ELMO1 was investigated by reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemistry, and enzyme-linked immunosorbent assay (ELISA) in cancer tissues and sera obtained from CRC patients. RESULTS: ELMO1 knockdown suppressed tumor cell proliferation in SW480 and DLD1 cells. ELMO1 knockdown-induced apoptosis through up-regulation of caspase-3, -7, and PARP activities and down-regulation of the anti-apoptotic Mcl-1 protein. ELMO1 knockdown-induced cell-cycle arrest by decreasing cyclin D1, cyclin-dependent kinase 2, 4 and 6, and the 25C cell division cycle (CDC25C). ELMO1 knockdown suppressed tumor cell invasion and migration. The expression of E-cadherin was increased, while that of Vimentin and Claudin 1 decreased following ELMO1 knockdown. The phosphorylation levels of PDK1, Akt, and GSK-3ß and were down-regulated after ELMO1 knockdown. The expression of ELMO1 was found up-regulated in cancer tissues and sera taken from CRC patients. ELMO1 expression was significantly associated with tumor stage, lymph node metastasis, distant metastases, and poor survival. CONCLUSION: ELMO1 mediates tumor progression by increasing tumor cell motility and inhibiting apoptosis in human CRC.

Differences in clinical outcomes according to the time interval between the bridge to surgery stenting and surgery for left-sided malignant colorectal obstruction.

BACKGROUND: Self-expandable metal stent (SEMS) placement is commonly used as a bridge to surgery (BTS) for left-sided malignant colorectal obstruction (MCO). However, the optimal time interval between BTS stenting and surgery for left-sided MCO is unclear, and the results of previous studies are conflicting. This study aimed to determine the differences in clinical outcomes according to the time interval between BTS stenting and surgery in left-sided MCO. METHODS: Data from 594 patients who underwent SEMS placement for MCO between January 2009 and December 2018 were reviewed. Among them, 148 patients who underwent SEMS placement as BTS treatment and curative surgery were enrolled. The enrolled patients were divided into three groups according to the interval between BTS stenting and surgery: group 1 (interval ≤2 weeks), group 2 (interval 2-3 weeks), and group 3 (interval >3 weeks). RESULTS: Group 2 and 3 patients underwent significantly higher rates of laparoscopic surgery than those in group 1 (83.7, 81.0 vs. 53.2 %, respectively; P=0.003, P=0.003, respectively). Also, rates of stoma formation directly after resection were significantly higher in group 1 compared to groups 2 and 3 (21.3 vs 2.3, 6.9%, respectively; P=0.008, P=0.043, respectively). Bridging interval had no effect on SEMS-related complications, resection-related complications, 90-day mortality, permanent stoma formation, 3-year disease-free survival, and 3-year overall survival. CONCLUSIONS: A bridging interval of > 2 weeks between BTS stenting and surgery for left-sided MCO is preferable for lower stoma formation rates and higher rates of laparoscopic approach operation, with no difference in short-term and long-term outcomes including complication, mortality, and survival.

Prediction model for curative endoscopic submucosal dissection of undifferentiated-type early gastric cancer.

BACKGROUND: Endoscopic submucosal dissection (ESD) is an effective treatment for early gastric cancer (EGC); however, its curative resection rate is low for undifferentiated-type EGC. We developed and externally validated a prediction model for curative ESD of undifferentiated-type EGC. METHODS: In this cross-sectional study, we included 448 patients who underwent ESD for undifferentiated-type EGC at 18 hospitals in Korea between 2005 and 2015 in the development cohort and 1342 patients who underwent surgery at two hospitals in the validation cohort. A prediction model was developed using the logistic regression model. RESULTS: Endoscopic tumor size 1-2 cm (odds ratio [OR], 2.40; 95% confidence interval [CI] 1.54-3.73), tumor size > 2 cm (OR, 14.00; 95% CI 6.81-28.77), and proximal tumor location from the lower to upper third of the stomach (OR, 1.45; 95% CI 1.03-2.04) were independent predictors of non-curative ESD. A six-score prediction model was developed by assigning points to endoscopic tumor size > 2 cm (five points), tumor size 1-2 cm (two points), upper third location (two points), and middle third location (one point). The rate of curative ESD ranged from 70.6% (score 0) to 11.6% (score 5) with an area under the receiver operating characteristic curve (AUC) of 0.720 (95% CI 0.673-0.766). The model also showed good performance in the validation cohort (AUC, 0.775; 95% CI 0.748-0.803). CONCLUSIONS: This six-score prediction model may help in predicting curative ESD and making informed decisions about the treatment selection between ESD and surgery for undifferentiated-type EGC.

Application of Current Image-Enhanced Endoscopy in Gastric Diseases.

Image-enhanced endoscopy (IEE) plays an integral role in endoscopic diagnosis and treatment. IEE enables an early and accurate detection of cancer and characterization of lesions prior to therapeutic decisions. Ideal IEE can serve as an optical or digital chromoscopic endoscopy, as well as an optical biopsy that predicts exact histopathology. Several IEE modalities have recently been developed and are used in the clinical field. The stomach is a challenging organ for imaging because of its complex secretion function and status of Helicobacter pylori infection. Therefore, understanding the current IEE modalities for their clinical applicability in an evidence-based approach is warranted. Along with technology refinements, the new paradigm will be available for the diagnosis of gastric cancer or other conditions in the stomach in the near future.

A Disintegrin and Metalloprotease 12 Promotes Tumor Progression by Inhibiting Apoptosis in Human Colorectal Cancer.

A disintegrin and metalloprotease 12 (ADAM12) has been implicated in cell growth, tumor formation, and metastasis. Therefore, we evaluated the role of ADAM12 in colorectal cancer (CRC) progression and prognosis, and elucidated whether targeted downregulation of ADAM12 could lead to therapeutic sensitization. The effect of ADAM12 on tumor cell behavior was assessed in CRC cell lines, CRC tissues, and a mouse xenograft model. ADAM12 overexpression enhanced proliferation, inhibited apoptosis, and acted as positive regulator of cell cycle progression in CRC cells. Phosphorylation of PTEN was decreased and that of Akt was increased by ADAM12 overexpression. These results were reversed upon ADAM12 knockdown. ADAM12 overexpression was significantly associated with the cancer stage, depth of invasion, lymph node metastasis, distant metastasis, and poor survival in CRC patients. In a mouse xenograft model, tumor area, volume, and weight were significantly greater for the ADAM12-pcDNA6-myc-transfected group than for the empty-pcDNA6-myc-transfected group, and significantly lower for the ADAM12-pGFP-C-shLenti-transfected group than for the scrambled pGFP-C-shLenti-transfected group. In conclusion, ADAM12 overexpression is essential for the growth and progression of CRC. Furthermore, ADAM12 knockdown reveals potent anti-tumor activity in a mouse xenograft model. Thus, ADAM12 may serve as a promising biomarker and/or therapeutic target in CRC.

Long-term Outcomes of Undifferentiated-Type Early Gastric Cancer with Positive Horizontal Margins after Endoscopic Resection.

Background/Aims: This study examined the long-term outcomes of undifferentiated-type early gastric cancer (UD EGC) with positive horizontal margins (HMs) after endoscopic resection (ER) and compared them between additional surgery and nonsurgical management. Methods: From 2005 to 2015, a total of 1,124 patients with UD EGC underwent ER at 18 tertiary hospitals in Korea. Of them, 92 patients with positive HMs as the only noncurative factor (n=25) or with both positive HMs and tumor size >2 cm (n=67) were included. These patients underwent additional surgery (n=40), underwent additional endoscopic treatment (n=6), or were followed up without further treatment (n=46). Results: No lymph node (LN) metastasis was found in patients who underwent additional surgery. During a median follow-up of 57.7 months (interquartile range, 27.6 to 68.8 months), no LN or distant metastases or gastric cancer-related deaths occurred in the overall cohort. At baseline, the residual cancer rate was 57.8% (26/45) after additional surgery or ER. The 5-year local recurrence rate was 33.6% among patients who were followed up without additional treatment. The 5-year overall survival rates were 95.0% and 87.8% after additional surgery and nonsurgical management (endoscopic treatment or close follow-up), respectively (log-rank p=0.224). In the multivariate Cox regression analysis, nonsurgical management was not associated with an increased risk of mortality. Conclusions: UD EGC with positive HMs after ER may have favorable long-term outcomes and a very low risk of LN metastasis. Nonsurgical management may be suggested as an alternative, particularly for patients with old age or chronic illness.

Diode Laser-Can It Replace the Electrical Current Used in Endoscopic Submucosal Dissection?

BACKGROUND/AIMS: A new medical fiber-guided diode laser system (FDLS) is expected to offer high-precision cutting with simultaneous hemostasis. Thus, this study aimed to evaluate the feasibility of using the 1,940-nm FDLS to perform endoscopic submucosal dissection (ESD) in the gastrointestinal tract of an animal model. METHODS: In this prospective animal pilot study, gastric and colorectal ESD using the FDLS was performed in ex vivo and in vivo porcine models. The completeness of en bloc resection, the procedure time, intraprocedural bleeding, histological injuries to the muscularis propria (MP) layer, and perforation were assessed. RESULTS: The en bloc resection and perforation rates in the ex vivo study were 100% (10/10) and 10% (1/10), respectively; those in the in vivo study were 100% (4/4) and 0% for gastric ESD and 100% (4/4) and 25% (1/4) for rectal ESD, respectively. Deep MP layer injuries tended to occur more frequently in the rectal than in the gastric ESD cases, and no intraprocedural bleeding occurred in either group. CONCLUSION: The 1,940-nm FDLS was capable of yielding high en bloc resection rates without intraprocedural bleeding during gastric and colorectal ESD in animal models.

Clinical outcomes of endoscopic resection for undifferentiated intramucosal early gastric cancer larger than 2 cm.

BACKGROUND: This study investigated the long-term clinical outcomes of endoscopic resection (ER) for undifferentiated-type (UD) early gastric cancer (EGC), with tumor size > 2 cm as the only non-curative factor. METHODS: From among 1123 patients who underwent ER for UD EGC at 18 tertiary hospitals in Korea between 2005 and 2014, we identified 216 patients with UD intramucosal EGC > 2 cm, which was completely resected, with negative resection margins, and absence of ulceration and lymphovascular invasion. The patients were divided into the additional surgery (n = 40) or observation (n = 176) groups, according to post-ER management and were followed up for a median duration of 59 months for recurrence and 90 months for overall survival. RESULTS: Lymph node (LN) or distant metastasis or cancer-related mortality was not observed in the surgery group. In the observation group, two (1.1%) patients developed LN or distant metastasis with a 5-year cumulative risk of 0.7%, and one (0.6%) patient died of gastric cancer. The 5- and 8-year overall survival rates were 94.1% and 89.9%, respectively, in the observation group and 100.0% and 95.2%, respectively, in the surgery group (log-rank P = 0.159). Cox regression analysis did not reveal an association between the observation group and increased mortality. CONCLUSION: The risk of LN or distant metastasis was not negligible, but as low as 1% for patients undergoing non-curative ER for UD EGC, with tumor size > 2 cm as the only non-curative factor. Close observation may be an alternative to surgery, especially for older patients or those with poor physical status.

Risk factors of lymph node metastasis after non-curative endoscopic resection of undifferentiated-type early gastric cancer.

BACKGROUND: This study aimed to investigate risk factors for lymph node (LN) or distant metastasis after non-curative endoscopic resection (ER) of undifferentiated-type early gastric cancer (EGC). METHODS: Of 1124 patients who underwent ER for undifferentiated-type gastric cancer at 18 tertiary hospitals across six geographic areas in Korea between 2005 and 2014, 634 with non-curative ER beyond the expanded criteria were retrospectively enrolled. According to the treatment after ER, patients were divided into additional surgery (n = 270) and follow-up (n = 364) groups. The median follow-up duration was 59 months for recurrence and 84 months for mortality. RESULTS: LN metastasis was found in 6.7% (18/270) of patients at surgery. Ulcer [odds ratio (OR) 3.83; 95% confidence interval (CI) 1.21-12.13; p = 0.022] and submucosal invasion (OR 10.35; 95% CI 1.35-79.48; p = 0.025) were independent risk factors. In the follow-up group, seven patients (1.9%) developed LN or distant recurrence. Ulcer [hazard ratio (HR) 7.60; 95% CI 1.39-35.74; p = 0.018], LVI (HR 6.80; 95% CI 1.07-42.99; p = 0.042), and positive vertical margin (HR 6.71; 95% CI 1.28-35.19; p = 0.024) were independent risk factors. In the overall cohort, LN metastasis rates were 9.6% in patients with two or more risk factors and 1.2% in those with no or one risk factor. CONCLUSIONS: LVI, ulcer, submucosal invasion, and positive vertical margin are independently associated with LN or distant metastasis after non-curative ER of undifferentiated-type EGC. Surgical resection is strongly recommended for patients with two or more risk factors.

Engulfment and cell motility 1 promotes tumor progression via the modulation of tumor cell survival in gastric cancer.

BACKGROUND/AIM: Engulfment and cell motility 1 (ELMO1) protein has been implicated in phagocytosis of apoptotic cells, cell migration, neurite outgrowth, cancer cell invasion and metastasis, and poor prognosis in various cancers. We investigated the role of ELMO1 in mediating the oncogenic behavior of gastric cancer (GC) cells. We also investigated the correlation between expression of ELMO1 in GC tissues and various clinicopathological parameters. METHODS: We studied the impact of ELMO1 on tumor cell behavior using the pcDNA-myc vector and small interfering RNA in AGS and SNU1750 GC cell lines. We performed western blotting and immunohistochemistry to investigate the expression of ELMO1 in GC cells and tissues. RESULTS: ELMO1 overexpression inhibited apoptosis via the modulation of PARP, caspase-3 and caspase-7 in GC cells. ELMO1 overexpression led to significant increase in the number of migrating and invading GC cells. The expression of E-cadherin decreased and that of Snail increased in GC cells upon ELMO1 overexpression. Phosphorylation of PI3K/Akt and GSK-3ß was increased and that of ß-catenin was decreased upon ELMO1 overexpression in GC cells. These results were reversed after ELMO1 knockdown. ELMO1 expression was significantly associated with tumor size, cancer stage, lymph node metastasis and survival. ELMO1-positive tumors had significantly higher mean of Ki-67 labeling index than ELMO1-negative tumors. There was no significant relationship between ELMO1 expression and the mean value of the apoptotic index. CONCLUSIONS: Our results indicate that ELMO1 promotes tumor progression by modulating tumor cell survival in human GC.

Forkhead­box A1 regulates tumor cell growth and predicts prognosis in colorectal cancer.

Forkhead box A1 (FOXA1) functions as a tumor suppressor gene or an oncogene in various types of cancer; however, the distinct function of FOXA1 in colorectal cancer is unclear. The present study aimed to evaluate whether FOXA1 affects the oncogenic behavior of colorectal cancer cells, and to investigate its prognostic value in colorectal cancer. The impact of FOXA1 on tumor cell behavior was investigated using small interfering RNA and the pcDNA6­myc vector in human colorectal cancer cell lines. To investigate the role of FOXA1 in the progression of human colorectal cancer, an immunohistochemical technique was used to localize FOXA1 protein in paraffin­embedded tissue blocks obtained from 403 patients with colorectal cancer. Tumor cell apoptosis and proliferation were evaluated using a terminal deoxynucleotidyl transferase­mediated dUTP nick­end labeling assay and Ki­67 immunohistochemical staining, respectively. FOXA1 knockdown inhibited tumor cell invasion in colorectal cancer cells, and induced apoptosis and cell cycle arrest. FOXA1 knockdown activated cleaved caspase­poly (ADP­ribose) polymerase, upregulated the expression of p53 upregulated modulator of apoptosis, and downregulated BH3 interacting domain death agonist and myeloid cell leukemia­1, leading to the induction of apoptosis. FOXA1 knockdown increased the phosphorylation level of signal transducer and activator of tran-scription­3. By contrast, these results were reversed following the overexpression of FOXA1. The overexpression of FOXA1 was associated with differentiation, lymphovascular invasion, advanced tumor stage, depth of invasion, lymph node metastasis and poor survival rate. The mean Ki­67 labeling index value of FOXA1­positive tumors was significantly higher than that of FOXA1­negative tumors. However, no significant association was observed between the expression of FOXA1 and the mean apoptotic index value. These results indicate that FOXA1 is associated with tumor progression via the modulation of tumor cell survival in human colorectal cancer.

Cardiac tamponade after radiofrequency ablation for hepatocellular carcinoma: Case report and literature review.

RATIONALE: Radiofrequency ablation (RFA) is a safe and effective local treatment modality with a low complication rate and is commonly used to treat hepatocellular carcinoma (HCC). The clinical outcome of RFA may be closely related to the location, size, and shape of index tumors, and major complications, including hemorrhage, liver abscess, infarction, visceral organ perforation, hemothorax, pneumothorax, tumoral seeding, and hepatic failure. Cardiac tamponade is a rare and serious life-threatening complication associated with RFA. To date, a review of the medical literature reported 5 cases of cardiac tamponade after RFA for HCC. Herein, we report another case of cardiac tamponade after RFA for HCC in a 56-year-old man. PATIENT CONCERNS: He had suffered from liver cirrhosis due to alcohol abuse. He had chronic obstructive pulmonary disease. Magnetic resonance imaging showed a 3.0-cm exophytic subcapsular HCC in segment IVa of left hepatic lobe. As the patient was at high risk for surgery because of poor lung function, RFA was selected as the treatment of choice. The index tumor was located in the vicinity of the diaphragm and colon. During RFA procedure, thermal injury to the adjacent diaphragm and colon was minimized by introducing artificial ascites. Bleeding or tumoral seeding was prevented by ablating the electrode track during electrode retraction. DIAGNOSIS: Two hours after RFA, the patient presented with dyspnea, chest discomfort, and low blood pressure (80/60 mm Hg), suggesting cardiac tamponade. Immediate follow-up contrast-enhanced computed tomography image depicted the slightly high attenuated hemopericardium. Transthoracic echocardiography (TTE) showed a moderate amount of pericardial effusion with tamponade and a large hematoma. INTERVENTIONS: Under fluoroscopy and portable echocardiography guidance, a cardiologist immediately inserted a 7-French pigtail catheter into the pericardial space and collected more than 200 cc of bloody pericardial fluid. OUTCOMES: After pericardiocentesis, the patient's symptoms and hemodynamic status were dramatically improved. Follow-up TTE showed scanty amount of pericardial effusion and the drainage catheter was removed. The patient was discharged. LESSONS: When treating HCC in the left lobe (especially segments II and IVa), attention should be paid to cardiac tamponade. The early diagnosis and immediate treatment of cardiac tamponade may increase the chance of cure.