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.

Expression of ADAM12 in Gastric Cancer and its Relation to Tumor Cell Behavior and Prognosis.

BACKGROUND/AIM: A disintegrin and metalloprotease (ADAM) 12 expression has been found up-regulated in various cancer types. The aim of the study was to evaluate whether ADAM12 affects oncogenic behavior of gastric cancer (GC) cells and investigate its prognostic value. MATERIALS AND METHODS: The effect of ADAM12 on tumor cell behavior was examined using the small interfering RNA and pcDNA6-myc vector in human GC cell lines. Expression of ADAM12 in GC tissues was confirmed by immunohistochemistry. Apoptosis and proliferation were determined by a terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay and immunohistochemical staining for Ki-67. RESULTS: ADAM12 overexpression enhanced tumor cell migration and invasion in AGS and SNU638 cells. Down-regulation of caspase-3 and PARP activity due to ADAM12 overexpression enhanced tumor cell proliferation and inhibited apoptosis. The expression of Snail and Vimentin increased and that of E-cadherin decreased following ADAM12 overexpression. In contrast, ADAM12 knockdown reversed these effects. ADAM12 overexpression increased the phosphorylation of Akt and GSK-3ß. The mean Ki-67 labeling index value of ADAM12-positive tumors was significantly higher compared to that of ADAM12-negative tumors. ADAM12 expression was associated with age, tumor size, cancer stage, depth of invasion, lymph node metastasis, and poor survival. CONCLUSION: ADAM12 enhances tumor progression by increasing cell mobility, enhancing cell proliferation, and inhibiting apoptosis in GC cells. Also, ADAM12 is associated with adverse clinicopathological features and poor survival. It may be used as a molecular marker for the prediction of clinical outcomes of patients with GC.

Gut microbiome composition can predict the response to nivolumab in advanced hepatocellular carcinoma patients.

BACKGROUND: Immunotherapy has revolutionized the clinical outcomes of intractable cancer patients. Little is known about the intestinal nonpathogenic bacterial composition of hepatocellular carcinoma (HCC) patients treated by immunotherapy. AIM: To determine whether there is a correlation between gut bacterial composition and prognosis in HCC patients. METHODS: From September 2019 to March 2020, we prospectively collected fecal samples and examined the gut microbiome of 8 advanced HCC patients treated with nivolumab as a second- or third-line systemic treatment. Fecal samples were collected before the start of immunotherapy. Fecal samples of patients with progression during treatment were collected at the time of progression, and fecal samples of patients who showed good response to nivolumab were collected after 5-7 mo as follow-up. Metagenomic data from 16S ribosomal RNA sequencing were analyzed using CLC Genomics Workbench. Microbiome data were analyzed according to therapeutic response. RESULTS: All 8 patients were male, of which 6 had underlying chronic hepatitis B. A higher Shannon index was found in the responders than in the non-responders after nivolumab therapy (P = 0.036). The unweighted beta diversity analysis also showed that the overall bacterial community structure and phylogenetic diversity were clearly distinguished according to therapeutic response. There was no significant difference in the diversity or composition of the patient gut microbiome according to the immunotherapy used. Several taxa specific to therapeutic response were designated as follows: Dialister pneumosintes, Escherichia coli, Lactobacillus reteri, Streptococcus mutans, Enterococcus faecium, Streptococcus gordonii, Veillonella atypica, Granulicatella sp., and Trchuris trichiura for the non-responders; Citrobacter freundii, Azospirillum sp. and Enterococcus durans for the responders. Of note, a skewed Firmicutes/Bacteroidetes ratio and a low Prevotella/Bacteroides ratio can serve as predictive markers of non-response, whereas the presence of Akkermansia species predicts a good response. CONCLUSION: The current presumptive study suggests a potential role for the gut microbiome as a prognostic marker for the response to nivolumab in treatment of HCC patients.

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.

A Case of Metastatic Melanoma in the Liver Mimicking Hepatocellular Carcinoma.

The liver is one of the most common sites of metastasis. Although most metastatic liver cancers are hypovascular, some hypervascular metastases, such as those from melanoma, need to be differentiated from hepatocellular carcinoma (HCC) because they may show similar radiologic findings due to their hypervascularity. We encountered a case of multinodular liver masses with hyperenhancement during the arterial phase and washout during the portal venous and delayed phases, which were consistent with imaging hallmarks of HCC. The patient had a history of malignant melanoma and had undergone curative resection 11 years earlier. We performed a liver biopsy for pathologic confirmation, which revealed a metastatic melanoma of the liver. Metastatic liver cancer should be considered if a patient without chronic liver disease has a history of other primary malignancies, and caution should be exercised with hypervascular cancers that may mimic HCC.

Pneumocystis pneumonia after use of corticosteroids in a man with severe alcoholic hepatitis: A case report.

RATIONALE: Severe alcoholic hepatitis (AH) has a very high mortality rate. Current guidelines recommend oral corticosteroids as first-line agents in individuals with severe AH to reduce short-term mortality. However, systemic corticosteroids have serious adverse effects. In individuals with AH, infection, which is one of the complications of steroid use, can result in serious outcomes, such as acute-on-chronic liver failure. Pneumocystis pneumonia (PCP) is a life-threatening opportunistic infection which may occur when high-dose corticosteroids are prescribed for more than 1 month. Therefore, when high-dose corticosteroids are used, providing PCP prophylaxis is warranted. Although trimethoprim-sulfamethoxazole (TMP-SMX) is the drug of choice for the prophylaxis of PCP, its hepatotoxicity limits its use in patients with severe AH who are on high-dose corticosteroids. Moreover, there is a lack of consensus on which drugs should be used for PCP prophylaxis in individuals with severe AH who are on glucocorticoid treatment. Herein, we report a case of a 43-year-old male with fatal PCP that occurred after the use of corticosteroids for severe AH. PATIENT CONCERNS: A 43-year-old alcoholic man presented with a hematoma on his right leg. His liver function was poor, and he was he was diagnosed with severe AH and treated with oral corticosteroids for 26 days. After glucocorticoid treatment, he developed a productive cough. DIAGNOSES: A sputum PCR test was positive for Pneumocystis jirovecii. INTERVENTIONS: He was initially treated with TMP-SMX and required artificial ventilation. OUTCOMES: He developed disseminated intravascular coagulation and multi-organ failure, and died 10 days after starting TMP-SMX. LESSONS: To date, prevention of PCP in individuals with severe AH who are on corticosteroids has been overlooked. This case illustrates the need for prophylaxis of PCP in individuals with severe AH taking corticosteroids.

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.

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.

Subjective taste to polyethylene glycol is associated with efficacy of right colon preparation.

AIM: A prospective observational trial with preparations using polyethylene glycol (PEG) to compare patient compliance and adverse events according to individual subjective taste. METHODS: A total of 299 outpatients (mean ± standard deviation [SD] 56.5 ± 13.8 years, 172 males) were recruited for our study. We assessed the efficacy of bowel preparation, subjective taste to their regimens, compliance and adverse events during the preparation. RESULTS: We achieved adequate preparation in 267 (89.3%). A total of 124 patients (41.5%) had 'unacceptable taste' to their regimens. The patients with acceptable taste had better compliance than the patients with unacceptable taste (p = .009). The patients with unacceptable taste had more frequent adverse events such as nausea, vomiting and abdominal bloating than the patients with acceptable taste (all p < .001, Table 2). Patients with unacceptable taste (16.1%) had more frequent inadequate preparation in overall colon than patients with acceptable taste (6.9%, p = .011). There was a significant difference in the efficacy of preparation of right colon between the two groups (p = .004). CONCLUSION: Subjective taste to PEG is associated with efficacy of right colon preparation. In addition, subjective taste to PEG is associated with compliance and adverse events.

Endoscopic retrograde cholangiopancreatography in patients with previous acute coronary syndrome.

BACKGROUND/AIMS: Endoscopic retrograde cholangiopancreatography (ERCP) is considered a high-risk procedure in patients with previous acute coronary syndrome (ACS); however, clinical studies are rare in the literature. The aim of this study was to investigate the safety and efficacy of ERCP in patients with previous ACS. METHODS: We retrospectively reviewed the medical records of patients with previous ACS who underwent ERCP between January 2007 and August 2012. The clinical characteristics, ERCP diagnoses, treatment results, and complications were analyzed. RESULTS: Fifty patients underwent ERCP an average of 41.6 months after ACS. The most common indication for ERCP was calculous cholangitis. After deep biliary cannulation, endoscopic sphincterotomy, biliary stone removal and endoscopic biliary drainage were successfully performed. Immediate postsphincterotomy bleeding occurred in seven patients, which was successfully controlled using endoscopic therapy. Elevation of cardiac troponin I levels were observed in three patients (6%) before ERCP, and all of these patients were diagnosed with pancreatobiliary disease combined with recurrent ACS, which was treated with coronary artery stent insertion (n=2) and balloon angioplasty (n=1). CONCLUSIONS: Therapeutic ERCP is effective and safe in patients with previous ACS. Cardiac troponin I elevation should be considered a warning sign for recurrent ACS in patients who undergo ERCP.

The need for second-look endoscopy to prevent delayed bleeding after endoscopic submucosal dissection for gastric neoplasms: a prospective randomized trial.

BACKGROUND/AIMS: Many authors recommend performing a second-look endoscopy (SLE) to reduce the frequency of delayed bleeding after endoscopic submucosal dissection (ESD) for gastric neoplasms, but these recommendations have been made despite a lack of reliable evidence supporting the effectiveness of SLE. METHODS: From January 2012 to May 2013, we investigated 441 gastric neoplasms treated by ESD to assess the risk factors for delayed bleeding. Delayed bleeding occurred in four of these lesions within 1 postoperation day. Therefore, we enrolled the patients with the remaining 437 lesions to determine the utility of SLE performed on the morning of postoperative day 2. All lesions were randomly assigned to SLE (220 lesions) groups or non-SLE (217 lesions) groups. RESULTS: Delayed bleeding occurred in 18 lesions (4.1%). A large tumor size (>20 mm) was the only independent risk factor for delayed bleeding (p=0.007). The chance of delayed bleeding was not significantly different between the patients receiving a SLE (eight cases) and those patients not receiving a SLE (six cases, p=0.787). Furthermore, SLE for lesions with a large tumor size did not significantly decrease delayed bleeding (p=0.670). CONCLUSIONS: SLE had little or no influence on the prevention of delayed bleeding, irrespective of the risk factors.

Risk factors for patients with stage IVB hepatocellular carcinoma and extension into the heart: prognostic and therapeutic implications.

PURPOSE: To evaluate the risk factors of hepatocellular carcinoma (HCC) extension into the right atrium (RA) and determine poor prognostic factors for HCC extension to the heart. MATERIALS AND METHODS: A total of 665 patients who were newly diagnosed with HCC were analyzed retrospectively from January 2004 to July 2012. The patients were divided into two groups: 33 patients with HCC extending into the RA and 632 HCC patients during the same period. The patients with HCC extending into the RA were subdivided into shorter survival group (<2 months) and longer survival group (≥2 months). RESULTS: The prevalence of HCC extending to the RA was 4.96%. In multivariate analysis, a modified Union Internationale Contre le Cancer (UICC) stage higher than IVA, hepatic vein invasion, concomitant inferior vena cava and portal vein invasion, and multinodular tumor type were risk factors for HCC extending to the RA. In multivariate analysis, Cancer of the Liver Italian Program (CLIP) score>3 (p=0.016, OR: 13.89) and active treatment (p=0.024, OR: 0.054) were associated with prognostic factors in patients HCC extending into the RA. Active treatment such as radiation (n=1), transcatheter arterial chemoembolization (TACE) (n=11), Sorafenib (n=1), and combined modalities (n=2) were performed. CONCLUSION: Modified UICC stage higher than IVA, vascular invasion and multinodular tumor type are independent risk factors for HCC extending to the RA. Active treatment may prolong survival in patients HCC extending into the RA.

[Comparison on the long term outcome between endoscopic submucosal dissection and surgical treatment for undifferentiated early gastric cancer].

BACKGROUND/AIMS: There are controversies on the efficacy and safety of endoscopic submucosal dissection (ESD) for un-differentiated early gastric cancer (EGC) despite the expansion of ESD indications. The aim of this study was to evaluate the long term outcome of ESD compared to that of surgical treatment in patients with undifferentiated EGC. METHODS: A total of 76 patients who underwent ESD for undifferentiated EGC and 149 patients who met the ESD indication and received surgical treatment from January 2005 to December 2010 at Chonnam National University Hwasun Hospital were included. RESULTS: In the ESD group, en bloc resection and complete resection were achieved in 84.2% (64/76) and 76.3% (58/76) of patients, respectively. Among these patients, 58 (76.3%) met the ESD indication (indication group), and the remaining 18 (23.7%) did not meet the ESD indication (above indication group). Complete resection rates for indication group and above indication group were 86.2% (50/58) and 44.4% (8/18), respectively (p<0.05). The mean follow-up period was 42.2 ± 19.2 months. Total recurrence rates in the ESD group and operation group were 14.1% (9/76) and 0.7% (1/149), respectively (p<0.05). The main complication of ESD was bleeding (5.2%, 4/76). In the operation group, 2 (1.3%) patients died from postoperative bleeding and leakage of anastomosis site. CONCLUSIONS: ESD may be a feasible and safe treatment modality compared to that of surgical treatment for undifferentiated EGC when managed according to the expanded criteria. However, close endoscopic surveillance is required in this group because of higher incidence of intragastric recurrence.

Risk factors for hepatocellular carcinoma in patients with drug-resistant chronic hepatitis B.

AIM: To investigate the risk factors and characteristics of hepatocellular carcinoma (HCC) in the patients with drug-resistant chronic hepatitis B (CHB). METHODS: A total of 432 patients with drug-resistant CHB were analyzed retrospectively from January 2004 to December 2012. The patients were divided into two groups: the HCC group (n = 57) and the non-HCC group (n = 375). Two groups compared using logistic regression for various patients and viral characteristics in order to identify associated risk factors for HCC. Secondarily, patient and tumor characteristics of HCC patients with naïve CHB (N group, n = 117) were compared to the HCC group (R group, n = 57) to identify any difference in HCC characteristics between them. RESULTS: A significant difference was found for age, platelet count, alpha-fetoprotein (AFP), positivity of HBeAg, seroconversion rate of HBeAg, virologic response, the Child-Pugh score, presence of rtM204I, and the duration of antiviral treatment in non-HCC and HCC group. Cirrhosis, age (> 50 years), HBeAg (+), virologic non-responder status, and rtM204I mutants were independent risk factors for the development of HCC. The R group had lower serum C-reactive protein (CRP) and AFP levels, earlier stage tumors, and a shorter mean tumor surveillance period than the N group. However, the total follow-up duration was not significantly different between the two groups. CONCLUSION: 13.2% of patients with drug-resistant CHB developed HCC. Age, cirrhosis, YIDD status, HBeAg status, and virologic response are associated with risk of HCC. Patients with drug-resistant CHB and these clinical factors may benefit from closer HCC surveillance.

Predictive factors for recurrence and survival in hepatocellular carcinoma in South Korea.

AIM: To evaluate the factors predicting for recurrence and to analyze survival of patients with hepatocellular carcinoma (HCC). PATIENTS AND METHODS: A total of 743 patients who were consecutively diagnosed and treated with HCC were retrospectively analyzed from January 2004 to December 2012 at our institution. We analyzed their survival and tumor recurrence. RESULTS: On multivariate analysis, age >50 years, CLIP score <3, ALP <120 U/l, LDH <450 IU/l, CRP <0.8 mg/dl, tumor size <6 cm, no distant metastasis, and curative treatment modality were predictors for 1-year survival. CRP <0.8 mg/dl, Child-Pugh score <7, curative treatment modality and tumor size <6 cm were predictors for 3-year survival. Absence of vascular invasion and uninodular tumor type were predictors for 5-year survival. Multinodular tumor, tumor size >4 cm, and palliative treatment were independent risk factors for 1-year recurrence after initial treatment. CONCLUSION: This large study provides a comprehensive overview of the survival outcomes and prognostic factors regarding HCC, according to clinical characteristics, various treatment modalities, and the results will help in the selection of effective treatment strategies future.