Correlation of N-myc downstream-regulated gene 1 expression with clinical outcomes of colorectal cancer patients of different race/ethnicity

AIM： To evaluate the role of N-myc downstream- regulated gene 1 （NDRG1） expression in prognosis and survival of colorectal cancer patients with different ethnic backgrounds. METHODS： Because NDRG1 is a downstream target of p53 and hypoxia inducible factor-1α （HIF-1α）, we examined NDRG1 expression together with p53 and HIF-1α by irnmunohistochernistry. A total of 157 colorectal cancer specimens including 80 from Japanese patients and 77 from US patients were examined. The correlation between protein expression with clinicopathological features and survival after surgery was analyzed. RESULTS： NDRG1 protein was significantly increased in colorectal tumor compared with normal epithelium in both Japanese and US patient groups. Expression of NDRG1 protein was significantly correlated with lymphatic invasion, venous invasion, depth of invasion, histopathological type, and Dukes＇ stage in Japanese colorectal cancer patients. NDRG1 expression was correlated to histopathological type, Dukes＇ stage and HIF-1α expression in US-Caucasian patients but not in US-African American patients. Interestingly, Kaplan-Meier survival analysis demonstrated that NDRG1 expression correlated significantly with poorer survival in US-African American patients but not in other patient groups. However, in p53-positive US cases, NDRG1 positivity correlated significantly with better survival. In addition, NDRG1 expression also correlated significantly with improved survival in US patients with stages Ⅲ and IV tumors without chemotherapy. In Japanese patients with stages Ⅱ and Ⅲ tumors, strong NDRG1 staining in p53- positive tumors correlated significantly with improved survival but negatively in patients without chemotherapy. CONCLUSION： NDRG1 expression was correlated with various clinicopathological features and clinical outcomes in colorectal cancer depending on the race/ethnicity of the patients. NDRG1 may serve as a biological basis for the disparity of clinical outcomes of colorectal cancer patients with different ethnic backgrounds.

广东五种菊头蝠的核型分析

本文用蝙蝠的新鲜肺组织和尾椎进行组织培养,然后在光学显微镜下计数30个染色体分散良好的中期分裂相细胞,并进行摄影、剪贴和测量。分析了广东地区5种菊头蝠的核型,即小菊头蝠的核型为2n =6 2 ,FN =6 0 ;角菊头蝠的核型为2n =6 2 ,FN =6 0 ;中菊头蝠的核型为2n =6 2 ,FN =6 0 ;大耳菊头蝠的核型为2n =6 2 ,FN =6 0 ;中华(栗黄)菊头蝠的核型为2n =36 ,FN =6 0。大耳菊头蝠的核型为首次报道。角菊头蝠和中菊头蝠的核型与前人报道的结果基本相同。中华(栗黄)菊头蝠的核型(2n =36 )与张维道报道的鲁氏菊头蝠相同,而与印度和斯里兰卡产R rouxii的核型2n =5 6迥异。

掠出射微区X射线荧光分析系统的建立及其在薄膜分析中的应用

建立了应用导管X光透镜的掠出射微区X射线荧光分析系统,并将该系统应用于纳米薄膜的分析。为了提高入射X射线的强度并提高系统的空间分辨率,选用焦斑为41.7μm的会聚透镜对原级X射线进行会聚,并在探测器前加上50μm的狭缝以提高掠出射角扫描的角度分辨率。为了提高工作效率,编写了该系统的自动控制软件,实现了样品的自动扫描。利用该系统对采用金属蒸汽真空电弧(MEVVA)源离子束和薄膜沉积技术制备的纳米薄膜进行了掠入射X射线荧光和二维扫描分析。实验结果表明:该系统能有效地分析纳米厚度的薄膜,通过对薄膜进行掠出射角扫描分析和表面的二维扫描分析,得到了薄膜的厚度,密度及均匀性等信息。微区分析的空间分辨率可达到41.7μm,实际空间分辨率为扫描步长50μm。系统可用于分析薄膜样品,且荧光强度高,所需时间短,获得的信息全面丰富,数据可靠。

Biomarkers of gastric cancer:Current topics and future perspective

Gastric cancer(GC) is one of the most prevalent malignant types in the world and an aggressive disease with a poor 5-year survival. This cancer is biologically and genetically heterogeneous with a poorly understood carcinogenesis at the molecular level. Although the incidence is declining, the outcome of patients with GC remains dismal. Thus, the detection at an early stage utilizing useful screening approaches, selection of an appropriate treatment plan, and effective monitoring is pivotal to reduce GC mortalities. Identification of biomarkers in a basis of clinical information and comprehensive genome analysis could improve diagnosis, prognosis, prediction of recurrence and treatment response. This review summarized the current status and approaches in GC biomarker, which could be potentially used for early diagnosis, accurate prediction of therapeutic approaches and discussed the future perspective based on the molecular classification and profiling.

Ulcerative colitis-associated colorectal cancer

The association between ulcerative colitis(UC) and colorectal cancer(CRC) has been acknowledged. One of the most serious and life threatening consequences of UC is the development of CRC(UC-CRC). UC-CRC patients are younger, more frequently have multiple cancerous lesions, and histologically show mucinous or signet ring cell carcinomas. The risk of CRC begins to increase 8 or 10 years after the diagnosis of UC. Risk factors for CRC with UC patients include young age at diagnosis, longer duration, greater anatomical extent of colonic involvement, the degree of inflammation, family history of CRC, and presence of primary sclerosing cholangitis. CRC on the ground of UC develop from non-dysplastic mucosa to indefinite dysplasia, lowgrade dysplasia, high-grade dysplasia and finally to invasive adenocarcinoma. Colonoscopy surveillance programs are recommended to reduce the risk of CRC and mortality in UC. Genetic alterations might play a role in the development of UC-CRC. 5-aminosalicylates might represent a favorable therapeutic option for chemoprevention of CRC.

Current status in remnant gastric cancer after distal gastrectomy

Remnant gastric cancer(RGC) and gastric stump cancer after distal gastrectomy(DG) are recognized as the same clinical entity. In this review, the current knowledges as well as the non-settled issues of RGC are presented. Duodenogastric reflux and denervation of the gastric mucosa are considered as the two main factors responsible for the development of RGC after benign disease. On the other hand, some precancerous circumstances which already have existed at the time of initial surgery, such as atrophic gastritis and intestinal metaplasia, are the main factors associated with RGC after gastric cancer. Although eradication of Helicobacter pylori(H. pylori) in remnant stomach is promising, it is still uncertain whether it can reduce the risk of carcinogenesis. Periodic endoscopic surveillance after DG was reported useful in detecting RGC at an early stage, which offers a chance to undergo minimally invasive endoscopic treatment or laparoscopic surgery and leads to an improved prognosis in RGC patients. Future challenges may be expected to elucidate the benefit of eradication of H. pylori in the remnant stomach if it could reduce the risk for RGC, to build an optimal endoscopic surveillance strategy after DG by stratifying the risk for development of RGC, and to develop a specific staging system for RGC for the standardization of the treatment by prospecting the prognosis.

Management of hepatitis B virus infection during treatment for hepatitis B virus-related hepatocellular carcinoma

Although liver resection is considered the most effective treatment for hepatocellular carcinoma(HCC), treatment outcomes are unsatisfactory because of the high rate of HCC recurrence. Since we reported hepatitis B e-antigen positivity and high serum hepatitis B virus(HBV) DNA concentrations are strong risk factors for HCC recurrence after curative resection of HBV-related HCC in the early 2000 s, many investigators have demonstrated the effects of viral status on HCC recurrence and post-treatment outcomes. These findings suggest controlling viral status is important to prevent HCC recurrence and improve survival after curative treatment for HBV-related HCC. Antiviral therapy after curative treatment aims to improve prognosis by preventing HCC recurrence and maintaining liver function. Therapy with interferon and nucleos(t)ide analogs may be useful for preventing HCC recurrence and improving overall survival in patients who have undergone curative resection for HBV-related HCC. In addition, reactivation of viral replication can occur after liver resection for HBV-related HCC. Antiviral therapy can be recommended for patients to prevent HBV reactivation. Nevertheless, further studies are required to establish treatment guidelines for patients with HBVrelated HCC.

Role of hepatitis B virus DNA integration in human hepatocarcinogenesis

Liver cancer ranks sixth in cancer incidence, and is the third leading cause of cancer-related deaths worldwide. Hepatocellular carcinoma (HCC) is the most common type of liver cancer, which arises from hepatocytes and accounts for approximately 70%-85% of cases. Hepatitis B virus (HBV) frequently causes liver inflammation, hepatic damage and subsequent cirrhosis. Integrated viral DNA is found in 85%-90% of HBV-related HCCs. Its presence in tumors from non-cirrhotic livers of children or young adults further supports the role of viral DNA integration in hepatocarcinogenesis. Integration of subgenomic HBV DNA fragments into different locations within the host DNA is a significant feature of chronic HBV infection. Integration has two potential consequences: (1) the host genome becomes altered (“cis” effect); and (2) the HBV genome becomes altered (“trans” effect). The cis effect includes insertional mutagenesis, which can potentially disrupt host gene function or alter host gene regulation. Tumor progression is frequently associated with rearrangement and partial gain or loss of both viral and host sequences. However, the role of integrated HBV DNA in hepatocarcinogenesis remains controversial. Modern technology has provided a new paradigm to further our understanding of disease mechanisms. This review summarizes the role of HBV DNA integration in human carcinogenesis.

Rho/ROCK signaling in motility and metastasis of gastric cancer

Gastric cancer is one of the most frequent and lethal malignancies worldwide because of high frequency of metastasis. Tumor cell motility and invasion play fundamental roles in cancer metastasis. Recent studies have revealed that the Rho/Rho-associated protein kinases(ROCK) pathway plays a critical role in the regulation of cancer cell motility and invasion. In addition,the Rho/ROCK pathway plays important roles in invasion and metastasis on the basis of its predominant function of cell cytoskeletal regulation in gastric cancer. According to the current understanding of tumor motility,there are two modes of tumor cell movement:mesenchymal and amoeboid. In addition,cancer cell movement can be interchangeable between the mesenchymal and amoeboid movements under certain conditions. Control of cell motility through the actin cytoskeleton creates the potential for regulating tumor cell metastasis. In this review we discuss Rho GTPases and ROCK signaling and describe the mechanisms of Rho/ROCK activity with regard to motility and metastasis in gastric cancer.In addition,we provide an insight of the therapeutic potential of targeting the Rho/ROCK pathway.

Quality of ulcer healing in gastrointestinal tract:Its pathophysiology and clinical relevance

In this paper, we review the concept of quality of ulcer healing （QOUH） in the gastrointestinal tract and its role in the ulcer recurrence. In the past, peptic ulcer disease （PUD） has been a chronic disease with a cycle of repeated healing/remission and recurrence. The main etiological factor of PUD is Helicobacter pylori （H. pylorl~, which is also the cause of ulcer recur- rence. However, H. pylori-negative ulcers are pres- ent in 12%-20% of patients; they also recur and are on occasion intractable. QOUH focuses on the fact that mucosal and submucosal structures within ulcer scars are incompletely regenerated. Within the scars of healed ulcers, regenerated tissue is immature and with distorted architecture, suggesting poor QOUH. The abnormalities in mucosal regeneration can be the basis for ulcer recurrence. Our studies have shown that persistence of macrophages in the regenerated area plays a key role in ulcer recurrence. Our studies in a rat model of ulcer recurrence have indicated that proinflammatory cytokines trigger activation of macro- phages, which in turn produce increased amounts of cytokines and chemokines, which attract neutrophils to the regenerated area. Neutrophils release proteolytic enzymes that destroy the tissue, resulting in ulcer re- currence. Another important factor in poor QOUH can be deficiency of endogenous prostaglandins and a defi- ciency and/or an imbalance of endogenous growth fac- tors. Topically active mucosal protective and antiulcer drugs promote high QOUH and reduce inflammatory cell infiltration in the ulcer scar. In addition to PUD, the concept of QOUH is likely applicable to inflammatory bowel diseases including Crohn＇s disease and ulcer- ative colitis.

Prognostic significance of the lymphocyte-to-monocyte ratio in patients with metastatic colorectal cancer

AIM:To evaluate the prognostic significance of the lymphocyte to monocyte ratio(LMR) in patients with unresectable metastatic colorectal cancer who received palliative chemotherapy.METHODS:A total of 104 patients with unresectable metastatic colorectal cancer who underwent palliative chemotherapy were enrolled. The LMR was calculated from blood samples by dividing the absolute lymphocyte count by the absolute monocyte count. Pretreatment LMR values were measured within one week before the initiation of chemotherapy,while posttreatment LMR values were measured eight weeks after the initiation of chemotherapy.RESULTS:The median pre-treatment LMR was 4.16(range:0.58-14.06). We set 3.38 as the cut-off level based on the receiver operating characteristic curve. Based on the cut-off level of 3.38,66 patients were classified into the high pre-treatment LMR group and 38 patients were classified into the low pretreatment LMR group. The low pre-treatment LMR group had a significantly worse overall survival rate(P = 0.0011). Moreover,patients who demonstrated low pre-treatment LMR and normalization after treatmentexhibited a better overall survival rate than the patients with low pre-treatment and post-treatment LMR values.CONCLUSION:The lymphocyte to monocyte ratio is a useful prognostic marker in patients with unresectable metastatic colorectal cancer who receive palliative chemotherapy.

Noninvasive assessment of liver fibrosis in patients with chronic hepatitis B

Infection with hepatitis B virus is an important healthproblem worldwide:it affects more than 350 millionpeople and is a leading cause of liver-related morbidity,accounting for 1 million deaths annually.Hepatic fibrosis is a consequence of the accumulation of extracellular matrix components in the liver.An accurate diagnosis of liver fibrosis is essential for the management of chronic liver disease.Liver biopsy has been considered the gold standard for diagnosing disease,grading necroinflammatory activity,and staging fibrosis.However,liver biopsy is unsuitable for repeated evaluations because it is invasive and can cause major complications,including death.Several noninvasive evaluations have been introduced for the assessment of liver fibrosis:serum biomarkers,combined indices or scores,and imaging techniques including transient elastography,acoustic radiation force impulse,real-time tissue elastography,and magnetic resonance elastography.Here,we review the recent progress of noninvasive assessment of liver fibrosis in patients with chronic hepatitis B.Most noninvasive evaluations for liver fibrosis have been validated first in patients with chronic hepatitis C,and later in those with chronic hepatitis B.The establishment of a noninvasive assessment of liver fibrosis is urgently needed to aid in the management of this leading cause of chronic liver disease.

Nutritional status in relation to lifestyle in patients with compensated viral cirrhosis

AIM:To assess the nourishment status and lifestyle of non-hospitalized patients with compensated cirrhosis by using noninvasive methods.METHODS:The subjects for this study consisted of 27 healthy volunteers,59 patients with chronic viral hepatitis,and 74 patients with viral cirrhosis,from urban areas.We assessed the biochemical blood tests,anthropometric parameters,diet,lifestyle and physical activity of the patients.A homeostasis model assessment-insulin resistance(HOMA-IR) value of ≥ 2.5 was considered to indicate insulin resistance.We measured height,weight,waist circumference,arm circumference,triceps skin-fold thickness,and handgrip strength,and calculated body mass index,arm muscle circumference(AMC),and arm muscle area(AMA).We interviewed the subjects about their dietary habits and lifestyle using health assessment computer software.We surveyed daily physical activity using a pedometer.Univariate and multivariate logistic regression modeling were used to identify the relevant factors for insulin resistance.RESULTS:The rate of patients with HOMA-IR ≥ 2.5(which was considered to indicate insulin resistance) was 14(35.9%) in the chronic hepatitis and 17(37.8%) in the cirrhotic patients.AMC(%)(control vs chronic hepatitis,111.9% ± 10.5% vs 104.9% ± 10.7%,P = 0.021;control vs cirrhosis,111.9% ± 10.5% vs 102.7% ± 10.8%,P = 0.001) and AMA(%)(control vs chronic hepatitis,128.2% ± 25.1% vs 112.2% ± 22.9%,P = 0.013;control vs cirrhosis,128.2% ± 25.1% vs 107.5% ± 22.5%,P = 0.001) in patients with chronic hepatitis and liver cirrhosis were significantly lower than in the control subjects.Handgrip strength(%) in the cirrhosis group was significantly lower than in the controls(control vs cirrhosis,92.1% ± 16.2% vs 66.9% ± 17.6%,P < 0.001).The results might reflect a decrease in muscle mass.The total nutrition intake and amounts of carbohydrates,protein and fat were not significantly different amongst the groups.Physical activity levels(kcal/d)(control vs cirrhosis,210 ± 113 kcal/d vs 125 ± 74 kcal/d,P = 0.001),number of steps(step/d)(control vs cirrhosis,8070 ±3027 step/d vs 5789 ± 3368 step/d,P = 0.011),and exercise(Ex)(Ex/wk)(control vs cirrhosis,12.4 ± 9.3 Ex/wk vs 7.0 ± 7.7 Ex/wk,P = 0.013) in the cirrhosis group was significantly lower than the control group.The results indicate that the physical activity level of the chronic hepatitis and cirrhosis groups were low.Univariate and multivariate logistic regression modeling suggested that Ex was associated with insulin resistance(odds ratio,6.809;95% CI,1.288-36.001;P = 0.024).The results seem to point towards decreased physical activity being a relevant factor for insulin resistance.CONCLUSION:Non-hospitalized cirrhotic patients may need to maintain an adequate dietary intake and receive lifestyle guidance to increase their physical activity levels.

Inflammation-based factors and prognosis in patients with colorectal cancer

Several parameters for predicting survival in patients with colorectal cancer have been identified, including the performance status, age, gender and tumor-nodemetastasis(TNM) stage. Although the TNM stage is important and useful for predicting the prognosis and determining the appropriate treatment, it is well known that the survival time varies widely, even in patients with the same stage of disease. Therefore, the identification of new parameters capable of more precisely predicting patient survival is needed to help select the optimal treatment, especially in patients in the advanced stage of disease. Although the TNM stage reflects the tumor characteristics, cancer progression and survival are not determined solely based on the local characteristics of the tumor, but also the host systemic immune/inflammatory response. Therefore, using a combination of parameters that reflect both tumor characteristics and the host systemic inflammatory status is thought to be important for accurately predicting patient survival.

Usefulness of noninvasive transient elastography for assessment of liver fibrosis stage in chronic hepatitis C

AIM：To evaluate the method of noninvasive transient elastography for assessment of histological stage of liver fibrosis in patients with chronic hepatitis C （CHC）.METHODS： Two hundred and thirty-seven patients with CHC were included in this study. Liver biopsy was performed under ultrasonography on 217 of the patients, excluding twenty with clear clinical evidence of liver cirrhosis. Fifty subjects without liver disease were enrolled as a control group （stage 0）. Twentyfive patients with sustained virological response （SVR） to interferon （IFN） therapy were also enrolled. These patients underwent liver biopsy before IFN therapy. Examination of liver stiffness （LS） was performed by elastography.RESISTS： Medians （50% levels） of LS were 4.1 （3.5-4.9）, 6.3 （4.8-8.5）, 8.8 （6.8-12.0）, 14.6 （10.5-18.6）, and 22.2 （15.4-28.0）, respectively, in the fibrosis stages 0-4 （P 〈 0.001）. LS was significantly correlated with four serum fibrosis markers. LS values in patients with SVR were 3.8 （3.5-5.6）, 5.2 （4.4-6.8）, 6.8 （6.1-7.6）, and 6.1 （3.6-7.9）, respectively, in the fibrosis stages 1-4. In all stages, LS for patients with SVR was significantly lower than that for patients who did not undergo IFN therapy. LS was significantly correlated with serum concentrations of hyaluronic acid, type Ⅳ collagen, type Ⅳ collagen 7S, and type Ⅲ procollagen N peptide.CONCLUSION： LS correlated well with the histological stage of fibrosis. Changes in liver fibrosis stage may thus be estimated noninvasively using transient elastography.

Risk factors for bleeding after endoscopic mucosal resection

AIM： To clarify the risk factors for bleeding after endoscopic mucosal resection （EMR）. METHODS： A total of 297 consecutive patients who underwent EMR were enrolled. Some of the patients had multiple lesions. Bleeding requiring endoscopic treatment was defined as bleeding after EMR. Odds ratios （OR） with 95% confidence intervals （CI）, calculated by logistic regression with multivariate adjustments for covariates, were the measures of association. RESULTS： Of the 297 patients, 57 （19.2%） patients with bleeding after EMR were confirmed. With multivariate adjustment, the cutting method of EMR, diameter, and endoscopic pattern of the tumor were associated with the risk of bleeding after EMR. The multivariate-adjusted OR for bleeding after EMR using endoscopic aspiration mucosectomy was 3.07 （95%CI, 1.59-5.92） compared with strip biopsy. The multiple-adjusted OR for bleeding after EMR for the highest quartile （16-50 mm） of tumor diameter was 5.63 （95%CI, 1.84-17.23） compared with that for the lowest （4-7 mm）. The multiple-adjusted OR for bleeding after EMR for depressed type of tumor was 4.21 （95%CI, 1.75-10.10） compared with elevated type. CONCLUSION： It is important to take tumor charactedstics （tumor size and endoscopic pattern） and cutting method of EMR into consideration in predicting bleeding after EMR.

Fibroblast growth factor receptor signaling as therapeutic targets in gastric cancer

Fibroblast growth factor receptors(FGFRs) regulate a variety of cellular functions, from embryogenesis to adult tissue homeostasis. FGFR signaling also plays significant roles in the proliferation, invasion, and survival of several types of tumor cells. FGFR-induced alterations, including gene amplification, chromosomal translocation, and mutations, have been shown to be associated with the tumor initiation and progression of gastric cancer, especially in diffuse-type cancers. Therefore, the FGFR signaling pathway might be one of the therapeutic targets in gastric cancer. This review aims to provide an overview of the role of FGFR signaling in tumorigenesis, tumor progression, proliferation, and chemoresistance. We also discuss the accumulating evidence that demonstrates the effectiveness of using clinical therapeutic agents to inhibit FGFR signaling for the treatment of gastric cancer.

Hepatitis B virus infection and alcohol consumption

Hepatocellular carcinoma(HCC) is the most common type of primary liver cancer, and the second most common cause of cancer deaths worldwide. The top three causes of HCC are hepatitis B virus(HBV),hepatitis C virus(HCV), and alcoholic liver disease. Owing to recent advances in direct-acting antiviral agents, HCV can now be eradicated in almost all patients. HBV infection and alcoholic liver disease are expected, therefore, to become the leading causes of HCC in the future. However, the association between alcohol consumption and chronic hepatitis B in the progression of liver disease is less well understood than with chronic hepatitis C. The mechanisms underlying the complex interaction between HBV and alcohol are not fully understood, and enhanced viral replication, increased oxidative stress and a weakened immune response could each play an important role in the development of HCC. It remains controversial whether HBV and alcohol synergistically increase the incidence of HCC. Herein, we review the currently available literature regarding the interaction of HBV infection and alcohol consumption on disease progression.

Sentinel node navigation surgery for gastric cancer: Overview and perspective

The sentinel node(SN) technique has been established for the treatment of some types of solid cancers to avoid unnecessary lymphadenectomy. If node disease were diagnosed before surgery, minimal surgery with omission of lymph node dissection would be an option for patients with early gastric cancer. Although SN biopsy has been well ascertained in the treatment of breast cancer and melanoma, SN navigation surgery(SNNS) in gastric cancer has not been yet universal due to the complicated lymphatic flow from the stomach. Satisfactory establishment of SNNS will result in the possible indication of minimally invasive surgery of gastric cancer. However, the results reported in the literature on SN biopsy in gastric cancer are widely divergent and many issues are still to be resolved, such as the collection method of SN, detection of micrometastasis in SN, and clinical benefit. The difference in the procedural technique and learning phase of surgeons is also varied the accuracy of SN mapping. In this review, we outline the current status of application for SNNS in gastric cancer.

Recent advances in the HER2 targeted therapy of gastric cancer

Recent advances in molecular targeted therapies, including targeting human epidermal growth factor receptor 2(HER2), had a major forward step in the therapy for gastric cancer patients. Application of HER2-targeted therapies, in particular trastuzumab in combination with chemotherapy in metastatic HER2-positive gastric cancers, resulted in improvements in response rates, time to progression and overall survival. Nevertheless, as with breast cancer, many patients with gastric cancer develop resistance to trastuzumab. Several promising therapies are currently being developed in combination with chemotherapy to increase the efficacy and overcome the cancerresistance. Here we review the current overview of clinical application of agents targeting HER2 in gastric cancer. We also discuss the ongoing trials supporting the use of HER2-targeted agents combined with cytotoxic agents or other monoclonal antibodies.