RNAi在肝病治疗中的研究进展

0引言小RNA为20多个核苷酸组成的短双链RNA,其核心技术RNA干扰(RNAi)已广泛应用于生命科学各个领域。在肝炎的研究中,目前已发现小分子干扰RNA(siRNA)可以通过特异性地沉默病毒基因以抑制HCV、HBV表达和复制;通过关闭Fas基因防治免疫相关性肝炎的发生;同时RNAi开始应用于治疗肝癌的研究。实验结果也具有诱人的苗头。不难推测,随着研究的不断深入,相信RNAi在肝病的预防和治疗方面将会有非常广阔的应用前景。

胃周淋巴结解剖与胃癌根治术的关系研究进展

当今胃癌的手术治疗已进入方案设计合理化、术式标准化的阶段,但在我国的发展却很不平衡,即使在技术条件较好的医疗单位,在术式选择、淋巴结清扫范围、胃及受累组织切除范围和消化道重建等方面也存在较大差异。其原因除了地域与技术条件等限制外,也与对胃癌淋巴结的分站、分号缺乏统一认识不无关系。作者通过查阅文献,参考导师最近开展的胃癌外科规范化治疗项目相关内容,对胃周淋巴结解剖与胃癌规范化治疗的关系作一综述,希望对规范我国胃癌手术方法有所帮助。

血清乙型肝炎病毒DNA水平的生物学梯度与肝细胞肝癌的风险性相关

Context: Serum hepatitis B virus (HBV) DNA level is a marker of viral replication and efficacy of antiviral treatment in individuals with chronic hepatitis B. Objective: To evaluate the relationship between serum HBV DNA level and risk of hepatocellular carcinoma. Design, Setting, and Participants: Prospective cohort study of 3653 participants (aged 30-65 years), who were seropositive for the hepatitis B surface antigen and seronegative for antibodies against the hepatitis C virus, recruited to a community-based cancer screening program in Taiwan between 1991 and 1992. Main Outcome Measure: Incidence of hepatocellular carcinoma during follow-up examination and by data linkage with the national cancer registry and the death certification systems. Results: There were 164 incident cases of hepatocellular carcinoma and 346 deaths during a mean follow-up of 11.4 years and 41 779 person-years of follow-up. The incidence of hepatocellular carcinoma increased with serum HBV DNA level at study entry in a dose-response relationship ranging from 108 per 100 000 person-years for an HBV DNA level of less than 300 copies/mL to 1152 per 100 000 person-years for an HBV DNA level of 1 million copies/mL or greater. The corresponding cumulative incidence rates of hepatocellular carcinoma were 1.3%and 14.9%, respectively. The biological gradient of hepatocellular carcinoma by serum HBV DNA levels remained significant (P< .001) after adjustment for sex, age, cigarette smoking, alcohol consumption, serostatus for the hepatitis B e antigen (HBeAg), serum alanine aminotransferase level, and liver cirrhosis at study entry. The dose-response relationship was most prominent for participants who were seronegative for HBeAg with normal serum alanine aminotransferase levels and no liver cirrhosis at study entry. Participants with persistent elevation of serum HBV DNA level during follow-up had the highest hepatocellular carcinoma risk. Conclusion: Elevated serum HBV DNA level (>10 000 copies/mL) is a strong risk predictor of hepatocellular carcinoma independent of HBeAg, serum alanine aminotransferase level, and liver cirrhosis.

围手术期化疗与单纯手术治疗可切除性胃食管癌的比较

BACKGROUND:A regimen of epirubicin,cisplatin,and infused fluorouracil(ECF) improves survival among patients with incurable locally advanced or metastatic gastric adenocarcinoma.We assessed whether the addition of a perioperative regimen of ECF to surgery improves outcomes among patients with potentially curable gastric cancer.METHODS:We randomly assigned patients with resectable adenocarcinoma of the stomach,esophagogastric junction,or lower esophagus to either perioperative chemotherapy and surgery(250 patients) or surgery alone(253 patients) .Chemotherapy consisted of three preoperative and three postoperative cycles of intravenous epirubicin(50 mg per square meter of body-surface area) and cisplatin(60 mg per square meter) on day 1,and a continuous intravenous infusion of fluorouracil(200 mg per square meter per day) for 21 days.The primary end point was overall survival.RESULTS:ECF-related adverse effects were similar to those previously reported among patients with advanced gastric cancer.Rates of postoperative complications were similar in the perioperative-chemotherapy group and the surgery group(46 percent and 45 percent,respectively) ,as were the numbers of deaths within 30 days after surgery.The resected tumors were significantly smaller and less advanced in the perioperative-chemotherapy group.With a median follow-up of four years,149 patients in the perioperative-chemotherapy group and 170 in the surgery group had died.As compared with the surgery group,the perioperative-chemotherapy group had a higher likelihood of overall survival(hazard ratio for death,0.75;95 percent confidence interval,0.60 to 0.93;P = 0.009;five-year survival rate,36 percent vs.23 percent) and of progression-free survival(hazard ratio for progression,0.66;95 percent confidence interval,0.53 to 0.81;P < 0.001) .CONCLUSIONS:In patients with operable gastric or lower esophageal adenocarcinomas,a perioperative regimen of ECF decreased tumor size and stage and significantly improved progression-free and overall survival.

便秘患者的生活质量问卷调查的开发与确认

Objective. Chronic constipation is characterized by difficult, infrequent, or seemingly incomplete bowel movements. The Patient Assessment of Constipation Quality of Life (PACQOL) questionnaire was developed to address the need for a standardized, patient-reported outcomes measure to evaluate constipation over time. Material and methods. Items for the PAC-QOL were generated from the literature, clinical experts, and patients. Following principal components and multitrait analyses, 28 items were retained forming four subscales (worries and concerns, physical discomfort, psychosocial discomfort, and satisfaction) and an overall scale. Validation studies were conducted in the United States, Europe, Canada, and Australia, to evaluate the internal consistency reliability (Cronbach’s alpha), reproducibility (Intraclass Correlation Coefficients (ICCs)), validity (analysis of variance models), and responsiveness (effect size) of the PAC-QOL scales. Results. The PAC-QOL scales were internally consistent (Cronbach’s alpha >0.80) and reproducible (ICCs > 0.70, except for the satisfaction subscale ICC = 0.66). PAC-QOL scale scores were significantly associated with abdominal pain (p < 0.001) and constipation severity (p < 0.05). Effect sizes in patients reporting improvements in constipation over a 6-week period were moderate to large, with subscale effect sizes ranging from 0.76 to 3.41 and the overall scale effect size = 1.77. Similar findings were observed in validation studies conducted in Europe, Canada, and Australia. Conclusions. The PAC-QOL is a brief but comprehensive assessment of the burden of constipation on patients’ everyday functioning and well-being. Multinational studies demonstrate that the PAC-QOL is internally consistent, reproducible, valid, and responsive to improvements over time.

根据循证医学方法将血清钠指标加入终末期肝病模型

Background &Aims: Serum sodium (Na) concentrations have been suggested as a useful predictor of mortality in patients with end-stage liver disease awaiting liver transplantation. Methods: We evaluated methods to incorporate Na into model for end-stage liver disease (MELD), using a prospective, multicenter database specifically created for validation and refinement of MELD. Adult, primary liver transplant candidates with end-stage liver disease were enrolled. Results: Complete data were available in 753 patients, in whom the median MELD score was 10.8 and sodium was 137 mEq/L. Low Na (< 130 mEq/L) was present in 8%of patients, of whom 90%had ascites. During the study period, 67 patients (9%) died, 243 (32%) underwent transplantation, 73 (10%) were withdrawn, and 370 were still waiting. MELD score and Na, at listing, were significant (both, P < .01) predictors of death within 6 months. After adjustment for MELD score and center, there was a linear increase in the risk of death as Na decreased between 135 and 120 mEq/L. A new score to incorporate Na into MELD was developed: “MELD-Na" = MELD +1.59 (135 -Na) with maximum and minimum Na of 135 and 120 mEq/L, respectively. In this cohort, “MELD-Na" scores of 20, 30, and 40 were associated with 6%, 16%, and 37%of risk of death within 6 months of listing, respectively. If this new score were used to allocate grafts, it would affect 27%of the transplant recipients. Conclusions: We demonstrate an evidence-based method to incorporate Na into MELD, which provides more accurate survival prediction than MELD alone.

直肠上皮瘤行内镜黏膜下层切除术

Background and Study Aims: The technique of endoscopic submucosal dissection (ESD) has recently been developed for en-bloc resection of gastric tumors. For oncological reasons and in order to improve the patients’quality of life, it may be desirable to use the same technique for rectal neoplasia. Patients and Methods: Thirty-five consecutive patients with rectal neoplasia who had a preoperative diagnosis of large intraepithelial neoplasias with submucosal fibrosis or located on the rectal folds were enrolled. ESD was carried out with the same technique previously described for the stomach, with some modifications. The efficacy, complications, and follow-up results of the treatment were assessed. Results: The rates of en-bloc resection and en-bloc plus RO resection were 88.6%(31 of 35) and 62.9%(22 of 35), respectively. Hemoglobin levels did not drop by more than 2 g/dl in any of the patients after ESD. None of the patients had to receive blood transfusions or undergo emergency colonoscopy due to bleeding during ESD or hematochezia after ESD. Perforation during ESD occurred in two patients (5.7%), who were managed with conservative medical treatment after endoscopic closure of the perforation. Excluding three patients in whom additional surgery was carried out, all but one of 32 patients were free of recurrence during a mean follow-up period of 36 months (range 12-60 months). The exception was a patient in whom a multiple-piece resection was required; the recurrent (residual) tumor, found 2 months after ESD, was a small adenoma that was again treated endoscopically. Conclusions: ESD is applicable in the rectum with promising results, but the technique is still at a developmental stage and patients should be informed of the potential risks.

非酒精性脂肪肝活组织检查的抽样变异性

Background &Aims: In nonalcoholic fatty liver disease (NAFLD), the distinction between steatosis and steatohepatitis (NASH) and the assessment of the severity of the disease rely on liver histology alone. The aim of this study was to assess the sampling error of liver biopsy and its impact on the diagnosis and staging of NASH. Methods: Fifty-one patients with NAFLD underwent percutaneous liver biopsy with 2 samples collected. The agreement between paired biopsy specimens was assessed by the percentage of discordant results and by the κreliability test. Results: No features displayed high agreement; substantial agreement was only seen for steatosis grade; moderate agreement for hepatocyte ballooning and perisinusoidal fibrosis; fair agreement for Mallory bodies; acidophilic bodies and lobular inflammation displayed only slight agreement. Overall, the discordance rate for the presence of hepatocyte ballooning was 18%, and ballooning would have been missed in 24%of patients had only 1 biopsy been performed. The negative predictive value of a single biopsy for the diagnosis of NASH was at best 0.74. Discordance of 1 stage or more was 41%. Six of 17 patients with bridging fibrosis (35%) on 1 sample had only mild or no fibrosis on the other and therefore could have been under staged with only 1 biopsy. Intraobserver variability was systematically lower than sampling variability and therefore could not account for most of the sampling error. Conclusions: Histologic lesions of NASH are unevenly distributed throughout the liver parenchyma; therefore, sampling error of liver biopsy can result in substantial misdiagnosis and staging inaccuracies.

聚乙二醇干扰素α-2a、拉米夫定以及两者联合治疗HBeAg阳性的慢性乙型肝炎

BACKGROUND: Current treatments for chronic hepatitis B are suboptimal. In the search for improved therapies, we compared the efficacy and safety of pegylated interferon alfa plus lamivudine, pegylated interferon alfa without lamivudine, and lamivudine alone for the treatment of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B. METHODS: A total of 814 patients with HBeAg-positive chronic hepatitis B received either peginterferon alfa-2a (180 μ g once weekly) plus oral placebo, peginterferon alfa-2a plus lamivudine (100 mg daily), or lamivudine alone. The majority of patients in the study were Asian (87 percent). Most patients were infected with hepatitis B virus (HBV) genotype B or C. Patients were treated for 48 weeks and followed for an additional 24 weeks. RESULTS: After 24 weeks of follow-up, significantly more patients who received peginterferon alfa-2a monotherapy or peginterferon alfa-2a plus lamivudine than those who received lamivudine monotherapy had HBeAg seroconversion (32 percent vs. 19 percent [P < 0.001] and 27 percent vs. 19 percent [P=0.02], respectively) or HBV DNA levels below 100,000 copies per milliliter (32 percent vs. 22 percent [P=0.01] and 34 percent vs. 22 percent [P=0.003], respectively). Sixteen patients receiving peginterferon alfa-2a (alone or in combination) had hepatitis B surface antigen (HBsAg) seroconversion, as compared with 0 in the group receiving lamivudine alone (P=0.001). The most common adverse events were those known to occur with therapies based on interferon alfa. Serious adverse events occurred in 4 percent, 6 percent, and 2 percent of patients receiving peginterferon alfa-2a monotherapy, combination therapy, and lamivudine monotherapy, respectively. Two patients receiving lamivudine monotherapy had irreversible liver failure after the cessation of treatment - one underwent liver transplantation, and the other died. CONCLUSIONS: In patients with HBeAg-positive chronic hepatitis B, peginterferon alfa-2a offers superior efficacy over lamivudine, on the basis of HBeAg seroconversion, HBV DNA suppression, and HBsAg seroconversion.

非酒精性脂肪肝疾病自然史:一项基于大样本人群队列研究

Background & Aims: The natural history of nonalcoholic fatty liver disease (NAFLD) in the community remains unknown. We sought to determine survival and liver- related morbidity among community- based NAFLD patients. Methods: Four hundred twenty patients diagnosed with NAFLD in Olmsted County, Minnesota, between 1980 and 2000 were identified using the resources of the Rochester Epidemiology Project. Medical records were reviewed to confirm diagnosis and determine outcomes up to 2003. Overall survival was compared with the general Minnesota population of the same age and sex. Results: Mean (SD) age at diagnosis was 49 (15) years; 231 (49% ) were male. Mean follow- up was 7.6 (4.0) years (range, 0.1- 23.5) culminating in 3192 person- years follow- up. Overall, 53 of 420 (12.6% ) patients died. Survival was lower than the expected survival for the general population (standardized mortality ratio, 1.34; 95% CI, 1.003- 1.76; P = .03). Higher mortality was associated with age (hazard ratio per decade, 2.2; 95% CI, 1.7- 2.7), impaired fasting glucose (hazard ratio, 2.6; 95% CI, 1.3- 5.2), and cirrhosis (hazard ratio, 3.1, 95% CI, 1.2- 7.8). Liver disease was the third leading cause of death (as compared with the thirteenth leading cause of death in the general Minnesota population), occurring in 7 (1.7% ) subjects. Twenty- one (5% ) patients were diagnosed with cirrhosis, and 13 (3.1% ) developed liver- related complications, including 1 requiring transplantation and 2 developing hepatocellular carcinoma. Conclusions: Mortality among community- diagnosed NA- FLD patients is higher than the general population and is associated with older age, impaired fasting glucose, and cirrhosis. Liver- related death is a leading cause of mortality, although the absolute risk is low.

结肠清洁程度对结肠镜检查质量和诊断范围的影响:欧洲胃肠内窥镜经费小组的一项欧洲多中心研究

Background: The quality of colon cleansing is a major determinant of quality o f colonoscopy. To our knowledge, the impact of bowel preparation on the quality of colonoscopy has not been assessed prospectively in a large multicenter study. There fore, this study assessed the factors that determine coloncleansing qualit y and the impact of cleansing quality on the technical performance and diagnosti c yield of colonoscopy.Methods: Twenty-one centers from 11 countries participat ed in this prospective observational study. Colon-cleansing quality was assesse d on a 5-point scale and was categorized on 3 levels.The clinical indication fo r colonoscopy, diagnoses, and technical parameters related to colonoscopy were r ecorded. Results:A total of 5832 patients were included in the study (48.7%men, mean age 57.6 [15.9] years). Cleansing quality was lower in elderly patients and in patients in the hospital. Procedures in poorly prepared patients were longer , more difficult, and more often incomplete. The detection of polyps of any size depended on cleansing quality: odds ratio (OR) 1.73: 95%confidence interval(CI )[1.28, 2.36] for intermediate-quality compared with low-quality preparation; and OR 1.46: 95%CI[1.11, 1.93]for high-quality compared with low-quality pr eparation. For polyps >10 mm in size, corresponding ORs were 1.0 for low-qualit y cleansing, OR 1.83: 95%CI[1.11, 3.05] for intermediate-quality cleansing, an d OR 1.72: 95%CI[1.11,2.67] for high-quality cleansing. Cancers were not detec ted less frequently in the case of poor preparation. Conclusions:Cleansing quali ty critically determines quality,difficulty, speed,and completeness of colonosco py, and is lower in hospitalized patients and patients with higher levels of com orbid conditions.The proportion of patients who undergo polypectomy increases wi th higher cleansing quality, whereas colon cancer detection does not seem to cri tically depend on the quality of bowel preparation.