肝硬化失代偿期并发自发性细菌性腹膜炎的危险因素分析

目的：探讨肝硬化失代偿期并发自发性细菌性腹膜炎(SBP)危险因素,提高早期诊断率.方法：我院近2年住院的肝硬化失代偿期患者共163例.对性别、年龄、肝性脑病、消化道出血、饮酒史、血清胆红素水平、血清蛋白水平、转氨酶、腹水白蛋白含量、肝硬化病因、既往SBP史、腹外感染灶及有无脾功能亢进等因素,用Logistic回归分析.结果：性别、年龄、肝性脑病、消化道出血、饮酒、病因是否为乙肝、及脾功能亢进等因素与肝硬化失代偿期并发SBP无相关性(P＞0.05)；而血清胆红素(OR=7.461,P＜0.01)、蛋白(总蛋白：OR=2.455,P＜0.05；白蛋白：OR=22.696,P＜0.01)、及转氨酶水平(ALT：OR=2.067,P＜0.05；AST：OR= 3.370,P＜0.01),腹水白蛋白水平(OR=36.692,P＜0.01),既往SBP史(OR=14.359,P＜0.01)以及腹外感染灶(OR=3.633,P＜0.05)等因素与肝硬化失代偿期并发SBP有相关性结论：血清胆红素,白蛋白,AST,腹水白蛋白,以及既往有SBP发病史是肝硬化失代偿期并发SBP的高危因素.血清总蛋白、ALT和有腹外感染灶是失代偿期肝硬化并发SBP的危险因素.     

肝硬化发生自发性细菌性腹膜炎的危险因素分析

目的探讨肝硬化自发性细菌性腹膜炎（SBP）发生的危险因素。方法 398例肝硬化患者被分为SBP组（135例）和无SBP组（263例）,比较两组年龄、性别、病程、既往SBP史、腹水时间、糖尿病史、腹水总蛋白、消化道出血、肝功能Child-Pugh分级、抗生素预防、重要生化及凝血指标等因素。结果两组患者在既往SBP史、腹水时间、糖尿病史、腹水总蛋白、消化道出血、Child-Pugh分级、抗生素预防、血Na＋、TBil、ALB、PT等方面差异有非常显著性意义（P〈0.01）。结论肝硬化SBP发生与一些因素高度相关,应予以及时有效的防治,以减少SBP的发生。     

Multivariate predictive model for asymptomatic spontaneous bacterial peritonitis in patients with liver cirrhosis

BACKGROUND Spontaneous bacterial peritonitis(SBP) is a detrimental infection of the ascitic fluid in liver cirrhosis patients, with high mortality and morbidity. Early diagnosis and timely antibiotic administration have successfully decreased the mortality rate to 20%-25%. However, many patients cannot be diagnosed in the early stages due to the absence of classical SBP symptoms. Early diagnosis of asymptomatic SBP remains a great challenge in the clinic.AIM To establish a multivariate predictive model for early diagnosis of asymptomatic SBP using positive microbial cultures from liver cirrhosis patients with ascites.METHODS A total of 98 asymptomatic SBP patients and 98 ascites liver cirrhosis patients with negative microbial cultures were included in the case and control groups, respectively. Multiple linear stepwise regression analysis was performed to identify potential indicators for asymptomatic SBP diagnosis. The diagnostic performance of the model was estimated using the receiver operating characteristic curve.RESULTS Patients in the case group were more likely to have advanced disease stages, cirrhosis related-complications, worsened hematology and ascites, and higher mortality. Based on multivariate analysis, the predictive model was as follows: y(P) = 0.018 + 0.312 × MELD(model of end-stage liver disease) + 0.263 × PMN(ascites polymorphonuclear) + 0.184 × N(blood neutrophil percentage) + 0.233 × HCC(hepatocellular carcinoma) + 0.189 × renal dysfunction. The area under the curve value of the established model was 0.872, revealing its high diagnostic potential. The diagnostic sensitivity was 73.5%(72/98), the specificity was 86.7%(85/98), and the diagnostic efficacy was 80.1%.CONCLUSION Our predictive model is based on the MELD score, polymorphonuclear cells, blood N, hepatocellular carcinoma, and renal dysfunction. This model may improve the early diagnosis of asymptomatic SBP.     

Physiopathology of bacterial translocation and spontaneous bacterial peritonitis in cirrhosis

The key pathogenic mechanism initiating spontaneous bacterial peritonitis (SBP) is bacterial translocation (BT), a process through which enteric bacteria cross the intestinal barrier and infect the mesenteric lymph nodes, thus entering the blood circulation and ascitic fluid. The high rate of bacterial translocation in cirrhosis is due to injury to the three pilars composing the intestinal mucosal barrier (the balance of intraluminal bacterial flora, the integrity of the intestinal epithelial barrier, and the local immune system). Blood dissemination and microbial growth in ascitic fluid resulting from SBP are a consequence of damage to the immune system in cirrhosis. Hyperproduction of proinflammatory cytokines and other vasoactive substances contributes to the arterial vasodilation and renal failure that frequently complicate the course of SBP. Even in the absence of SBP, translocation of bacteria and bacterial products from the intestinal lumen contribute to systemic inactivation of immune cells in cirrhosis.     

Renal dysfunction after spontaneous bacterial peritonitis in cirrhosis: incidence and risk factors]

BACKGROUND/AIMS: Deterioration of renal function in patients with cirrhosis and spontaneous bacterial peritonitis (SBP) is the most sensitive predictor of in-hospital mortality. It has been shown that high dose intravenous albumin in addition to antibiotics reduces the incidence of renal impairment and improve hospital survival in these patients. Besides, it is important to know which patients would benefit from albumin infusion. Therefore, we conducted a retrospective study to elucidate the incidence and risk factors of renal dysfunction in cirrhotic patients with SBP. METHODS: All medical records of 76 consecutive episodes of SBP in 60 patients were analyzed. Renal dysfunction after SBP was defined as elevation of BUN >30 mg/dL or serum creatinine >1.5 mg/dL in patients without preexisting renal insufficiency, or elevation of more than 50% of the baseline level in patients with renal dysfunction at the diagnosis of infection. RESULTS: Of the 76 episodes, renal dysfunction was present in 31 (40.8%). Age, concurrent use of diuretics, large volume paracentesis (LVP) with volume expander, initial BUN and creatinine level were significant risk factors on univariate analysis. Of these, age and LVP were independent risk factors on logistic regression model. CONCLUSIONS: Renal dysfunction occurs in 40.8% of hospitalized patients after SBP. Considering poor prognosis of patients with renal dysfunction in SBP, close monitoring of renal function is needed and high dose intravenous albumin with antibiotics should be used especially in the elderly and those with LVP.     

Incidence and predictive factors of first episode of spontaneous bacterial peritonitis in cirrhosis with ascites: relevance of ascitic fluid protein concentration.

To investigate the long-term probability of the appearance of the first episode of spontaneous bacterial peritonitis in cirrhosis with ascites and to identify predictors of this complication, we closely followed throughout their illness 127 patients consecutively admitted to our unit for the treatment of an episode of ascites without prior spontaneous bacterial peritonitis (follow-up period: 21 +/- 22 mo). Thirteen patients (10%) had the first spontaneous bacterial peritonitis episode during follow-up. The appearance probability of this complication is 11% at 1 yr and 15% at 3 yr. Thirty-three variables obtained at admission (including clinical data, standard liver and kidney function test results, ascitic fluid protein concentrations and hemodynamic parameters) were analyzed in relation to their value in predicting spontaneous bacterial peritonitis development. In univariate analysis (Kaplan-Meier curves) five variables reached statistical significance (p less than 0.05) as predictive factors for the development of the first spontaneous bacterial peritonitis episode. These five variables were poor nutritional status, increased serum bilirubin levels, increased serum AST levels, decreased prothrombin activity and reduced total protein concentration in ascitic fluid. When these five variables were introduced in a multivariate analysis, only the ascitic fluid protein concentration was found to correlate independently with spontaneous bacterial peritonitis development (p = 0.002). The probability of first spontaneous bacterial peritonitis after 3 yr of follow-up was 24% and 4% in patients with ascitic fluid protein content lower than 1 gm/dl and greater than or equal to 1 gm/dl, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Bacterial infections other than spontaneous bacterial peritonitis in cirrhosis

Cirrhotic patients are immunocompromised with a high risk of infection.Proinflammatory cytokines and hemodynamic circulation derangement further facilitate the development of serious consequences of infections.Other than spontaneous bacterial peritonitis,bacteremia and bacterial infections of other organ systems are frequently observed.Gram-negative enteric bacteria are the most common causative organism.Other bacterial infections,such as enterococci,Vibrio spp.,Aeromonas spp.,Clostridium spp.,Listeria monocytogenes,Plesiomonas shigelloides and Mycobacterium tuberculosis are more prevalent and more virulent.Generally,intravenous third generation cephalosporins are recommended as empirical antibiotic therapy.Increased incidences of gram-positive and drug-resistant organisms have been reported,particularly in hospitalacquired infections and in patients receiving quinolones prophylaxis.This review focuses upon epidemiology,microbiology,clinical features and treatment of infections in cirrhosis other than spontaneous bacterial peritonitis,including pathogen-specific and liver diseasespecific issues.     

Escherichia Coli capsular polysaccharide and spontaneous bacterial peritonitis in cirrhosis

Spontaneous bacterial peritonitis (SBP) is a frequent and severe complication of cirrhosis. Escherichia coli is the most frequent bacterium isolated in this condition. The presence of capsular antigens, mainly the K1 capsular polysaccharide, has been associated with invasiveness in E coli infections. Capsular serotypes of E coli causing SBP were determined in 37 cirrhotic patients. Twenty-seven strains were encapsulated (72.9%), 9 of them (24.3%) with K1 capsular polysaccharide, and 10 were nonencapsulated. Patients with encapsulated E coli showed a significantly higher incidence (92.5% vs. 50%; P < .01) and number of complications per patient (1.9 ± 1.1 vs. 0.8 ± 1.0; P < .01) than patients with nonencapsulated strains. Although mortality was higher in patients with encapsulated strains (44.4% vs. 20%), the difference did not reach statistical significance. Considering patients infected by encapsulated strains, the incidence of complications and mortality were similar in patients with or without K1 strains. These data suggest that the presence of encapsulated strains could have a prognostic significance in SBP caused by E coli in cirrhotic patients.     

Ascites and spontaneous bacterial peritonitis in patients with liver cirrhosis

Liver cirrhosis is a frequent phenomenon in chronic liver diseases such as hepatitis B, hepatitis C, alcohol-related liver damage, autoimmune hepatitis and hemochromatosis. Ascites is the most frequent complication of cirrhosis. We discuss pathogenesis, diagnosis and state-of-the-art clinical management of ascites with emphasis on recent promising developments, such as covered transjugular intrahepatic portosystemic shunt (TIPS). Spontaneous bacterial peritonitis occurs in up to 10% of patients with ascites because of bacterial overgrowth with translocation through the increased permeable small intestinal wall and impaired defence mechanisms. The addition of albumin to standard antibiotic therapy may decrease mortality of spontaneous bacterial peritonitis by decreasing the incidence of renal insufficiency. Patients with coexistent marked hyperbilirubinaemia or pre-existent renal impairment could benefit from adjuvant albumin. Probiotics (bacterial food supplements) have been claimed to improve the state of underlying liver disease and may be useful in the primary and secondary prevention of spontaneous bacterial peritonitis.     

肝硬化合并自发性细菌性腹膜炎的处理

自发性细菌性腹膜炎（SBP）是肝硬化失代偿合并腹水患者的严重并发症,随着发生次数的增加,处理难度加大,患者的病死率提高。SBP的发生机制主要是肠黏膜防御功能低下和通透性增加,细菌通过肠粘膜易位至腹腔。腹水穿刺并多形核细胞计数仍然是诊断SBP最快捷、敏感和特异的手段。急性消化道大出血、腹水白蛋白低于10 g/L、发生过SBP等,是发生或再发SBP的高危因素。使用包括喹诺酮类在内的抗生素可有效预防SBP。治疗上应该从改善肝功能、处理肝脏原发病、补充白蛋白和合理使用抗生素等诸方面综合考虑。     

Prognosis of patients with liver cirrhosis and spontaneous bacterial peritonitis

BACKGROUND/AIMS: Patients with liver cirrhosis and ascites have a high risk of spontaneous bacterial peritonitis, but the prognostic impact of spontaneous bacterial peritonitis has not been well examined. METHODOLOGY: Patients with liver cirrhosis and ascites were included at the time of their first paracentesis during hospitalization in the Department of Hepatology, Aarhus University Hospital, Denmark, between September 1992 and September 2000. Cox regression was used to estimate the mortality of patients with spontaneous bacterial peritonitis (ascites leukocyte count > or = 250 per mm3) relative to controls without spontaneous bacterial peritonitis. Furthermore, we used Cox regression to estimate the change in mortality when controls developed spontaneous bacterial peritonitis during follow-up. RESULTS: Of 286 patients, 76 (27%) had spontaneous bacterial peritonitis at the first paracentesis. The mortality ratio of patients with spontaneous bacterial peritonitis relative to controls was 1.0 (95% confidence interval 0.7-1.5) after adjustment for age, gender, comorbidity, and alcohol abuse. Of the 210 controls, 42 (20%) were found to have spontaneous bacterial peritonitis at a later paracentesis. Their mortality rate more than doubled with the onset of spontaneous bacterial peritonitis. CONCLUSIONS: Spontaneous bacterial peritonitis at the first paracentesis did not affect the prognosis of patients with liver cirrhosis, whereas development of spontaneous bacterial peritonitis during follow-up doubled the mortality risk. This may be due to a longer diagnostic delay in those who developed spontaneous bacterial peritonitis during follow-up.     

Intestinal dysfunction in liver cirrhosis: Its role in spontaneous bacterial peritonitis

Spontaneous bacterial peritonitis is a common illness in patients with cirrhosis and ascites that occurs without any apparent focus of infection. Bacterial translocation plays an important role in spontaneous bacterial peritonitis and it is evident from a variety of studies that the gut is a major source of this bacteria. Gut motility alterations, along with bacterial overgrowth and changes in intestinal permeability, probably play a role in this bacterial translocation. The present review looks at the role of the intestine in spontaneous bacterial peritonitis induced by liver cirrhosis and the factors influencing bacterial translocation in this disease.     

Small intestinal bacterial overgrowth in patients with cirrhosis: prevalence and relation with spontaneous bacterial peritonitis

OBJECTIVES: The significance of small intestinal bacterial overgrowth in patients with cirrhosis is not fully understood and its diagnostic criteria are not uniform. We examined the association of small intestinal bacterial overgrowth with spontaneous bacterial peritonitis and compared various microbiological criteria. METHODS: Jejunal secretions from 70 patients with cirrhosis were cultivated quantitatively and classified according to various definitions. Clinical characteristics of patients were evaluated and the incidence of spontaneous bacterial peritonitis was monitored during a 1-yr follow-up. RESULTS: Small intestinal bacterial overgrowth, defined as > or = 10(5) total colony-forming units/ml jejunal secretions, was present in 61% of patients. Small intestinal bacterial overgrowth was associated with acid-suppressive therapy (p = 0.01) and hypochlorhydria (p < 0.001). Twenty-nine patients with persistent ascites were observed. Six episodes of spontaneous bacterial peritonitis occurred after an average 12.8 wk. Occurence of spontaneous bacterial peritonitis correlated with ascitic fluid protein concentration (p = 0.01) and serum bilirubin (p = 0.04) but not with small intestinal bacterial overgrowth (p = 0.39). Its association with acid-suppressive therapy was of borderline significance (hazard ratio = 7.0, p = 0.08). CONCLUSIONS: Small intestinal bacterial overgrowth in cirrhotic patients is associated with acid-suppressive therapy and hypochlorhydria, but not with spontaneous bacterial peritonitis. The potential role of acid-suppressive therapy in the pathogenesis of spontaneous bacterial peritonitis merits further studies.     

Increasing frequency of Gram-positive bacteria in spontaneous bacterial peritonitis.

AIM: To evaluate the characteristics and possible recent changes of the microbial causes of spontaneous bacterial peritonitis (SBP) in cirrhotic patients. METHODS: We retrospectively evaluated 42 cirrhotic patients with positive ascitic fluid culture and without evidence of secondary peritonitis who were admitted consecutively to our Department between 1998 and 2002. RESULTS: Twenty (48%) of 42 patients with positive ascitic fluid culture were diagnosed during 1998-1999 (period A) and the remaining 22 (52%) patients during 2000-2002 (period B). Gram-negative bacteria were the cause of SBP in 15 (75%) of the 20 patients during period A and in only nine (41%) of the 22 patients during period B (P=0.026). SBP patients with Gram-positive bacteria compared with those with Gram-negative bacteria were less frequently in Child class C (P=0.058) and had significantly higher ascitic fluid protein (P=0.014) and albumin concentrations (P=0.009) and lower ascitic fluid neutrophil count (P=0.008). Resistance to quinolones was detected significantly more frequently in the isolated Gram-positive than Gram-negative bacteria (P<0.001). CONCLUSION: Culture-positive SBP in cirrhotic patients are caused more frequently by Gram-positive bacteria during the recent years, which are, in their vast majority, resistant to quinolones.     

Trimethoprim-sulfamethoxazole versus norfloxacin in the prophylaxis of spontaneous bacterial peritonitis in cirrhosis

BACKGROUND: The prognosis of patients with chronic liver disease and spontaneous bacterial peritonitis is poor, being of great importance its prevention. AIM: To compare the effectiveness of trimethoprim-sulfamethoxazole versus norfloxacin for prevention of spontaneous bacterial peritonitis in patients with cirrhosis and ascites. PATIENTS AND METHODS: Fifty seven patients with cirrhosis and ascites were evaluated between March 1999 and March 2001. All of them had a previous episode of spontaneous bacterial peritonitis or had ascitic fluid protein concentration < or = 1 g/dL and/or serum bilirubin > or = 2.5 mg/dL. The patients were randomly assigned to receive either 800/160 mg/day of trimethoprim-sulfamethoxazole 5 days a week or 400 mg of norfloxacin daily. The mean time of observation was 163 days for the norfloxacin group and 182 days for the trimethoprim-sulfamethoxazole group. In the statistical analysis, differences were considered significant at the level of 0.05. RESULTS: According to the inclusion criteria, 32 patients (56%) were treated with norfloxacin and 25 (44%) with trimethoprim-sulfamethoxazole. Spontaneous bacterial peritonitis occurred in three patients receiving norfloxacin (9.4%) and in four patients receiving trimethoprim-sulfamethoxazole (16.0%). Extraperitoneal infections occurred in 10 patients receiving norfloxacin (31.3%) and in 6 patients receiving trimethoprim-sulfamethoxazole (24.0%). Death occurred in seven patients (21.9%) who received norfloxacin and in five (20.0%) who received trimethoprim-sulfamethoxazole. Side effects occurred only in the trimethoprim-sulfamethoxazole group. CONCLUSION: In spite of the reduced number of patients and time of observation, trimethoprim-sulfamethoxazole and norfloxacin were equally effective in spontaneous bacterial peritonitis prophylaxis, suggesting that trimethoprim-sulfamethoxazole is a valid alternative to norfloxacin.     

Immunological and biochemical factors associated with spontaneous bacterial peritonitis

A prospective study (June 1988-December 1989) of all patients admitted with ascites due to cirrhosis was undertaken: Biochemical and immunological factors which may have significance in the development of spontaneous bacterial peritonitis were determined. Among 56 patients (44 males and 12 females) SBP developed in 16% of the group. No age differences were found and the etiology of the cirrhosis was mainly alcoholic. Patients with SBP had lower alpha-2 globulin concentrations: 0.43 +/- 0.12 vs. 0.60 +/- 0.18 g/dl (p less than 0.05) and a lower prothrombin time: 41 +/- 13% vs. 69.5 +/- 13 vs. 69.5 +/- 21% (p less than 0.001). Patients with SBP had also lower ascitic fluid total protein 0.99 +/- 0.4 vs. 1.64 +/- 1.1 g/dl (p less than 0.01) as well as lower alfa-2 globulin: 0.065 +/- 0.012 vs. 0.096 +/- 0.067 g/dl (p less than 0.05); beta globulin, 0.11 +/- 0.047 vs. 0.2 +/- 0.17 g/dl (p less than 0.05); gamma globulin, 0.32 +/- 0.1 vs. 0.52 +/- 0.4 g/dl (p less than 0.05); IgG, 275 +/- 157 vs. 477 +/- 335 g/dl (p less than 0.05); C3, 9.2 +/- 3.2 vs. 17 +/- 13 mg/dl (p less than 0.01) and C4, 2.83 +/- 1.5 vs. 4.66 +/- 3.9 mg/dl (p less than 0.05) than patients without this complication.     

细胞因子和一氧化氮在肝硬化自发性细菌性腹膜炎的临床意义

目的 为探讨炎性细胞因子对肝损伤和肝硬化并发症的致病作用。方法 我们对62例,即20例自发性细菌性腹膜炎、18例消化道恶性肿瘤伴腹水、24例肝硬化腹水除NO用Griess法外,其余用经典的放免方法进行检测。结果 ①血清内IL-6、IL-12、TNF-α和NO水平高于腹水中IL-6、IL-12、TNF-α和NO的水平;②SBP患者血清和腹水中上述三指标水平高于其它两组水平(P<0.01或P<0.001)。结论 血清和腹水炎性细胞因子的升高可能表明它们参于肝损伤和肝硬化并发症的发生,上述4项指标的检测有助于SBP的诊断和预后的估价。     

肝硬化合并自发性细菌性腹膜炎病原学特征分析

目的分析自发性细菌性腹膜炎(SBP)的病原学及耐药特点、实验室特征指标,为早期预警、快速诊断和及时治疗提供客观依据。方法对解放军第三○二医院2011年1月至2013年12月诊断为SBP的1340例住院患者的临床资料及实验室指标进行回顾性分析,对比不同种类病原菌的SBP的分布特点和实验室特征,明确不同种类病原菌的耐药特点。药敏结果采用WHONET5软件进行分析,统计学分析采用CHISS统计软件,计量资料采用t检验,计数资料采用χ2检验。结果 1340例肝硬化合并SBP患者中,感染革兰阴性杆菌(G-b)591例(44.10%),革兰阳性球菌(G+C)746例(55.67%),真菌1例(0.07%)、革兰阳性杆菌(G+b)2例(0.15%)。G-b合并其他部位感染、血中性粒细胞、腹水白细胞数(WBC)、多形核白细胞(PMN)、ALT、AST、TBil、外源性凝血酶原活动度(PTA)、血肌酐(Cr)等实验室指标的异常率,明显高于G+C感染(P0.05)。大肠杆菌和肺炎克雷伯菌产生超广谱β-内酰胺酶(ESBL)阳性率分别为40.00%和36.03%。鲍曼不动杆菌对阿米卡星、磺胺甲恶唑/甲氧苄啶、亚胺培南耐药率为42.42%、57.57%、57.58%;铜绿假单胞菌对头孢哌酮和替卡西林/克拉维酸耐药率分别为45.45%、36.36%。甲氧西林耐药金黄色葡萄球菌构成比43.33%,甲氧西林耐药凝固酶阴性葡萄球菌构成比78.09%,对万古霉素和替考拉宁的敏感率为100%。结论 SBP的病原菌以G+C和G-b为主,耐药严重,辅助诊断血中性粒细胞、腹水WBC、腹水PMN、ALT、AST、TBil、PTA、Cr可预测G-b感染,治疗应依据感染病原的类型和药敏及患者病情选择抗生素。     

Long-term prognosis of cirrhosis after spontaneous bacterial peritonitis treated with ceftriaxone

Spontaneous bacterial peritonitis (SBP) is a frequent infection in cirrhotic patients with ascites, with a poor prognosis. The aims of this study were to determine the long-term survival of cirrhotic patients with SBP treated with ceftriaxone and to identify predictive factors related to survival. We studied 47 first episodes of SBP treated with ceftriaxone with a mean follow-up of 272 days. Nineteen variables were recorded to evaluate their relation to survival. The most frequent organism that caused SBP was Escherichia coli (40%). Spontaneous bacterial peritonitis resolution was achieved in 67% of patients. After resolution, SBP recurrence was observed in 44% of patients. The cumulative probability of survival was 68.1% at 1 month and 30.8% at 6 months. After uni-and multivariate analyses of all cases, SBP resolution ( p = 0.0001) and international normalized ratio (INR) ( p = 0.0057) were found to be related to survival. Another analysis performed after SBP resolution and SBP recurrence showed that ascitic fluid-positive culture ( p = 0.0344) and INR ( p = 0.0218) had statistical significance as variables predictive of long-term survival. We conclude that the survival of cirrhotic patients is very short after the first episode of SBP, a fact probably related to advanced liver disease, as liver dysfunction (INR) is the most important factor related to long-term patient survival.