切缘冷冻对原发性肝癌切除术后局部复发的预防作用

目的 探讨降低原发性肝癌切除术后局部复发的方法,改善肝癌患者的长期生存率.方法 自1998年4月至2002年4月,我院行肝癌切除术切缘距肿瘤不足1 cm的患者共45例,分为冷冻组和单纯切除组两组.冷冻组23例,常规肿瘤切除后以扁平探头对肝切缘进行接触冷冻,冷冻深度控制在1.0～1.5 cm;单纯切除组22例,单纯行常规肝癌切除手术,不予冷冻治疗.全部患者术后均定期随访复发及生存时间.结果 冷冻组术后1年、3年和5年复发率分别为8.7%、26.1%和34.8%,术后1年、3年和5年生存率分别为82.6%、56.5%和30.4%,与单纯切除组比较,其中3年（χ^2=5.021,P=0.025）、5年复发率差异有统计学意义（χ^2=12.465,P=0）;冷冻组的3年、5年生存率较单纯切除组呈现明显升高的趋势.结论 肝癌切除后切缘冷冻能有效地降低术后局部复发率,提高治疗效果,且有可能延长肝癌患者的长期生存时间.     

ChildA级单个直径≤5cm肝细胞肝癌行肝移植与肝切除的预后比较

目的比较ChildA级、单个、直径≤5cm肝细胞肝癌行肝移植与肝切除术的预后。方法回顾性分析笔者所在医院肝移植中心2007～2011年期间行肝切除术及肝移植术的ChildA级、单个、直径≤5cm肝细胞肝癌患者的临床资料,比较2组患者术后无瘤生存率及总体生存率。结果本研究共纳入263例患者,其中肝移植组36例,肝切除组227例。肝移植组与肝切除组患者术后1、3及5年无瘤生存率分别为91．7％、85．3％及81．0％和80．6％、59．8％及50．8％,肝移植组高于肝切除组（P=-0．003）;术后1、3及5年总体生存率分别为100％、87．5％及83．1％和96．9％、83．8％及76．1％,2组间差异无统计学意义伊=0．391）。以肿瘤直径〈3em为标准再予以分析,其肝移植组与肝切除组术后1、3及5年无瘤生存率分别为92．3％、92．3％及92．3％和80．2％、62．5％及50．5％,肝移植组高于肝切除组（P=-0．019）;术后1、3及5年总体生存率分别为100％、91．7％及91．7％和97．7％、87．5％及79．5％,2组间差异也无统计学意义（p0．470）。结论ChildA级、单个、直径≤5cm肝细胞肝癌患者肝切除术后复发率高于肝移植,但两种治疗方式的术后总体生存率相似。     

冷冻综合治疗肝癌

目的　探讨冷冻综合治疗肝癌的疗效。方法　应用 L SC- 2 0 0 0型冷冻机对 5 3例肝癌分别采取冷冻加手术切除 ;冷冻加肝动脉、门静脉置管化疗 ;冷冻加手术切除和肝动脉、门静脉置管化疗。结果　全组无手术死亡及严重并发症 ;冷冻后 1、2、3年生存率分别为 73.6 %、6 2 .5 %、5 2 .8% ,其中 12例≤ 5 mm的小肝癌分别为 91.7%、83.3%、75 %。结论　冷冻综合治疗为中晚期肝癌提供了有效的治疗途径 :切除肿瘤或 /和行肝动脉、门静脉置管化疗能够降低肝癌术后的复发     

以手术切除为主的综合疗法治疗原发性肝癌:附108例报告

目的 探讨和总结以手术切除为主的综合疗法治疗原发性肝癌的方法和疗效。方法 回顾分析1999年1月～2002年9月实施的以手术切除为主的综合疗法治疗108例原发性肝癌的临床资料。综合疗法包括手术切除肝癌，配合射频、经肝动脉化疗栓塞、经皮酒精注射、皮下药物输注系统化疗栓塞、冷冻、生物治疗等方法。结果 手术死亡率0．9％，术后并发症发生率18．7％，1年内肝内复发转移率56．1％，远处转移者为17．9％，1，2，3年生存率分别为79．46％，61．83％，36．61％。结论 以手术切除为主的综合疗法治疗原发性肝癌疗效满意，其治疗后肝内复发及远处转移率低，能提高原发性肝癌的无瘤生存率和长期存活率。     

Tissue—Link和Cusa术的评价联合应用于肝癌切除

目的比较肝门阻断钳夹法与应用Tissue-Link联合Cusa无阻断肝癌切除的临床疗效。方法回顾2003年1月至2006年9月中山大学附属第三医院肝胆外科105例肝癌手术患者的临床资料,其中使用Tissue—Link和Cusa无阻断切肝55例（非阻断组）,肝门阻断钳夹法切肝50例（对照组）。结果非阻断组切缘距离大于对照组[（1．1±0．3）cmVS．（0．7±0．5）cm,（P〈0．05）],切缘癌残留率和复发率均低于对照组（0％VS．4％,P〈0．05;和0％VS．6％,P〈0．05）,切缘以外复发率无统计学差异。非阻断组切肝时间比对照组长．失血量比对照组少。非阻断组术后第7天血清胆红素水平小于对照组。非阻断组术后补充白蛋白量小于对照组。非阻断组与对照组的1年、2年和3年无瘤生存率分别为90．9％、87．3％和80．0％VS．90．0％、74．0％和66．0％．无统计学差异。结论使用Tissue-Link和Cusa无阻断肝癌切除疗效优于肝门阻断钳夹法肝癌切除。具有术野清晰、术中失血量少、肝损害小、切缘癌残留率和复发率低的优势。     

肝癌肝段切除术结合肝段门静脉阻断并灌注化疗的临床研究

目的比较B超引导下肝段门静脉阻断灌注化疗并肝段染色后肝切除术与常规肝切除术的临床疗效。方法41例肝癌病人术中应用B超引导肝段门静脉阻断灌注化疗并肝段染色后肝切除术，35例应用常规肝切除术，术后定期复查肝功能、AFP，CT及MRI变化，并随访。结果B超引导下肝段门静脉阻断灌注化疗并肝段染色后肝切除组较常规肝段切除组术中出血少，对肝功能影响小，其术后5年生存率分别为37．8％和24．3％(P=0．040)；局部复发率分别为31．7％和1157．1％(P=0．037)。结论B超引导下肝段门静脉阻断灌注化疗并肝段染色后肝切除术的临床疗效优于常规肝切除术。     

肝动脉栓塞化疗对大肝癌根治术后复发率及生存率的影响

目的探讨肝动脉栓塞化疗对于预防原发性大肝癌根治术后复发的疗效。方法对1997年1月～2002年12月我院68例行大肝癌根治术的患者按术后是否行介入治疗分为TACE组（24例）和对照组（44例），对比分析两组患者术后1、2、3年的累积复发率和生存率。结果对68例原发性大肝癌行根治性切除后的患者，术后随访最长49个月。TACE组术后l、2、3年累积复发率分别为16．7％、34．3％、49．5％：1、2、3年的累积生存率分别为83．3％、70．2％、53．7％。对照组1、2、3年的累积复发率分别为36．4％、58．0％、68．5％：1、2、3年的累积生存率分别为63．6％、48．3％、25.3％，两组差异有显著性（P〈0．05）。结论原发性大肝癌根治术后辅以介入治疗是预防肝癌术后复发的有效手段，能显著提高远期生存率。     

肝动脉栓塞化疗在预防小肝癌术后复发中的应用

目的 采用小剂量碘油对小肝癌病人进行肝动脉预防性栓塞化疗．以期降低其术后复发率。方法 试验组22例应用碘油10ml加常规化疗药于术前1月或术后2～3周内及术后每3～6个月进行栓塞化疗，平均栓塞2·1次。结果 其术后6月、1年、2年复发率(分别为9%、14%、25%)明显低于对照组(分别为42％、42％、66%)(P<0．05)。而术后2年、3年生存率试验组为81%及71％明显高于对照组(43％、27%)(P<0．05)。结论 初步研究表明预防性肝动脉桂塞化疗是降低小肝癌术后复发率的有效措施。     

CLIP评分系统评价肝癌患者手术方式及预后

目的 探讨CLIP评分系统对可手术切除性肝癌术式选择的作用及与患者无瘤生存率的关系.方法 回顾分析1996-2004年157例行根治性肝切除肝癌患者的临床病理资料.并按CLIP评分系统0分、1分、2分和大于等于3分的标准分组,比较各组患者的无瘤生存率,比较规则性肝切除和不规则性肝切除患者的无瘤生存率.结果 本组患者1、3、5年无瘤生存率分别为63.6%、45.2%、35.7%,各组间的无瘤生存率比较差异有统计学意义(P＜0.01).在CLIP评分0分组中,行规则性肝切除与不规则性肝切除患者的术后无瘤生存率比较,差异有统计学意义(P＜0.01),其他组中规则性肝切除和不规则性肝切除患者的术后无瘤生存率差异无统计学意义(P＞0.05).结论 CLIP评分系统是评价原发性肝癌术后复发的有效工具;CLIP评分0分的肝癌患者作规则性肝切除的术后复发率远低于行不规则性肝切除.     

肝动脉化疗栓塞对原发性肝癌患者术后生存及肿瘤复发的影响

目的探讨原发性肝癌患者手术后肝动脉化疗栓塞（TACE）对肿瘤复发率及患者术后生存率的影响，为原发性肝癌的临床综合治疗提供指导。方法原发性肝癌患者手术后行TACE治疗22例（手术＋TACE组）、仅行手术切除而不行TACE治疗患者20例（单纯手术组），对两组患者术后肿瘤复发率及患者生存率进行比较。结果手术＋TACE组与单纯手术组比较，前者肿瘤1年复发率显著低于后者（P〈0．05），但两组2年复发率差异无显著性（P〉0．05）。手术＋TACE组1年及2年生存率（76．1％，48．2％）均明显高于单纯手术组（52．8％，23．6％）（P〈0．05）。结论原发性肝癌手术后结合TACE治疗，可明显降低肿瘤近期复发率且显著提高患者生存率。     

Cryohepatectomy for hepatocellular carcinoma--results in 84 patients

BACKGROUND: Recurrence after resection of hepatocellular carcinoma (HCC) is frequent and is a major cause of a poor outcome. Most recurrence may occur from the spreading of the original lesion via the intrahepatic portal vein. Cryosurgery has been used for the treatment of various tumors for decades. The aim of this study was to determine whether cryohepatectomy is potentially beneficial in reducing the recuurence and prolonging survival. METHODS: The study included 84 patients who underwent cryohepatectomy, cryosurgery with liquid nitrogen (-196 degrees C) followed by the resection of the frozen tumor by conventional technique, for HCC and were closely follow-up after surgery. Recurrence and survival rates were calculated by the life-table method. RESULTS: The postoperative course of cryohepatectomy in all of the 84 patients was uneventful, there being no operative mortality or severe complications. The 1-, 3-, and 5-year survival rates after cryohepatectomy were 98.7%, 83.9%, and 64.0%, respectively. The 1-, 3-, and 5-year recurrence rates after cryohepatectomy were 15.1%, 30.1% and 39.0%, respectively. CONCLUSIONS: Cryohepatectomy for HCC is a safe procedure and may be potentially beneficial in reducing recurrence and prolonging survival. More time is needed to further define whether this procedure will improve long-term survival as compared with conventional resection.     

Clinical management of recurrent hepatocellular carcinoma.

OBJECTIVE: The aim of this study was to evaluate the long-term benefits of the aggressive treatments with resection or transarterial chemoembolization (TACE) for recurrent hepatocellular carcinoma (HCC). SUMMARY BACKGROUND DATA: Primary HCC is one of the most fatal malignancies in Taiwan. The result of resection for HCC remains unsatisfactory, primarily due to the high recurrence rate. To improve surgical results, recurrent HCC must be treated with aggressive resection or TACE. METHODS: The authors evaluated the results of repeated hepatic resection among 25 patients with recurrent HCC and of TACE among 12 patients with resectable recurrent HCC. The outcomes of an additional 64 patients with unresectable recurrent HCC were also evaluated. RESULTS: During the follow-up period from 2-112 months, 52% (13/25) of patients receiving repeat resection (group 1) were alive, whereas 42% (5/12) of patients receiving TACE (group 2) were alive. No perioperative deaths within 30 days after surgery occurred in the repeated resection group. The cumulative survival rates at 1, 2, 3, and 5 years after the first operation were 92%, 84%, 71.6%, and 65.1% in group 1 and 83.3%, 75%, 75%, and 22.5% in group 2. The survival rates at 6 months and at 1, 2, and 3 years after recurrence were 92%, 72%, 64%, and 44.8% in group 1 and 83.3%, 75%, 66.7%, and 48% in group 2. The survival of patients with unresectable recurrent HCC was much worse: 1-, 2-, 3-, and 5-year survival after surgery was 57.8%, 29.8%, 15.5%, and 0%; and 6-month and 1-, 2-, and 3-year survival after recurrence was 46.5%, 29.2%, 12.5% and 7.8%. CONCLUSIONS: More aggressive treatment with repeated hepatic resection can prolong survival time after recurrence of HCC in selected patients. However, TACE can also achieve good results although it is not thought of as curative.     

Liver resection for hepatocellular carcinoma on cirrhosis: univariate and multivariate analysis of risk factors for intrahepatic recurrence

OBJECTIVE: To evaluate prognostic factors that could affect disease-free survival and recurrence after liver resection for hepatocellular carcinoma (HCC) on cirrhosis. SUMMARY BACKGROUND DATA: Tumor recurrence is the main cause of poor survival after liver resection for HCC on cirrhosis. METHODS: Two hundred twenty-four liver resections for HCC on cirrhosis were retrospectively reviewed. Univariate and multivariate analyses were performed on several clinicopathologic variables to analyze factors affecting long-term outcome and intrahepatic recurrence. The relation between preoperative aminotransferase level and recurrence rate was evaluated in the overall group, and separately in HCV-positive and in HBsAg-positive patients. Median follow-up was 35.6 months. RESULTS: The 1-, 3-, and 5-year overall survival rates were 83%, 62.8%, and 42.5%, respectively. The 1-, 3-, and 5-year disease-free survival rates were 70.3%, 43%, and 27.4%, respectively. The 1-, 3-, and 5-year recurrence rates were 20.8%, 38.6%, and 54.4% respectively. Tumor recurrence appeared in 93 patients (41.5%) and was the main cause of death in 51 patients (56%). Number of nodules, tumor capsule, microvascular portal vein thrombosis, and preoperative serum aspartate aminotransferase (AST) level significantly affected disease-free survival and recurrence rates. On multivariate analysis, single nodules and preoperative AST level less than twice normal (2N) were related to a better 5-year disease-free survival and lower tumor recurrence. In particular, among HCV-positive patients the recurrence rate was strongly affected by the preoperative AST level. CONCLUSIONS: Child A patients with single nodules are the best candidates for liver resection. Tumor recurrence is strictly linked to the status of the underlying liver disease, and a preoperative AST level equal to 2N seems to be a sensitive cutoff among patients with different risks of recurrence. HCV-positive patients with AST levels above 2N have the highest risk for intrahepatic recurrence and should be monitored carefully or offered alternative treatments.     

Outcome of patients with huge hepatocellular carcinoma after primary resection and treatment of recurrent lesions

BACKGROUND: Tumour recurrence is common after hepatic resection of hepatocellular carcinomas (HCCs) greater than 10 cm in diameter. This study evaluated the outcome of patients with huge HCC after primary resection and treatment of recurrent lesions. METHODS: A retrospective review was undertaken of clinical data for 100 patients with huge HCC who underwent liver resection. RESULTS: Mean(s.d.) tumour diameter was 13.3(3.0) cm; 80 per cent were single lesions. Systematic and non-systematic resections were performed in 80 and 20 per cent of patients respectively, with R0 resection achieved in 86 per cent. Overall 1-, 3- and 5-year disease-free survival rates were 43, 26 and 20 per cent respectively. Risk factors for HCC recurrence were resection margin less than 1 cm and macrovascular invasion. Extensive tumour necrosis of 90 per cent or more after preoperative transarterial chemoembolization was not a prognostic factor. Some 85 per cent of patients with recurrence received various treatments, and these patients had a longer post-recurrence survival than those who were not treated. Overall 1-, 3- and 5-year survival rates were 66, 44 and 31 per cent respectively. CONCLUSION: In patients with huge HCC, hepatic resection combined with active treatment for recurrence resulted in longer-term survival. Frequent protocol-based follow-up appears to be beneficial for the early detection and timely treatment of recurrence.     

Liver resection for hepatocellular carcinoma in non-cirrhotic liver without underlying viral hepatitis

BACKGROUND: Hepatocellular carcinoma (HCC) arising in normal liver parenchyma is rare and the outcome after hepatectomy is not well documented. METHODS: Between June 1998 and September 2003, 33 patients without viral hepatitis underwent resection for HCC in a non-cirrhotic, non-fibrotic liver. Data were analysed with regard to operative details, pathological findings including completeness of resection, and outcome as measured by tumour recurrence and survival. RESULTS: Twenty-three major hepatectomies and ten segmentectomies or bisegmentectomies were performed. After potentially curative resection, 19 of 29 patients were alive at a median follow-up of 25 months, with calculated 1- and 3-year survival rates of 87 and 50 per cent respectively. Survival was significantly better after resection of tumours without vascular invasion (3-year survival rate 89 versus 18 per cent; P = 0.024). Disseminated recurrence developed in nine of 29 patients, leading to death within 28 months of operation in all but one of the nine. CONCLUSION: These data justify hepatic resection for HCC arising in non-cirrhotic, non-fibrotic liver without underlying viral hepatitis. Liver transplantation is rarely indicated because the outcome is good after resection of tumours without vascular infiltration, whereas vascular invasion is invariably associated with diffuse extrahepatic recurrence.     

肝癌切除术后早/晚期复发的危险因素与治疗

目的 探讨影响原发性肝癌根治性切除术后早／晚期复发和预后的危险因素以及复发后的最佳治疗方式。方法 回顾性分析1997年1月至2002年12月我院收治的169例经病理证实为肝细胞性肝癌（HCC）根治性切除的病例，经随访2年以上，选择18项临床、病理及治疗等指标分析对早／晚复发的影响。结果 全组有76例复发，复发率44．6％，早期复发（≤12个月）49例，晚期复发（〉12个月）27例。AFP和血管侵犯是早期复发的危险因素，而肝硬化则是晚期复发的惟一危险因素。早期复发的1，3年生存率分别为69．3％和14．3％；晚期复发相应的生存率分别为100％和29．6％。尽管复发后的治疗方式大致相同，但复发病例中经再次切除和肝移植治疗组的1，3年生存率分别为94．7％和52．6％，而非手术治疗组的相应的生存率分别为71．9％和7．1％。结论 辨别病例存在的危险因素对于选择手术病例与术后辅助治疗有积极的意义。对于复发的病例，采取适当的治疗措施将明显延长生存期，取得较好的疗效。肝移植对于肝癌复发的治疗值得进一步探讨。     

First-line liver resection and salvage liver transplantation are increasing therapeutic strategies for patients with hepatocellular carcinoma and child a cirrhosis

AIM: The present study focused on nine patients with hepatocellular carcinoma (HCC) associated with Child A liver cirrhosis undergoing first-line liver resection and salvage liver transplantation (SLT) for liver tumor recurrence. PATIENTS AND METHODS: Forty-six patients with HCC underwent liver transplantation (OLT); 37 (80.5%) were primary liver transplantations (PLTs) and 9 (19.5%) were SLTs. All patients who underwent SLT received minor transabdominal liver resections. RESULTS: The posttransplant 1-, 3-, and 5-year overall survival rates for SLT (88.9%, 88.9%, and 88.9%) were similar to those for PLT (78%, 62.7%, and 62.7%). Four (10.8%) patients in the PLT group had HCC recurrence, while there was zero recurrence in the SLT group. The 1-, 3-, 5-year disease-free survival rates for PLT (89%, 74%, and 74%) were similar to those for SLT (100%, 100%, and 100%). The 1-, 3-, 5-year disease-free survival rates after PLT were 89%, 74%, and 74%, and after SLT were 100%, 100%, and 100%, respectively. The operative mortality, intraperioperative bleeding, operative time, intensive care unit stay, in-hospital stay, and overall incidence of postoperative complications were similar in the two groups. CONCLUSIONS: In our experience, SLT for HCC is a feasible procedure with similar results in terms of overall survival, disease-free survival, and postoperative complications to those reported for patients who underwent PLT at our institute. An important role exists for SLT as shown by the fact that such a strategy has been used in the 20% of the patients undergoing OLT for HCC.     

原发性肝癌的外科治疗:20年7566例的临床经验

目的 总结原发性肝癌外科治疗的临床经验.方法 回顾性分析复旦大学附属中山医院肝癌研究所1988年1月至2007年12月7566例原发性肝癌外科治疗的临床资料.采用Kaplan-Meier法计算术后生存率和无复发生存率,Log-rank检验比较组间差异,多因素分析采用Cox回归模型.结果 7164例肝癌肝切除患者术后3、5、10年生存率分别为56.29%、41.76%、26.70%,无复发生存率分别为63.92%、56.12%、42.97%,围手术期死亡率为1.54%.肿瘤直径≤5 cm的小肝癌患者术后5、10年生存率分别为58.20%、38.47%.肿瘤直径5 cm的大肝癌患者术后5、10年生存率分别为31.42%、20.43%,两者比较差异有统计学意义(X2=535.568,P<0.01).110例肿瘤降期后切除患者、515例术后复发再次切除患者、168例肝癌合并门静脉主干癌栓患者的5年生存率分别为51.26%、67.28%、26.81%,5年无复发牛存率分别为77.44%、13.01%(统计始于第1次手术)、34.90%.402例肝癌肝移植患者术后3、5年生存率及无复发牛存率分别为60.81%、55.63%及64.47%、58.52%.肿瘤直径、数目、分化程度及大血管侵犯是影响肝癌肝切除患者牛存率及无复发生存率的独立预后因素(X2=200.539,27.536,96.964,216.156,P<0.01).结论 肝癌早期筛查和治疗,手术安全性的提高,综合治疗模式的开展,预防转移、复发研究的突破,显著地提高了肝癌外科治疗的效果.     

Resection or transplantation for hepatocellular carcinoma in cirrhotic patients: outcomes based on indicated treatment strategy

BACKGROUND: Surgical resection has been the treatment of choice for hepatocellular carcinoma (HCC), but the resection rate remains low in cirrhotic patients and recurrence is common. Unfavorable results compared with benign disease and the shortage of organ donors have led to a restricted indication for orthotopic liver transplantation (OLT) for HCC. STUDY DESIGN: The aim of this study was to analyze the results of our surgical approach to HCC in patients with cirrhosis. The first treatment strategy indicated in these patients was OLT. From January 1990 to May 1999, 85 patients underwent OLT and the remaining 35 had surgical resection. RESULTS: One-, 3-, and 5-year survival rates were 84%, 74%, and 60% versus 83%, 57%, and 51%, respectively, in the OLT and resection groups (p = 0.34). Hepatic tumor recurrence was much less frequent in the OLT group than in the resection group. The 1-, 3-, and 5-year disease-free survival rates were 83%, 72%, and 60% versus 70%, 44%, and 31%, respectively (p = 0.027). In the multivariate Cox regression analysis, macroscopic vascular invasion was the only factor independently associated with death or recurrence after OLT (p = 0.006). After partial liver resection, the tumors significantly associated with mortality and recurrence in the multivariate analysis were solitary or multiple tumors greater than 2cm with microscopic vascular invasion (pathologic pT3) (p = 0.01). CONCLUSIONS: Our results confirm that in cirrhotic patients, OLT may provide better outcomes than liver resection in carefully selected HCC and that longterm survival is similar to the results of OLT in cirrhotic patients without tumors.     

Hepatic resection for large hepatocellular carcinoma.

BACKGROUND: Long-term survival and prognostic factors after hepatic resection for large hepatocellular carcinoma (HCC) remain to be proved. METHODS: The surgical outcome in 133 consecutive patients with HCC in diameter of > or = 5 cm (large HCC; L group) undergoing hepatic resection was retrospectively clarified and compared with that of 253 patients with HCC in diameter of < 5 cm (small HCC; S group). Postresection prognostic factors were evaluated by univariate and multivariate analysis using Cox's proportional hazards model. RESULTS: The disease-free 3- and 5-year survival rates between L group and S group were 26% versus 42% and 20% versus 25%, respectively (P = 0.0032). The overall 3- and 5-year survival rates between L group and S group were 38% versus 67% and 28% versus 47%, respectively (P < 0.0001). Multivariate analysis revealed that large amount of intraoperative blood transfusion was an independently significant factor of poor disease-free and overall survivals. CONCLUSIONS: Long-term survival in patients with large HCC remains unsatisfactory compared with that in patients with non-large HCC. Restriction of intraoperative blood transfusion may play an important role in the improvement of survival and recurrence in such patients.