免疫检查点抑制剂治疗骨髓增生异常综合征的研究进展

免疫检查点抑制剂(ICI)通过抑制肿瘤细胞逃逸、增强免疫应答而作为MDS潜在的治疗方式,本文回顾性分析了针对PD-1/PD-L1和CTLA-4的ICI治疗MDS的临床试验,分析了ICI治疗的疗效和不良反应。ICI单药或与去甲基化药物(HMA)合用是可耐受的。尽管目前单药ICI治疗的疗效有限,但和HMA可能具有协同作用,且对于HMA无效患者可作为一种潜在的选择。尽管存在免疫相关不良反应(irAEs),但多数可通过类固醇逆转。     

子痫性妊娠毒血症及妊娠肾病尸检1例

患者女 ,剖宫产术后 11h死亡。临床诊断为妊娠高血压综合征 (产前子痫 ) ,死胎 ,产前感染。尸检 :肝重 195 0 g ,大小 2 6cm× 18cm× 9cm ,肝被膜下弥漫出血 ,外观呈地图状 ,切面红黄相间。肾周围脂肪囊明显水肿。左侧小脑扁桃体处Ⅱ度脑疝。镜检 :肝被膜下广泛出血 (图 1) ,肝细胞水肿 ,小叶周边肝细胞坏死 ,坏死处肝窦扩张充血 ,纤维素渗出沉着 ,坏死周围有少量中性粒细胞浸润 ,汇管区炎细胞浸润 ,汇管区小血管及小叶肝窦内有微血栓 (图 2 )。脾窦扩张 ,小体周围及红髓内有中性粒细胞 ,脾中央动脉玻璃样变。部分肺泡腔内有水肿液 ,肺小血…     

2,4,6—三硝基氯苯诱发小鼠迟发型变态反应肝损伤模型的复制及某些中药的保护作用观察

昆明种小鼠经腹腔注射大剂量环磷酰胺处理后,用2,4,6—三硝基氯苯(PC)两次外涂腹部致敏,再用PC经皮肝穿刺攻击,可诱发迟发型变态反应(PC—DTH)性肝损伤,其血清ALT、AST显著升高,病理解剖见肝脏明显肿大,肝细胞变性、坏死,汇管区炎细胞浸润。具有免疫调节活性的中药复方肝得宁、乙肝宁对该模型有显著治疗作用。     

乙酸消融胆道的实验研究

目的探讨乙酸消融家兔胆道后病理及肝功改变,为临床应用消融栓塞胆道治疗肝内胆管结石提供实验依据。方法观察家兔右外叶胆道于25%至5%浓度乙酸消融后肝脏功能状态、肝组织病理改变和术后存活情况。结果25%乙酸胆道消融造成右外叶肝脏大块坏死,仅肝叶边缘有少量存活肝组织。20%乙酸胆道消融后近肝门部肝实质以汇管区为中心的坏死,肝叶中部见汇管区及周围少量肝细胞坏死,肝叶边缘见汇管区点状坏死。15%乙酸胆道消融后近肝门部见汇管区及周围少量组织坏死,肝叶中部及边缘组织见胆管无明显改变,周围组织点状坏死。10%乙酸胆道消融后近肝门部汇管区胆管坏死,周围充血,肝叶中部胆管上皮完整,周围组织充血,肝叶边缘胆管完整,周围少量肝细胞肿胀。5%乙酸胆道消融后近肝门部胆管上皮坏死,肝叶中部胆管上皮完整,仅充血或少量肝细胞肿胀。结论20%为乙酸消融胆道较理想的浓度。     

ctDNA与免疫治疗相关的假性进展和超进展北大核心CSCD

以细胞毒性T淋巴细胞相关抗原4(CTLA-4)、程序性死亡受体1(PD-1)及其配体PD-L1/PD-L2为主的免疫检查点抑制剂(ICI)在肿瘤免疫治疗中扮演重要角色,部分患者对该治疗反应良好,但仍有部分患者会出现非常规反应(假性进展、超进展及解离反应等),如何早期鉴别假性进展和超进展在临床中非常必要。循环肿瘤DNA(ctDNA)因其源于凋亡和/或坏死后的肿瘤细胞而成为肿瘤早期检测的有力指标。接受ICI治疗的患者中,ctDNA减少和增加可分别见于假性进展和超进展患者,给临床医生早期识别假性进展和超进展提供了可能。本文就假性进展和超进展的定义、机制及ctDNA在鉴别假性进展和超进展中的作用进行综述。     

单一庚型肝炎病毒感染的临床和病理与免疫组化的相关性探讨

目的 探讨单由庚型肝炎病毒（ＨＧＶ）感染对肝脏的致病性。方法 用酶联免疫吸附法检测３６例血清抗－ＨＧＶ，用ＨＧＶ的ＮＳ５片段单克隆抗体（ＭｃＡｂ）对２０例临床和病理确诊为单一庚型肝炎者行肝组织免疫组化，其中急性肝炎１０例，慢性肝炎７例，亚急性重型肝炎１例，慢性重型肝炎２例。结果 ①临床表现：急性肝炎呈急性起病，表现为发热、乏力、恶心、厌油等症状，个别有呕吐现象；慢性肝炎起病缓慢，症状轻；重型肝炎呈急性起病，有高度乏力、严重消化道症状，重者发生肝昏迷。②ＡＬＴ和ＡＳＴ改变：急性肝炎和重型肝炎呈中度升高，慢性肝炎呈轻度升高，重型肝炎可出现“酶胆分离”现象。③肝组织的病理损害：急性肝炎以肝细胞肿胀和汇管区炎症细胞浸润为主。慢性肝炎以肝细胞肿胀、小叶内碎屑样或灶状坏死、汇管区轻度炎症细胞浸润和／或纤维组织轻度增生为主。     

丙型肝炎的病理观察

为确立我国丙型肝炎病理形态学特点，我们观察了７０例经临床确诊的丙型肝炎肝穿标本，其中８９％有输血及血制品使用史。按病程分为急性丙型肝炎２０例，慢性丙型肝炎５０例，其中合并乙型肝炎者７例。与乙型肝炎相比，丙型肝炎特征的组织学改变有：汇管区淋巴细胞集聚、小胆管损伤及较明显的肝细胞脂变。此外，急性丙型肝炎尚见片状的肝细胞明显大小不等，伴大泡脂变。慢性丙型肝炎伴小胆管损伤淋巴细胞集聚，以Ｔ细胞为主，致汇管区扩大为其特征。中度以上慢性活动型丙型肝炎常见宽大的汇管区－汇管区桥接坏死及纤维化，碎屑坏死相对较轻。本研究为丙型肝炎的病理诊断及与乙型肝炎的鉴别诊断提供了依据。     

肝细胞肝癌肿瘤血管生成及其临床病理意义

目的　探讨肝细胞肝癌 (HCC)肿瘤血管生成与临床病理的意义 ,及其调控因素 p5 3与血管内皮生长因子 (VEGF)和微血管密度 (MVD)之间的内在联系。方法　经手术治疗的HCC 6 0例 ,分别进行HE染色和 p5 3、VEGF和CD34的免疫组化染色。根据CD34阳性结果计数测定MVD。记录HCC患者的手术及临床病理特征如AFP结果、包膜情况、肝内转移、病理分级汇管区癌栓等资料 ,并将 p5 3、VEGF和MVD结果分别与上述指标进行统计分析。 结果　MVD值在汇管区癌栓组 (2 2 0 76± 89 84 )和肝内转移组 (2 2 5 31± 87 17)高于无汇管区癌栓组 (16 8 79± 87 5 7)和无肝内转移组 (173 0 5± 89 4 0 ) ,差异有显著性 (P <0 0 5 )。VEGF表达的阳性率在汇管区癌栓组 (71 4 3% )、肝内转移组 (75 % )和包膜完整组 (75 % )中均高于无汇管区癌栓组 (4 1 0 3% )、无肝内转移组 (4 3 18% )和无包膜 (4 0 % )或包膜不完整组 (35 2 9% ) ,差异有显著性 (P <0 0 5 )。p5 3蛋白表达的阳性率在汇管区癌栓组 (5 7 14 % )、肝内转移组 (6 2 5 0 % )和中低分化组 (4 1 30 % )中均高于无汇管区癌栓组(2 0 5 1% )、无肝内转移组 (2 2 75 % )和高分化组 (7 14 % ) ,差异有显著性 (P <0 0 5 )。当 p5 3蛋白表达阳性时 ,MVD值增高(2 2 1 90± 73     

三磷酸腺苷氯化镁治疗氨基半乳糖所致实验性肝坏死的病理组织学研究

本实验用D—氨基半乳糖复制大白鼠急性肝坏死动物模型,分别用ATP及ATP—MgCl_2治疗,肝组织分别用HE,PAS法肝糖元及快速线粒体染色法染色,光镜检查。结果发现:ATP—MgCl_2组肝组织坏死程度较轻,与模型组及ATP治疗组比较,灶性坏死及片状融合性坏死差异均有显著性(P<0.05)。线粒体及肝糖元颗粒数量,ATP—MgCl_2组较对照组及ATP组更为丰富。同时观察到在ATP—MgCl_2治疗组中,汇管区周围出现较多双核肝细胞及双层肝细胞板。这些病理形态学上的改变,提示:①ATP—MgCl_2对肝细胞的再生、修复有效;②证明Hirasawa认为在肝缺血、缺氧的情况下以ATP—MgCl_2形式给药这一理论的可靠性。     

姜黄素和γ-干扰素对肝纤维化大鼠肝组织病理变化及TIMP-1表达的作用

目的:观察肝纤维化大鼠肝组织病理学变化及金属蛋白酶组织抑制因子-1(TIMP-1)的表达水平,探讨姜黄素和γ-干扰素及两者联合治疗抗肝纤维化的作用。方法:将40只雄性SD大鼠随机分为正常对照组、模型组和治疗组,治疗组中又分为姜黄素治疗、γ-干扰素治疗及联合治疗3个亚组,采用CCl4腹腔注射制作大鼠肝纤维化模型。各治疗组采取相应药物和剂量平行治疗4周,第10周末将各组大鼠处死,取肝组织切片HE染色观察组织病理学变化(包括肝纤维化程度);用半定量RT-PCR方法检测各组肝组织TIMP-1mRNA相对表达量。结果:肝组织病理学观察显示,模型组大鼠肝索排列紊乱,肝细胞变性坏死,汇管区和小叶内出现局限性纤维化,部分区域出现纤维纵隔,甚至假小叶形成,纤维化分级为Ⅳ～Ⅴ级(Ⅴ级为主),TIMP-1mRNA相对表达量较正常对照组明显升高(P<0.01);各治疗组肝组织病理变化明显改善,肝细胞变性坏死减少,肝纤维化程度明显减轻(以Ⅲ级为主),TIMP-1mRNA表达量明显低于模型组(P<0.01)。结论:姜黄素和γ-干扰素及两者联合治疗均能减轻肝纤维化大鼠组织病理学变化并下调肝组织TIMP-1mRNA表达,改善和逆转肝纤维化进程。     

The role of liver biopsy in evaluating acute allograft dysfunction following liver transplantation: a clinical histologic correlation of 34 liver transplants

One hundred six liver biopsy specimens from 34 orthotopic liver transplant (OLT) patients were examined and the histologic findings correlated with the clinical course of the patients to determine if specific morphologic patterns were associated with specific causes of acute allograft dysfunction. The principle causes of allograft injury in these patients appeared to be acute rejection and ischemic injury, with rarer cases of viral infection and biliary obstruction. Graft rejection causing transient liver dysfunction was associated with a mixed inflammatory infiltrate in the portal tracts and involving the interlobular bile ducts. Rejection resulting in severe, persistent dysfunction was associated with destruction and loss of the interlobular bile ducts or portal inflammation, followed by acute centrilobular hepatocyte necrosis. Ischemic liver injury was characterized by hepatocyte ballooning and/or hepatocyte necrosis. Ischemic injury causing transient graft dysfunction demonstrated focal, limited areas of hepatocyte necrosis or transient centrilobular hepatocyte ballooning. Severe ischemic injury resulting in persistent dysfunction caused diffuse hepatocyte necrosis or centrilobular ballooning followed by centrilobular hepatocyte loss and severe cholestasis with evidence of bile duct epithelial injury. The histologic patterns observed were not pathognomonic; radiologic studies, bile cultures, and other laboratory tests were necessary to rule out biliary or vascular obstruction and bacterial cholangitis. However, liver biopsies, especially serial biopsies, were helpful in suggesting the probable cause of liver dysfunction and in predicting subsequent allograft recovery or failure.     

The pathology of halothane hepatotoxicity in a guinea-pig model: a comparison with human halothane hepatitis.

The pathology of halothane hepatotoxicity is described in detail in a guinea-pig model. Twenty-two of 40 guinea-pigs developed liver damage after exposure to 1% halothane in 21% O2 for 4 h. The other 18 animals showed no evidence of hepatic injury. Two distinct patterns of damage were identified: mild damage, in which livers had focal areas of necrosis, and severe damage, where necrosis was confluent around the terminal hepatic venules, often extending to the portal tracts. Serum alanine aminotransferase activity was significantly elevated in guinea-pigs with severe liver damage. Hepatocytes in the damaged areas showed degenerative changes ranging from vacuolization to ballooning degeneration and necrosis. Inflammatory cells, predominantly lymphocytes, were often present in the areas of necrosis. The pathology of mild and severe liver injury in the guinea-pig closely resembles the spectrum of injury observed in non-fatal halothane hepatitis in man.     

The pathology of halothane hepatotoxicity in a guinea-pig model: a comparison with human halothane hepatitis

The pathology of halothane hepatotoxicity is described in detail in a guinea-pig model. Twenty-two of 40 guinea-pigs developed liver damage after exposure to 1% halothane in 21% O2 for 4 h. The other 18 animals showed no evidence of hepatic injury. Two distinct patterns of damage were identified: mild damage, in which livers had focal areas of necrosis, and severe damage, where necrosis was confluent around the terminal hepatic venules, often extending to the portal tracts. Serum alanine aminotransferase activity was significantly elevated in guinea-pigs with severe liver damage. Hepatocytes in the damaged areas showed degenerative changes ranging from vacuolization to ballooning degeneration and necrosis. Inflammatory cells, predominantly lymphocytes, were often present in the areas of necrosis. The pathology of mild and severe liver injury in the guinea-pig closely resembles the spectrum of injury observed in non-fatal halothane hepatitis in man.     

Chronic active liver disease. The range of histologic lesions, their response to treatment, and evolution

Histologic study of serial biopsy specimens in a prospective, controlled, double blind, randomized trial of treatment involving 63 patients with predefined clinical and biochemical criteria of severe chronic active liver disease revealed five different histologic patterns of hepatic injury on initial biopsy: chronic persistent hepatitis, chronic aggressive hepatitis, subacute hepatitis with bridging, subacute hepatitis with multilobular necrosis, and cirrhosis. The initial biopsies in the fatal cases revealed cirrhosis, subacute hepatitis with multilobular necrosis, or subacute hepatitis with bridging. Patients with subacute hepatitis with bridging and with multilobular necrosis more frequently revealed stigmata of viral hepatitis and more frequently developed cirrhosis than chronic aggressive hepatitis, regardless of treatment. The severe forms of hepatitis more frequently remitted to the histologic features of chronic persistent hepatitis in patients treated with prednisone and a combination of prednisone and azathio-prine than with azathioprine or placebo alone. Serial biopsy specimens frequently revealed changes in the histologic pattern before remission to chronic persistent hepatitis. Histologic progression to cirrhosis may occur by bouts of intralobular and multilobular necrosis as well as by piecemeal necrosis. Sampling error in needle biopsy of cirrhosis is so great that the condition either may be missed or may be impossible to accurately classify into portal and postnecrotic cirrhosis. Observations at autopsy always revealed postnecrotic cirrhosis characterized by extensive parenchymal loss and incomplete regeneration. We conclude that the evolution of any lesion is influenced by at least two factors: the original histologic pattern and the therapy applied.     

Severe eosinophilic cholangitis with parenchymal destruction of the left hepatic lobe due to hydatid disease

Hydatid cysts of the liver are known to occasionally rupture into the bile ducts and cause cholangitis. The histological features of this complication have not been adequately described in the literature. Herein is reported a case of severe eosinophilic cholangitis of the left hepatic lobe, occurring in a 24-year-old man with a large (16 cm) hydatid cyst, which obstructed and eroded the left hepatic duct. The patient presented with upper abdominal discomfort and low-grade fever of 3 weeks' duration. Sections of the left lobectomy specimen showed marked inflammatory infiltrates in the portal tracts, predominantly composed of eosinophils, extensively involving bile ducts of all sizes. Occasional small bile ducts were replaced by epithelioid cell granulomas surrounding eosinophilic microabscesses. The inflammatory infiltrates extended into the lobules, resulting in marked hepatocyte loss. This case demonstrates that echinococcosis may cause severe eosinophilic cholangitis with extensive parenchymal destruction, apparently resulting from a hypersensitivity reaction to parasitic antigens.     

"Piecemeal" necrosis: renamed troxis necrosis

Piecemeal necrosis, currently called interface hepatitis, is a feature of viral hepatitis as well as autoimmune hepatitis and steatohepatitis. The mechanism of liver cell loss and piecemeal necrosis needs to be determined. We hypothesize that piecemeal necrosis in hepatitis is due to a piecemeal removal of hepatocyte cytoplasm by lymphocytic ingestion. To test this hypothesis, 61 consecutive liver biopsies were examined by light microscopy, by immunohistochemistry and by electron microscopy, and the lymphocytic-hepatocytic interaction was morphologically assessed. In cases of hepatitis C, hepatitis B, autoimmune hepatitis, primary biliary cirrhosis, and steatohepatitis, piecemeal necrosis was found. Using cytokeratin stains, it was apparent that the lymphocyte-hepatocyte interaction and piecemeal necrosis leads first to binding of the lymphocyte to hepatocyte plasma membrane and then blebbing or indentation of the hepatocyte by the lymphocyte, followed by endocytosis of liver cell cellular components and digestion in the lymphocyte lysosomes. This process is repeated while the cytoplasm and the nucleus of the hepatocyte disappear bite by bite, and only nubbins of residual hepatocytic cytoplasm remain, either attached to intact hepatocytes or surrounded and sequestered within scar tissue and lymphocytes. We conclude that piecemeal necrosis is a gradual disappearance of hepatocytes as a result of lymphocyte-hepatocyte binding and ligand internalization of liver surface molecules by the lymphocyte. This gradual process leads to a slow reduction of hepatocyte size and eventual disappearance at the interface between the lobule and portal tracts. To term this new kind of necrosis, we propose the name troxis necrosis, after the Greek noun meaning "nibbling."     

Hepatitis E virus: A new entity

Hepatitis E virus (HEV) is a RNA enterically transmitted virus that causes large waterborne epidemics of acute hepatitis E in endemic regions (Asia and Africa). Sporadic hepatitis E is an emerging disease in developed countries such as France. The majority of acute hepatitis E in France is indigenous (non travel-associated) and is due to infection with HEV genotype 3. Diagnosis is made on the presence of specific serum antibodies and on viral RNA detection in serum or stools. Characteristic pathological signs of acute hepatitis E are severe intralobular necrosis, polymorph inflammation and acute cholangitis in portal tract with numerous neutrophils. Severe forms of hepatitis are associated with underlying chronic liver disease such alcoholic disease. In immunocompetent patients, HEV causes acute resolutive hepatitis and there is no chronic evolution. Conversely, chronic hepatitis E is frequent in immunocompromised patients with a risk of rapid evolution to cirrhosis. Histologic lesions of chronic hepatitis E are similar to those observed in patients chronically infected with hepatitis C virus with dense lymphocytic portal infiltrate, constant peacemeal necrosis and fibrosis.     

Two distinct types of hepatitis in experimental hepatitis B virus infection.

The course of experimental hepatitis B in chimpanzees was studied, and two biochemically, serologically, and histopathologically distinctive types were identified. The first type was self-limiting, rapidly resolving hepatitis with spiking and short-term elevation of SGPT starting at around 5 weeks after the appearance of HBs antigenemia. The second type was smoldering and persistent hepatitis with low-plateau-forming persistent transanimase abnormality developing around 10 weeks after the appearance of HBsAg. Anti-HBc became positive before the transaminase elevation in the second type, while in the first type it became positive after the SGPT elevation. Histologically, the second type was characterized by marked infiltration of lymphoid cells in portal areas with lymphoid follicles. This was seen even before the histologic manifestations of liver cell injury and the elevation of SGPT in two cases. The portal inflammatory cell infiltration became evident at 6 to 9 weeks after the HBsAg appearance and became increasingly more severe thereafter. The intralobular changes remained mild, with rare liver cell necroses. Chronic hepatitis developed subsequently in two cases. In the first type, the portal changes developed almost simultaneously with intralobular changes and were not prominent. In contrast to the second type, the intralobular changes with multiple liver cell necrosis were more severe.     

Pathological examination for liver transplantation

Liver biopsy plays an important role in the histopathological evaluation of the transplanted liver. In this review, we would like to describe the histological features of various forms of diseases such as allograft rejections occurring in transplanted livers. When severe steatosis is found in the donor liver, transplantation is contraindicated. Ischemic liver damage caused by transplant hypoperfusion is called harvesting or re-perfusion injury and characterized by the histological features of liver-cell ballooning, centrilobular cholestasis, and apoptosis of hepatocytes. Acute rejection occurring more commonly in the first few weeks after transplantation is defined by the diagnostic triad of portal inflammatory infiltrates, endothelialitis, and bile duct damage, whereas chronic rejection is characterized by the presence of ductopenia and foam cell arteriopathy. Obstruction of the hepatic artery leads to severe centrilobular necrosis of the allograft. Among viral infections affecting the allografts, cytomegalovirus infection occurs most frequently, and typical intranuclear or cytoplasmic inclusions are hallmarks of the infection. Post-transplantation lymphoproliferative disorders are closely associated with Epstein-Barr virus infection. Therapeutic drugs such as azathioprine and cyclosporin A also cause liver damage, but specific histological features of drug-induced injury have not yet been clarified. Recurrence of original diseases such as viral hepatitis or malignant tumors is also evaluated by the liver biopsy.