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VEGF与凝血因子在肾癌的相关性

VEGF与凝血因子在肾癌的相关性
VEGF与凝血因子在肾癌的相关性

Oncology

The Relationship of Vascular

Endothelial Growth Factor and

Coagulation Factor(Fibrin and Fibrinogen) Expression in Clear Cell Renal Cell Carcinoma Henk M.W.Verheul,Karen van Erp,Marjolein Y.V.Homs,G.S.Yoon,

Petra van Der Groep,Craig Rogers,Donna E.Hansel,George https://www.wendangku.net/doc/3d13770614.html,to,and Roberto Pili OBJECTIVES To investigate the relationship between angiogenesis and coagulation markers in tumor tissues of primary renal cell carcinoma(RCC).Tumors stimulate angiogenesis and activate the coag-

ulation cascade.The importance of the interplay between these pathways for RCC is unknown. METHODS In all,69clear cell RCC specimens were analyzed by immunohistochemical staining applied to tissue microarrays.The expression of vascular endothelial growth factor(VEGF),hypoxia-

inducible factor-1?,?brinogen and?brin,and microvessel density were visually analyzed.Finally,

staining patterns were related to clinical variables and survival.

RESULTS The VEGF expression was detected in100%of tumors,with68%showing a high expression, whereas hypoxia-inducible factor-1?staining was low(only26%had a moderate to high

staining).Fibrinogen was expressed adjacent to the tumor cells in26%of cases,whereas in84%

it was expressed around the blood vessels.In30%of tumors,expression of?brin was detected.

High tumor VEGF expression correlated with high?brin staining(P?.05).From a multivariate

analysis,microvessel density(P?.033)and?brinogen adjacent to tumor cells(P?.046)were

independent factors related to VEGF expression.

CONCLUSIONS In this study,we found clinical evidence for the permeability activity of VEGF as re?ected by extravascular?brinogen expression adjacent to tumor cells in the extracellular matrix.In

addition,VEGF and?brin expression were associated,indicative for concomitant activation of

the coagulation cascade and angiogenesis in RCC.Taken together,these data indicate that

activation of angiogenesis and coagulation are related in RCC.UROLOGY75:608–614,2010.

?2010Elsevier Inc.

A ngiogenesis is essential for tumor development

and metastasis formation.Vascular endothelial

growth factor(VEGF)plays a major role in stimulating new blood vessel formation in several biolog-ical processes including tumor angiogenesis.

Tumors cannot grow beyond the critical size of1-2mm (or about106cells)without angiogenesis because of the limited diffusion of oxygen and nutrients.1An important factor in the switch to an angiogenic phenotype is the increase in hypoxia in the microenvironment of a grow-ing microscopic tumor.Hypoxia-inducible factor(HIF) plays an essential role in the O2homeostasis.2During hypoxia,HIF-?binds to HIF-?.Subsequently,the HIF ?/?heterodimer activates genes that regulate adaptation to hypoxia by increasing VEGF production and stimulat-ing angiogenesis.3The formation of tumor vasculature has been extensively studied.Tumor blood vessels are structurally and functionally irregular,with dead ends, disordered blood?ow,and increased permeability.1 VEGF plays a crucial role in the formation of new ves-sels.4High VEGF expression in renal cell carcinoma (RCC)tissues has been shown previously.5

Tumor vascularity,assessed histologically as microves-sel density(MVD),has been suggested as a potential prognosticator.In lung cancer,highly vascularized tumor, re?ected by a high MVD,appears to be associated with higher likelihood for metastasis and poor prognosis.6 However,in contrast to initial expectations based on other tumor types and the importance of the VHL mu-tation in renal tumors pathogenesis,a high MVD does

H.M.W.Verheul and K.van Erp contributed equally to this work.

From the Department of Medical Oncology,VU Medical Center,Amsterdam,The Netherlands;Department of Oncology,The Johns Hopkins University,Baltimore, Maryland;Department of Medical Oncology,University Medical Center Utrecht, Utrecht,The Netherlands;Department of Pathology,The Johns Hopkins University, Baltimore,Maryland;Department of Pathology,University Medical Center Utrecht, Utrecht,The Netherlands;and Department of Urology,The Johns Hopkins University, Baltimore,Maryland

Reprint requests:Roberto Pili,M.D.,Roswell Park Cancer Institute,Elm&Carlton St,Buffalo,MD21231.E-mail:roberto.pili@https://www.wendangku.net/doc/3d13770614.html,

Submitted:December6,2008,accepted(with revisions):May30,2009

not correlate with poor prognosis in RCCs.7-10This ?nd-ing might well be due to the type of tumor vessels that are being analyzed.In a study of Yao et al,10a difference in prognostic value between undifferentiated and more dif-ferentiated microvessel densities was observed.In addi-tion,in RCC the relationship between the expression of the angiogenic factor,VEGF,and MVD has not been found.5,11,12This lack of a relationship might be due to the presence of pre-existent kidney tissue that is highly vascularized.

However,the importance of angiogenesis for RCC is re?ected by the ef?cacy of antiangiogenic therapy.In the past 2years,a number of antiangiogenic agents have shown clinical activity in RCC.13-16The clinical devel-opment of these angiogenesis inhibitors has been com-plicated by new types of side effects.The most common side effects are hypertension,fatigue,skin toxicities,gas-trointestinal perforations,thrombotic events,bleeding,and impaired wound healing.Although the underlying mechanisms are not completely understood,some of these side effects are related to the interaction between angiogenesis and the hemostatic

Activation of the coagulation in stim-ulation of angiogenesis and vice angio-genic factors stimulate activation of cas-cade.18For example,VEGF stimulates tissue factor (TF)expression on endothelial cells.TF is the main regulator of the coagulation cascade by inducing thrombin forma-tion,which in turn activates platelets and converts ?-brinogen into ?brin,resulting in clot formation.17Fibrin can be assessed as a marker for activation of the coagu-lation cascade.Activation of the coagulation cascade has been recognized in several types of cancer.It has been suggested that activation of the coagulation cascade may contribute to the tumor biology of RCC.Clinical evi-dence of such an interaction has been seen in patients with intravascular tumor thrombi formations indicative for the hypercoagulable state of this tumor type.

The aim of this retrospective study was to investigate the importance of the concomitant activation of angio-genesis and the coagulation cascade in RCC.Expression of angiogenic markers (VEGF,MVD,and HIF)and co-agulation factors ?brinogen and ?brin in resected RCC lesions was assessed by immunohistochemistry.The rela-tionship between the expression patterns was studied and the expression was related to the prognosis of these patients with RCC,although the design of this retrospec-tive study was not powered for prognostic relations.

MATERIAL AND METHODS

The study included 69patients with clear cell RCC who un-derwent surgery between May 1984and July 2002at the Johns Hopkins Hospital,Baltimore,MD.Surgical specimens were analyzed and stored in the Pathology Department of the Johns Hopkins University.Patient and tumor characteristics are shown in Table 1.Immunohistochemistry

For tissue microarray (TMA),representative paraf?n tumor blocks were selected by primary evaluation of hematoxylin-eosin-stained slides before TMA preparation.Normal kidney tissue adjacent to the tumor in all specimens was used for internal control.From each specimen,4tumor and 4benign tissue “spots”were represented on the TMA.

For immunohistochemical analysis,4-?m thick TMA sec-tions were deparaf?nized and rehydrated.Epitope retrieval was performed with citrate buffer in a steamer for 30minutes,with the exception of ?brinogen staining where proteinase K (In-vitrogen,Carlsbad,CA)was used at 37°C for 5minutes.En-dogenous peroxidase activity was blocked for 30minutes in methanol containing 0.3%hydrogen peroxidase.Thereafter the catalyzed signal ampli?cation (CSA)system (DAKO,Glostrup,Denmark)was used for HIF-1?staining with the mouse mono-clonal antibody (Abcam,Cambridge,UK)according to the manufacturer’s instruction.The other antibodies were detected by the avidin–biotin complex (ABC)method with the VECTASTAIN ABC Kit (Vector laboratories,Burlingame,CA).Slides were incubated overnight at 4°C with one of the follow-ing primary antibodies:mouse-anti-human VEGF 1:500(R&D Systems,Minneapolis,MN),mouse-anti-human CD311:200(Dako),rabbit-anti-human ?brinogen 1:500(Dako),mouse-anti-human ?brin 1:250(Accurate Chem and Science,Corp,Westbury,NY).Stainings were developed with diaminobenzi-dine.Appropriate negative controls (obtained using the IgG isotype controls and omission of the primary antibody)and positive controls were used throughout the staining procedures.Immunohistochemical staining scoring methods were de-signed by 3investigators (H.V.,K.v.E.,and G.N.)based on previously published methods and staining patterns.The TMAs were independently scored for staining patterns by 2indepen-dent investigators (H.V.and K.v.E.)who were unaware of clinicopathologic variables.For VEGF,staining of the tumor cells and the vasculature were separately scored and the pattern of staining was described (focal,multifocal,or diffuse).A semi-quantative scoring system was used:?,no staining;?,mild staining;??,moderate staining;and ???,strong staining.These were then categorized as low staining (?/?)and high staining (??/???).Microvessel density was determined at 200?magni?cation,counting the whole tissue core on the TMA,excluding areas with prominent necrosis.For HIF-1?,

Table 1.Patient and tumor characteristics of 69patients with clear cell renal cell carcinoma

N (%)

Age (yr ?SD)61.1?11.4Range 28-87

Stage I 10(16)II 4(6)III 43(68)IV 6(10)

Surgery

Radical nephrectomy 61(95)Partial nephrectomy 2(3)Resection metastasis 1(2)

Tumor size (cm ?SD)8.1?2.8Range 3-15

Fuhrman nuclear grade 230(44)333(48)4

6(9)

the immunochemical results were classi?ed as follows:(no staining),?(nuclear staining in?10%of cells),??(10%-30%staining),???(30%-100%staining)and were then categorized as low staining(?/?)and high staining(??/???).For?brinogen,the staining matrix adjacent to tumor cells and the staining around the blood vessels were separately scored similar to the VEGF staining.For?brin,the intensity of staining was described(?[none],?[?5%],??[5%-25%], and???[?25%])and categorized as no staining and positive staining and whether the staining was located mainly intravas-cularly or extravascularly.

Statistical Analysis

Immunohistochemistry results were correlated with clinical and pathologic variables and survival.For each tumor,average val-ues for VEGF and HIF-1?,MVD,?brin,and?brinogen were calculated from all informative TMA spots and categorized as described previously.The relationship between VEGF,HIF-1?,?brinogen,and?brin were analyzed using?2test.MVD in relation to these markers was analyzed with the nonparametric Mann–Whitney test and correlations were calculated with Spearman correlation coef?cient.A multivariate logistic anal-ysis was performed including VEGF as a dependent factor and MVD,HIF-1?,?brinogen staining adjacent to tumor cells,?brinogen adjacent to vessels,?brin,tumor stage,tumor size and Fuhrman nuclear grade as independent factors.First,a univariate analysis was performed,and then variables with signi?cance?0.20were selected for the multivariate analysis. Survival rates were calculated using the Kaplan–Meier method. Differences in survival for the different markers or patient and tumor characteristics were analyzed using log-rank test.P?.05 was considered statistically signi?cant.All statistical analyses were performed with the statistical software SPSS version15.0. RESULTS

Angiogenic Markers

The expression of VEGF was detected in100%of the tumors,with68%showing a high expression(Fig.1A). Staining patterns were mainly multifocal or diffuse(Ta-ble2).VEGF staining of the vessels was slightly lower, with96%showing expression including56%high ex-pression.The mean MVD was54vessels per counted tissue core with a standard deviation of35(range8-161) (Fig.1B).HIF-1?expression was low in74%of patients; only26%of patients had moderate to high staining(Fig. 1C).Staining was localized to the nuclei of the cells. Coagulation Markers

High?brinogen staining adjacent to tumor cells in the extracellular matrix was seen in18patient samples (26%)compared with staining adjacent to blood vessels in58patient samples(84%)(Fig.1D).Activation of the coagulation cascade was found only in a minority of the tumors as documented by the low?brin-staining rates. Forty-eight specimens(70%)showed no expression,13 (19%)showed a focal expression,and only8(12%) showed a multifocal or diffuse expression(Fig.1E).The localization was intravascular in62%(n?13)and extravascular in38%(n?8).Relationship Between Angiogenic

Factors and Coagulation Factors

A higher VEGF staining of the tumor correlated with a lower MVD(P?.05)(Table3).No association was observed between VEGF and HIF-1?staining,neither for HIF-1?staining and MVD(Table3).High VEGF staining was associated with high?brin staining(P?.05).From the univariate analysis,MVD,?brinogen ad-jacent to tumor cells,and?brinogen adjacent to vessels were selected for multivariate analysis(P?.20).From this multivariate analysis,MVD(P?.033)and?brino-gen adjacent to tumor cells(P?.046)were independent factors related to VEGF expression.

Prognostic Factors

Complete follow-up data were available for61patients, of which38patients had died.Mean survival was7.7 years(95%con?dence interval6.2-9.1).A high stage of disease(P?.029)and a higher Fuhrman nuclear grade (P?.049)were associated with decreased survival(Fig.

2).Although overall,patients with higher tumor VEGF expression appeared to have a worse rate of survival,the relationship between VEGF expression and survival was not statistically signi?cant(P?.13),(Fig.2).None of the other markers were of prognostic signi?cance. COMMENT

This study indicates that activation of angiogenesis and coagulation is present in RCC.In addition,this is the ?rst study in patients,showing that the vascular per-meability activity of VEGF is re?ected by?brinogen extravasation.The association between VEGF and?-brin expression indicates concomitant activation of the coagulation cascade and angiogenesis.Second,this study provides evidence that in RCC,higher VEGF expression is not associated with higher MVD,and it even suggests that there may be an inverse relationship between the2parameters.

VEGF expression was related to?brinogen staining adjacent to tumor cells in the extracellular matrix. VEGF,also known as the vascular permeability factor, can induce leakage of plasma proteins from the intravas-cular compartment into the extravascular compartment by activation of the tumor vascular cells.Therefore,the expression of the plasma protein?brinogen is increased in tumors that express high VEGF levels.Extravasated ?brinogen can be converted by thrombin in the local tumor microenvironment into?brin.18

In this study,we found that high VEGF expression was related to high?brin expression.Fibrin was expressed in30%of the tumor tissues,whereas?brinogen ex-pression adjacent to tumor cells was abundantly ex-pressed(64%showed mild staining and26%,moderate to high staining).

Fibrin stabilizes platelet aggregates at the sites of vas-cular injury,thus stabilizing hemostatic plugs.Fibrin is an activation marker of the coagulation cascade.The?brin

A

B

C

D

E

Figure1.VEGF,MVD,HIF-1?,?brin and?brinogen expression in renal cell carcinoma.(A)VEGF:left,low staining;right,high staining,(B)MVD:left,low MVD,arrows point to vessels;right,high MVD,(C)HIF-1?:left,low staining;right,high staining, (D)Fibrinogen:left,low staining;right,high staining adjacent to tumor cells,(E)Fibrin:left,low staining;right,high staining.

matrix is essential for physiological and pathologic events,including in?ammation,hemostasis,wound heal-ing,and tumor angiogenesis.Fibrin may provide a pro-visional proangiogenic scaffold that supports vessel for-mation and stimulates endothelial cell proliferation during tumor development.One explanation for the low ?brin staining in our TMA stainings might be that the

activation of the coagulation cascade is relatively low. Alternatively,the expression of?brin may be low due to the activity of plasmin.In the cascade of wound healing and repair,?brinolysis plays an essential role to regain the homeostasis of the endothelial cell lining of the vascula-ture.Plasmin is generated by the conversion of plasmin-ogen into plasmin by either urokinase plasminogen acti-vator(uPA)or tissue-type plasminogen activator on endothelial or other cells,including tumor cells.Plasmin breaks down?brin into?brin-degradation products.We did not analyze the proteins involved in the?brinolysis pathway such as uPA or tissue-type plasminogen activa-tor expression or plasmin activity.However,previous studies have detected a high expression of uPa in RCC,supporting the latter hypothesis,and a high uPA was correlated with metastasis formation.19Fibrinolysis might be regulated by the VHL pathway as well.20Therefore,in future experiments the expression of TF,uPA,and plas-min should be considered.In our study,only paraf?n-embedded TMA tissue was available,whereas frozen tis-sue sections are required for accurate analysis of TF,uPA, and plasmin.Currently,we are developing a TMA of frozen tissue sections of RCC and are planning to perform these additional stainings.

The inverse relation between VEGF expression and MVD,and the lack of a relationship between MVD and survival or prognostic factors(Fuhrman nuclear grade, tumor stage)is surprising,but it may be speci?c to RCC.

Table2.VEGF staining of TMA in69surgical specimens of clear cell renal cell carcinomas

VEGF HIF-1?Fibrinogen Fibrin Tumor staining(%)

?0(0)10(15)7(10)48(70)?22(32)38(59)44(64)13(19)??32(47)10(15)17(25)4(6)???14(21)7(11)1(1)4(6) (Adjacent to)

vessel

staining(%)

?3(4)0(0)

?27(40)11(16)

??31(46)46(67)

???7(10)12(17)

Table3.VEGF staining in relation to MVD,HIF-1?,and coagulation markers?brinogen

and?brin

VEGF Low VEGF

High P

MVD*

Mean6847.052

HIF

Low1434.18

High89

Fibrinogen

Adjacent to tumor cells

Low1931.10

High315

Fibrinogen

Adjacent to vessels

Low47?.20

High1839

Fibrin

No staining1929.048*

Staining317

*Spearman correlation coef?cient VEGF staining with mean

MVD:r??0.26P?.04.

Figure2.Survival curves.(A)Survival curve according to

stage of disease divided into stages1/2and3/4.(B)

Survival curve according to Fuhrman nuclear grade divided

into stages2and3/4.(C)Survival curve according to VEGF

expression in renal cell carcinoma.

VEGF plays an important role in the development and maintenance of the early vasculature in the healthy kid-ney.VEGF remains continuously expressed in a normal adult kidney in comparison with other organs.It has been hypothesized that VEGF plays a speci?c functional role in the glomerulus by regulating vascular permeability.21 The inverse relationship between VEGF expression and MVD might exist because VEGF is continuously ex-pressed in kidneys.Yao et al described2types of endo-thelial cells in RCC,differentiated(CD34?)and undif-ferentiated(CD31?/CD34?),lining the vasculature. CD31is expressed in both differentiated and undifferen-tiated endothelial cells.These investigators found that a higher differentiated MVD was correlated with longer survival and a higher undifferentiated MVD was corre-lated with a relatively shorter survival.10Previous studies showing an inverse relationship between MVD and sur-vival mostly analyzed differentiated vessels(CD34?).7-9 CD31expression represents both and did not show a relationship with survival in the study of Yao et al,10 which we con?rmed in this study.Further studies are needed to explore the relationship between VEGF and differentiated and undifferentiated MVD.It might be that the newly formed vessels due to VEGF tumor expression are less differentiated,and therefore less organized compared with the high number of differentiated vessels in the healthy kidney,resulting in a reduced MVD.

HIF-1?expression was relatively low in this study and was not related to VEGF expression or survival.HIF-?family members include HIF-1?,HIF-2?,and HIF-3?. HIF-1?and HIF-2?are the main factors involved in hypoxia-driven binding to HIF-?.In vitro and in vivo studies revealed that with loss of the tumor suppressor gene VHL,HIF-2?might be the most important HIF isoform associated with angiogenesis.HIF-1?expression in VHL-mutated tumors might be proapoptotic and can be even antiproliferative.HIF-1?seems to have tumor-promoting and tumor-inhibiting functions depending on the cell type.22,23Only a few studies have described immunohistochemical staining of HIF-1?in human RCC.Zhong et al2showed?rst in their study overexpres-sion of HIF-1?in different tumor types and a higher expression in metastatic breast cancer.Only1RCC was included in that study.A small study revealed in73% (8/11)of the tumors an elevated expression of HIF-1?in sporadic RCC24and another small study showed in83% (10/12)of tumors an elevated expression of HIF-1?in patients with VHL disease.25In a study with31RCC tissues,40%of tumors had high expression levels of HIF-1?,which was correlated with VEGF expression.26 The only study performed with a high number of patients (216patients with RCC)revealed that57%of tumors (123/216)had a high HIF-1?expression level.27In this study,patients with a high HIF-1?expression tended to have a better prognosis.Taken together,HIF-1?expres-sion might be less important compared with HIF-2?expression in human RCC with regard to survival.

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肾癌晚期的三大症状

肾癌晚期的三大症状 大家熟知的肾癌三联征一般都出现在肾癌晚期,治愈的可能性基本没有。要想得到好的疗效,还是提依靠体检时的早期发现。如果出现以下晚期症状,恐怕只能对症治疗,止痛,提高生活质量了: 1、血尿:约40%的肾癌病人出现血尿,可为肉眼血尿,也可为镜下血尿。如果身体无其他不适,肉眼可见的血尿也很容易被忽视。因此,有高危因素的人群应定期检查小便。镜下血尿的隐匿性就更强了,需要到医院作专门的检查。大量血尿有血块形成时可出现肾绞痛、排尿痛、排尿困难,甚至尿潴留。 2.、疼痛:腰痛是因肿瘤长大后肾包膜张力增加或侵犯周围组织而发生,表现为持续性钝痛。肿瘤出血致肾被膜下血肿也可出现钝痛或隐痛。肿瘤侵犯临近组织器官如腰大肌或神经可引起持续而严重的腰背部疼痛。疼痛发生率为20%~40%。如果肿瘤发生远端转移,则会引起相关转移部位的症状及疼痛不适。 3、肿块:肾脏位于腹膜后,位置深,腹部触诊时摸不到,只有当肿瘤较大或位于肾下极才可触及到肿块,约10%~40%患者可扪及腹部肿块,有时可为唯一的症状。肾癌到后期发现肾积水伴肿块,很可能已发生转移了。 肾癌三联征基本上只能算是局部症状,到了肾癌晚期,还会出现全身症状,如高血压、贫血、体重减轻、恶病质、发热等等,预后不良。

人参中的“黄金”成分——人参皂苷Rh2,具有较强的抗肿瘤功效,对传统化疗有增效作用,可减轻化疗毒副作用,提高机体免疫力。经一定的临床研究与实践,被视为当今最具潜力的天然抗癌食物。 研究证明:长期服用人参皂苷Rh2(护命素)可以增加抵抗力,缩小肿瘤,降低放化疗危害,防止并发症黄疸、疼痛、腹水、浮肿的发生,也能较好地提高晚期胰腺癌患者的生活质量,延长生命。 人参皂苷Rh2能减轻放、化疗的毒副作用,能明显改善患者白细胞降低、疲乏无力、易感染、食欲不振、睡眠不佳、恶心、呕吐、脱发等症状,提高患者生活质量,延长生存时间。 人参皂苷Rh2可以通过调控肿瘤细胞增殖周期、诱导细胞分化和凋亡来发挥抗肿瘤作用,且对多种肿瘤细胞具有广泛的抗肿瘤活性。与西药联合应用可减少西药用量,降低毒副作用,增强患者依从性。另外,人参皂苷Rh2具有很好的安全性,对神经系统、呼吸系统、心血管系统无明显影响,这与其它抗癌化疗药物有明显不同。人参皂苷Rh2作为一种天然抗肿瘤成分将为临床有效防治肿瘤疾病、为广大癌症患者解除病痛,预防癌症,癌症保养,使癌症康复成为可能。 人参皂苷rh2主要功效:人参皂苷Rh2可通过调节免疫功能,抑制肿瘤的浸

肾癌的临床分期

肾癌的临床分期 *导读:肾癌的临床表现变化多端,可无任何症状,但此时 肿瘤在体内已有广泛进展,甚至出现肺、骨等处转移征象。…… 肾癌的临床表现变化多端,可无任何症状,但此时肿瘤在体内已有广泛进展,甚至出现肺、骨等处转移征象。除血尿、腰痛和肿块三大典型症状外,肾癌还存在不少非泌尿系统的肾外表现如高热、肝功能异常、贫血、高血压、红细胞增多症和高钙血症等。 (1)局部肿瘤引起的症状: 血尿为最常见的症状,可为肉眼血尿和/或镜下血尿。腰痛是因 肿瘤长大后肾包膜张力增加或侵犯周围组织而发生,表现为持续性钝痛。肾癌患者腰部或上腹部可触及肿块约为10%,有时可为唯一的症状。精索静脉曲张常发生在左侧,为肿瘤压迫精索静脉引起,为继发性病变,平卧后曲张静脉不消失,表示静脉内有阻塞(或癌栓)。当下腔静脉受侵,可同时有下肢水肿出现。 (2)全身毒性症状: 由于肾癌为一高度恶性肿瘤,不少病人求诊时已有明显消瘦、贫血、低热、食欲减退等恶病体质,也可有肺或骨骼转移。发热为肾癌常见的肾外表现之一,有低热或高热,高热者可高达39~40℃,持续不退。贫血可由失血引起,但临床上有些肾癌患者没有血尿病史,却有明显贫血,说明患者的贫血除血尿引起外,还有其他原因,有作者认为可能与肿瘤毒素或大量肾组织破坏抑制了造血

有关。 (3)内分泌紊乱的症状: 根据大量实验研究和临床报道,肾癌能分泌多种内分泌素引起系列症状,一种肿瘤分泌多种内分泌素是肾细胞癌的特征。肾癌患者合并红细胞增多症的约占2%。10%~15%的肾癌病人有高血压。肾癌患者中的3%~16.8%有高钙血症,且大多为晚期病变。有研究报道肾癌组织内分泌肠高血糖素和血内高糖原分解素样活性 物质,导致胃肠道动态及吸收功能异常。少数肾癌并发促性腺激素增高,在男性引起乳腺增大、乳晕色素沉着及性欲减退,女性则引起多毛及闭经等。

肾细胞癌分子生物学研究进展与病理分型

肾细胞癌分子生物学研究进展与病理分型 肾细胞癌(renalcellcarcinoma,RCC)是泌尿系统常见的恶性肿瘤之一,长期危害着人类健康。近十年来,对肾细胞癌的分子生物学研究取得了长足的进展,使我们对肾细胞癌有了更深刻的认识。本文就肾细胞癌各种病理分型的分子生物学研究进展进行综述。 1肾细胞癌发生的分子生物机制 肾癌的发生发展是多阶段、多步骤的过程,包括癌基因激活和抑癌基因(tumorsuppressorgene,TSG)失活在内的一系列遗传学改变。抑癌基因的缺失或失活是肿瘤发生发展过程中重要的分子事件之一。肿瘤常在抑癌基因位点出现染色体基因缺失,表现为等位基因杂合性缺失(lossofheterozygosity,LOH),通过检测分析肿瘤LOH及其规律,可在染色体一定范围内发现肿瘤的抑癌基因及易感基因。为了能较全面的了解导致肾细胞癌发生发展的关键分子事件,不同学者对肾细胞癌全基因组进行了不同的研究,发现肾细胞癌发生高频率LOH主要见于以下几个染色体:3p、5q、8p、9p、10q、14q、17和18q染色体。 1.13号染色体:3号染色体短臂的部分缺失是肾癌基因改变中的高发事件。其中定位于3p25-26的VHL抑癌基因被认为是这些基因改变的首要目标。在以前的研究中,VHL在肾透明细胞癌(cc-RCC)中的失活机制主要为等位基因缺失和突变,DNA超甲基化很少见。刘宁等利用PCR限制性片段长度多态性法对3号染色体上的VHL基因的两个单核苷酸多态性位点进行检测来分析VHL基因的杂合性缺失失情况,发现,42%(8/19)发生VHL基因LOH,并未发现VHL基因失活与肿瘤的分期、分级存在联系。 有杂合性缺失研究显示,有可能在染色体3p上存在另外的RCC相关抑癌基因。定位于染色体3p14.2上包含最常见的FRA3B脆性位点的FHIT基因作为候选抑癌基因日益受到关注。Velickovic等通过选择性的检测FHIT区域的LOH发生情况认为这个基因在ccRCC的发展过程中起到很重要的作用。并且发现在cc-RCC中染色体3p的LOH发生率达76%。Farkas等对88例肾细胞癌病例进行LOH研究,选取了3p14.2-p25范围内16个位点采用PCR技术进行LOH分析,结果显示VHL基因和FHIT基因区域,透明细胞癌的LOH发生率高达96%,而乳头状细胞癌和嫌色细胞癌仅为10%和18%,并且LOH的发生率与肿瘤大小、分期、分级无关。从而认为VHL和FHIT的等位基因缺失是肿瘤发生的早期事件。 1.25号染色体:1986年APC基因首次在一位患有息肉病及多种其它先天性畸形患者的5号染色体长臂片段先天性中间缺失中得到证实,确切的基因位点随后由定位克隆确定。Pecina-SlausN等利用相对外显子11和15的特殊寡核苷酸引物

(整理)中国医科大学外科学复习题.

中国医科大学《外科学》复习题 第一章无菌术 一、名词解释 1.无菌术 2.灭菌法 3.抗菌法 二、问答题 1.药物浸泡消毒法适用于哪些器械?其注意事项是什么? 2.病人手术区的准备其目的是什么?若腹部手术区曾用胶布粘贴过,应如何用消毒? 第二章外科病人的体液失调 一、名词解释 1.高渗性脱水 2.反常性酸性尿 3.酸碱平衡 二、问答题 1.补钾时应注意哪些问题? 2.试述代谢性碱中毒的常见原因、临床表现和诊断依据。 第三章输血 一、名词解释 1.冷沉淀 2.自体输血 二、问答题 1.自体输血的禁忌证有哪些? 2.如何预防溶血反应,治疗重点有哪些? 第四章外科休克 一、名词解释 1.动静脉短路 2.中心静脉压 3.弥散性血管内凝血 4.毛细血管充盈 二、问答题 1.简述各项监测的临床意义及正常值。 2.简述皮质类固醇在休克治疗中的作用和用法。

第五章多系统器官功能不全综合征 一、名词解释 1.MODS 2.少尿和无尿 二、问答题 1.简述急性肾衰多尿期补液原则。 2.高血钾的常用药物治疗方法有哪些? 第六章麻醉 一、名词解释 1.全身麻醉 2.基础麻醉 3.最低肺泡有效浓度(MAC) 4.局部麻醉 5.全脊椎麻醉 6.蛛网膜下腔阻滞 7.硬膜外阻滞 8.表面麻醉 9.Mendelson综合征 10.分离麻醉 11.控制性降压 12.低温麻醉 二、问答题 1.腰麻后发生头痛的原因是什么? 2.气管内麻醉的优点? 3.腰麻血压下降的原因和处理。 第七章颅内压增高 一、名词解释 1.柯兴反应 2.颅内压增高 3.慢性颅内压增高三主征 4.颅内压体积压力反应 5.脑疝 6.血管源性脑水肿 7.细胞毒性脑水肿 二、问答题 1.什么是小脑幕切迹疝?主要有哪些临床表现? 2.何谓枕骨大孔疝?最常见的症状有哪些?

肾癌的基因表达谱及其临床意义的研究进展

肾癌的基因表达谱及其临床意义的研究进展 张守波 1,2△ ,肖耀军1(综述),廖贤平 1,2※ (审校) (1.武警广东省总队医院泌尿外科,广州510507;2.河北医科大学,石家庄050001) 中图分类号:R737.11 文献标识码:A 文章编号:1006- 2084(2012)14-2194-03摘要:基因芯片技术是近年来形成和发展的一项新的分子生物学技术。基因芯片技术能在转录 水平高通量、大规模、平行地处理大量基因信息,尤其是近来全基因组基因芯片技术的出现,使全面、综合分析某些生命现象成为可能。应用基因芯片技术检测肾肿瘤组织获得其基因表达谱,通过对表达谱的分析处理,发现肾肿瘤相关的特征性分子标志物,为肾癌的临床诊断、治疗、预后评估、病理分型, 以及新药开发等方面提供帮助。它的作用越来越巨大,正日益受到人们的重视。关键词:肾癌;肾肿瘤;基因芯片;基因表达谱;原蛋白转化酶 Research Progress of Gene Expression Profiling in Renal Carcinoma and the Clinical Significance ZHANG Shou-bo 1,2,XIAO Yao-jun 1,LIAO Xian-ping 1,2 .(1.Department of Urology ,Chinese People's Armed Police Forces Guangdong Provincial Corps Hospital ,Guangzhou 510507,China ;2.Hebei Medical University ,Shijiazhuang 050001,China ) Abstract :Gene microarray is a new molecular biological technique developed in recent years ,which can simultaneously deal with lots of gene information by high throughput ,especially that the emergence of ge-nome-wide gene-chip technology in recent years makes it possible to analyze some phenomenon of life com-prehensively.The profile of measured samples of renal tumor tissue can be gained ,then through the analysis of he expression profile ,characteristic molecular markers of the disease can be discovered to help the clinical diagnosis ,treatment ,prognosis assessment ,pathological classification and new medicine development ,which displays a growing function drawing more attention nowadays. Key words :Renal cell carcinoma ;Kidney tumor ;Gene microarray ;Gene expression profiling ;Pro-protein convertase 肾癌又称肾细胞癌,是成人最常见的一种肾实质恶性肿瘤。肾癌仅次于膀胱癌居泌尿系恶性肿瘤的第二位。肾癌的其他病理类型如乳头状肾细胞 癌、 嫌色细胞癌、集合管癌均呈一种下降趋势[1] 。研究更好的早期诊断技术是降低肾癌患者病死率、提高治愈率的关键。分子生物学技术已成为肾癌防治的关键途径之一,大多数肿瘤中抑癌基因和细胞周 期相关基因的表达皆有异常变化, 其在肾癌中变化将有助于肾癌的早期诊断、治疗及预后的评估。应 用基因表达谱技术研究肾癌组织的发生、 发展的分子生物学机制,有助于肾肿瘤的诊治和预后评估。现概述肾癌基因表达谱基因芯片分析技术方法及常用分子标志物的意义和对肾肿瘤分类、治疗和预后评估的意义及研究进展。 1肾癌基因表达谱基因芯片技术概述 肾癌基因表达谱基因芯片技术是一种基于分子水平利用芯片技术分析和筛选肿瘤标志物的新方法。肿瘤的发生和发展是许多基因相互作用和表达改变累积的结果,因此,研究基因表达谱比研究单个 基因更有利于认识肿瘤发生的分子机制[2] 。由于比较基因组杂交、差异显示技术、表达系列分析、基因芯片和人类基因组测序等几种基因表达谱技术的发展,使得人们能够更好地监控和研究导致肿瘤发生 和进展的层叠复杂的分子事件。其中, 基因芯片技术简单易行,不需要大规模DNA 测序,能够进行多 个样品数千个基因的定量分析[3] 。特异的基因组群往往与肿瘤的特定属性,如侵袭力、肿瘤血管生成及临床预后等方面相关联。基因表达谱还能用于肿瘤病理分类,细分出新的肿瘤亚类,并可与临床预后或药物疗效建立相关联。 2基因表达谱数据分析方法 基因表达谱分析产生大 量的原始数据, 需要用统计学方法的分析处理,为进一步研究提取有价值的信息[4] , 在进行进一步处理前须先进行数据标准化处理。该文只简单介绍两种常 用计算方法, 即无监督分析方法和监督分析方法[5] 。前者只处理原始数据,不结合患者的信息,用于基因表达谱具有较多相似性的不同基因簇中,找出不同 样品之间基因簇的较细微差异性, 是一种无主观偏见的分析方法。此法应用实例之一是通过分析基因 表达谱差异用分级聚类法分析鉴别出肾癌的病理亚型[6] 。后者则要结合患者的临床资料,进行数据等分析,鉴别出相关的特异性基因,揭示临床表现和分 析数据之间的相关性,为临床具体分组提供参数,比如肿瘤复发可能性[7] 。 3基因表达谱和染色体异常及原蛋白转化酶家族的关系 分析比较基因表达谱和原蛋白转化酶及其加工成熟的神经肽因子活性表达的差异。肾癌分子水平的分类可以借鉴细胞遗传学研究染色体异常的方法,如运用常规的G 带显带技术、小随体分析法和杂合子丢失等方法研究染色体的变异(非整倍性)与各 种肾癌组织类型的相关性[8] 。肾嫌色细胞癌以丢失1、2、6、10、13和17中两个或以上的染色体为特征,使用比较基因组微列阵分析法(comparative genomic microarray analysis CGMA )能从芯片数据间接预测染 色体异常[9] 。由于肿瘤细胞染色体的异常导致基因表达谱的异常,所以通过分析基因表达谱可以推测 · 4912·医学综述2012年7月第18卷第14期Medical Recapitulate , Jul.2012,Vol.18,No.14

肿瘤细胞株

Tca8113-P160人舌癌细胞株 TSCCA人舌鳞癌细胞株 CaES-17人食管癌细胞株 Ec109人食管癌细胞株 Hep-2人喉癌细胞株 SPC-A1人肺癌细胞株 A549人肺癌细胞株 GLC-15人肺腺癌细胞株 HAC-84人肺泡癌细胞株 ACC-M人唾液腺性肺癌高转移细胞株NCL-H446人肺癌细胞株 M14人肺癌细胞株 H460人大细胞肺癌细胞株 Calu-6人肺癌细胞系未分化癌细胞株 95-D人高转移肺癌细胞株 95-C人低转移肺癌细胞株 H292人表皮肺癌细胞株 DMS153人小细胞肺癌细胞株 PG49人肺腺癌细胞株 PG-BE1人肺巨细胞癌PG的高转移亚系PG-LH7人肺巨细胞癌PG的低转移亚系A2人肺腺癌细胞株 973人肺腺癌细胞株 LTEP-a-2人肺腺癌细胞株 Z-HL16C人胚肺成纤维细胞突变癌细胞株HS-746T人胃癌细胞株 AGS人胃腺癌细胞株 Hs746T人胃癌细胞株 MGC-803人胃腺癌细胞株 SGC7901人胃癌细胞株 BSG823人胃癌细胞株 T-24人移行细胞膀胱癌细胞株 BIU-87膀胱癌细胞株 HT-1376人膀胱癌细胞株 MG-63人成骨肉瘤细胞株 Saos-2人生骨肉瘤细胞株 HOS人骨肉瘤细胞株 U-2OS人骨肉瘤细胞株 OS-732人骨肉瘤细胞株 RPMI-8226人多发骨髓瘤 A-204人横纹肌肉瘤细胞株 HT1080人纤维肉瘤细胞株 HT-1080人纤维肉瘤细胞株 U251星形胶质瘤细胞株

DaudiBurkitts淋巴瘤细胞株 CA46Burkitts淋巴瘤细胞株 ACHN人肾癌细胞株 769-P人肾癌细胞株 A498人肾癌细胞株 786-O人肾透明细胞腺癌细胞株 SW13人肾上腺皮质瘤细胞株 Ketr-3人肾癌瘤株细胞株 RCC-krause人肾癌细胞株 SK-RC-42人肾癌细胞株 H4人脑神经胶质瘤细胞株 BT-325人脑多形性胶质母细胞瘤细胞株SGH44人脑胶质细胞瘤细胞株 TJ905人脑恶性胶质瘤细胞株 U-373MG人脑胶质瘤细胞株 SF126人脑瘤细胞株 SF17人脑瘤细胞株 SF763人脑瘤细胞株 SF767人脑瘤细胞株 SH-SY5Y人成神经细胞瘤细胞株 M17人神经母细胞瘤细胞株 LAN-5人神经母细胞瘤细胞株 SK-N-SH人神经母细胞瘤细胞株 LAN-6人神经母细胞瘤细胞株 SK-N-DZ人成神经瘤细胞-骨髓 PC-3人前列腺癌细胞株 DU145人前列腺癌细胞株 LNCaP人前列腺癌细胞株LNCaPCloneFGC人前列腺癌细胞株 Tsu-Prl人非雄激素依赖型前列腺癌细胞株22RV1人前列腺癌细胞株 PC-3M1E8人前列腺癌细胞高转移亚系PC-3M2B4人前列腺癌细胞低转移亚系SW1990人胰腺腺癌细胞株 PANC-1人胰腺腺癌细胞株 PL45人胰腺导管腺癌细胞株 HPAC人胰腺癌细胞株 Panc03.27人胰腺癌细胞株 Panc08.13人胰腺癌细胞株 Panc10.05人胰腺癌细胞株 Panc05.04人胰腺癌细胞株 Panc02.03人胰腺癌细胞株 F56人腺癌细胞株 ACC-2人诞腺腺样囊性癌细胞株

外科护理学B第5次作业

A.疼痛发热肿块 B.血尿肿块高血压 C.血尿肿块疼痛 D.血尿疼痛高血压 E.血尿发热肿块 A.绝对卧床休息2-4周,至血尿消失 B.恢复后一个月禁止剧烈活动或体力活动 C.肾动脉内膜损伤行血管吻合术应在损伤24小时内做手术 D.开放性肾损伤应尽早行手术治疗 E.非手术治疗适合肾挫伤、轻度肾裂伤及无其他合并脏器损伤的病人 A.舌后坠 B.口腔分泌物误吸 C.口腔异物阻塞气道 D.喉头水肿 E.气管导管扭折 A.梗阻的程度 B.梗阻发生速度 C.梗阻是否绞窄 D.梗阻的部位 E.梗阻的原因

A.补充血容量 B.纠正酸碱失衡 C.应用血管活性药物 D.应用皮质激素 E.心肺复苏 A.腹痛腹胀 B.腹泻 C.肠梗阻 D.高血糖 E.恶心呕吐 A.拔管前必须做T管造影 B.病人无发烧.腹痛、黄疸等症状 C.拔管前要做夹管实验 D.引流造影剂后,再次夹管2-3天,无不适即可拔管。 E.术后10天可拔除 A.可出现于损伤程度成比例的血尿 B.可出现腰腹部疼痛 C.腰腹部包块 D.发热 E.可引起失血性休克 A.24小时内脓液<10ml B.24小时内引流量<60ml C.无呼吸困难 D.X线提示肺膨胀良好 E.无气体溢出

A.维持负压吸引 B.引流管没入液面10cm C.水柱波动范围在2-4cm D.水柱无波动可能提示肺不张 E.低于胸腔50cm A.粪便变细 B.粘液血便 C.全身症状 D.肿块 E.直肠刺激症状 A.颈项强直,强迫头位 B.生命体征紊乱较早 C.意识改变较早 D.突然呼吸不规则或停止 E.会出现颅内压增高症状 A.8h B.10h C.12h D.24h E.6h A.输尿管结石 B.肾癌伴有血块 C.肾盂肾炎 D.肾下垂 E.肾脏结石

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