Predictive value of expression of p16INK4A, retinoblastoma and p53 proteins for the prognosis of non-small-cell lung cancers

The predictive value of expression of p16INK4A, retinoblastoma (Rb) and p53 proteins for prognosis was evaluated in 76 patients with non-small-cell lung cancers (NSCLCs) that were potentially curatively resected between 1990 and 1995, using the results of immunostaining analyses of these proteins as reported in our previous study (Kinoshita et al, 1996). Of these NSCLCs, 22 (29%) lacked p16 protein expression and eight (11%) Rb protein, while 30 (39%) showed positive (altered) p53 protein expression. Survival of patients with p16-negative tumours was not significantly different from that of patients with p16-positive tumours (5-year survival rates 67% and 72% respectively, P = 0.8), nor was survival of patients with Rb-negative tumours significantly different from that of patients with Rb-positive tumours (5-year survival rates 42% and 69% respectively, P = 0.9). Moreover, survival of patients with p16/Rb-negative (either p16- or Rb-negative) tumours was not significantly different from that of patients with p16/Rb-positive (both p16- and Rb-positive) tumours (5-year survival rates 67% and 68% respectively, P = 0.7). In contrast, survival of patients with p53-positive (altered) tumours tended to be shorter than that of patients with p53-negative (unaltered) tumours (5-year survival rates 56% and 78% respectively, P = 0.06). In univariate analysis of potential prognostic factors, p16, Rb and p16/Rb proteins were not significant prognostic factors in the present cohort of potentially curatively resected NSCLCs. Altered p53 protein status tended to be a negative prognostic factor (P = 0.06 by the univariate analysis). These results indicate that loss of p16 protein alone, or in combination with loss of Rb protein, does not predict the clinical outcome of patients with resected NSCLCs.     

p16、Rb蛋白在非小细胞肺癌中的表达及意义

 目的 探讨视网膜母细胞瘤蛋白质（Rb）和p16蛋白在非小细胞肺癌（NSCLC）中的表达及其与临床病理因素之间的关系。方法 采用免疫组化SP法检测80例NSCLC组织中Rb和p16蛋白的表达。结果 在80例NSCLC组织中， 分别有56例（70.00 %）和47例（58.75 %）显示Rb和p16蛋白表达缺失。两者之间有一定相关性（P＜0.05）。p16蛋白在鳞状细胞癌比腺癌中有较高的表达（P＜0.05），而Rb蛋白的表达异常与肿瘤分期有关（P＜0.05）。结论 Rb／p16路径的中断是肺癌的发生、发展中常见事件。     

PML、P53和P16INK4A在肺癌中的表达及其与临床预后的关系

背景与目的 作为肿瘤抑制因子,早幼粒细胞白血病(PML)蛋白同P53和P16INK4A在肺癌中的表达关系、以及PML与肺癌临床预后关系不明.本研究旨在揭示三者在肺癌中的表达关系,以及与临床和预后之间的联系.方法 构建包含144例肺癌,12例肺良性肿瘤和正常组织的组织芯片,利用SP免疫组化检测蛋白表达.阳性率比较采用列联表法.Kaplan-Meier法用来估计生存差异,组间比较应用Log rank检验.Cox风险比例模型用来进行单因素和多因素生存分析.结果 PML在121例非小细胞肺癌(NSCLC)和23例小细胞肺癌(SCLC)细胞浆的表达率分别为14.0%和39.1%(P=0.010),在细胞核的表达率分别为31.4%和8.7%(P=0.026);PML阳性SCLC患者的5年生存率50%,显著高于阴性者的23%(P=0.047);多因素分析显示PML表达是SCLC预后的保护因素.P53在肺癌的阳性率为33.3%,在肺良性肿瘤和正常组织无表达(P=0.038);P16INK4A在肺癌(28.5%)尤其在分化低和未分化肺癌(36.5%)、SCLC(69.6%)中高表达.肺癌中PML细胞核表达与P16INK4A表达呈负相关,P53与P16INK4A在肺癌和腺癌的表达呈正相关,PML与P53在鳞癌的表达呈负相关.结论 作为肿瘤抑制因子,PML在鳞癌中与P53基因突变存在联系,并可能与P16INK4A共同成为SCLC的标记物;肺癌中高表达的P16INK4A蛋白可能是基因突变产物,与突变型P53蛋白存在相关性.     

Differential retinoblastoma and p16(INK4A) protein expression in neuroendocrine tumors of the lung

BACKGROUND: Neuroendocrine neoplasms of the lung represent a wide spectrum of phenotypically and biologically distinct entities. Their histopathologic diagnosis, which carries therapeutic and prognostic significance, may sometimes be difficult because of their overlapping features. We previously demonstrated that large cell neuroendocrine carcinomas (LCNECs) and small cell lung carcinomas (SCLCs) failed to show positive nuclear staining of RB protein (RB-), whereas typical and atypical carcinoids (TCs and ACs) showed nuclear RB immunostaining (RB+). METHODS: In the current study, a series of 58 surgically resected lung tumors, of which 33 tumors were initially diagnosed as SCLCs and 25 as TCs or ACs, were studied for RB and p16 protein expression by immunohistochemistry. They were also reviewed for their pathologic diagnosis; the reviewers were blinded to the RB and p16 protein status. RESULTS: Nineteen tumors were diagnosed as TCs, 5 as ACs, 7 as LCNECs, and 27 as SCLCs. Three of seven LCNECs were RB+, whereas the other four were RB-. In contrast, all 19 TCs were RB+ and all 27 SCLCs were RB-. In addition, two of five ACs were RB+, whereas the other three were RB-. Interestingly, all 3 RB+ LCNECs and the 1 RB+ AC tested failed to show nuclear staining of p16 protein in any tumor cells (p16-), although some normal stromal cells showed nuclear staining of p16 protein (p16+) as positive internal controls, indicating loss of p16 function in these tumors. It is also noteworthy that the three RB+ LCNECs were initially diagnosed as SCLCs and one of the RB- ACs was initially considered a TC. With the exception of TCs, tumors were significantly more prevalent among heavy smokers with >20 pack-years compared with nonsmokers and light smokers with < or = 20 pack-years (P < 0.01). CONCLUSIONS: These findings suggest that all SCLCs and LCNECs have abnormalities in the p16:RB pathway, as do at least certain ACs, whereas the p16:RB pathway is normal in TCs.     

Mutation and abnormal expression of P16INK4a in hepatocellular carcinoma

Objective: To investigate the relationship between p16^INK4a and primary hepatocellular carcinoma (HCC), especially hepatitis B-related HCC. Methods: p16^INK4a and its protein in HCC were analyzed with PCR-SSCP and the immunohistochemistry methods respectively. Results: The positive incidence of p16^INK4 protein expressing in HCC was lower than that of normal liver tissue (P<0.05), and the absence of p16^INK4 protein was associated with HCC metastasis (P<0.05). The low frequency of mutation of p16^INK4 exon1 and exon2 upstream fragment was found in HCC. Conclusion: Absence of p16^INK4 protein in HCC was not associated with HBV-infection.     

肺癌组织SKP2和p16蛋白表达及其临床意义的探讨

达降低共同在肺癌的发生发展中起促进作用,且它们对肿瘤的恶性程度也有相反的影响,但它们之间相互作用的具体机制尚需进一步研究.     

Intragenic mutations of the p16INK4, p15INK4B and p18 genes in primary non-small-cell lung cancers

The p15^INK4B, pp16^INK4 and p18 genes are members of the gene family coding for inhibitors of cyclin-dependent kinases 4 and 6. p15^INK4B and p16^INK4 are located at 9p21, a chromosomal region frequently deleted in many human neoplasms. To examine the role of these 3 genes in lung carcinogenesis, somatic mutations within the genes were analyzed by single-strand conformation polymorphism and DNA sequencing in 71 non-small-cell lung cancer (NSCLC) samples. Six somatic mutations in the p16^INK4 gene and 3 cases with a polymorphic allele were observed. Loss of heterozygosity in the p18 gene was found in I sample. We did not find any, intragenic mutations in the p15^INK4B orp18 genes. We conclude that p16^INK4 mutations play a role in the formation of some NSCLCs, whereas the involvement of p15^INK4B and p18 is uncommon. © 1996 Wiley-Liss, Inc.     

P16INK4A和PTEN在高危型HPV相关宫颈癌组织中的表达及意义

背景与目的:高危型人乳头状瘤病毒(high-risk human papillomavirus,HR-HPV)是宫颈癌最主要的致病因素,目前研究发现,在宫颈上皮癌变过程中,P16INK4A的异常表达和HR-HPV感染密切相关;同时,另一抑癌基因PTEN也参与了宫颈上皮肿瘤的形成.本研究旨在探讨宫颈上皮癌变过程中P16INK4A、PTEN表达与HR-HPV感染的关系及其意义.方法:应用免疫组织化学方法检测P16INK4A蛋白和PTEN蛋白在30例正常宫颈组织、11例原位癌、24例宫颈浸润癌组织中的表达.用第二代杂交捕获法(HC-2)检测每一病例的13种HR-HPV DNA.结果:HR-HPV和P16INK4A阳性率浸润癌组(91.7%、87.5%)和原位癌组(90.9%、81.8%)都明显高于正常宫颈组(30.0%、6.7%),差异有统计学意义(P＜0.001).P16INK4A过表达(中、强阳性)和HR-HPV阳性同时出现有30例,其中原位癌组9例,浸润癌组21例;两者同时阴性有23例,其中正常宫颈组20例,原位癌组1例,浸润癌组2例.相关性分析结果显示,HR-HPV感染与P16INK4A表达呈正相关(rs=0.690,P＜0.001).26例PTEN中、强阳性表达均在正常宫颈组,其阳性率在浸润癌组(37.5%)和原位癌组(36.4%)明显低于正常宫颈组(83.3%),差异有统计学意义(P＜0.01).相关性分析证实,HR-HPV感染与PTEN表达的相关性无统计学意义(rs=-0.174,P=0.167).结论:在HR-HPV感染的宫颈癌中,P16INK4A出现过表达,其蛋白的肿瘤抑制功能不明显;PTEN独立于HR-HPV途径,以其功能下调促进宫颈癌的发生、发展.     

鼻咽癌组织中P16、CD4和CD8的表达及其与预后的关系

目的 探讨鼻咽癌组织中P16、CD4和CD8的表达及其与鼻咽癌患者临床特点及预后的关系.方法 采用免疫组化法检测133例鼻咽癌组织中P16、CD4和CD8的表达情况,分析其表达与鼻咽癌临床病理特征及预后的关系.结果 133例鼻咽癌组织中,P16的阴性表达率为75.9％(101/133),阳性表达率为24.1％(32/133);CD4的阴性表达率为75.2％(100/133),阳性表达率为24.8％(33/133);CD8阴性表达率为76.7％(102/133),阳性表达率为23.3％(31/133).P16与CD4在鼻咽癌组织中的表达差异有统计学意义(P＜0.05),二者呈正相关趋势(r=0.206,P=0.094);P16、CD4和CD8在不同性别、年龄、民族、吸烟史、肿瘤家族史、临床分期患者中的表达差异均无统计学意义(P＞0.05),但P16表达在不同性别患者(P=0.069)、CD8表达在不同临床分期患者(P=0.085)中的差异均为临界值;P16、CD4、CD8阴性表达和阳性表达患者5年总生存率差异无统计学意义(P＞0.05),但CD4阳性表达与阴性表达患者5年无瘤生存率(P=0.002)及5年无局部复发生存率(P=0.024)差异均有统计学意义.结论 P16、CD4和CD8表达与鼻咽癌患者性别、临床分期有关.CD4阳性表达患者预后可能更佳,联合检测P16、CD4和CD8在鼻咽癌中的表达或可作为判定鼻咽癌患者生物学行为及预后评估的依据.     

Prognostic significance of p16 and CDK4 proteins in localized prostate carcinoma

BACKGROUND: In prostate carcinoma, a very low frequency of point mutations of the tumor suppressor gene CDKN2/MTS1 (p16(INK4) ) has been reported, but deletions of 9p21 and inactivation by promoter methylation are observed more frequently. In the current study the authors evaluated the expression of p16 and CDK4 proteins and their prognostic significance in patients with clinically localized prostate carcinoma. METHODS: The levels of p16 and CDK4 proteins were quantitated by immunofluorescence flow cytometry, using paraffin embedded material, in 104 adenocarcinomas of the prostate after radical prostatectomy. These levels then were compared with 25 cases of benign prostate hyperplasia (BPH). RESULTS: In prostatic carcinoma specimens, p16 protein was elevated significantly compared with BPH, with a median fluorescence index (FI) of 15.4 versus 10.7, respectively (P = 0.010). This was not the case for CDK4 protein, although p16 protein expression correlated significantly with CDK4 protein expression in BPH (Spearman rank correlation [R(S)] = 0.63) and carcinoma (R(S) = 0.78). In univariate survival analysis of the first 5 years, high levels of p16 protein expression (FI > 11.7) (P = 0.005), tumor greatest dimension, World Health Organization (WHO) histologic grade, capsular penetration, seminal vesicle invasion, positive surgical margins, lymph node involvement, and preoperative serum prostate specific antigen > 20 ng/mL all were significant predictors of biochemical failure. In multivariate survival analysis, high p16 protein expression (P = 0.015), age, WHO histologic grade, capsular penetration, and seminal vesicle involvement remained as independent predictors of biochemical failure. CONCLUSIONS: These data suggest that increased expression of p16 protein, but not CDK4 protein, may be involved in the development of prostate carcinoma and may represent an independent predictor of biochemical failure after radical prostatectomy.     

P16INK4a Overexpression is Associated with Poor Clinical Outcome in Ovarian Carcinoma

Abstract

Tigecycline is the first Food and Drug Administration (FDA) approved glycylcycline antibiotic. It has shown remarkable in vitro activity against a wide variety of Gram-positive, Gram-negative and anaerobic bacteria including many multidrug resistant (MDR) strains. However, it has minimal activity against Pseudomonas aeruginosa and Proteus spp. To date, little resistance to tigecycline has been reported. Clinical trials studying complicated skin and skin-structure infections (cSSSIs) demonstrated that tigecycline has equivalent efficacy and safety compared with the combination of van-comycin and aztreonam. For complicated intra-abdominal infections (cIAIs), tigecycline was found to be as effective as imipenem/cilastatin. Adverse events related to tigecycline therapy, i.e. nausea and vomiting, were tolerable. Currently available data suggest that tigecycline may play an important role in the future as a monotherapy alternative to older broad-spectrum antibiotics, such as advanced generation cephalosporins, carbapenems, fluoroquinolones, piperacillin/tazobactam, and Gram-positive directed agents (e.g. daptomycin, linezolid and quinupristin/dalfopristin) for which resistance is being increasingly reported from all parts of the world.     

P16INK4A、Brn-3a、C-myc及端粒酶在宫颈癌中的诊断价值研究

目的 探讨P16INK4A、Brn-3a及C-myc基因表达及端粒酶活性在宫颈癌诊断中的价值。方法 选取2012年3月至2014年5月接受手术治疗的宫颈癌患者40例,检测宫颈癌组织中P16INK4A、Brn-3a、C-myc的表达情况及端粒酶活性水平。同时选取40例宫颈上皮内瘤样病变（CIN）组织和28例正常宫颈组织作对比。采用受试者工作特征曲线（ROC）评价组织中P16INK4A、Brn-3a、原癌基因C-myc及端粒酶活性水平在宫颈癌诊断中的价值。结果 宫颈癌组织中P16INK4A、Brn-3a和C-myc的阳性表达率分别为100.0％、95.0％和100.0％,均高于正常宫颈和CIN组织,差异有统计学意义（P＜0.05）;CIN Ⅱ和CIN Ⅲ组织的P16INK4A阳性表达率高于正常宫颈和CINⅠ组织（P＜0.05）;正常宫颈组织中Brn-3a和C-myc阳性表达率均为7.14％,明显低于其他组织（P＜0.05）;宫颈癌组织中端粒酶活性水平为（44.38±3.82）U／g,高于其余各组,差异有统计学意义（P＜0.05）。Brn-3a、C-myc诊断宫颈癌的曲线下面积Az＞0.8,且灵敏度和特异度均在80.0％以上,而P16INK4A及端粒酶活性水平的诊断效能相对较低,但4个指标联合检测的诊断效能获提高,灵敏度和特异度分别为89.5％和83.4%,曲线下面积Az为0.879。结论 宫颈癌组织中P16INK4A、Brn-3a、C-myc表达水平和端粒酶活性异常,可能与宫颈癌的发生发展有密切关系,可作为宫颈癌诊断的参考指标。     

P16INK4A在宫颈上皮内瘤变中的表达及与HPV感染的关系

目的 探讨抑癌基因P16INK4A在宫颈上皮内瘤变中的表达情况及其与HPV感染的相关性.方法 采用免疫组化染色法,对59例宫颈上皮瘤变(CIN)标本、30例病理检查为正常宫颈组织的标本进行检测.结果 CIN Ⅰ级组织中ILK表达阳性率62.50％、CIN Ⅱ～Ⅲ级为65.71％,均显著高于正常宫颈组织(23.33％),且差异均具有统计学意义(x2=8.472,P=0.004＜0.05;x2=11.675,P=0.001 ＜0.05);CIN Ⅰ级组织中ILK表达阳性率与CIN Ⅱ～Ⅲ级比较差异无统计学意义(x2=0.064,P =0.800 ＞0.05).P16INK4A在HPV16、HPV18 2种高危型宫颈HPV感染中的表达显著高于其他高危型或者低危型(HPV53、HPV58、HPV6).结论 P16INK4A在宫颈上皮内瘤变(CIN)中显著高表达,同时P16INK4A高表达可能与HPV16、HPV18的阳性表达具有协同作用.     

P16 P15及VEGF蛋白在原发性卵巢癌中的表达及临床意义

  目的   探讨P16、P15及血管内皮生长因子(VEGF)在原发性卵巢癌中表达情况及其与临床病理特征的关系。   方法   采用免疫组织化学S-P法对170例原发性卵巢癌、60例交界性肿瘤及60例良性肿瘤组织进行P16、P15和VEGF蛋白检测。   结果   P16在卵巢癌的表达率为40.0%(68/170), 明显低于良性肿瘤组65.0%(39/60)和交界性肿瘤组56.7%(34/60)(P < 0.05);P15在卵巢癌组的阳性表达率为45.3%(77/170), 显著低于良性肿瘤组68.3%、交界性肿瘤组61.7%(37/60)(P < 0.05);VEGF在卵巢癌组的阳性表达率为71.2%(14/170), 明显高于良性肿瘤组45.0%(27/60)和交界性肿瘤组53.3%(32/60)(P < 0.05)。在卵巢癌组中, P16和P15表达呈正相关(r=0.294, P < 0.01), VEGF与P16和P15的表达呈负相关(r值分别为-0.461和-0.251, P < 0.01)。三者表达强度与肿瘤分化程度、临床分期、淋巴结转移有显著相关性, 肿瘤分化越低、临床分期越高、淋巴结转移者P16、P15阳性表达率越低(P < 0.05), VEGF阳性表达率越高(P < 0.05)。P16和P15的表达与有无脉管瘤栓无关, VEGF在有脉管瘤栓组的表达高于无脉管瘤栓组。   结论   P16和P15的低表达与VEGF蛋白高表达在卵巢癌的发展过程中可能起协同作用, 共同促进卵巢癌的恶性发展进程。      

肺癌p14ARF和p16INK4a基因协同表达缺失及其意义

目的：研究抑癌基因位点ＩＮＫ４ａ－ＡＲＦ在肺肿瘤细胞中的表达状况,揭示ｐ１４ＡＲＦ和ｐ１６ＩＮＫ４ａ协同表达缺失与肺癌发生发展的相关性。方法：用ＲＴ－ＰＣＲ和Ｗｅｓｔｅｒｎ ｂｌｏｔ对６株肺癌细胞（ＳＰＣ－Ａ－１,Ｃａｌｕ－１,Ｈ４４６,ＳＨ７７,Ａ５４９,Ｈ４６０）的ＩＮＫ－４ａ－ＡＲＦ基因位点在ｍＲＮＡ、蛋白水平上进行检测,对ＰＣＲ产物进行纯化和测序分析。结果：６株肺癌细胞中,有３株细胞（Ｈ４     

Clinical significance of IGF1R expression in non-small-cell lung cancer

BackgroundThe purpose of the current study was to clarify the clinical role of insulin-like growth factor receptor-1 (IGF1R) in NSCLC.Patients and MethodsTumor specimens were collected from 285 patients who underwent complete resection for adenocarcinoma (AD, n = 182), squamous cell carcinoma (SCC, n = 77), and other histologic types of cancer (n = 26) of the lung. The expression of IGF1R and Ki-67 was evaluated by immunohistochemical (IHC) analysis.ResultsPositive expression of IGF1R was detected in 87 (30.5%) of 285 cases, of which 43 (23.6%) of 182 cases were AD, 36 (46.8%) of 77 cases were SCC, and 8 (30.8%) of 26 cases were other histologic types (SCC vs. AD, p < .001; SCC vs. non-SCC, p < .001). Positive IGF1R expression was also identified in 20 (44.4%) and 67 (27.9%) of the patients with and without recurrence, respectively (p = .027). Multivariate logistic regression models indicated that positive staining for IGF1R expression was an independent factor in AD associated with tumor recurrence (p = .040) but not in NSCLC, SCC, and other types of cancer. A positive IGF1R expression tended to demonstrate a poor disease-free survival (DFS) in NSCLC according to the Kaplan-Meier DFS curves (p = .053). The tumors showing a positive expression of IGF1R were observed more frequently in tumors with a positive expression of Ki-67 than in the tumors with a negative expression of Ki-67 (p = .010).ConclusionIGF1R expression was associated with reduced DFS correlating with postoperative recurrence. In addition, a significant relationship was also observed between IGF1R and Ki-67 expression in NSCLC. However, in subgroup analysis, a significant correlation was not observed. IGF1R expression predicts postoperative recurrence in patients with AD, but not in those with non-AD of NSCLC.     

Clinical significance of p21 expression in non-small-cell lung cancer.

PURPOSE: The clinical significance of p21 expression remains unclear, whereas many experimental studies have demonstrated that p21, the product of the WAF1/CIP1/SDI1 gene, plays an important role in regulation of the cell cycle as an inhibitor of cyclin-dependent kinases. The purpose of this study was to clarify the clinical significance in resected non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: A total of 233 consecutive patients with completely resected pathologic stage I to IIIA NSCLC were retrospectively reviewed. Expression of p21 and the status of p53 were examined immunohistochemically. Proliferative activity was also evaluated immunohistochemically. The incidence of apoptotic cell death was evaluated by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end-labeling staining. RESULTS: Expression of p21 was positive in 120 patients (51.5%). The 5-year survival rate of p21-positive patients was 73.8%, significantly higher than that of p21-negative patients (60.7%; P =.006). Aberrant expression of p53 was positive in 98 patients (42.1%). When combined with p53 status, the prognostic value of p21 status was enhanced: the 5-year survival rate of p21-positive and p53-negative patients was 80.7%, markedly higher than that of p21-negative and p53-positive patients (50.0% for both; P =.001). Multivariate analysis confirmed that positive expression of p21 was a significant factor for predicting a favorable prognosis. There was no significant correlation between p21 expression and p53 status, proliferative activity, or incidence of apoptosis. CONCLUSION: p21 expression was shown to be an independent prognostic factor in NSCLC.