Expression of cyclin D2 is an independent predictor of the development of hepatic metastasis in colorectal cancer

Introduction Cyclin D1 has been implicated in the progression of several cancers by virtue of its influence on progression of the G1/S phase of the cell cycle. However, little is known about the possible roles of cyclin D2 and D3 in colorectal cancers (CRCs). Method We investigated the expression levels of cyclin D2 and D3 in 84 CRC specimens. Antigen expression was determined by immunohistochemical analysis of cyclin D1, D2, D3, p16INK4A and Ki67 on tissue microarrays constructed using core samples from tumour centres and margins. Results For the whole cohort, expression of cyclin D2 at the margin was associated with vascular invasion (P = 0.039), lymph node metastasis (P = 0.020) and liver metastasis (P < 0.001). In patients with stage I and II tumours (n = 84), elevated cyclin D2 and D3 were associated with vascular invasion (P = 0.014 and 0.028 respectively), liver metastasis (P = 0.001 and 0.007 respectively) and reduced disease specific survival (Cyclin D2, P < 0.022). No association was noted between the proliferative marker Ki‐67 and the D‐type cyclins. Conclusion These findings suggest that cyclin D2 expression at the invasive margin of CRCs is associated with liver metastasis and may serve as a useful prognostic marker and indicator of the need for adjuvant therapy.     

Cyclin D1、p27、ki-67在膀胱移行细胞癌中的表达及其意义

目的探讨Cyclin D1、p27、ki-67在膀胱移行细胞癌（BTCC）中的表达及其临床意义。方法采用免疫组化SP法检测72例BTCC和8例正常膀胱黏膜组织中Cyclin D1、p27、ki-67的表达。结果CyclinD1及ki-67在BTCC中的表达明显高于正常对照，而p27的表达低于正常对照，且均与膀胱肿瘤的分级分期相关。结论Cyelin D1、p27、ki-67的表达可能与BTCC的生物学行为有关。     

Evaluation of p21WAF1/CIP1 and cyclin D1 expression in the progression of superficial bladder cancer

Immunoreactivity of p21^WAF1/CIP1 and cyclin D₁ proteins was assessed in a cohort of 207 patients with superficial (pTa-pT₁) bladder cancer followed up for a mean of 4.9 years. The results of the immunostainings were compared with T category, WHO grade, tumor cell proliferation rate (MIB-1 score), the expressions of p53 and bcl-2 as well as survival. Sixty-eight percent and 75% of the tumors were p21^WAF1/CIP1 positive (≥5% of cells positive) and cyclin D₁ positive (≥10% of cells positive), respectively. The p21^WAF1/CIP1 expression was related to cyclin D₁ immunolabelling (P < 0.001) but not to the other variables studied. The expression of cyclin D₁ was inversely associated with T category (P=0.001), WHO grade (P=0.006), MIB-1 score (P=0.014), p53 expression (P=0.001), and bcl-2 (P=0.011) immunoreactivity. In univariate analysis, T category (P=0.0001), WHO grade (P < 0.0001), MIB-1 score (P < 0.0001), bcl-2 (P=0.0092), p53 (P=0.0016) and p21^WAF1/CIP1 (P=0.009) expressions were significant prognostic factors with regard to tumor progression, whereas cyclin D₁ was without any prognostic significance (P=0.1). Out of 123 p21 positive tumors 21 progressed, whereas only 2 out of 58 p21 negative tumors progressed. In multivariate analysis, the MIB-1 score was the only independent predictor of cancer-specific survival (P=0.03), whereas tumor grade (P=0.002) and cyclin D₁ expression (P=0.04) were independent predictors of tumor recurrence. Only the WHO grade (P=0.04) retained its prognostic value indicating the risk of progression. We suggest that in superficial bladder cancer p21^WAF1/CIP1 and cyclin D₁ immunohistochemistry provide no additional prognostic information compared with already established prognostic factors for predicting the risk of progressive disease. Received: 13 September 1999 / 22 March 2000     

Significance of preoperative butyrylcholinesterase as an independent predictor of survival in patients with muscle-invasive bladder cancer treated with radical cystectomy

ObjectivesButyrylcholinesterase (BChE) is an alpha-glycoprotein found in the nervous system and liver. Its serum level is reduced in many clinical conditions, such as liver damage, inflammation, injury, infection, malnutrition, and malignant disease. In this study, we analyzed the potential prognostic significance of preoperative BChE levels in patients with muscle-invasive bladder cancer (MIBC) undergoing radical cystectomy (RC).Methods and materialsWe retrospectively evaluated 327 patients with MIBC who underwent RC from 1996 to 2013 at a single institution. Serum BChE level was routinely measured before operation in all patients. Covariates included age, gender, preoperative laboratory data (anemia, BChE, lactate dehydrogenase, and C-reactive protein), clinical T (cT) and N stage (cN), tumor grade, and RC with/without neoadjuvant chemotherapy. Univariate and multivariate analyses were performed to identify clinical factors associated with overall survival (OS) and disease-free survival (DFS). Univariate analyses were performed using the Kaplan-Meier and log-rank methods, and the multivariate analysis was performed using a Cox proportional hazard model.ResultsThe median BChE level was 187 U/l (normal range: 168–470 U/l). The median age of the enrolled patients was 69 years, and the median follow-up period was 51 months. The 5-year OS and DFS rates were 69.6% and 69.3%, respectively. The 5-year OS rates were 90.1% and 51.3% in the BChE≥168 and<168 U/l groups, respectively (P<0.001). The 5-year DFS rates were 83.5% and 55.4% in the BChE≥168 and≤167 U/l groups, respectively (P<0.001). In the univariate analysis, BChE, cT, cN, and RC with/without neoadjuvant chemotherapy were significantly associated with both OS and DFS. Multivariate analysis revealed that BChE was the factor most significantly associated with OS, and BChE, cT, and cN were significantly associated with DFS.ConclusionsThis study validated preoperative serum BChE levels as an independent prognostic factor for MIBC after RC.     

P-cadherin as a prognostic indicator and a modulator of migratory behaviour in bladder carcinoma cells

OBJECTIVE

To identify changes associated with P‐cadherin expression in bladder cancer and evaluate the potential role of such events in determining the clinical outcome and cell behaviour, as the function of P‐cadherin in normal epithelium is unknown, as is its potential role in neoplastic progression in different cancers.

MATERIALS AND METHODS

In all, 536 bladder tumour specimens from 408 patients were assembled in seven tissue microarrays. Paraffin sections from each array were processed for immunohistochemistry to assess the expression of P‐cadherin. The expression of P‐cadherin was forced using lipofectin, followed by an assessment of migration and invasion potential using standard in vitro assays.

RESULTS

The absence of P‐cadherin staining was associated with muscle‐invasive disease, grade 3 (P < 0.001) and nodal disease (P = 0.009). Similar results were obtained when considering cytoplasmic and unrestricted localization of P‐cadherin (P < 0.001), except for nodal involvement. The group with cytoplasmic location of P‐cadherin showed a shorter cancer‐specific survival than the group with membrane location of P‐cadherin (P = 0.03). Forced expression of P‐cadherin in EJ and UM‐UC‐3 cells, that constitutively lack P‐cadherin expression, resulted in modulation of catenin expression and enhanced migration of EJ and UM‐UC‐3/P‐cadherin transfectants (>200%).

CONCLUSIONS

These results showed that loss of expression, cytoplasmic relocation or unrestricted tissue location of P‐cadherin was associated with a poor clinical outcome and prognosis in bladder cancer. From the in vitro work it is evident that P‐cadherin plays a role in regulating the migration potential of bladder carcinoma cells.     

Human epidermal growth factor receptor 2 expression status provides independent prognostic information in patients with urothelial carcinoma of the urinary bladder

OBJECTIVE

To test whether the expression of human epidermal growth factor receptor 2 (HER‐2) is of prognostic value in a contemporary cohort of patients with urothelial carcinoma of the urinary bladder (UCB).

PATIENTS AND METHODS

Tissue microarrays of 198 patients were constructed and immunohistochemical stainings were performed on the primary tumours and on lymphatic nodal metastases. All patients were treated with radical cystectomy (RC) and regional lymphadenectomy for UCB. HER‐2 expression was assessed using continuous HER‐2 expression scores (ranging from 0.1 to 3.9) generated using an automated cellular imaging system. Scores of ≥1.0 in at least 10% of tumour cells were regarded as HER‐2 positive. We correlated HER‐2 scores with pathological and clinical variables, including disease recurrence and cancer‐specific mortality.

RESULTS

Of 198 patients undergoing RC with lymphadenectomy, there was HER‐2 positivity in 55 primary tumours (27.8%) compared with 44.2% of the evaluable positive lymph nodes (P < 0.001). HER‐2 positivity was significantly associated with the presence of lymphovascular invasion (LVI; P= 0.026). With a median (range) follow‐up of 35.4 (1.3–176.1) months, 101 patients (51.0%) had UCB recurrence and 82 patients (41.4%) died from the disease. In multivariable analyses that adjusted for the effects of pathological tumour stage, grade, LVI, lymph node metastasis and adjuvant chemotherapy, HER‐2 positive patients were at increased risk for both UCB recurrence (hazard ratio [HR] 1.955, P= 0.003) and UCB‐specific mortality (HR 2.066, P= 0.004) compared with patients with negative HER‐2 expression.

CONCLUSION

A positive HER‐2 status is associated with aggressive UCB and provides independent prognostic information for UCB recurrence and mortality. Assessment of HER‐2 status can be used to identify patients at high risk of disease progression who may benefit from adjuvant HER‐2‐targeted mono‐ or combined therapy after RC.     

Telomerase as an independent prognostic factor in head and neck squamous cell carcinoma

BACKGROUND: Telomerase activity has been found to be associated with many cancers, including head and neck squamous cell carcinoma (HNSCC). We examined the association of telomerase activity with the clinical outcome of patients with HNSCC. METHODS: A PCR-based enzyme immunoassay method was used to measure telomerase activity in 217 matched (grossly normal and cancerous) tissues from patients with HNSCC. Pearson chi-square test was used to analyze the correlation of telomerase activity with clinicopathologic parameters. Kaplan-Meier method and Cox logistic regression model were used for prognostic analysis. RESULTS: Of the 217 tissues assayed, 4.1% of the normal and 63.3% of the cancer tissues had high levels of telomerase activity. Telomerase activity was shown to be statistically correlated with extracapsule spreading (ECS) of lymph nodes (p =.005) and overall survival (p =.003). On multivariant analysis, overall stage (p =.007), tumor depth (p =.045), and telomerase activity (p =.008) showed independent variables associated with poor survival. CONCLUSIONS: Telomerase activity has been shown to be an independent prognostic factor for survival in cases of HNSCC. Telomerase may be a potential molecular target for clinical use in prognostication and therapy in cases of the disease.     

Association of the A870G cyclin D1 gene polymorphism with genetic susceptibility to nasopharyngeal carcinoma

BACKGROUND: Nasopharyngeal cancer (NPC) is multifactorial, and the genetic background may be a crucial etiologic factor. Cyclin D1 (CCND1) is a key regulator of the cell cycle, and its altered activity is associated with the development of cancer. METHODS: We analyzed the A870G CCND1 polymorphism by polymerase chain reaction/restriction fragment length polymorphism (PCR-RFLP) in 281 individuals, including 94 patients with NPC and 187 healthy individuals. RESULTS: Our results indicate that individuals carrying two G alleles have a 2.17-fold increase in the risk for the development of NPC (odds ratio [OR], 2.17; 95% confidence interval [CI], 1.19-3.98; p = .016). Age-adjusted logistic regression analysis confirmed this association (adjusted odds ratio [aOR], 2.14; 95% CI, 1.14-4.04; p = .018). Multivariate analysis demonstrates an independent association between GG CCND1 genotype (aOR, 2.06), male sex (aOR, 2.66), and age at diagnosis (aOR, 2.02) regarding the development of undifferentiated NPC. The proportion of NPC cases attributable to the GG CCND1 genotype was 14.76%. CONCLUSIONS: Our results may be important in the definition of a biologic predictive profile for the development of NPC within our population.     

Survivin在膀胱移行细胞癌中的表达及其临床意义

目的:检测抗凋亡(IAP)家族中生存素(Survivin)基因在膀胱移形细胞癌(BTCC)组织及癌旁组织的表达,探讨Survivin的表达在膀胱癌发生发展中的意义.方法:采用免疫组织化学和实时荧光定量逆转录聚合酶链反应(RT-QPCR)方法,对30例BTCC患者中Survivin基因在癌组织和癌旁组织中的表达进行检测.结果:免疫染色标本中,在癌旁组织、BTCC和胚胎癌组织中Survivin的阳性表达率分别为0、60%和100%.同一患者,Survivin在BTCC的表达量远大于癌旁组织,Survivin在BTCC组织中的-△△CT值是癌旁组织的10.2829(9.0034～11.5624)倍,同时在病理分级之间和临床分期之间均有统计学意义(P＜0.05).结论:Survivin基因在癌旁组织中有少量表达,而在BTCC组织中的表达量远远高于癌旁组织;其表达量与病理分级和临床分期均有相关性.     

Assessment of cyclin D1 overexpression as a prognostic factor in soft tissue sarcomas: role of laparoscopy and core needle biopsy

Background This study was designed to test cyclin D1 as a prognostic marker in patients with soft tissue sarcomas (STS), and to evaluate the usefulness of laparoscopy for determining cyclin D1 overexpression. Methods The records of 62 patients with STS were collected: 28 with retroperitoneal STS (RSTS) and 34 with extremity STS (ESTS). A total of 51 patients underwent surgical resection, whereas 11 did not undergo surgery because of advanced tumor stage. Preoperative–intraoperative laparoscopic staging was performed for patients judged to be resectable at preoperative imaging. Results: Cyclin D1 was overexpressed in 30 (58.8%) of 51 resected patients and in 10 (90.9%) of 11 nonresected patients. Laparoscopy avoided unnecessary laparotomy in 9 (32.1%) of 28 RSTS patients. Conclusions: High tumor grade, positive surgical margins, local recurrence, distant metastases, and cyclin D1 overexpression were related to poor survival. Multivariate analysis demonstrated cyclin D1 to be the only independent factor. Laparoscopy was shown to be useful for avoiding useless laparotomies.     

Radial clearance in resection of hypopharyngeal cancer: an independent prognostic factor

BACKGROUND: The depth of infiltration of tumor is of particular relevance in hypopharyngeal cancers, because most of them are seen late, and extensive infiltration into the muscle wall and the cartilage are not uncommon. METHODS: The resected specimens of hypopharyngeal cancers were studied with whole-organ step-serial sectioning. The extent of infiltration into the thickness of the wall and the radial clearance were carefully documented. These parameters were correlated with the tumor recurrence and survival rates. RESULTS: Most patients with hypopharyngeal cancer had a minimal radial margin; the radial clearance was <1 mm in 56% of the patients. Despite such a minimal margin, the local recurrence rate was only 19% and occurred mainly in the upper and lower resection margins. Radial clearance was an independent prognostic factor for overall survival, disease-free survival, and nodal recurrence-free survival on multivariate analysis. CONCLUSION: Radial clearance is an important independent prognostic factor, and it is recommended to be included in the routine pathologic reporting of the resected specimen in hypopharyngeal cancer.     

Prognostic significance of platelet-derived endothelial cell growth factor/thymidine phosphorylase expression in stage pT1 G3 bladder cancer

BACKGROUND: The management of patients with pT1 G3 bladder cancer remains controversial because of the high incidence of recurrence with muscle invasion. Thymidine phosphorylase (dThdPase) is identical to platelet-derived endothelial cell growth factor (PD-ECGF) and has angiogenic activity. The aim of this study was to determine whether the expression of PD-ECGF/dThdPase in bladder cancer tissue was associated with tumor progression and recurrence in patients with pT1 G3 bladder cancer. METHODS: Fifteen patients who were pathologically diagnosed as having pT1 G3 transitional cell carcinoma of the bladder were treated with transurethral resection. Sections of paraffin-embedded bladder tissue were immunohistochemically stained with either mAb654-1, a monoclonal antibody against human PD-ECGF or anti-CD34 monoclonal antibody, respectively. When more than 10% of tumor cells were positively stained with mAb654-1, this section was defined as positive in this study. RESULTS: Eight of 15 sections from patients with pT1 G3 bladder cancer (53%) were positive with PD-ECGF/dThdPase. During follow up, patients in the negative group had no disease progression and only two patients had local recurrence. In contrast, seven of eight positives had recurrence (P < 0.05) and progression was also observed in four recurrent patients. However, there was no statistical relationship between PD-ECGF and CD34 expression in any of the patients. CONCLUSION: The expression of PD-ECGF/dThdPase appears to be an important prognostic factor of pT1 G3 bladder cancer and did not show any significant relationship between PD-ECGF/dThdPase expression and vascular density.