Neuroendocrine serum tumour markers in hormone-resistant prostate cancer

OBJECTIVE: The primary aim of the study was to assess the prevalence of elevated serum levels of neuron-specific enolase (NSE) and chromogranin A (CgA) in hormone-resistant prostate cancer (HRPC), and to evaluate these markers' prognostic significance. Secondarily we wanted to assess any change in serum levels of NSE or CgA after palliative radiotherapy. METHODS: Serum samples from patients with painful bone metastases or symptomatic pelvic tumours due to HRPC were analyzed for prostate specific antigen (PSA), NSE and CgA before and after palliative radiotherapy. RESULTS: Forty-six of 138 patients (33%) had elevated NSE before radiotherapy, while 80 (58%) had elevated CgA, without correlation between the two markers or with PSA. After radiotherapy the median NSE level was significantly reduced (p=0.004), whereas CgA (p=0.009) and PSA (p=0.019) increased. In the multivariate survival analysis, a reduced performance status, >20 bone metastases on bone scan, low hemoglobin, and pre-radiotherapy elevated NSE levels indicated a short survival. CONCLUSION: Together with known clinical parameters, NSE predicts survival in patients with HRPC. NSE could become a valuable prognostic marker in patients with this condition.     

p53、p21、Ki-67和VEGF与膀胱癌分级、分期以及预后的关系

目的：探讨p53、p21、Ki-67和VEGF的表达与膀胱癌的病理分级、分期以及预后足否相关。方法：应用免疫组织化学染色的方法,对40例手术证实的膀胱移行细胞癌患者的病理切片进行p53、p2l、Ki-67和VEGF的化学染色。将免疫组化结果与病理分级、分期以及预后情况进行分析。结果：在40个肿榴标本中．p53、p21、Ki-67和VEGF的表达有改变的分别有31个（77.5％）．22个（55.0％）．16个（40.0％）．17个（42.5％）：其中至少1个标记物表达异常35例（87.5％）．而4个标记物均表达异常者有7例（17.5％）。患者平均随访51个月。除了Ki-67、VEGF与病理分级以及Ki-67与分期之间无统计学意义外．4个标记物多少都与膀胱癌的病理分级、分期相关。p53（＋）／p21（-）以及4个标记物同时异常是与疾病相关死亡率有关的独立因素（P＜0.05,P＜0.01）。而Ki-67、VEGF均不是膀胱癌相关死亡率的独立因素（P〉0．05）。越多标记物表达异常,则膀胱癌的死亡率增加。结论：p53、p21、Ki-67和VEGF多少都与膀胱癌的病理分级、分期相关。联合检测p53、p21、Ki-67和VEGF可以更加准确地预测膀胱癌的预后。     

Prognostic value of p53, proliferating cell nuclear antigen, and Ki-67 expression in undifferentiated nasopharyngeal carcinomas

In this study the prognostic importance of p53, proliferating cell nuclear antigen (PCNA), and Ki-67 expression was analyzed along with the clinical parameters in 35 consecutive patients with undifferentiated nasopharyngeal carcinomas. Immunohistochemistry was used to detect p53, PCNA, and Ki-67 staining. Among the clinical findings, stage IV disease (P = 0.01), cranial nerve paralysis (P = 0.02), and lymph node metastasis (P = 0.06) were associated with shorter survival. The p53 positivity correlated with the presence of lymph nodes, but it was not a significant factor to predict the outcome. PCNA expression was not found to be a prognostic indicator. On the other hand, the proliferative value of Ki-67 staining was suggestive of prognosis. A proliferation index of Ki-67 less than 10% indicated longer survival (P = 0.03). There was no correlation between Ki-67 staining and PCNA index. As a result, the prognostic value of Ki-67 may alert the physician to more aggressive and adjuvant treatment modalities.     

The prognostic value of p53, Ki-67 and matrix metalloproteinases MMP-2 and MMP-9 in transitional cell carcinoma of the renal pelvis and ureter

AIM: To investigate the prognostic and predictive relevance of p53 protein, Ki-67 antigen, MMP-2 and MMP-9 in patients with transitional cell carcinoma (TCC) of the upper urinary tract. METHODS: The expression of p53 protein, Ki-67 antigen, MMP-2 and MMP-9 was examined by immunohistochemistry in 69 patients with TCC of the upper urinary tract. Correlation of p53, Ki-67, MMP-2 and MMP-9 over-expression with conventional pathological parameters and patient survival was examined. RESULTS: p53 over-expression was significantly correlated with histological grade (P < 0.05), but not with pathological stage, vascular invasion, lymphatic invasion or lymph node metastasis. Ki-67 over-expression was significantly correlated with stage, grade, lymphatic invasion and vascular invasion (P < 0.05). In survival analyses, Ki-67 over-expression was a significant prognostic factor in the univariate analysis (P < 0.05), but it did not have a significant impact on survival in the multivariate analysis. Ki-67 labeling index was a significant prognostic factor in patients with a low p53 labeling index, but not in patients with a high p53 labeling index. CONCLUSION: Ki-67 over-expression is of prognostic value in TCC of the upper urinary tract, while p53, MMP-2 and MMP-9 are of limited value.     

Intrahepatic cholangiocarcinoma in Korea

We reviewed surgically treated patients with intrahepatic cholangiocarcinoma to evaluate the clinical and pathologic features of intrahepatic cholangiocarcinoma that may affect long-term survival in Korean patients with the disease. Between 1990 and 1997, 28 patients with intrahepatic cholangiocarcinoma underwent laparotomy. Resection was performed in 25 patients, and wedge resection alone in 3 patients. The liver resections consisted of right lobectomy in 5 patients, right trisegmentectomy in 1, left lobectomy in 7, extended left lobectomy in 3, hepatopancreatoduodenectomy in 2, and segmentectomy in 7. Curative resection was performed in 15 patients. Histological sections of all resected specimens were immunohistochemically stained with p53 and Ki-67 monoclonal antibodies to assess the biological behavior of the tumor cells. Cumulative survival rate and clinicopathological factors that may influence the prognosis, including biological markers (p53, Ki-67), were analyzed statistically. Patients who underwent curative resection survived significantly longer than patients who underwent noncurative resection. The median survival time of the patients who underwent curative resection was 24 months (mean, 34 ± 8 months), with 1-, 2-, and 3-year survival rates of 66.6%, 44.4%, and 35.6%, respectively. The median survival time of the patients who underwent noncurative resection was 3 months (mean, 8 ± 3 months), with 1- and 2-year survival rates of 26.7% and 13.4%, respectively. Univariate analysis showed that positive regional lymph nodes correlated significantly with poor outcome (P = 0.004) and that curative resection significantly correlated with better prognosis (P = 0.001). Age, sex, tumor size, degree of cell differentiation, gross type of tumor, and p53 and Ki-67 labeling index were not significantly correlated with outcome. Our findings support the concept that aggressive liver resection, along with regional lymph node dissection, be recommended for long-term survival. The validity of molecular biologic tumor markers (p53, Ki-67) as prognostic factors has not yet been clearly demonstrated. Received for publication on Dec. 14, 1998; accepted on Dec. 15, 1998     

Human telomerase reverse transcriptase (hTERT) and Ki-67 are better predictors of survival than established clinical indicators in patients undergoing curative hepatic resection for colorectal metastases

BACKGROUND: We evaluated hTERT and Ki-67 expression in patients who underwent curative resection of hepatic colorectal metastases to determine if these markers of cell proliferation correlated better with survival than an established scoring system that is based on clinical predictors. METHODS: Patients operated on between 1993 and 1997 whose survival time was known were analyzed. For each patient, the clinical prognostic score was derived on the basis of primary node status, disease-free interval, number of hepatic tumors, largest tumor, and carcinoembryonic antigen level, and tumor specimens were analyzed for Ki-67 and hTERT with use of standard immunohistochemical techniques. The immunohistochemical analysis was blinded to all patient characteristics. RESULTS: The study included 66 patients. Twenty-six survived less than 2 years after surgery, 19 survived 2-5 years, and 21 survived more than 5 years. Ki-67 positivity and hTERT positivity (labeling indexes greater than or equal to 50%) were observed in 24 patients and 23 patients, respectively. The clinical score did not predict survival, although there was a weak trend toward a lower score in patients with better survival. Both Ki-67 (P =.04) and hTERT (P =.0001) correlated better with survival than did the clinical score. CONCLUSIONS: In patients undergoing curative resection of hepatic colorectal metastases, hTERT and Ki-67 are better predictors of survival than is a score based on clinical features.     

Is a proliferation index of cancer cells a reliable prognostic factor after hepatectomy in patients with colorectal liver metastases?

BACKGROUND: In spite of many reports focusing on prognostic factors after hepatectomy in patients with colorectal liver metastases, few studies have investigated pathological factors, eg, fibrous pseudocapsulation, growth pattern at the tumor margin, and proliferation activity of cancer cells, other than histological type and surgical margin. The aim of the present study was to investigate whether absence of pseudocapsulation, infiltrative growth pattern of metastases, and higher proliferation of cancer cells shown by Ki-67 immunohistochemical reactivity were associated with poorer survival after hepatectomy among patients with colorectal liver metastases. METHODS: Between 1988 and 1998, 221 patients underwent hepatic resection of colorectal metastases with curative intent in our institution. Pathology analyses were focused on pseudocapsulation of liver metastases, growth pattern at the tumor edge, and Ki-67 labelling index (Ki-67 LI) of cancer cell nuclei. Univariate analyses of survival and of disease-free survival were performed for several clinicopathological factors, and multivariate analyses of survival and disease-free survival were also performed. RESULTS: The univariate survival analyses showed that pseudocapsulation, growth pattern, and Ki-67 LI were significant prognostic factors, besides synchronous versus metachronous occurrence of metastases, carcinoembryonic antigen level before hepatectomy, and number of metastases. A multivariate analysis showed that Ki-67 labeling index was the most reliable prognostic factor of survival. In addition, Ki-67 LI and microscopic growth pattern were multivariately predictive factors of disease-free survival. CONCLUSIONS: This large single-institution study showed that investigation of cancer cell proliferation and pathologic characteristics of the tumor margin are major prognostic factors.     

Prognostic and predictive factors in patients with androgen-independent prostate cancer treated with docetaxel and estramustine: a single institution experience

OBJECTIVES: To investigate potential prognostic and predictive factors in patients with androgen-independent prostate cancer (AIPC) treated with docetaxel chemotherapy. METHODS: This analysis included 94 consecutive AIPC patients who were treated between March 2001 and May 2006 with biweekly docetaxel 45 mg/m(2) (day 2) and estramustine 140 mg three dimes daily (days 1-3). RESULTS: Prostate-specific antigen (PSA) responses were observed in 45 of 84 evaluable patients (53%), whereas objective responses were observed in 16 of 40 patients with measurable disease (40%). Median survival (OS) was 16.2 mo (95% confidence interval [CI], 12.9-19.4) and median time to PSA progression (TTP) 5.0 mo (95%CI, 3.6-7.1). OS was independently associated with pain score baseline PSA and weight loss. Patients with only extraosseous disease had higher PSA response rate (87% vs. 49%, p=0.014) and superior TTP compared with patients with bone metastases with or without extraosseous disease (7.3 vs. 4.3 vs. 4 mo, p=0.002). Concurrent bone and extraosseous metastases were associated with worse prognosis compared with each site alone (median OS: 12.3 vs.19 vs.18.3 mo, p=0.007). CONCLUSIONS: Among patients with AIPC treated with biweekly docetaxel and estramustine, baseline PSA >100, existence of pain, weight loss, and simultaneous extraosseous and bone disease were associated with worse prognosis. Extraosseous metastases seem to be more sensitive than bone disease to this chemotherapy.     

Roles of p53 and MDM2 in tumor proliferation and determination of the prognosis of transitional cell carcinoma of the renal pelvis and ureter

BACKGROUND: The significance of p53 overexpression for the prognosis of transitional cell carcinoma (TCC) of the renal pelvis and ureter remains controversial. Simultaneous evaluation of p53 and MDM2 may enable better prediction of tumor proliferation and patient prognosis than that obtained with evaluation of p53 alone. METHODS: Immunohistochemical detection of p53 protein, MDM2 protein and Ki-67 antigen as proliferation markers was performed for tissue samples obtained from 74 patients with TCC of the renal pelvis and ureter. The correlations of p53/MDM2 overexpression with conventional pathological features, Ki-67 labelling index (LI) and patient survival were studied. RESULTS: Overexpression of p53 was related to progression of each of the pathological features examined (grade, stage, type of infiltration, vascular invasion and lymphatic invasion) and Ki-67 LI was significantly higher with high p53 expression than with low p53 expression. However, overexpression of MDM2 was related to neither disease progression nor Ki-67 LI. Survival analyses were performed for 66 patients. Univariate analysis showed p53 to be a useful prognostic indicator, but in a multivariate analysis only type of infiltration and Ki-67 LI were independent survival markers, while p53 was not. Overexpression of MDM2 was unrelated to patient survival, and the combination of p53 and MDM2 for survival indication was found not to be useful. CONCLUSIONS: Overexpression of p53 is related to disease progression, increased tumor proliferation and patient survival for TCC of the renal pelvis and ureter, but the independent prognostic value of p53 did not reach statistical significance. Combined analysis of MDM2 with p53 cannot be recommended for examination of the malignant potential of TCC of the renal pelvis and ureter.     

The expression profile of p14, p53 and p21 in tumour cells is associated with disease-specific survival and the outcome of postoperative chemotherapy treatment in muscle-invasive bladder cancer

Purpose: We investigated the effects of alterations in the biological markers p14, p53, p21, and p16 in relation to tumour cell proliferation, T-category, N- category, lymphovascular invasion, and the ability to predict prognosis in patients with muscle-invasive bladder cancer (MIBC) treated with cystectomy and, if applicable, chemotherapy.Materials and methods: We prospectively studied patients with urinary bladder cancer pathological stage pT1 to pT4 treated with cystectomy, pelvic lymph node dissection and postoperative chemotherapy. Tissue microarrays from paraffin-embedded cystectomy tumour samples were examined for expression of immunostaining of p14, p53, p21, p16 and Ki-67 in relation to other clinical and pathological factors as well as cancer-specific survival.Results: The median age of the 110 patients was 70 years (range 51-87 years), and 85 (77%) were male. Pathological staging was pT1 to pT2 (organ-confined) in 28 (25%) patients and pT3 to pT4 (non-organ-confined) in 82 (75%) patients. Lymph node metastases were found in 47 patients (43%). P14 expression was more common in tumours with higher T-stages (P?=?0.05). The expression of p14 in p53 negative tumours was associated with a significantly shorter survival time (P=0.003). Independently of p53 expression, p14 expression was associated with an impaired response to chemotherapy (P=0.001). The expression of p21 in p53 negative tumours was associated with significantly decrease levels of tumour cell proliferation detected as Ki-67 expression (P=0.03).Conclusions: The simultaneous expression of the senescence markers involved in the p53-pathway shows a more relevant correlation to the pathological outcome of MIBC than each protein separately. P14 expression in tumours with non-altered (p53-) tumours is associated with poor prognosis. P14 expression is associated with impaired response to chemotherapy. P21 expression is related to decreased tumour cell proliferation.     

Prognostic value of carbonic anhydrase IX expression in penile squamous cell carcinoma: A pilot study

ObjectivesTo determine whether carbonic anhydrase IX (CA IX) has prognostic value of lymph node metastases and cancer-specific survival in penile squamous cell carcinoma treated with surgery.Materials and methodsCA IX expression was detected in the primary disease of 73 penile cancer patients using the method of immunohistochemistry. The expression levels of CA IX were categorized into 2 groups according to the cutoff of 10% of positively stained tumor cells. Associations between CA IX expression and clinicopathologic characteristics, immunoreactivity of p53 and Ki-67, and outcomes were analyzed.ResultsHigh CA IX expression was observed in 31 (42.5%) of cases. CA IX expression was not associated with patient age, T stage, grade, lymphovascular invasion, and Ki-67 expression, but was associated with p53 expression (P = 0.015). Both univariate and multivariate analysis failed to show CA IX expression was a statistically significant predictor of lymph node metastases and cancer-specific survival.ConclusionsImmunohistochemical expression of CA IX did not associate with lymph node metastases and cancer-specific survival in penile squamous cell carcinoma. A panel of prognostic markers that reflect the characteristic of tumor cell and organ microenvironment may be more suitable for prognostication in penile cancer.     

Immunohistochemical studies of p53, Ki-67, E-cadherin and beta-catenin on renal pelvic and ureteral cancers

PURPOSE: We reviewed prognosis and bladder recurrence of 31 patients with renal pelvic and ureteral cancer concerning clinicopathological and immunohistochemical factors. METHODS: The patients consisted of 19 males and 12 females. The median age was 69 years, ranging from 43 to 84 years. Median follow-up period was 79 months. Immunohistochemistry for p53, Ki-67, E-cadherin and beta-catenin was performed on sections from tumor tissue. RESULTS & CONCLUSIONS: The overall 5-year cause-specific survival rate was 77.4%. Univariate analysis indicated tumor number, grade, infiltrating pattern, lymphatic involvement to be significant prognostic factors. Moreover, multivariate analysis with Cox's proportional hazard model revealed tumor number and lymphatic involvement to be independent prognostic factors for cause-specific survival rate. The overall 5-year bladder recurrence free rate was 60.9%. Univariate analysis revealed expression of E-cadherin to be a significant factor for bladder recurrence free rate.     

Patients with penile carcinoma benefit from immediate resection of clinically occult lymph node metastases

PURPOSE: In this retrospective study we compared the clinical outcome of early vs delayed excision of lymph node metastases in patients with penile squamous cell carcinoma. MATERIALS AND METHODS: A total of 40 patients with a T2-3 penile carcinoma with lymph node metastases were included in this study. All patients initially presented with bilateral impalpable lymph nodes. In 20 patients (50%) metastases were removed when they became clinically apparent during meticulous followup (median interval 6 months, range 1 to 24). There were 20 patients (50%) who underwent resection of inguinal metastases detected on dynamic sentinel node biopsy before they became palpable. The histopathological characteristics of the tumors and lymph nodes were reevaluated. RESULTS: The 2 populations were similar in terms of patient age, T-stage, pathological tumor grade, vascular invasion and infiltration depth. Disease specific 3-year survival of patients with positive lymph nodes detected during surveillance was 35% and in those who underwent early resection, 84% (log rank p = 0.0017). In multivariate analysis early resection of occult inguinal metastases detected on dynamic sentinel node biopsy was an independent prognostic factor for disease specific survival (p = 0.006). CONCLUSIONS: Early resection of lymph node metastases in patients with penile carcinoma improves survival.     

p53 and Ki-67 expression as prognostic factors in cystosarcoma phyllodes

We have reviewed the histopathological, clinical outcome and immunohistochemical status in 21 women with cystosarcoma phyllodes (CSP) tumors of the breast. We assessed 12 tumors as histopathologically benign and 9 tumors as malignant. The median patient ages in benign and malignant CSP tumors were 39.6 and 45.4 years of age, respectively. The stromal cellularity, stromal cellular atypism, high mitotic activity, atypic mitoses, stromal overgrowth, infiltrative tumor contour, and heterologous stromal elements were significant features of the malignant CSP tumors. Benign CSP tumors were predominantly of fibroadenomatous architecture with cellular stroma (mild or moderate) and some distortion and elongation of glandular elements. Five malignant CSP tumors were stained positively with p53, and 6 malignant CSP tumors were stained immunohistochemically with Ki-67. All benign CSP tumors were negatively stained for p53 and Ki-67. The patients with benign CSP tumors were treated with local excision ( n = 11) and with subcutaneous mastectomy ( n = 1). Malignant CSP tumors were treated with wide local excision ( n = 1), partial mastectomy ( n = 1), simple mastectomy ( n = 2), and modified radical mastectomy ( n = 5). Two patients with a high mitotic rate and high values of p53 and Ki-67 received additional radiotherapy and chemotherapy. One case had liver metastasis. This tumor had high mitotic figures, stromal overgrowth, severe stromal cellularity, and 20% Ki-67 and mild p53 positivity. We suggest that p53 and Ki-67 can play an important role in predicting prognosis and yielding additional therapy besides conventional prognostic factors in the treatment of the CSP patients.     

Molecular markers and their prognostic impact in patients with advanced prostate cancer undergoing intermittent androgen suppression

OBJECTIVE: Tumour features were evaluated during intermittent androgen suppression (IAS), and their prognostic impact on the first off-treatment time was analysed. PATIENTS AND METHODS: Twenty patients with advanced prostate cancer underwent three consecutive prostate biopsies during the first cycle, namely at the beginning of androgen deprivation, 8 months after continuous therapy and at the time of prostate-specific antigen (PSA) progression above 20 ng/ml. Biopsy specimens were immunohistochemically processed and analysed for the apoptotic index (AI), Ki-67, p53 and Bcl-2 to investigate eventual changes over time. Correlations and regression analysis were performed to assess the prognostic significance of clinical and pathological parameters in predicting the first off-treatment time. RESULTS: In contrast to the AI, p53 and Bcl-2, Ki-67 was the only marker that significantly changed over time (P=0.008). The first off-treatment time correlated significantly with pretreatment PSA (r=-0.594; P<0.01), testosterone recovery time (r=0.590; P=0.013) and biopsy grade (r=-0.738; P<0.01); only the latter gaining an independent factor in the multivariate analysis (P=0.022). CONCLUSIONS: During IAS, Ki-67 was the only molecular marker that consistently changed over time. However, it did not correlate with off-treatment time that was predicted independently by the initial biopsy grade only. First off-treatment time was best predicted by clinical parameters and molecular markers from needle biopsies did not further contribute to a better patient selection.     

Expression of p53 and Proliferation Index as Prognostic Factors in Gastrointestinal Sarcomas

Background:Sarcomas arising in the gastrointestinal (GI) tract are rare tumors. Molecular markers could be associated with prognosis in these types of tumors.Methods:We performed a retrospective analysis of adult patients with sarcomas arising in the GI tract at the National Institute of Medical Sciences in Mexico City and the University of Alabama at Birmingham Hospital. All histological types were included. Patient, tumor, and treatment factors were analyzed, with overall survival as the main outcome variable. Expression of p53 and cellular proliferation antigen Ki-67 was also analyzed. Statistical analysis was performed by log-rank test and Cox regression. Significance was defined as P < .05.Results:Forty-seven patients were analyzed. The median patient age was 53 years (range, 16–82 years). Twenty-five patients (53%) were women. The stomach was the most common site of presentation. The mean tumor size was 14 cm (2–45 cm). A complete resection was achieved in 40 patients. With a median follow-up of 30 months, the actuarial 3-year survival was 68%. Univariate analysis identified overexpression of p53 and Ki-67, high tumor grade, tumor size >10 cm, and incomplete resection as significant negative prognostic factors. Hispanic race and good performance status were significantly associated with prolonged survival. On multivariate analysis, overexpression of p53 was the only independent negative prognostic factor.Conclusions:Overexpression of p53 is the strongest predictor of poor prognosis in patients with sarcomas of the GI tract.     

The comparative values of bone marrow aspirate and trephine for obtaining bone scan-targeted metastases from hormone-refractory prostate cancer

Samples of metastatic prostate cancer to bone are difficult to obtain. The aim of this study was to compare the results of bone marrow aspirate and trephine biopsy for obtaining metastatic hormone-refractory prostate cancer (HRPC) samples using previous diagnostic planar 99(m)Tc-HDP bone scans to guide the procedure. All samples taken were for the purposes of research and molecular studies on HRPC. Twenty patients with HRPC had bone marrow aspirate and trephines taken from lesions in the posterior superior iliac spine or sacro-iliac region when shown on diagnostic 99(m)Tc-HDP bone scans. Three patients also underwent plain X-ray, 18F-positron emission tomography bone scan, pelvic MRI scan and 99(m)Tc nanocolloid bone marrow scans. These images were used to assess if the extra imaging information provided, such as three-dimensional localisation of the bone metastases, was of value for target bone metastases. Cancer cells were obtained in 15/20 (75%) cases in which a trephine biopsy was attempted and 0/20 of cases in which a bone marrow aspiration was attempted. The additional information provided by the range of other imaging investigations was of little benefit in obtaining tumour samples, but did suggest why negative biopsies were obtained in some cases after targeting with planar bone scans. We recommend the use of bone marrow trephine biopsy alone, guided by previous diagnostic 99(m)Tc planar bone scan as a practical method to obtain prostate cancer cells from bone metastases.     

Prognostic value of the expression of Ki-67, CD44 and vascular endothelial growth factor, and microvessel invasion, in renal cell carcinoma

OBJECTIVE: To determine if use of cell proliferation, cell adhesion, level of angiogenesis-related factors and presence of microscopic vascular invasion (MVI) could better predict the biological behaviour of renal cell carcinoma (RCC), which has a widely variable clinical outcome despite the use of conventional prognostic factors (staging and grading). MATERIALS AND METHODS: The expression of Ki-67, CD44H and vascular endothelial growth factor (VEGF) were assessed immunohistochemically in formalin-fixed, paraffin-embedded tissues from 48 RCCs, using a Ki-67 labelling index (LI), CD44 LI and level of VEGF expression, respectively. In addition all the pathological slides were reviewed retrospectively for the presence and absence of MVI. The prognostic value of all the variables assessed was then evaluated, and correlated with the usual prognostic variables and cancer-specific survival. RESULTS: Univariate analysis of cancer-specific survival showed that tumour stage (P < 0.001), tumour size (P = 0.005), metastasis, MVI, Ki-67 LI, CD44H LI and VEGF expression (all P < 0.001) were predictors of tumour-related death. There was a statistical correlation between CD44H LI and each of Ki-67 LI (r = 0.61), expression level of VEGF (r = 0.72) and presence of MVI (r = 0.71). Independent predictors of cancer-specific survival in a multivariate analysis were: in all patients with RCC, the MVI (P = 0.003) and VEGF expression (P = 0.01); in those with no metastases, MVI (P = 0.01); in patients with no MVI, VEGF (P = 0.04); and in patients with MVI, Ki-67 LI (P = 0.003). No independent predictor was identified in patient with metastases. CONCLUSION: This study suggests that cell proliferation, cell adhesion, the level of VEGF expression and the presence of MVI represent a complex tumour-host interaction that may favour the progression of RCC. Cell proliferation, CD44H and VEGF expression appear to be powerful markers for identifying patients with an adverse prognosis.     

A prospective phase II clinical trial of continuous FUDR regional chemotherapy for colorectal metastases to the liver using a totally implantable drug infusion pump.

A prospective phase II evaluation of regional FUDR chemotherapy using a totally implantable drug infusion pump was conducted in 81 patients with colorectal metastases to the liver. The survival results were compared to a historical control group of 129 patients with isolated liver metastases. The two groups were comparable with respect to their dominant prognostic factors. The pump patients received their continuous chemotherapy on an outpatient basis and had an 88% response rate, as evidenced by a fall in their serum CEA levels by one-third or greater after two cycles of chemotherapy. By four criteria, the regional chemotherapy patients had an improved survival rate compared to the control series. First, the 1 year survival and median survival was better for the entire group of pump patients vs. controls (82% vs. 36%, 26 months vs. 8 months, p less than 0.0001). The survival for the regional chemotherapy patients was not influenced by the extent of tumor involvement, whether previous systemic 5-FU was given, or whether the patient had symptomatic disease. Second, the entire group of regional chemotherapy patients (including nonresponders) had a greater 1 year survival compared to the most favorable subgroup of control patients with the following characteristics: normal liver function tests, no symptoms, and only one lobe involved (82% vs. 66%, p = 0.009). Third, a subgroup of 49 pump patients, whose initial treatment for metastatic disease was regional chemotherapy (within 3 months of diagnosis) had a better 1 year survival than an exactly matched group of 49 control patients (67% vs. 30%, p = 0.000003). Fourth, the actuarial survival for all 81 pump patients was significantly better than predicted by a mathematical model constructed to predict the patient's clinical course based upon the seven dominant prognostic variables identified in a multifactorial analysis (82% survival at 1 year vs. 33% predicted survival). While liver metastases could be controlled in most patients, the major cause of death was tumor progression in extrahepatic sites, particularly lung metastases and abdominal carcinomatosis. Although it appears that regional chemotherapy with an implantable pump appears to prolong life by 12 to 18 months more than matched historical controls, these results must be confirmed by a randomized (phase III) prospective clinical trial.