Angiogenesis as a predictor of survival after surgical resection for stage I non-small-cell lung cancer

OBJECTIVES: Some patients with surgically resected stage I non-small-cell lung cancer eventually have metastatic disease. A histologic marker of metastatic potential and diminished survival for stage I non-small-cell lung cancer may distinguish this patient population. This study evaluates the degree of angiogenesis as a predictor of cancer-related death after operation for stage I non-small-cell lung cancer. METHODS: Demographic, surgical, and histopathologic data, including presence of vascular invasion, were reviewed for 106 patients with stage I non-small-cell lung cancer from 1985 through 1990. Visual quantitation of microvessels immunostained with factor VIII-related antigen and CD31 in 5 microm sections from the paraffin blocks of tissue defined rumor angiogenesis. RESULTS: Follow-up was 95.1% complete, mean 5.2 +/- 3.0 years. Lung cancer-related mortality rate was 24.4% at 5 years. Mean microvessel counts were 20.7 +/- 11.2 for FVIII and 29.6 +/- 18.1 for CD31. Univariate analysis revealed an FVIII count of at least 20 (p = 0.025) and blood vessel invasion (p = 0.017) to be significant predictors of disease-related death. After adjustment for other patient and tumor characteristics, multivariate Cox regression analysis found an FVIII count of at least 20 (hazard ratio 2.9) and blood vessel invasion (hazard ratio 3.7) to be significant independent correlates of lung cancer death (p = 0.018 and p = 0.011, respectively). CD31 quantitation did not predict survival on univariate or multivariate analyses and did not correlate strongly with FVIII quantitation (Spearman's rank correlation r = 0.19). CONCLUSIONS: This analysis reveals a significant association between tumor neovascularization and cancer-related mortality rate among patients with stage I non-small-cell lung cancer. Microvessel quantitation of FVIII, as an indicator of tumor angiogenesis and metastatic potential, may define a subset of patients with stage I non-small-cell lung cancer who could benefit from adjuvant therapy after surgical resection.     

Extended lymphadenectomy is associated with a survival benefit for node-negative gastric cancer

BACKGROUND: The activation of the zymogen plasminogen to the serine protease plasmin by urokinase-type (uPA) and tissue-type (tPA) plasminogen activators (PA) is an important event in a variety of physiologic and pathophysiologic processes in mammals. Enhanced PA activity occurs during angiogenesis and has been correlated in vitro and in vivo with increased tumor aggressiveness and is an indicator of poor prognosis in a variety of tumors in humans. Preliminary studies suggest that the antiulcer drug irsogladine maleate (IM) diminishes PA activity in vitro and may inhibit angiogenesis in vivo. To define the precise mechanism of angiogenesis inhibition by IM in vivo, we tested the ability of IM to blunt angiogenesis in a mouse cornea neovascularization model performed in wild-type and PA-knockout mice. METHODS: Three days prior to pellet implantation, groups of C57Bl/6 wild-type, uPA-deficient (upA-/-), and tPA-deficient (tPA-/-) mice received IM (300 mg/kg), IM (500 mg/kg), or vehicle (0.5% carboxymethylcellulose) via oral gavage. After 3 days of treatment, hydron polymer-coated pellets of sucrose aluminum sulfate containing 100 ng of basic fibroblast growth factor (bFGF) were inserted into surgically created pockets in the cornea of each mouse. On postoperative day 6, the neovascularization of each cornea was evaluated by a blinded observer using slit lamp microscopy and photographed. Angiogenesis was quantified by calculating vascular area (mm2) +/- SEM using a modified formula for a half ellipse that incorporates calibrated vessel measurements [Vessel length (mm) x Clock hours x pi x 0.2]. RESULTS: IM treatment (300 and 500 mg/kg/day) resulted in a dose-dependent reduction of angiogenesis in wild-type mice by 21 and 45.3% (P < 0.02, P < 0.001), in tPA-deficient mice by 42.6 and 46% (P < 0.001, P < 0.001), and in uPA-deficient mice by 27.2 and 46% (P < 0.05, p < 0.001), respectively. No quantitative differences in neovascularization were observed in either treatment group between transgenic mouse strains. No toxicity was noted in any group. CONCLUSION: IM inhibits bFGF-induced angiogenesis in wild-type, tPA-knockout, and uPA-knockout mice. The observation that IM significantly diminishes angiogenesis in both PA-deficient mice and wild-type mice suggests that the mechanism of action of IM may be independent of plasminogen activation.     

Cell proliferation as an independent predictor of survival for patients with advanced nasopharyngeal carcinoma

Commonly used clinical and pathologic criteria are often of limited value in predicting the outcome of patients with undifferentiated nasopharyngeal carcinoma, and new parameters related to the biology of growth of neoplastic cells are still required for better definition of the aggressiveness of these tumors. The prognostic significance of DNA ploidy, measured by image cytometry on isolated cells, and of the mitotic index, proliferating cell nuclear antigen, and p53 protein, all measured by image cytometry in histologic sections, were evaluated on archival tumor tissues from 53 patients with Stage III or IV nasopharyngeal carcinomas. Patients were staged according to the criteria of the International Union Against Cancer and were irradiated according to a conventional radiotherapy schedule. No significant associations were found between biologic parameters and clinical features. Only the stage and the mitotic index were related to patient survival, and, when examined in a proportional hazard regression analysis, both provided independent information. When patients with compromised skull and/or cranial nerves (T4 tumors), who had a very short survival, were eliminated from the analysis, only the mitotic index and proliferating cell nuclear antigen allowed discrimination of a subset of patients with poor prognoses. This study shows that the assessment of cell proliferative activity can provide useful information for better predicting the clinical course of high-risk patients with nasopharyngeal carcinomas and improve therapeutic strategies.     

Alcoholism: independent predictor of survival in patients with head and neck cancer

BACKGROUND: Despite recognition of the high prevalence of alcoholism among patients with head and neck cancer, the prognostic importance of alcoholism has not been evaluated adequately. Previous investigators have speculated that alcoholic patients may have a poorer prognosis than nonalcoholic patients because of more advanced stage of cancer, the immunosuppressive effects of alcohol, and an increased rate of death due to other alcohol-related diseases. PURPOSE: The goal of this population-based study was to identify the features of alcoholism that are associated with survival for patients with head and neck cancer and to develop an alcoholic severity staging system from a composite of the independent features of alcoholism. METHODS: This prospective study included 649 patients who were diagnosed with cancer of the oral cavity, oropharynx, hypopharynx, or larynx during the period from September 1, 1983, through February 28, 1987, in a three-county area of western Washington state that participates in the Surveillance, Epidemiology, and End Results Program of the U.S. National Cancer Institute. Details on lifetime alcohol consumption, treatment for alcoholism, abstinence from alcohol prior to the diagnosis of cancer, and alcohol-related health problems were ascertained through in-person interviews near the time of diagnosis. Patients were classified as either nonalcoholics or alcoholics according to their responses to questions from the Michigan Alcoholism Screening Test. The measures of alcohol consumption and abuse that were found to be independently associated with 5-year survival by logistic regression analysis were combined using conjunctive consolidation to create a final composite variable, called an alcoholic severity stage. Cox proportional hazards regression analysis was done to estimate the relative risk (R) of death within 5 years due to specific causes of death for each of the alcoholic severity stages. RESULTS: Alcoholism (RR = 2.06; 95% confidence interval [CI] = 1.43-2.98) and a history of alcohol-related systemic health problems (i.e., liver disease, pancreatitis, delirium tremens, or seizures) (RR = 2.76; 95% CI = 1.69-4.49) were associated with an increased risk of death, whereas abstinence (i.e., the consumption of fewer than one drink per week at 1 year prior to the diagnosis of cancer) (RR = 0.62; 95% CI = 0.39-0.97) was associated with a decreased risk of death. These associations were independent of age, site of cancer, anatomical stage, histopathologic grade, smoking, and type of antineoplastic treatment. Patients in the two worst alcoholic severity stages had an increased risk of dying not only of head and neck cancer but also of cardiovascular disease, pulmonary disease, and other alcohol-related causes. CONCLUSIONS: Alcohol abuse, measured by alcohol consumption, functional impairment, a history of alcohol-related health problems, or abstinence, can provide important prognostic information for patients with head and neck cancer. Our results suggest that sobriety among alcoholic patients can lead to prolonged survival.     

Validation of p53 accumulation as a predictor of distant metastasis at 10 years of follow-up in 1400 node-negative breast cancers

Most studies are in favor of a prognostic relevance of p53 accumulation determined by immunohistochemistry in breast cancer, but negative results are not lacking. On a series of 1400 patients with lymph node-negative cancers treated with local-regional therapy alone until relapse and with a median follow-up of 10 years, we validated the prognostic relevance for overall relapse and death of p53 accumulation observed in a pilot study and analyzed its predictivity on different adverse events. p53 protein accumulation was immunocytochemically detected using PAb1801. The case series had also been previously characterized for hormone receptor content [estrogen receptors (ERs) and progesterone receptors (PgRs)] and for cell proliferation [[3H]thymidine labeling index ([3H]dT LI)]. p53 expression, considered as a dichotomous variable with a cutoff value of 5% positive cells, significantly predicted the occurrence of overall relapse, distant metastasis, and death with an interaction with cell proliferation. p53 accumulation, cell proliferation, and their interaction term, along with tumor size and patient age, retained a predictive role for overall relapse, and together with tumor size and PgR, also for overall survival. When considered as continuous variables, we observed that the hazard of metastasis increased linearly with the increase of [3H]dT LI and decreased linearly with the increase of ER and PgR. Conversely, the hazard increased with the increase of p53-positive cells only for tumors with a [3H]dT LI lower than 7.5%. In multivariate analysis, the same prognostic factors for distant metastasis were identified when the biomarkers were considered as continuous or dichotomous variables.     

Anxiety as a predictor of behavioral therapy outcome for cancer chemotherapy patients.

Studied whether baseline anxiety levels are predictive of outcome on treatments designed to reduce the negative affect and conditioned nausea associated with cancer chemotherapy. 72 18–79 yr old patients classified as having low, moderate, or high anxiety received progressive muscle relaxation training, electromyograph (EMGH) biofeedback, and/or skin temperature biofeedback. Physiological, multiple affect adjective checklist, and postchemotherapy ratings were obtained during baseline, training, and follow-up sessions. Compared with moderate- and high-anxiety Ss, low-anxiety Ss reported less anxiety and depression before behavioral training but nonetheless exhibited significantly greater reductions in anxiety, depression, and diastolic blood pressure as a result of training. Baseline anxiety levels were not related to reduced nausea. Overall, these data suggest that cancer patients who have higher baseline levels of anxiety and who are perhaps most in need of an effective behavioral treatment may be the least likely to benefit from behavioral treatments aimed at reducing the distress associated with chemotherapy. (14 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Prognostic value of P53 gene mutations in a large series of node-negative breast cancer patients

The most important subgroup of breast cancer patients for which reliable prognostic factors are needed are women without axillary lymph node involvement. Although overall, these patients have a good prognosis, it is known that 20-30% will experience a recurrence of the disease. To determine the prognostic significance of P53 tumor suppressor gene mutation, specimens from 113 primary breast cancers were evaluated for the presence of P53 alterations, as detected by cDNA sequencing of the entire coding sequence of the gene. The median follow-up for patients was 105 months. P53 gene mutation was an independent prognostic marker of early relapse and death. Our results suggest that P53 gene mutations could be an important factor to identify node-negative patients who have a poor prognosis in the absence of adjuvant therapy. Prospective studies should be designed to determine which therapy should be performed in this subgroup of patients.     

Tamoxifen and chemotherapy for lymph node-negative, estrogen receptor-positive breast cancer

BACKGROUND: The B-20 study of the National Surgical Adjuvant Breast and Bowel Project (NSABP) was conducted to determine whether chemotherapy plus tamoxifen would be of greater benefit than tamoxifen alone in the treatment of patients with axillary lymph node-negative, estrogen receptor-positive breast cancer. METHODS: Eligible patients (n = 2306) were randomly assigned to one of three treatment groups following surgery. A total of 771 patients with follow-up data received tamoxifen alone; 767 received methotrexate, fluorouracil, and tamoxifen (MFT); and 768 received cyclophosphamide, methotrexate, fluorouracil, and tamoxifen (CMFT). The Kaplan-Meier method was used to estimate disease-free survival, distant disease-free survival, and survival. Reported P values are two-sided. RESULTS: Through 5 years of follow-up, chemotherapy plus tamoxifen resulted in significantly better disease-free survival than tamoxifen alone (90% for MFT versus 85% for tamoxifen [P = .01]; 89% for CMFT versus 85% for tamoxifen [P = .001]). A similar benefit was observed in both distant disease-free survival (92% for MFT versus 87% for tamoxifen [P = .008]; 91% for CMFT versus 87% for tamoxifen [P = .006]) and survival (97% for MFT versus 94% for tamoxifen [P = .05]; 96% for CMFT versus 94% for tamoxifen [P = .03]). Compared with tamoxifen alone, MFT and CMFT reduced the risk of ipsilateral breast tumor recurrence after lumpectomy and the risk of recurrence at other local, regional, and distant sites. Risk of treatment failure was reduced after both types of chemotherapy, regardless of tumor size, tumor estrogen or progesterone receptor level, or patient age; however, the reduction was greatest in patients aged 49 years or less. No subgroup of patients evaluated in this study failed to benefit from chemotherapy. CONCLUSIONS: Findings from this and other NSABP studies indicate that patients with breast cancer who meet NSABP protocol criteria, regardless of age, lymph node status, tumor size, or estrogen receptor status, are candidates for chemotherapy.     

Population-based study of long-term survival in patients with clinically localised prostate cancer

BACKGROUND: Choice of treatment in localised prostate cancer has been hampered by a lack of unbiased, representative data on outcome. Most existing data have come from small cohorts at specialised academic centres; precise overall and cancer-grade-specific data are not available, and the data are subject to differential staging bias. Randomised clinical trials have been undertaken, but the results will not be available for another decade. We have carried out a large population-based study to ascertain overall and prostate-cancer-specific survival in men treated by prostatectomy, radiotherapy, or conservative management. METHODS: Data for 59,876 cancer-registry patients aged 50-79 were analysed. We examined the effect of differential staging of prostate cancer by analysing the data both by intention to treat and by treatment received. Estimated survival was calculated by the Kaplan-Meier method. FINDINGS: By the intention-to-treat approach, 10-year prostate-cancer-specific survival for grade 1 cancer was 94% (95% CI 91-95) after prostatectomy, 90% (87-92) after radiotherapy, and 93% (91-94) after conservative management. The corresponding survival figures in grade 2 cancers were 87% (85-89), 76% (72-79), and 77% (74-80); those in grade 3 cancer were 67% (62-71), 53% (47-58), and 45% (40-51). Although the intention-to-treat and treatment-received analyses yielded similar results for radiotherapy and conservative management, the 10-year disease-specific survival after prostatectomy differed substantially (83% [81-84] by intention to treat vs 89% [87-91] by treatment received). INTERPRETATION: The overall and cancer-grade-specific survival found in this study differ substantially from those in previous studies. Previous studies that used a treatment-received approach have generally overestimated the benefits of radical prostatectomy. We found that grade 3 tumours are highly aggressive irrespective of stage.     

Mitosin (a new proliferation marker) correlates with clinical outcome in node-negative breast cancer

Tumor proliferation rate is an important prognostic factor in breast cancer, and S-phase fraction (SPF), as measured by flow cytometry, is the most clinically validated of several methods for measuring it. However, flow cytometry is not well suited to evaluating the formalin-fixed, paraffin-embedded tumors that are routinely available or to the increasing number of small breast cancers. These and other limitations have motivated research into alternative methods for measuring proliferation, including immunohistochemistry (IHC) against cell cycle-related antigens, which are better suited for the evaluation of small archival tissue samples. Mitosin is a recently described 350 kD nuclear phosphoprotein that is expressed in the late G1, S, G2, and M phases of the cell cycle but not in G0. Using a new monoclonal antibody (14C10), this pilot study evaluated mitosin expression by IHC in a series of 386 node-negative, formalin-fixed, archival breast cancers and correlated the results with several prognostic factors and clinical outcome (median follow-up, 78 months; range 3-214 months). The median and range of mitosin positive cells were 7% and 1-47%, respectively. There was a strong positive correlation between mitosin and SPF (r = 0.57; P = 0.0001), and there were significant negative correlations with estrogen receptor, progesterone receptor, and patient age. Mitosin was not related to overall survival in this pilot study. However, in a univariate cutpoint analysis of disease-free survival (DFS), patients with high levels of mitosin (>9% positive cells) had significantly worse DFS than did patients with lower levels (68% versus 84% at 5 years, respectively). In a multivariate analysis of DFS, large tumor size (>2 cm) and high mitosin were the only independently significant predictors of recurrence (relative risks = 2.47 and 1.72, respectively) in a model containing the additional factors estrogen receptor, progesterone receptor, patient age, and SPF. These preliminary results suggest that mitosin as assessed by IHC may be superior to SPF as a prognostic factor in node-negative breast cancer, but additional studies are necessary to validate these promising findings.     

ERCC1对胃癌患者手术及化疗后生存预测的意义

Objective:The aim of this study was to evaluate the effect of the excision repair cross-complementing (ERCC1) expression on survival in advanced gastric cancer patients who underwent surgical resection and treated with oxaliplatin-based adjuvant chemotherapy. Methods: Sixty-three patients who underwent surgical resection for cure and treated with oxaliplatin-based adjuvant chemotherapy were included in this study. The expressions of ERCC1 of gastric cancer were examined by immunohistochemistry and the patients were categorized into ERCC1-(+) and ERCC1-(-) groups. The relation between ERCC1 expression and survival of patients was examined. Results: Of the 63 eligible patients, 36 patients (57.1%) had tumor with a positive expression of ERCC1 and the remaining 27 patients had tumor with a negative ERCC1 expression. Expression differences of ERCC1 didn't correlated with age (P - 0.827), gender (P = 0.12), differentiation (P = 0.113), historical type (P = 0.942), site of tumor (P = 0.221), size of tumor (P = 0.608), stage (P = 0.815) and lymphatic invasion (P = 0.165). Overall survival (OS) was significantly longer in patients without ERCC1 expression, when compared to patients with ERCC1 expression (P = 0.023). Multivariate analysis revealed that ERCC1 expression significantly impacted on OS (MR: 4.049; P = 0.000). Conclusion: We concluded that resected and treated with oxaliplatin-based adjuvant chemotherapy gastric cancer patients without ERCC1 expression have a better survival when compared to patients with ERCC1 expression. ERCC1 expression will hopefully provide a rational basis for improving adjuvant chemotherapeutic strategies for gastric cancer patients. ERCC1, itself, may be a prognostic factor for gastric cancer.     

Angiogenesis inhibitors as cancer therapy

Angiogenesis inhibitors target a tumor's need to obtain nourishment from the host. In general, they are predicted to be chiefly cytostatic--that is, they stabilize tumors and perhaps prevent metastasis rather than being curative. Nevertheless, it remains conceivable that these agents may trigger tumor cell death. Novel evaluative strategies will be essential to define their potential roles.     

Effect of age on the survival of breast cancer patients

Despite numerous studies, the effect of patient age on the prognosis of breast cancer is still uncertain. The aim of this study was to assess the influence of age on long-term relative survival, to control the results for the extent of disease at diagnosis and assess the association between biological markers and age of the patients. A population-based survival study was made to assess the 5- and 10-year relative survival. All 17,856 female breast cancer patients diagnosed in Finland and reported to the Finnish Cancer Registry in 1977-1986 were included. The results were controlled for the extent of the disease. The markers of biological aggressiveness of tumours and patients' age were correlated in a prospectively collected subset of 2107 patients from the Tampere University area. The relative 5-year and 10-year survival rates (RSRs) were highest in women 46-50 years of age, whereas there was no significant difference between younger and older age groups. No consistent survival trends were observed among the age groups in local, node-negative disease, whereas in node-positive disease the 10-year relative survival was best for women 41-45 years (49%) and poorest in women over 75 years (35%). The youngest age groups were significantly more often oestrogen receptor-negative, but only small differences were observed for S-phase fraction and progesterone receptor positivity.     

Tumor clearance of technetium 99m-sestamibi as a predictor of response to neoadjuvant chemotherapy for locally advanced breast cancer

PURPOSE: Since we have previously shown that the efflux rate of technetium 99m (99mTc) sestamibi, a transport substrate of P-glycoprotein (Pgp), is directly correlated with Pgp levels in untreated breast carcinoma, we tested whether tumor clearance of 9mTc-sestamibi may be predictive of therapeutic response to neoadjuvant chemotherapy in patients with locally advanced breast cancer. PATIENTS AND METHODS: Thirty-nine patients with stage III disease, median tumor diameter 5.8 cm (range, 3 to 10) were enrolled onto this prospective clinical trial and underwent 99mTc-sestamibi scan before neoadjuvant chemotherapy. Patients were injected intravenously (i.v.) with 740 MBq of 99mTc-sestamibi; a 15-minute dynamic study was performed, and static planar images were obtained at 0.5, 1, 2, and 4 hours. The time to half clearance of 99mTc-sestamibi was calculated in each patient from decay corrected time-activity curves using a monoexponential fitting. Patients were treated with epirubicin 150 mg/m2 i.v. every 2 weeks for three courses and then underwent surgery within 3 weeks from the completion of chemotherapy. Residual tumor was assessed by pathologic examination of mastectomy specimens. RESULTS: Seventeen of 39 patients showed a rapid tumor clearance of 9mTc-sestamibi (time to half clearance [t1/2] < or = 204 minutes) and 15 of these 17 (88%) showed a highly cellular macroscopic residual tumor at histology that indicated lack of tumor response to neoadjuvant chemotherapy. In contrast, only eight of 22 (36%) with prolonged retention of 99mTc-sestamibi (t1/2 > 204 minutes) showed residual macroscopic tumor at histology (Fisher's exact test, P < .01). CONCLUSION: A rapid tumor clearance of 99mTc-sestamibi may predict lack of tumor response to neoadjuvant chemotherapy with drugs affected by the multidrug-resistant phenotype in patients with locally advanced breast carcinoma.     

Positive developments for patients with breast cancer as a result of the sentinel node biopsy procedure

As an increasing number of large prospective studies show a high accuracy of the sentinel node for the staging of the axilla in women with invasive breast cancer, there is no need to test the value of this new technique in a randomised trial. Much more emphasis should be given to a reliable implementation of the technique in general practice, requiring a closely co-operating multidisciplinary team meticulously performing the different steps of the technique. The guidelines designed by the Dutch Working Group on the Sentinel Node in Breast Cancer include a learning phase of--arbitrarily--50 procedures in patients also undergoing a complete axillary dissection. What remains is the need for a treatment trial aimed at reducing the morbidity of the treatment of axillary metastases while retaining equal regional tumour control and patient survival. As the indication for adjuvant systemic treatment has shifted from the N-stage to T-stage parameters (size, grade, mitotic activity), the axillary nodal status has become less important as a staging tool. Thus, comparison of surgery or radiotherapy of sentinel node positive patients in a randomised trial appears to be a logical next step.     

p53 nuclear protein overexpression in colorectal cancer: a dominant predictor of survival in patients with advanced hepatic metastases

PURPOSE: To determine whether p53 protein expression is similar within primary colorectal cancer (CRC) and synchronous regional and distant metastases and to assess whether p53 nuclear protein expression could predict outcome in patients with synchronous unresectable liver metastases treated by hepatic artery infusional (HAI) chemotherapy. MATERIALS AND METHODS: Paraffin sections from tumor and corresponding normal mucosa representative of 50 consecutive advanced CRC cases were examined for p53 nuclear protein expression by immunohistochemistry using the monoclonal antibody PAb 1801. Patterns of p53 nuclear expression were correlated with standard clinicopathologic variables and outcome, including response to HAI and survival. In a subset analysis, the pattern of nuclear p53 immunoreactivity was compared between primary CRC and lymph node and liver metastases. RESULTS: Positive nuclear immunoreactivity for p53 protein was found in 72% of cases. The pattern of p53 protein expression in lymph node and liver metastases was identical to that of the primary tumor. The median survival time was 21.0 months in patients with p53-positive tumors and 53.2 months in patients with p53-negative tumors (Wilcoxon test P = .038). Two-year survival rates were 41.7% and 78.6%, respectively (P < .01). No significant difference was found in the response rates to HAI chemotherapy between the two groups. By multivariate analysis, p53 protein status was the single best predictor of survival, with a relative risk of 6.312. CONCLUSION: Our results indicate that nuclear p53 protein status in primary CRC is similar to that in metastatic sites and may be the dominant predictor of survival in patients with advanced hepatic metastases.