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Predicting outcome after traumatic brain injury: development and validation of a prognostic score based on admission characteristics.

The early prediction of outcome after traumatic brain injury (TBI) is important for several purposes, but no prognostic models have yet been developed with proven generalizability across different settings. The objective of this study was to develop and validate prognostic models that use information available at admission to estimate 6-month outcome after severe or moderate TBI. To this end, this study evaluated mortality and unfavorable outcome, that is, death, and vegetative or severe disability on the Glasgow Outcome Scale (GOS), at 6 months post-injury. Prospectively collected data on 2269 patients from two multi-center clinical trials were used to develop prognostic models for each outcome with logistic regression analysis. We included seven predictive characteristics-age, motor score, pupillary reactivity, hypoxia, hypotension, computed tomography classification, and traumatic subarachnoid hemorrhage. The models were validated internally with bootstrapping techniques. External validity was determined in prospectively collected data from two relatively unselected surveys in Europe (n = 796) and in North America (n = 746). We evaluated the discriminative ability, that is, the ability to distinguish patients with different outcomes, with the area under the receiver operating characteristic curve (AUC). Further, we determined calibration, that is, agreement between predicted and observed outcome, with the Hosmer-Lemeshow goodness-of-fit test. The models discriminated well in the development population (AUC 0.78-0.80). External validity was even better (AUC 0.83-0.89). Calibration was less satisfactory, with poor external validity in the North American survey (p < 0.001). Especially, observed risks were higher than predicted for poor prognosis patients. A score chart was derived from the regression models to facilitate clinical application. Relatively simple prognostic models using baseline characteristics can accurately predict 6-month outcome in patients with severe or moderate TBI. The high discriminative ability indicates the potential of this model for classifying patients according to prognostic risk.

Adolescent↗

Is patient's age a prognostic factor for follicular thyroid carcinoma in the TNM classification system?

The knowledge of prognostic factors is essential for an optimal treatment of patients. The aim of our study was to find out if age is an independent prognostic factor for patients with follicular or Hürthle cell carcinoma. This retrospective study was carried out in 261 patients (median age, 62 years) with follicular or Hürthle cell thyroid carcinoma treated at our institute from 1972-2002. For all patients the follow-up was performed at our institute at least once per year. The data on gender and age of the patients, disease history, extent of disease, morphologic characteristics, mode of therapy, outcome, and survival were collected. Statistical correlation between possible prognostic factors and cause-specific survival was analyzed by univariate and Cox's multivariate survival analysis. The 10-year and 20-year survival of all 261 patients were 70% and 42%, respectively. Even 10 of 49 (20%) of our patients who were under 45 years of age (i.e., in stage II of the tumor, node, metastases [TNM] classification system) died of disease. Multivariate analysis showed that primary tumor size and distant metastases were independent prognostic factors for survival. Lymph node metastases as well as the age of patients were not found to be independent prognostic factors. Therefore, the patients with distant metastases or tumor stage T4 who are under 45 years of age cannot be considered to have favorable prognosis.

Adenoma, Oxyphilic↗

The disappearance of prognostic factors in Hodgkin's disease.

The purpose of this conceptual (and somewhat provocative) article is to analyse the reasons for the disappearance of prognostic factors in Hodgkin's disease (HD) and to explore the consequences for further research from a biometrical point of view. The very concept of prognostic factors is about to resolve in HD. Prognostic factors gradually loose their predictive power as treatment is successfully adapted to the disease burden. Freedom from treatment failure and overall survival curves of patients in early, intermediate and advanced stages of HD are superimposable with the best current treatment protocols of the German Hodgkin's Lymphoma Study Group. This disappearance of prognostic factors in HD necessitates a certain conceptual remodelling. It's time to think quantitatively and bivariately, and we need to (i) synthesise existing 'prognostic' factors into a quantitative measure of disease burden or severity; (ii) develop a quantitative measure of treatment strength and (iii) relate these two quantities in nomogram curves indicating how much treatment a patient with a given disease burden requires to have, say, a 85%, 90% and perhaps 95% expected chance of cure.

Combined Modality Therapy↗

Advanced ovarian cancer. An overview of multi-variate analyses of prognostic variables with special reference to the role of cytoreductive surgery.

BACKGROUND: Cytoreductive surgery is still widely believed to be a cornerstone in the management of advanced ovarian cancer. In the absence of data from prospective randomized trials, multi-variate analysis can assist in evaluating the role of optimal surgical cytoreduction relative to other possible prognostic variables. MATERIALS AND METHODS: Published analyses of prognostic variables have been reviewed and the consistency and reproducibility of variables have been considered. RESULTS: When reviewing the most recent literature it is obvious that there is a need to develop a consensus as to the most important patient characteristics which should be reported. Furthermore, these characteristics need to be standardized as do definitions such as toxicity, grading, and response criteria and duration. Subjective variables such as performance status, histological grading and typing, present a special problem as these lack reproducibility. The overview of multi-variate analyses for prognostic variables such as residual tumour size, tumour size prior to cytoreductive surgery, cisplatin therapy, grade, stage, histology, and performance status demonstrates that the impact of individual prognosticators depends on the indicators included in the analysis and that the importance of these variables could change as new technologies and treatments are introduced. CONCLUSIONS: The collection of a single data base including all known variables reported for each patient with appropriate attention to the careful evaluation of subjective indicators should be undertaken, with a view to establishing a prognostic index. This would allow the relative risk for individual patients to be assessed.

Clinical Trials as Topic↗

Prognostic variables for response and outcome in patients with extragonadal germ-cell tumors.

BACKGROUND: This investigation evaluates prognostic variables in patients with seminomatous and non-seminomatous extragonadal germ-cell tumors (EGCT) in order to identify relevant factors for long-term outcome following cisplatin-based chemotherapy. PATIENTS AND METHODS: Patients from six countries treated at 11 centers in Europe and the USA from 1975 to 1996 were evaluated retrospectively. Uni- and multivariate analyses of prognostic variables for survival and for response to chemotherapy were performed. RESULTS: Data were available for 635 EGCT patients, 104 with seminomatous and 524 with non-seminomatous EGCT (n = 7 not specified). For non-seminomatous EGCT the following independent adverse factors were identified: presence of either liver, lung or central nervous system metastases, primary mediastinal tumor or elevation of pretreatment beta-human gonadotropin; for extragonadal seminoma (only univariate) adverse factors were: presence of liver metastases, two or greater metastatic sites or International Germ Cell Cancer Collaborative Group (IGCCCG) grouping (intermediate versus good). Integration of these variables produced the following prognostic risk groupings: 'excellent prognosis', all seminomatous EGCT (89% 5-year survival rate); 'intermediate low', 'intermediate high' and 'poor', all non-seminomatous EGCT with a 69, 55 and 17% 5-year survival rate, respectively. The decreased survival among the different groups was due to a lower rate of favorable objective remissions and a higher rate of relapses. Classification and regression tree (CART) modeling confirmed histology and location of primary tumor as the major prognosticators. For the subgroup of patients with mediastinal non-seminoma, the 2-year survival rate ranged from 34 to 84%. Multivariate testing for the probability to respond to chemotherapy revealed non-seminomatous histology, primary mediastinal tumor site, and the presence of liver, lung or CNS metastases as independent adverse factors. CONCLUSIONS: In EGCT, prognostic variables for the outcome and for the response to chemotherapy could be identified, which in part differ from gonadal GCT. The proposed model might help to better understand the specific prognosis of EGCT and to tailor risk-adapted treatment strategies. In addition, CART analysis demonstrated the heterogenous prognosis of patients with mediastinal non-seminoma.

Abdominal Neoplasms↗

Prognostic molecular markers for planning adjuvant chemotherapy trials in Dukes' B colorectal cancer patients: how much evidence is enough?

The benefit of postoperative adjuvant chemotherapy in patients with Dukes' B colorectal cancer is still uncertain and its routine use is not recommended. Prognostic biomarkers may be useful for identifying high-risk patients with resected, node-negative disease, and this stratification may represent an innovative strategy for designing adjuvant chemotherapy trials. Featured prognostic molecular markers can be divided into the following categories: cell proliferation indices (Ki-67, Mib-1, proliferating cell nuclear antigen); oncogenes/tumor suppressor genes [p53, K-ras, Deleted in Colorectal Cancer (DCC), Bcl-2, c-erbB2]; DNA repair (microsatellite instability); markers of angiogenesis (vascular count, vascular endothelial growth factor); markers of invasion/metastasis (plasminogen-related molecules, matrix metalloproteinases); and biochemical markers (thymidylate synthase). Studies that have investigated their prognostic role in Dukes' B colorectal cancer patients are reviewed here. Current data do not provide sufficient evidence for the incorporation of available prognostic biomarkers into clinical practice. However, a biomarker-based approach could be an effective strategy for improving results of postoperative adjuvant treatments in high-risk Dukes' B colorectal cancer patients. Markers of altered DCC function have shown promising prognostic role and sufficient prevalence in retrospective investigations and they deserve further assessment in prospective studies.

Biomarkers, Tumor↗

Survival and prognostic factors after initiation of treatment in Waldenstrom's macroglobulinemia.

BACKGROUND: Waldenstrom's macroglobulinemia (WM) is an unusual lymphoplasmacytoid lymphoma characterized by the presence of a serum monoclonal immunoglobulin M. Although several studies have evaluated possible prognostic factors of this disease, few have focused on the survival and prognosis of symptomatic patients after the initiation of treatment. PATIENTS AND METHODS: Our study included 122 previously untreated patients with a median age of 67 years who required systemic treatment. Multiple variables were analyzed for their prognostic value on survival after initiation of treatment using univariate and Cox regression multivariate analysis. RESULTS: The median overall survival was 106 months. Pretreatment factors associated with shorter survival were age >/=65 years, splenomegaly, B-symptoms (weight loss, fever or night sweats), hemoglobin <10 g/dl, platelets <100 x 10(6)/dl, albumin <3.5 g/dl and bone marrow lymphoplasmacytic infiltrate >/=50%. In the multivariate analysis, the two variables with independent prognostic value were age >/=65 years and hemoglobin <10 g/dl. Furthermore, we were able to divide our patients into three risk groups based on the presence of two, one or none of these two adverse prognostic factors. The median survival times in the high-, intermediate- and low-risk groups were 46 months, 107 months and 172 months, respectively (P <0.0001). DISCUSSION: Our findings suggest that advanced age and anemia appear to be the two dominant prognostic factors for survival after initiation of treatment in patients with WM. These two readily available parameters can stratify the patients into three distinct subgroups and may help the selection of appropriate treatment.

Adult↗

Prognostic value of lymphovascular space invasion determined with hematoxylin-eosin staining in early stage cervical carcinoma: results of a multivariate analysis.

BACKGROUND: Our aim was to study the prognostic value of the presence of lymphovascular space invasion (LVSI) in patients with stage IB and II cervical carcinoma treated by initial surgery. PATIENTS AND METHODS: A retrospective analysis was performed on 193 patients who underwent, between 1985 and 1998, an initial radical hysterectomy with pelvic (+/- para-aortic) lymphadenectomy using midline laparotomy for stage IB (180 patients) or II (13 patients) cervical carcinoma. Postoperative therapy was delivered according to prognostic factors. RESULTS: The rate of LVSI correlated significantly with tumor stage, nodal status and the location of positive nodes. Using univariate analysis, tumor size (<4 or >/= 4 cm), LVS status and nodal status were prognostic factors. At multivariate analysis, two prognostic factors were identified: LVS status and nodal status. In a subgroup of 89 patients with a small tumor (</=2 cm) and absence of nodal or isthmic involvement, the overall survival was significantly correlated with the presence of LVSI. CONCLUSIONS: LVSI is a frequent occurrence in patients with early stage cervical cancer. It represents an unfavorable prognostic factor in univariate and multivariate analyses. Such results suggest that improvement is needed in the treatment of patients with a small tumor and LVS invasion.

Adult↗

Exercise ventilation inefficiency and cardiovascular mortality in heart failure: the critical independent prognostic value of the arterial CO2 partial pressure.

AIMS: In chronic heart failure (CHF) patients, the ventilation (Ve) needed to eliminate metabolically produced CO(2) during exercise (i.e. the Ve/Vco(2) slope) is a strong prognosticator. Ve/Vco(2) slope determinants are the dead space-tidal volume (Vd/Vt) ratio and the arterial CO(2) partial pressure (Paco(2)). We aimed at defining the respective prognostic role of these two variables. METHODS AND RESULTS: One hundred and twenty-eight stable CHF patients (average left ventricular ejection fraction 34+/-10%) underwent cardiopulmonary exercise testing and blood gas analysis. The prognostic relevance of the Ve/Vco(2) slope, Vd/Vt, and Paco(2) at peak exercise was evaluated by the Kaplan-Meier approach with log-rank testing and by multivariate Cox regression analysis. During a mean period of 31.3+/-20 months, 24 patients died from cardiac causes. In univariate analysis, predictors of death included the use of anti-aldosterone drugs, low peak Vo(2), peak Ve/Vo(2), peak Paco(2) and high Ve/Vco(2) slope, and peak Vd/Vt. Multivariate analysis identified a low peak Paco(2) (<35 mmHg) as the strongest independent prognostic indicator [hazard ratio 4.65, 95% confidence interval (CI) (1.695-12.751), P=0.003] that primarily accounts for the Ve/Vco(2) slope prognostic power. CONCLUSION: These findings imply that regulatory mechanisms involved in the tight control of ventilatory command and blood gas tension, rather than lung function abnormalities, play a critical pathophysiological role in the exercise ventilation inefficiency of CHF patients.

Blood Gas Analysis↗

Prognostic value of Y deletion analysis. The role of current methods.

Y chromosome microdeletions represent the most frequent genetic alteration in azoospermic and severely oligozoospermic men, and screening for microdeletions in AZFa, b and c are routinely performed in the major andrology and infertility centres. Since patients with Y microdeletions often require intracytoplasmic sperm injection (ICSI), the question of whether the type of the microdeletion present could have prognostic value for the presence of spermatozoa in the ejaculate or in the testes [by testicular sperm extraction (TESE)] is an interesting one. The review of the literature on this topic showed that there is still no clear genotype--phenotype relationship, i.e. similar testicular alterations may be caused by different types of microdeletions, and apparently identical microdeletions may be associated with diverse tubular damage. Even in azoospermic men, the localization of the microdeletion cannot be used as a valid prognostic parameter before TESE--ICSI to identify patients with spermatozoa in their testes. The only finding with absolute negative prognostic value is the presence of complete AZFa--c deletions, which are invariably associated with an absence of spermatozoa. Microdeletions in AZFa or AZFb seem to have promising prognostic value, but more data and gene-specific deletions have to be provided to draw clear conclusions. The absence of a clear genotype--phenotype relationship, and therefore of a prognostic value of Y deletion analysis, is probably due to the current methods used for the screening of the microdeletions. In fact, to date most centres do not use gene-specific markers but instead use anonymous primers that contribute little information to the pathogenic role of the microdeletions.

Gene Deletion↗

Prognostic factors for mortality in nasopharyngeal cancer: accounting for time-dependence of relative risks.

BACKGROUND: Few studies have assessed the role of prognostic factors for mortality from nasopharyngeal cancer and even fewer used multivariable methods. Most of these studies relied on the Cox model without testing the proportional hazards assumption. METHODS: A cohort of 76 cases of nasopharyngeal cancer recorded in the Rhône, France, between 1980 and 1985, was followed until 1995. Proportional hazards assumption was tested for each putative prognostic factor. Two multivariable models were built using forward selection of prognostic factors: the Cox model and a flexible model in which variables not meeting the proportional hazards assumption were represented by a time-varying hazard ratio. RESULTS: Only Epstein Barr Virus Nuclear Antigen (EBNA) serology, a marker of infection by the Epstein-Barr virus, and tumoral extent were selected in the analysis based on the Cox model. In contrast, four prognostic factors were significant at alpha = 0.05 level in the flexible model: initial EBNA serology, tumoral histology, age and tumoral extent, the last two not verifying the proportional hazards assumption. The relative risk of age increases with duration of follow-up whereas the effect of tumoral extent changes in a non-monotonic pattern. CONCLUSION: We showed the importance of taking into account the non-proportionality of hazards which can influence results and yield new insights about the role of prognostic factors in nasopharyngeal cancer. Because of the small size of our cohort, our results have to be confirmed in an independent study.

Adult↗

Prognostic factors in advanced non-small cell lung cancer: elevated serum levels of neuron specific enolase indicate poor prognosis.

BACKGROUND: Non-small cell lung cancer (NSCLC) is resistant to chemotherapy and prognosis of advanced NSCLC patients is considered to be dependent on various prognostic factors. METHODS: We analyzed prognostic factors in patients with advanced NSCLC who had been enrolled in clinical trials conducted by the Okayama Lung Cancer Study Group between 1978 and 1992 using two kinds of multivariate analysis, Cox's multivariate analysis and recursive partitioning and amalgamation (RPA) analysis. RESULTS: The first analysis was performed on 261 patients using 28 variables. Performance status (PS), clinical stage, liver metastasis or serum albumin level was an independent prognostic factor by Cox's analysis. In the second analysis performed on 128 patients having data on neuron specific enolase (NSE), NSE was the most important prognostic factor. Using the RPA method, three subgroups with significantly different survival potentials were defined. Among them, patients with normal serum NSE levels and good PS were found to obtain a markedly favorable prognosis [median survival time (MST) 22.1 months, 3-year survival rate 42.9%], whereas the survival of patients with elevated serum NSE levels and bone metastasis was extremely short (MST 4.7 months, 3-year survival rate 0%). CONCLUSIONS: These results indicate that analysis of prognostic factors including serum levels of NSE is useful for predicting the survival of patients with advanced NSCLC.

Adult↗

Prognostic significance of tumor necrosis in primary transitional cell carcinoma of upper urinary tract.

OBJECTIVE: We investigated the prognostic significance of tumor necrosis in primary transitional cell carcinoma (TCC) of upper urinary tract. METHODS: We retrospectively analyzed the records of 119 patients who received surgical management for primary TCC of upper urinary tract. The presence or absence of tumor necrosis was evaluated based on the macroscopic description of the tumor. Along with pathologic features of tumor necrosis, we assessed the impacts of various prognostic factors previously reported for TCC of upper urinary tract. RESULTS: Tumor necrosis was identified in 19 (16.0%) patients. Patients with tumor necrosis were more likely to have higher local stage, nodal involvement, higher tumor grade, lymphovascular invasion (LVI), and recurrence of disease. Among all subjects, disease-specific survival rates at 5 years after surgery for patients with and without macroscopic tumor necrosis were 36.7 and 83.2%, respectively (P = 0.0001). In multivariate analysis, only pathologic T stage, LVI and tumor necrosis were shown to be independent predictors for disease-specific survival. For solely the invasive tumors, variables including age, surgical margin and tumor necrosis were observed to be independent prognostic factors for disease-specific survival in multivariate analysis, with tumor necrosis showing the highest rank order of statistical significance. CONCLUSIONS: Our results suggest that macroscopic tumor necrosis may be a useful prognostic indicator for primary TCC of upper urinary, especially for invasive tumors. Further investigation would be warranted for the prognostic implications of tumor necrosis in TCCs of upper urinary tract and on actual pathogenesis of tumor necrosis in upper tract TCC.

Adult↗

Altered expression of retinoblastoma protein and known prognostic variables in locally advanced bladder cancer.

BACKGROUND: The clinical behavior of the tumor in patients with locally advanced bladder carcinoma is unpredictable. Current predictors of clinical behavior include depth of muscle invasion, presence of vascular invasion, proliferation rate, and loss of blood group antigens. Treatment selection would be facilitated by the development of a reliable marker of tumor progression. Functional retinoblastoma (RB) gene loss has been reported to occur in bladder carcinoma, but the significance of this loss is unknown. PURPOSE: We have evaluated the frequency of functional loss of the RB gene in locally advanced bladder carcinoma and have compared the results to known prognostic factors in the same cohort. METHODS: Forty-three study patients with pathologically well-characterized, locally advanced bladder carcinoma, who were placed in a protocol incorporating surgery and chemotherapy, were studied for known clinical and pathological prognostic indicators as well as for their Rb status. Formalin-fixed and paraffin-embedded archival primary tumor tissues were used for histological and immunohistochemical analyses. RESULTS: Altered Rb protein expression was documented in 37% of the tumor specimens. The high rate of altered Rb expression found in this cohort with advanced urothelial tumors strongly suggests that RB functional loss may be associated with tumor progression in this malignancy. Altered Rb protein expression was found to be independent of other known prognostic variables. A significantly poorer tumor-free survival rate also was noted for those patients who had a tumor with an altered Rb protein with or without vascular invasion. CONCLUSION: The high frequency of Rb alteration in locally advanced bladder carcinomas, plus the fact that a significant correlation could not be found between the Rb status and other known prognostic markers in this preliminary study, suggests that altered RB expression may be an independent prognostic marker of tumor progression in bladder cancer.

Gene Expression Regulation, Neoplastic↗

Comparison of prognostic factors and survival among black patients and white patients treated with irradiation for non-small-cell lung cancer.

BACKGROUND: Many studies have reported differences in cancer incidence and survival between populations of Blacks and Whites. A 45% higher death rate from lung cancer for Black men and a survival duration for Black patients with lung cancer that is generally shorter than that for White patients have also been reported. PURPOSE: The purpose of this study was to evaluate whether race affects known prognostic factors for non-small-cell lung cancer in Black versus White patients. This analysis attempts to determine which prognostic factors may contribute to the reported differences in disease outcome. METHODS: We used data from 1565 patients with non-small-cell lung cancer treated in four randomized prospective trials conducted by the Radiation Therapy Oncology Group (RTOG). The data were pooled for a retrospective analysis of survival and prognostic factors by race. RESULTS: Univariate analysis showed significant differences between Blacks and Whites with regard to sex, weight loss, histology, and RTOG T stage (P < .05), but the only clinically significant difference (P < or = .01) was weight loss. Despite these findings, overall survival for Blacks and Whites did not differ significantly (P = .67). Median survival for Blacks and Whites with a Karnofsky performance status (KPS) of 90 or more was 12.1 and 11.3 months, respectively (P = .45). Survival for Blacks and Whites with a KPS of less than 90 was 7.8 and 6.8 months, respectively. Cause of death did not differ between the two races. For both races, KPS, age, sex, weight loss, and RTOG T and N stages were significant prognostic factors for survival (P < .01), but race was not a significant prognostic factor. CONCLUSION: Further studies of the differential in cancer survival for Blacks and Whites may be indicated, but greater impact may be achieved by addressing socioeconomic factors, lifestyle and occupational risk factors, health education, and access to adequate health care.

Black People↗

Evaluating the potential usefulness of new prognostic and predictive indicators in node-negative breast cancer patients.

The incidence of breast cancer is increasing in all Western countries. Due both to a more widespread public education and to early diagnosis by mammography screening programs, the percentage of patients with node-negative breast cancer has gone up to 70%. Thus, node-negative breast cancer is a major public health problem and, consequently, clinical research in this setting is an expanding field. A recent overview analysis confirmed the results of five prospective randomized clinical trials suggesting that systemic adjuvant therapy can benefit node-negative breast cancer patients. Because of the heterogeneity of node-negative breast cancer, it is reasonable to attempt to avoid excessive treatment morbidity and costs by using selective prognostic markers to identify patients at high risk for disease recurrence who are eligible for postsurgical systemic adjuvant therapy. It is also desirable to use predictive markers in selecting the therapy to which each patient is more likely to respond. The need for additional prognostic and predictive factors has led to identification of a plethora of potentially useful markers. As a result, the selection of patients at different risks of developing node-negative breast cancer and the choice for appropriate therapy remain difficult and confusing for the clinician. Moreover, the majority of studies have examined new markers individually rather than by multivariate analysis and retrospectively rather than prospectively. Thus, there are also important methodologic biases in such studies. This analysis consists of (a) defining the clinical "problem," (b) defining the terms of prognostic and predictive factors, (c) suggesting more appropriate laboratory and clinical approaches to properly evaluate a new indicator, (d) identifying the subsets of patients in whom the use of new prognosticators is warranted and of particular importance, and (e) providing some direction for future research on this topic. Our ultimate goals are to facilitate the understanding of node-negative breast cancer prognostic markers among clinicians, to help them select the most appropriate indicator for specific situations, and to recommend methodology for future research.

Adult↗

Cytoplasmic accumulation of p53 protein: an independent prognostic indicator in colorectal adenocarcinomas.

BACKGROUND: Aberrations of the p53 gene (also known as TP53) frequently lead to the synthesis of mutant proteins that accumulate in the nuclei and/or cytoplasm of neoplastic cells. Intracellular p53 protein accumulation may be an unfavorable prognostic parameter in breast, lung, ovarian, gastric, and colorectal cancers. Specific classes of p53 gene mutations, assayed by characteristic subcellular p53 protein accumulation patterns, may be useful prognostic indicators. PURPOSE: The prognostic value of nuclear and cytoplasmic p53 protein accumulation in the tumor cells of patients with colorectal carcinoma was studied. METHODS: Antibodies PAb 1801 and CM1 were used for immunocytochemical assay of nuclear and cytoplasmic p53 protein accumulation in a retrospective series of colorectal carcinoma samples obtained from 206 patients who were followed for at least 5 years. Results were correlated with the following clinicopathologic parameters: patient sex and age; tumor site, stage, and grade; and DNA ploidy status of the tumors. Overall survival and disease-free survival were analyzed with the Kaplan-Meier method. Differences in distributions were analyzed using the Mantel-Cox method. Multivariate analysis was performed with the Cox proportional hazards model. RESULTS: Immunostaining with PAb 1801 revealed nuclear p53 accumulation in 46% (95) of 206 cases, whereas CM1 immunostaining of 197 cases showed nuclear and cytoplasmic p53 accumulation in 33% (65 cases) and 50% (99 cases) of the cases, respectively. In univariate analysis, both nuclear p53PAb 1801 and cytoplasmic p53CM1 protein accumulations were significantly associated with poor overall survival (P = .0198 and P = .0017, respectively) and with disease-free survival (P = .004 and P = .0016, respectively). When patients were analyzed according to site of their tumors, nuclear p53PAb 1801 protein accumulation was statistically significant only in the right colon (P = .027), whereas cytoplasmic p53CM1 protein accumulation was statistically significant in the left colon and rectum (P = .0016). In multivariate analysis, only cytoplasmic p53CM1 protein accumulation was associated with poor overall survival and with disease-free survival (P = .006 and P = .002, respectively). With the addition of DNA ploidy status, however, cytoplasmic p53CM1 protein accumulation remained significant only for disease-free survival (P = .035). In patients with tumors of the left colon and rectum, cytoplasmic p53CM1 protein accumulation was the most significant prognostic indicator for overall survival (P = .007) and disease-free survival (P = .002) after disease stage. CONCLUSION: Cytoplasmic p53CM1 protein accumulation, but not nuclear p53PAb 1801 protein accumulation, is an independent prognostic parameter in patients with colorectal carcinomas. IMPLICATIONS: Cytoplasmic p53CM1 accumulation may be a useful indicator of patients at high risk for disease recurrence who may benefit from aggressive adjuvant therapy.

Adenocarcinoma↗

The prognostic value of CEA, beta HCG, AFP, CA125, CA19-9 and C-erb B-2, beta HCG immunohistochemistry in advanced colorectal cancer.

BACKGROUND: Evaluation of the prognostic significance of a group of tumour markers and their ability to predict response to chemotherapy may allow better targeting of palliative treatment in advanced colorectal cancer. PATIENTS AND METHODS: Using a prospectively acquired database of 377 patients (pts) with advanced colorectal adenocarcinoma, the prognostic significance of serum CEA (342 pts), beta HCG (203 pts), AFP (208 pts), CA125 (150 pts), CA-19-9 (76 pts) as well as C-erb B-2 (197 pts). Serum markers were taken prior to 5-FU based chemotherapy and immunohistochemistry was performed on diagnostic samples RESULTS: Tumour markers of poor prognostic significance in the univariate analysis were CEA > or = 5 micrograms/l (p = 0.006; median survival (MS 59 weeks vs 38 weeks) and CA125 > or = 35 U/ml (p = 0.01 MS 51 weeks vs. 30 weeks). Tumour markers elevated at greater than 10 times the normal value which correlated with a poor prognosis were CEA (p = 0.001; MS 47 weeks vs. 35 weeks), Serum beta HCG (p < 0.0001; MS 44 weeks vs. 7 weeks) and CA125 (p < 0.0001; MS 38 weeks vs. 15 weeks). Poor performance status ( > 2) and poorly differentiated tumour histology were also correlated to poor survival. In the multivariate analysis, tumour markers of independent poor prognosis were CEA > or = 5 micrograms/l (Hazard Ratio (HR) 1.8; 95% Confidence Internal (CI) 2.8-1.2), CEA > or = 50 micrograms/l (HR 1.6; CI 2.1-1.2), CA125 > or = 35 U/ml (HR 1.5; CI 2.3-1.0), CA 125 > or = 350 U/ml (HR 5.0; CI 9.6-2.6) and serum BHCG > or = 0 IU/l (HR 11.7; CI 30-4.5). Poor performance status (HR 6.7-5.0) and poorly differentiated histology (HR 2.8-1.0) were the other important factors in the model. No pretreatment tumour marker correlated with response to chemotherapy. CONCLUSIONS: This is the largest prognostic study of each tumour marker in advanced disease and it clarifies previous conflicting reports. Serum AFP, CA19-9 and immunohistochemical stains beta HCG and C-erb B-2 have no prognostic significance. Serum CEA, beta HCG, CA125 in advanced colorectal cancer prior to chemotherapy do convey an independent poor prognosis which may reflect not just tumour burden but aggressive biology.

Adenocarcinoma↗