Independent Predictor Of Disease-free Survival Research Articles

MDM2 and p53 expression in gliomas: a multivariate survival analysis including proliferation markers and epidermal growth factor receptor.

p53 and the murine double minute 2 (MDM2) oncoprotein expression was evaluated in paraffin-embedded tissue from 61 patients with central nervous system gliomas (53 astrocytomas and eight oligodendrogliomas) and related to proliferation-associated markers [i.e. proliferating cell nuclear antigen (PCNA), Ki-67 and nuclear organizer regions (NORs)] and epidermal growth factor receptor (EGFR). We used the monoclonal antibodies PC-10, MIB-1, DO-1, 1B1O and EGFR 113 and the colloid silver nitrate (AgNOR) technique. MDM2 and p53 were co-expressed in 28% of cases. A p53-positive/MDM2-negative phenotype was observed in 15% and a p53-negative/MDM2-positive phenotype in 20% of cases. There was a positive correlation of p53 and MDM2 expression with grade and proliferation indices. Univariate analysis in the group of diffuse astrocytomas showed that older age, high histological grade, high PCNA labelling index (LI) and high AgNOR score were associated with reduced overall survival (P < 0.05). p53 LI, Ki-67 LI, AgNOR score, tumour location and grade influenced disease-free survival (P < 0.05), whereas the only parameters affecting post-relapse survival were histological grade and Ki-67 LI (P < 0.1). Multivariate analysis revealed that age, radiotherapy, PCNA LI and p53 LI were the independent predictors of overall survival. p53 LI, Ki-67 LI, MDM2 LI, EGFR LI, grade and type of therapy were independent predictors of disease-free survival, and grade was the only independent predictor of post-relapse survival. Our results indicate that p53 LI and MDM2 LI, EGFR expression as well as proliferation markers (PCNA and Ki-67) are useful indicators of overall and disease-free survival in diffuse astrocytoma patients.

Recurrence after resection for ductal adenocarcinoma of the pancreas.

We analyzed the pattern of failure and clinicopathologic factors influencing the disease-free survival of 78 patients who died after macroscopic curative resection for pancreatic cancer. Local recurrence was a component of failure in 56 patients (71.8%) and hepatic recurrence in 48 (61.5%), both accounting for 97% of the total recurrence rate. About 95% of recurrences occurred by 24 months after operation. Median disease-free survival time was 8 months, and cumulative 1-, 3-, and 5-year actuarial disease-free survival rates were 66%, 7%, and 3%, respectively. Multivariate analysis showed that tumor grade (p = 0.04), microscopic radicality of resection (p = 0.04), lymph node status (p = 0.01), and size of the tumor (p = 0.005) were independent predictors of disease-free survival. Patterns of failure and disease-free survival were not statistically influenced by the type of surgical procedure performed. Median survival time from the detection of recurrence until death was 7 months for local recurrence versus 3 months for hepatic or local plus hepatic recurrence (p < 0.05). From our experience and the data collected from the literature, it appears that surgery alone is an inadequate treatment for cure in patients with pancreatic carcinoma. Effective adjuvant therapies are needed to improve locoregional control of pancreatic cancer after surgical resection.

The Role of p53, MDM2 and c-erb B-2 Oncoproteins, Epidermal Growth Factor Receptor and Proliferation Markers in the Prognosis of Urinary Bladder Cancer

The immunohistological expression of p53 and MDM2 oncoproteins was examined in paraffin embedded tissue from 106 patients with transitional cell carcinoma of the urinary bladder and was related to various clinicopathological features, the expression of proliferation associated markers (proliferating cell nuclear antigen - PCNA - and Ki-67), c-erb B-2 oncoprotein and epidermal growth factor receptor (EGFR), as well as to survival. MDM2 immunoreactivity was seen in 38% of our cases, and in 14% was accompanied by p53 positive immunohistochemistry. The rate of p53 positivity was associated with grade, stage and papillary status, whereas MDM2 immunopositivity increased with grade and stage (Ta VS T1), and MDM2 labeling index (LI) with stage. MDM2 expression was related to p53 expression and less strongly to proliferation rate (Ki-67 LI). The simultaneous p53 and MDM2 expression was more frequently observed in higher grade and stage tumours. C-erb B-2, EGFR and proliferation marker expression increased with grade, stage and non-papillary configuration. In univariate analysis high grade, solid growth pattern, advanced T-category, cystectomy, EGFR and Ki-67 expression were linked to shorter overall survival but only Ki-67 LI, along with T-category and type of therapy, had independent prognostic value. C-erb B-2 expression and stage were the two independent predictors of disease-free survival and Ki-67 LI and EGFR LI the independent predictors of post-relapse survival. For patients with superficial tumors PCNA LI emerged as the single independent determinator of survival. p53 and MDM2 expression did not appear to have any significant impact on survival, although the simultaneous expression of p53 and MDM2 turned out to be a highly significant parameter of shortened overall survival in univariate analysis.

The significance of p53 mutation and over-expression in ovarian cancer prognosis

Mutation of the p53 tumor suppressor gene is the most commonly observed genetic abnormality in human tumors and associations between p53 aberration and patient survival have been shown for several tumor types. Previous studies have found that approximately 50% of epithelial ovarian carcinomas exhibit abnormalities in the p53 gene. The aim of this study, therefore, was to examine the potential prognostic significance of aberrant p53 in patients with primary epithelial ovarian carcinoma. Using immunohistochemistry (IHC) and the anti-p53 antibodies CM1, PAb240 and PAb1801, p53 over-expression was observed in 20/39 (51%) tumors. When these results were combined with previously reported IHC and sequencing analyses, 37/61 (61%) tumors exhibited a p53 aberration. Although there was no significant difference between sequencing and IHC results, several cases gave discordant results, indicating that a combination of both methods may be required to estimate accurately the proportion of tumors with p53 aberrations. Univariate statistical analysis showed that p53 aberrations were significantly associated with tumor grade 3/4, FIGO stage III/IV, serous tumors and the presence of bulk (>2 cm) residual disease following surgery. In univariate survival analysis, tumor grade and stage, ascites and post-surgical residual tumor> 2 cm were associated with both overall survival (OS) and disease-free survival (DFS). p53 status, however, was not a predictor of either OS or DFS. Using the Cox proportional hazards model, only FIGO stage and post-surgical residual disease> 2 cm had an independent effect on OS and only stage was found to be an independent predictor of DFS. In conclusion, p53 mutation and overexpression does not appear to be a significant indicator of patient survival in this series of ovarian carcinomas.

Elevated Levels of Apoptosis Regulator Proteins P53 and BCL-2 are Independent Prognostic Biomarkers in Surgically Treated Clinically Localized Prostate Cancer

Purpose The tumor suppressor gene (TSG) p53 and the proto-oncogene bcl-2 have been shown to be involved in the regulation of cell growth and apoptosis and have been implicated in hormone refractory prostate cancer (PC) and poor prognosis. The goal of this study was to determine the clinical utility of the presence of p53 and bcl-2 immunohistochemical (IHC) protein in the primary tumor as predictors of disease progression following radical prostatectomy (RP). Materials and Methods The expression of p53 and bcl-2 was evaluated in archival paraffin-embedded RP specimens from 175 patients followed from 1 to 9 years (mean = 4.6 years) and correlated with stage, grade, race and serologic (PSA) recurrence following surgery. Results Overexpression of bcl-2 was noted in 47 of 175 (26.9 percent) patients; these patients had a significantly higher 5-year failure rate than those who did not overexpress bcl-2 (67.0 percent versus 30.7 percent). Expression of p53 was noted in 114 of 175 (65.1 percent) patients with a 5-year failure rate of 51.1 percent compared with a 5-year failure rate of only 22 percent in p53 negative patients. When expression rates for p53 and bcl-2 were combined, the 5-year failure rate was 75.3 percent. Conversely, when both p53 and bcl-2 IHC staining were negative, the 5-year failure rate was 20.4 percent. Univariate Kaplan-Meier analysis showed a statistically significant difference between p53 and bcl-2 positive and negative patients (p less than 0.001). Multivariate Cox Regression Analysis with backward elimination controlling for age, race, stage and grade showed both p53 (p = .0185) and bcl-2 (p = .044) to be independent predictors of disease-free survival. Conclusion p53 and bcl-2 appear to be important biomarkers that predict recurrence in clinically localized PC after RP.

Endothelial area as a prognostic indicator for invasive breast carcinoma

BACKGROUND Vascular enumeration using antibodies to Factor VIII has been reported to be an independent prognostic indicator of invasive breast carcinoma. METHODS To eliminate potential subjectivity in distinguishing between individual vessels, especially in areas of tangled capillaries, total endothelial area (EA) was assessed using a Samba 4000 image analyzer. One hundred seventy-eight invasive breast carcinomas (Stage 1 and 2, mean follow-up: 71 months) were immunostained for the presence of CD34, the human hematopoietic progenitor cell antigen also present in endothelium, and EA was quantitated within 5 adjacent 20× fields (0.74 mm2). Additionally, these same vessels were manually counted from the image analyzer. Manual counts were also made from a photomicrograph representative of a single 10× field (1.06 mm2). RESULTS High grade carcinomas contained greater endothelial area than low grade carcinomas (P = 0.0001). Endothelial area was prognostically significant (P = 0.004) in univariate analysis of disease-free survival (DFS) and overall survival (OS), as were stage of disease, tumor size, and combined histologic grade (P;cc 0.024). Manual vessel counts from the monitor were significant for OS only. Manual vessel counts from photomicrographs showed no statistically significant association with DFS or OS. In multivariate analysis, EA, but not vessel enumeration, remained as an independent predictor for OS (lymph node negative patients only, n = 87) and for DFS (lymph node positive patients only, n = 91). For the entire group of patients (lymph node negative and lymph node positive) independent predictors of DFS and OS were tumor grade and size (P;cc 0.006). CONCLUSIONS Of the three methods used to evaluate tumor angiogenesis, total endothelial area, as objectively evaluated by image analysis, was the only independent prognostic indicator for OS for patients with lymph node negative invasive breast carcinoma. Cancer 1996;77:2077-85.

Prognostic significance of SCC antigen in the serum of patients with head and neck cancer.

SCC antigen (Ag) is a tumor-associated Ag (TAA) obtained from squamous cell carcinoma of the uterine cervix. This study reports the evaluation of this TAA in patients with head and neck malignant diseases and its possible prognostic value. Serum samples from 28 patients with benign head and neck diseases from 399 patients with cancer were obtained prior to treatment. SCC Ag serum levels were determined by radioimmunoassay using 2.5 ng/ml as the upper limit of normality. Elevated SCC Ag serum levels were found in 14% of 28 patients with benign diseases, in 29% of 217 patients with primary tumors, in 48% of 46 patients with recurrence (43% in locoregional, 64% in metastases) and in 4% of 136 patients with no evidence of disease. In patients with primary tumors, SCC Ag serum levels were related to nodal involvement and tumor location with significantly higher levels in node-positive patients (p = 0.001) and in tumors located in the nasopharynx and piriform sinus (p = 0.02). Presurgical SCC Ag serum levels in patients with primary tumors had prognostic value with shorter disease-free survival in those patients with abnormal values of this TAA (p < 0.001), in both, node-negative and node-positive patients (p < 0.01). Multivariate analyses showed that SCC Ag is a significant independent predictor of disease-free survival even when other prognostic factors are considered. In conclusion, pretreatment SCC Ag serum levels are an independent prognostic indicator in patients with head and neck malignancies.

DNA Ploidy as a Significant Predictor of Recurrence-Free Survival in Male Patients with Breast Cancer

: DNA flow cytometry has been extensively studied in female breast carcinoma. However, there is limited data evaluating DNA ploidy in male breast cancer. In order to further assess the prognostic significance of DNA ploidy in male breast carcinoma, we retrospectively reviewed 55 cases (52 patients) of histologically proven male breast carcinoma treated at our institution from January 1971 through January 1992. Of the 55 cases, 32 paraffin-embedded blocks were available for DNA flow cytometry analysis. As of June 1993, median follow-up is 7.0 years. In the overall population of 55 cases, univariate analysis identified TNM stage, tumor size, and nodal status as significant prognostic indicators of overall survival and disease-free survival. In the 32 cases available for DNA flow cytometry, both local recurrences and distant metastases were more frequent in the aneuploid population. Univariate analysis revealed DNA ploidy to be a significant prognostic factor for local recurrence-free survival and distant metastasis-free survival. DNA ploidy correlated significantly with stage at diagnosis (p =.04), tumor size (p =.04) and nodal status (p =.02). In a multivariate analysis of 26 patients on whom all data were available (DNA ploidy, tumor size, clinical stage and nodal status), DNA ploidy was an independent predictor of disease-free survival (p =.05). In this retrospective analysis, we conclude that DNA ploidy has prognostic significance in male breast carcinoma.

Prognostic significance of flow cytometric analysis of DNA content in colorectal cancer: A prospective study

We prospectively analyzed the tumor DNA content by flow cytometry in 100 patients who underwent a curative resection for colorectal cancer between August 1989 and May 1992 in order to evaluate the prognostic significance of DNA ploidy and the DNA index (DI). Patients with aneuploid tumors were found to have a significantly shorter disease-free survival than those with diploid tumors (P = 0.014). In addition, patients who had tumors with a DI greater than 1.6 had a significantly shorter disease-free survival than those who had tumors with a DI of less than 1.6 (P = 0.0001). After stratification by stage, this association was only seen in Dukes' stage C disease (P = 0.0065). Cox's regression analysis demonstrated that the DI (below or above 1.6) rather than DNA ploidy was an important independent predictor of disease-free survival. These results suggest that the DI rather than DNA ploidy provides us with important prognostic information in patients undergoing curative surgery for colorectal cancer.

Pathologic stage III endometrial carcinoma. Prognostic factors and patterns of recurrence.

This review was done to assess the outcomes and patterns of recurrence in a group of patients with Stage III endometrial carcinoma that might help guide adjuvant therapy. A retrospective review was performed of 105 patients treated from 1970-1990 at three institutions. All patients underwent abdominal hysterectomy, with 60 having pathologic node assessment and 45 having cytologic examination of peritoneal washings. A single extrauterine site was involved in 75% of patients; 20% and 5% had two and three sites involved, respectively. All patients received postoperative external beam irradiation to the pelvis or pelvis and paraaortic regions for pathologically positive paraaortic nodes. Actuarial techniques were used to estimate the survival and recurrence rates. The 5-year disease-free survival rate for all patients was 64%. Univariate analysis revealed that the depth of myometrial penetration, the clear cell or papillary serous pathologic type, the histologic grade, and the number of extrauterine sites predicted disease-free survival. Cox regression revealed the grade and pathologic findings to be independent predictors of disease-free survival. The overall 5-year pelvic recurrence rate was 21%, with multivariate analysis revealing the grade to be the strongest prognostic factor. Pathologic findings and the number of involved extrauterine sites were the most important prognostic factors for abdominal recurrence and other sites of distant relapse. The subgroup of patients with low-grade endometrial tumors or superficial myometrial penetration has a low distant relapse rate. Local control remains the goal of therapy in these patients. Patients with high-grade tumors, deep myometrial penetration, clear cell or papillary serous histologic types, or two or more involved extrauterine sites are at high risk for distant recurrence that may include the abdomen. Investigative strategies delivering aggressive adjuvant therapy are appropriate.

Menstrual effects on surgical treatment for breast cancer

In 1989, Hrushesky et al. (1) reported preliminary results of a retrospective study which identified the timing of breast cancer surgery in relation to the menstrual cycle as an independent predictor of disease-free survival for 41 premenopausal women. At least a dozen reports have subsequently appeared, some supporting and others refuting the claim. The debate has been played out both in the medical literature and in the lay press, resulting in much confusion for patients and physicians alike. This review will examine the biological plausibility of the hypothesis that the menstrual cycle can influence surgical outcome, the results of clinical studies done to date, and the potential methodological pitfalls inherent in performing these retrospective reviews.

Presentation of cervical cancer

To determine how patients with invasive cervical cancer present and whether presentation affects disease-free survival (DFS), a review of 81 patients treated for cervical cancer by the Division of Gynecologic Oncology and Pelvic Surgery at the Southern California Permanente Medical Group between January 1, 1986, and December 31, 1986, was performed. Fifty-six percent of patients presented with abnormal vaginal bleeding, twenty-eight percent presented with abnormal Papanicolaou (Pap) smears, nine percent presented with pain, four percent presented with vaginal discharge, and four percent presented with other symptoms. Follow-up was 24 to 41 months. Patients presenting with abnormal Pap smears had DFS of 96%. Those presenting with abnormal vaginal bleeding had DFS of 51% and those presenting with pain had DFS of 29%. Presentation strongly influences DFS ( χ 2 = 16.8, P < 0.001). Of women presenting with abnormal Pap smears, 87% were Stage I and 13% were Stage II. Of women presenting with other than abnormal Pap smears, 40% were Stage I, 34% were Stage II, and 26% were Stage III or IV. Presentation with abnormal Pap smear and stage are significantly related ( χ 2 = 14.8, P < 0.001). Of women presenting with abnormal Pap smears, 89% had cancers 0 to 2 cm, 5% had cancers 2.1 to 4 cm, and 5% had cancers greater than 4 cm in diameter. Of women presenting with other than abnormal Pap smears, 21% had cancers 0 to 2 cm, 26% had cancers 2.1 to 4 cm, and 53% had cancers greater than 4 cm in diameter. Presentation with abnormal Pap smear is significantly associated with tumor size ( χ 2 = 25.4, P < 0.001). Logistic regression analysis was performed utilizing stage, tumor size, and presentation as independent variables with disease-free survival as the dependent variable. Once stage and tumor size had been controlled for, presentation with abnormal Pap smear no longer predicted disease-free survival ( P > 0.1). Abnormal Pap smears are a common presentation of invasive cervical cancer. Presentation with abnormal Pap smear is associated with early stage and small tumor size but is not an independent predictor of disease-free survival.

Influence of grade, histologic subtype, and timing of radiotherapy on outcome among patients with stage II carcinoma of the endometrium

In 1988, the Federation of International Gynecologic Oncologists (FIGO) adopted a new staging system mandating preradiotherapy surgical staging in endometrial cancer. To evaluate the potential impact of this recommendation on patients with cervical involvement (stage II), an analysis of 184 consecutive patients with clinical or pathologic stage II carcinoma of the endometrium treated with definitive intent at three institutions was performed. Median follow-up time was 5.7 years. Treatment consisted of total abdominal hysterectomy and bilateral salpingooophorectomy with preoperative radiation therapy (RT) (54%), postoperative RT (37%), or both (1%); definitive RT (7%); or radical hysterectomy (1%). The median total RT dose for combined intracavitary and external beam or either alone was 70.6 Gy with a range of 32.4–105.0 Gy. The overall 5-year survival rate and disease-free survival (DFS) rate at 5 years were 70 and 79%, respectively. Of patients treated with surgery and adjuvant radiation, 13% ( 22 168 ) had infield pelvic failure (PF) and 18% ( 31 168 ) had distant metastases (DM). Patterns of failure in patients receiving preoperative and postoperative radiotherapy are presented. Univariate analysis of pretreatment and treatment factors, including histology, grade, clinical stage, extent of cervical involvement, and timing of adjuvant radiation, revealed histology and grade to be significant predictors of DFS, PF, and DM. Clinical stage was a significant predictor of DFS only in univariate analysis. Multivariate analysis found only histology ( P < 0.001) and grade ( P = 0.002) to be predictors of DFS. From this review, we conclude that histology and grade are independent predictors of DFS, and more aggressive treatment should be directed at patients with stage II endometrial cancer found to have high grade adenocarcinoma or papillary serous/clear cell histologic variants. The timing of radiotherapy was not an independent predictor of outcome; therefore, preradiotherapy surgical staging should not impact on DFS and should provide surgicopathologic information to tailor treatment and predict prognosis. The FIGO clinical staging system used in this analysis was not an independent predictor of outcome, and future multivariate analyses will be necessary to test the predictive value on outcome of the new 1988 FIGO surgical staging.