Tumor Malignancy Grade Research Articles

Expression of Carbonic Anhydrase IX in Astrocytic Tumors Predicts Poor Prognosis

Carbonic anhydrase IX (CA IX) is a hypoxia-inducible enzyme, which is associated with neoplastic growth. Ectopic CA IX expression has been observed in several tumors, whose normal counterparts do not express this enzyme. Normal human brain tissue shows only slight or no expression of CA IX. We describe CA IX expression in human diffusely infiltrating astrocytomas. The association of CA IX is evaluated with clinicopathologic and molecular factors including cell proliferation and apoptosis as well as the expression of p53 and epidermal growth factor receptor. CA IX immunopositivity was observed in 284 cases of 362 (78%) tumors. The positive areas were often located in close proximity to necrotic regions (P < 0.001). The CA IX immunoreactivity showed strong association with tumor malignancy grades (P < 0.0001). CA IX showed no association with p53 expression nor did it correlate with epidermal growth factor receptor-amplification, apoptosis, or cell proliferation. CA IX intensity had significant prognostic value in univariate (P=0.0011, log-rank test) and multivariate survival analysis (P = 0.038, Cox analysis). CA IX expression is common in diffusely infiltrating high-grade astrocytomas. Our results suggest that CA IX is a useful biomarker for predicting poor prognosis of astrocytic tumors. It may also be a promising target molecule for the improvement of therapeutic interventions in astrocytomas.

Phosphorylated Akt1 in human breast cancer measured by direct sandwich enzyme-linked immunosorbent assay: Correlation with clinicopathological features and tumor VEGF-signaling system component levels

Protein kinase B (Akt) plays a major role in the regulation of breast cancer growth, survival, hormone, drug and radiosensitivity, but the clinical value of its expression and activation in human tumors is unclear. Activated Akt1 (pAkt1) expression was quantified in a series of 46 breast cancer and adjacent mammary gland samples by a direct Path-Scan PhosphoAkt1 (Ser473) sandwich ELISA kit. VEGF, sVEGFR1 and sVEGFR2 levels were measured simultaneously by standard ELISA kits. Forty-nine percent of the tumors had an increased pAkt1 level as compared to adjacent tissue. pAkt1 levels were significantly higher in stage IIb than in stage I-IIa tumors. The frequency of pAkt1 elevation was positively associated with tumor size and malignancy grade. pAkt1 was also twice as frequently increased in PgR-negative as in PgR-positive tumors, while its mean level was significantly higher in ER-positive than in ER-negative tumors. VEGF, sVEGFR1 and sVEGFR2 were increased in 73-85% of the tumors, but no associations with most clinicobiological factors and pAkt1 level were found. In conclusion, activation of Akt1 is not associated with VEGF signaling protein expression in breast cancer but is related to tumor size, grade of malignancy, and steroid receptor status.

Phosphorylated Akt1 in Human Breast Cancer Measured by Direct Sandwich Enzyme-Linked Immunosorbent Assay: Correlation with Clinicopathological Features and Tumor VEGF-Signaling System Component Levels

Protein kinase B (Akt) plays a major role in the regulation of breast cancer growth, survival, hormone, drug and radiosensitivity, but the clinical value of its expression and activation in human tumors is unclear. Activated Akt1 (pAkt1) expression was quantified in a series of 46 breast cancer and adjacent mammary gland samples by a direct Path-Scan™ PhosphoAkt1 (Ser473) sandwich ELISA kit. VEGF, sVEGFR1 and sVEGFR2 levels were measured simultaneously by standard ELISA kits. Forty-nine percent of the tumors had an increased pAkt1 level as compared to adjacent tissue. pAkt1 levels were significantly higher in stage IIb than in stage I-IIa tumors. The frequency of pAkt1 elevation was positively associated with tumor size and malignancy grade. pAkt1 was also twice as frequently increased in PgR-negative as in PgR-positive tumors, while its mean level was significantly higher in ER-positive than in ER-negative tumors. VEGF, sVEGFR1 and sVEGFR2 were increased in 73–85% of the tumors, but no associations with most clinicobiological factors and pAkt1 level were found. In conclusion, activation of Akt1 is not associated with VEGF signaling protein expression in breast cancer but is related to tumor size, grade of malignancy, and steroid receptor status.

Praxis der intravesikalen Instillationsprophylaxe beim oberflächlichen Harnblasenkarzinom - Ergebnisse einer Umfrage in Sachsen

For patients with superficial bladder cancer, adjuvant intravesical chemotherapy or immunotherapy with Bacillus Calmette-Guerin (BCG) is recommended in national and international guidelines. We analyzed whether the recommended therapeutic regimens are used in daily urological practice. Questionnaires concerning the adjuvant intravesical therapy were sent to 152 urologists in the German Federal State of Saxony. Of the surveyed physicians, 134 practiced in an outpatient medical facility and 18 in a hospital. Of the questionnaires, 73 (48.02 %) were returned and evaluated. An adjuvant intravesical therapy after transurethral bladder tumor resection was performed in every second patient (median value 50.07 %). The majority of the urologists (79.4 %) treated the bladder tumors with intravesical chemotherapy or BCG depending on tumor stage and grade of malignancy. Chemotherapeutic agents or BCG was exclusively used in 13.6 % and 4.1 % of treated patients, respectively. Chemotherapeutic agents were predominantly applied up to the primary tumor stage T1 and malignancy grade G2. In cases with recurrent T1 bladder tumors of G2 or higher grade of malignancy, BCG was the main agent for intravesical treatment. In patients with recurrent T1G3 tumors, the majority of urologist (57.1 %) preferred another therapeutic regimen than intravesical instillation. Only 23.2 % of the urologists believed that intravesical BCG is superior to chemotherapeutic agents. These data demonstrate that adjuvant intravesical instillation with chemotherapeutic agents and BCG is well established in urological practice. In contrast to the recommendations of national and international guidelines, chemotherapeutic agents are more frequently used in cases with a high risk of progression.

DNA ploidy as a prognostic factor in muscle invasive transitional cell carcinoma of the bladder.

Radical cystectomy represents the treatment of choice for muscle-infiltrative bladder carcinoma; however, about 50% of patients relapse and die from the disease. In the present study, the prognostic significance of the DNA ploidy in transitional cell carcinoma of the urinary bladder (TCCB) is analyzed. The study was carried out on 66 patients with TCCB who underwent radical cystectomy. DNA ploidy was determined by flow cytometry (FCM) on paraffin-embedded specimens, and the results were analyzed and correlated with the tumor malignancy grade and stage and the clinical course. Forty of the 66 tumors studied (63%) were aneuploid. Aneuploid status was correlated with higher tumor T stage (P < 0.001) and grade (P < 0.001). Median follow up was 68 months (range: 12-105). Median survival was significantly longer in patients with diploid tumors (> 60 vs 45 months, P < 0.001). All patients with diploid tumors were alive and free of bladder cancer during follow-up, in contrast to only 30% of patients with aneuploid tumors. DNA ploidy was an independent prognostic factor, as shown by multivariate analysis (P = 0.006). All patients with pT > or = 3b and diploid tumors were alive at the time of analysis as opposed to none with aneuploid tumors. The results of this study suggest that DNA ploidy can provide prognostic information on patients with muscle invasive carcinoma of the bladder and might represent a means of selection for postoperative management.

Cloning and Characterization of Glioma BK, a Novel BK Channel Isoform Highly Expressed in Human Glioma Cells

Voltage-dependent large-conductance Ca2+-activated K+ channels (BK channels) are widely expressed in excitable and nonexcitable cells. BK channels exhibit diverse electrophysiological properties, which are attributable in part to alternative splicing of their alpha-subunits. BK currents have been implicated in the growth control of glial cells, and BK channels with novel biophysical properties have recently been characterized in human glioma cells. Here we report the isolation, cloning, and functional characterization of glioma BK (gBK), a novel splice isoform of hSlo, the gene that encodes the alpha-subunits of human BK channels. The primary sequence of gBK is 97% identical to its closest homolog hbr5, but it contains an additional 34-amino-acid exon at splice site 2 in the C-terminal tail of BK channels. hSlo transcripts containing this novel exon are expressed ubiquitously in various normal tissues as well as in neoplasmic samples, suggesting that the novel exon may modulate important physiological functions of BK channels. Expression of gBK in Xenopus oocytes gives rise to iberiotoxin-sensitive (IbTX) currents, with an IC(50) for IbTX of 5.7 nm and a Hill coefficient of 0.76. Single gBK channels have a unitary conductance of similar250 pS, and the currents show significantly slower activation and higher Ca2+ sensitivity than hbr5. Ca2+ sensitivity was enhanced specifically at physiologically relevant [Ca2+]i (100-500 nm). Examination of biopsies from patients with malignant gliomas has revealed specific overexpression of BK channels in gliomas compared with nonmalignant human cortical tissues. Importantly, tumor malignancy grades have correlated positively with BK channel expression, suggesting an important role for the gBK channel in glioma biology.

Immunohistochemical markers for prognosis of oligodendroglial neoplasms.

Despite numerous previous studies, oligodendrogliomas continue to generate considerable controversy in the identification of prognostic factors, including single histopathological patterns, and grade of tumor malignancy. The prognostic significance of various pathological and immunohistochemical factors has been intensively examined but numerous studies have yielded conflicting results. In the present study, biopsy samples of 123 oligodendrogliomas were examined immunohistochemically to evaluate a possible association between expression of various tumor-associated antigens and clinical outcome. Both the progression-free and overall survival times were significantly reduced for high-grade tumors, for Ki-S1 labeling index (LI) > 10%, for p27 LI < 20% and for p18, p53, and vascular endothelial growth factor (VEGF)-positive tumors. For low-grade tumors survival rates were significantly reduced for p27 LI less than 20%, whereas high-grade oligodendrogliomas with Ki-S1 LI greater than 10%, and with p18 positivity revealed significantly shortened survival times. We found no differences in survival times in patients with or without p 14ARF, p21, mdm2, and pRb immunoreactivity. Multivariate analysis revealed that risk of oligodendroglioma progression is associated with high-grade tumors, with Ki-S1 LI > 10%, and with p27 LI < 20%; whereas risk of death is associated with high-grade tumors, with Ki-S1 LI > 10%, and with p18 positivity. CART modeling process identified four final groups of oligodendroglioma patients: (1) thirty-nine patients with low-grade tumors and p27 LI > 20%; (2) twenty patients with low-grade tumors and p27 LI < 20%; (3) thirty-four patients with high-grade tumors and Ki-S1 LI < 10%; and (4) thirty patients with high-grade tumors and Ki-S1 LI >10%. In summary, both the p27 and Ki-S1 scores were found to be the strong predictors of oligodendroglioma outcome together with the WHO tumor grade and they seem to be useful for assessing individual prognosis in routinely processed specimens.

Surface enhanced IR absorption of nucleic acids from tumor cells: FTIR reflectance study.

The data on surface enhanced IR absorption (SEIRA) of nucleic acids deposited on a metal substrate were obtained using FTIR in reflectance mode. A 200-400 A thick gold film on a glass plate was the metal substrate. The approximate enhancement factors of the SEIRA for different vibrations of nucleic acids in our experimental conditions were 3-5. The roughness of the Au surface was about 50 A. Application of this method to nucleic acids isolated from tumor cells revealed some possible peculiarities of their structural organization, namely, the appearance of unusual sugar and base conformations, modification of the phosphate backbone, redistribution of the H-bond net, and so forth. This method enhanced a set of the bands, which is impossible to observe in conventional IR geometry. The SEIRA spectra of the RNA from tumor cells showed more sensitivity to the grade of tumor malignancy than the spectra of the DNA. After application of the anticancer drug doxorubicin to sensitive and resistant strains, the DNA isolated from these strains had different spectral features, especially in the region of the phosphate I and II bands. As induced by anticancer drugs, the conformational changes in the DNA from resistant and sensitive cancer strains could be characterized with different levels of structure disordering.

Apoptosis and p53 status of the upper urothelial carcinomas from Balkan endemic nephropathy regions.

The upper urothelial carcinomas (UUC) associated with endemic nephropathy and analgesic nephropathy are considerably similar in many characteristics. These similarities diversify them from the same carcinomas in the general population w1x. Bilateral occurrence (simultaneous or successive) of the UUC is observed in about 8% cases of analgesic nephropathy and 10–14% in endemic Balkan nephropathy. Multiple occurrence is seen in up to one-third of cases, with every 15th patient developing cancer in the urinary bladder. By regular examinations for UUC during several years on haemodialysis, the tumour prevalence increased to 16 against 1 in endemic or analgesic nephropathy and remained 1 against 50 in patients with other kidney diseases. The maximum incidence of UUC in endemic regions is in the sixth to seventh decades of life. Those UUC slowly expand with rare metastases outside endemic regions; the median time of the UUC growth following clinical presentation is two times shorter. An epidemiological survey of the group of nephrectomized patients at the Clinic of Urology of Belgrade revealed a better survival of UUC patients from endemic regions, 8 against 3 years on average w2x. The impression of a slow evolutionary process contrasts with the presence of advanced tumour malignancy grade II and III. Routine histologic examination did not reveal any significant differences in characteristics of the UUC in relation to the settlement in large groups of patients during several decades.

Mammographic parenchymal patterns and breast cancer natural history--a case-control study.

The relationship between tumour size, malignancy grade and dense mammographic parenchymal patterns was evaluated by using a nested case-control design with 875 breast cancer cases and 2 601 matched controls. Wolfe's classification was used to assess mammographic parenchymal patterns. The dense P2/DY mammographic parenchymal patterns were significantly associated with invasive ductal grade 3 carcinoma (OR = 2.03; 95%, CI 1.13-3.62, p = 0.016). Stratified by tumour size, we found that the odds ratio for grade 3 invasive ductal NOS breast cancer measuring 15-19 mm associated with P2/DY mammographic parenchymal patterns was 3.46 (95% CI 1.12-10.68). For tumours larger than 30 mm, the odds ratio was 10.09 (95% CI 1.27-79.93). The highest risk of grade 3 cancers being in tumours measuring 30 mm + may be due to dedifferentiation of missed cancers, but there is some excess even in the < 20 mm tumours, suggesting an increased risk in association with dense mammographic patterns of some aggressive cancers which are grade 3 at inception. Our results are consistent with the model that breast cancer is a progressive disease, whose development can be arrested by screening, and that the point at which individual tumour progression is stopped is crucial for prognosis not simply in terms of stage of disease, but also of histological grade.

Biological role of thymidine phosphorylase in human astrocytic tumors

Thymidine phosphorylase (TP) has strong angiogenic activity and is overexpressed in a wide variety of malignant tumors. To elucidate the role of TP in human astrocytic tumors, we immunohistochemically investigated the expression of TP in 62 astrocytic tumors (12 astrocytomas, 12 anaplastic astrocytomas and 38 glioblastomas). Fifty-five astrocytic tumors (88.7%) were immunopositive for TP. The level of TP-expression was significantly correlated with the malignancy grade of astrocytic tumors; most of malignant gliomas highly expressed TP, while a small number of cells were positive in low grade astrocytomas (p < 0.001). Using double-immunostaining, we clarified that TP-expression was predominantly detectable in macrophages. There was no significant correlation between MIB-1 labeling index and TP-expression. However, TP-expression and the microvessel density were well correlated. These suggest that TP, mainly produced by the infiltrated macrophages, may play an important role in the progression of astrocytic tumors via neovascularization. Inhibitor of TP may represent a therapeutic modality for treating malignant gliomas.

Reduced expression of connexin-43 and functional gap junction coupling in human gliomas.

Gap junctions are an important means for intercellular communication during development, processes of tissue differentiation, and in maintenance of adult tissue homeostasis. We investigated the expression levels and distribution of connexin-43 (Cx-43), the most abundant astrocytic gap junction protein, in acutely isolated astrocytes and glioma cells from biopsy tissue obtained from patients diagnosed with glioblastoma multiforme (GBM), low-grade astrocytomas (LGAs), or mesial temporal lobe epilepsy. Western blot and immunohistochemical analyses indicated an inverse correlation between the amount of Cx-43 protein and tumor malignancy grade, as assessed by calculating tissue mitotic indexes (MI) obtained using anti-Ki-67 nuclear antigen staining. Samples from epilepsy patients had a low MI and were intensely positive for Cx-43 staining, while LGA tissue samples exhibited moderate staining for Cx-43 and average MI, and GBM biopsies showed significantly lower levels of Cx-43 and high MI. Functional coupling was assayed using fluorescence recovery after photobleach (FRAP). We found that cells from glioma cell lines and primary cultures of human astrocytes from GBM tissues displayed significantly lower degrees of gap junction intercellular communication (GJIC) as indicated by longer and less complete recovery from photobleaching. Mean recovery values were GBM 23.8% +/- 11.4%, LGA 49.4% +/- 47%, and nontumor astrocytes 67.2% +/- 8.4%. Western blot analysis of several human glioma cell lines and tissue biopsies showed variable expression levels of Cx-43, which correlated negatively with the extent of recovery in the same samples. Taken together, our findings suggest that high-grade brain tumors show reduced intercellular communication and a decrease in connexin-43 protein levels.

Mammographic Parenchymal Patterns and Breast Cancer Natural History?A Case-Control Study

The relationship between tumour size, malignancy grade and dense mammographic parenchymal patterns was evaluated by using a nested case-control design with 875 breast cancer cases and 2 601 matched controls. Wolfe's classification was used to assess mammographic parenchymal patterns. The dense P2/DY mammographic parenchymal patterns were significantly associated with invasive ductal grade 3 carcinoma (OR = 2.03; 95% CI 1.13-3.62; p = 0.016). Stratified by tumour size, we found that the odds ratio for grade 3 invasive ductal NOS breast cancer measuring 15-19 mm associated with P2/DY mammographic parenchymal patterns was 3.46 (95% CI 1.12-10.68). For tumours larger than 30 mm, the odds ratio was 10.09 (95% CI 1.27-79.93). The highest risk of grade 3 cancers being in tumours measuring 30 mm + may be due to dedifferentiation of missed cancers, but there is some excess even in the < 20 mm tumours, suggesting an increased risk in association with dense mammographic patterns of some aggressive cancers which are grade 3 at inception. Our results are consistent with the model that breast cancer is a progressive disease, whose development can be arrested by screening, and that the point at which individual tumour progression is stopped is crucial for prognosis not simply in terms of stage of disease, but also of histological grade.

口腔へん平上皮癌の治療期間別の予後因子の解析

The purpose of this study was to assess changes in prognostic factors related to modification of surgical treatment on the basis of grade of tumor malignancy and to contribute to improved surgical treatment of patients with oral squamous cell carcinoma. Fourhundred three patients with oral squamous cell carcinoma treated by surgery were classified according to treatment period as follows: f irst period, 1976-1986; second period, 1987-1991; and third period, 1992-1997.Three and 5-year cumulative disease-specific survival rates according to treatment period were as follows: first period (n=187), 78.6, 76.3%; second period (n=113), 76.6, 73.7%; and third period (n=103), 88.9, 87.2%. On univariate analysis of survival according to T, N, stage, growth pattern, and mode of invasion, significant differences (P<0.05) were found for all characteristics in the first and second periods, while in the third period no significant difference was found for growth pattern or mode of invasion.Cox regression analysis of disease-specific survival identified the following as independent prognostic factors: mode of invasion (1+2, 3, 4C+4D), growth pattern (exophytic, endophytic), and N (0, 1, 2) in the first period, mode of invasion (1-3, 4C+4D) and N (0, 1, 2+3) in the second period, and only N (0, 1, 2) in the third period.Owing to the improved outcome for highly invasive carcinoma, the prognostic values during the third period differed from those during the first and second periods.

Immunohistochemical analysis of metallothionein in astrocytic tumors in relation to tumor grade, proliferative potential, and survival

Metallothionein (MT) is the name for a family of predominantly intracellular protein thiol compounds involved in anticancer drug resistance. For certain tumors, MT is related to grade of tumor malignancy and prognosis. The authors evaluated the expression of MT in 114 astrocytic tumors in relation to the proliferative potential of tumors and the survival of patients. Paraffin embedded tissue sections were stained with monoclonal anti-metallothionein and MIB-1 Ki-67 antibodies by avidin-biotin complex immunohistochemistry. MT expression was observed in 2 of 6 pilocytic astrocytomas, in 10 of 24 Grade 2 astrocytomas, in 16 of 25 anaplastic astrocytomas, and in 47 of 59 glioblastomas. In addition to the tumor cells, microvascular endothelial proliferation and smooth muscle of tumor vessel walls were frequently MT positive. The glioblastomas had a significantly higher percentage of MT positive cells compared with low grade (P < 0.0001) and anaplastic (P < 0.04) astrocytomas. MT expression in astrocytomas had no correlation with tumor recurrence. The mean Ki-67 labeling index (LI) was significantly higher in the high grade (3-4) compared with the low grade (1-2) astrocytomas. MT positive astrocytic tumors had statistically significantly higher mean Ki-67 LI compared with MT negative tumors, irrespective of histologic grade. Although the levels of MT and Ki-67 LI varied in individual tumors, the mean Ki-67 LI increased in parallel to the increasing MT staining grade, and this difference attained statistical significance only for glioblastoma. MT positive anaplastic astrocytoma and glioblastoma patients did not survive as long as the MT negative patients, although this difference attained statistical significance only for anaplastic astrocytoma. The current study suggests that MT might play a significant role in the growth of astrocytic tumors, with an acquired enhanced ability to produce MT as the malignant potential of a tumor increases.

Contrast-enhanced MR imaging as a prognostic indicator of breast cancer.

Using contrast-enhanced MR imaging in the diagnosis of breast cancer may provide additional information not only on tumor extension but also on the biological behavior of tumors. Thus certain characteristics such as tumor angiogenesis and the proliferating activity of the tumor, which have been shown to correlate significantly with prognosis, are both potentially amenable to analysis by MR imaging. We compared contrast enhancement in 50 malignant breast tumors at MR imaging to several prognostic factors, such as tumor size, lymph-node status, histological grade of malignancy, tumor angiogenesis, and proliferating activity as shown by the mitotic count and PCNA immunoreactivity. There was significant correlation between contrast enhancement at MR imaging of breast cancer and both tumor angiogenesis and proliferative cellular activity as shown by PCNA immunoreactivity. Furthermore, there was a correlation between contrast enhancement and tumor malignancy grade as well as tumor invasiveness. These observations suggest that contrast enhancement at MR imaging may be influenced by factors that have prognostic value. If this assumption is correct, contrast-enhanced MR imaging may become a valuable prognostic tool in the pre-operative evaluation of breast cancers.

TUMOR CELL PROLIFERATION AND SURVIVAL IN PATIENTS WITH PROSTATE CANCER FOLLOWED EXPECTANTLY

Purpose Prostate cancers have different biological potentials, and aggressive tumors are difficult to identify when still localized. Tumor cell proliferation determined by MIB-1 expression has been suggested as an important predictor for outcome in several human cancers including the prostate. We test the possible prognostic value of tumor cellular proliferation in prostate cancer patients treated with no intent to cure. Materials and Methods Formalin fixed, paraffin embedded tumor tissue obtained at the time of diagnosis from 221 patients originating from a well known complete Danish prostate cancer population was immunohistochemically investigated. The tumor cell proliferation rate was determined using the MIB-1 antibody. Tumors were clinically localized in 57% of the patients. Results Tumor cell proliferation rate expressed by the MIB-1 score significantly correlated with tumor stage (p <0.001) and malignancy grade (p <0.001). The MIB-1 score, divided into low and high by the median value, showed significant association with disease specific survival in the entire study population (p <0.0001), as well as in the 125 patients suffering from clinically localized disease (p = 0.018). Multivariate analyses showed that MIB-1 was a significant (p = 0.0003) prognostic factor in the entire population, including advanced disease stages. However, in the theoretically curable clinically localized subpopulation MIB-1 was not significant (p = 0.08) contrary to histopathological grade (p = 0.02), erythrocyte sedimentation rate (p = 0.02) and T classification (p = 0.035). Conclusions Prostate tumor cell proliferation, expressed by MIB-1 immunoreactivity, demonstrated significant association with disease specific survival. However, MIB-1 is a close alternative to histopathological grade in describing the natural history of clinically localized prostate cancer. The additional prognostic value and the practical consequence of tumor cell proliferation remain to be clarified.

Is the expression of multidrug resistance gene product a prognostic indicator for the clinical outcome of patients with renal cancer?

To determine the significance of the expression of the multidrug resistance gene product (MDR-1) for the aggressiveness of renal cell carcinoma (RCC). The study comprised 31 patients with clinically locally confined RCC treated with radical nephrectomy (mean age 64.1 years, range 41-78; mean follow-up 5.4 years, range 4.3-7.3). Their survival time and disease-free period were evaluated retrospectively. The expression of the MDR-1 gene product was determined immunohistochemically using the JSB-1 antibody in formalin-fixed paraffin-embedded tumour samples from these patients. The significance of this variable and tumour stage and malignancy grade was assessed for predicting the survival and disease-free period using Kaplan-Meier plots (log-rank test or Tarone's test) and the Cox multiple hazard regression analysis. In a univariate analysis, tumour stage (P < 0.002), malignancy grade (P < 0.007) and MDR-1 (P < 0.03) were significant prognostic variables for both survival and disease-free period. Lower MDR-1 expression was correlated with poorer prognosis. On multivariate analysis, MDR-1 and tumour stage were significant factors for predicting the disease-free period, whereas tumour stage and malignancy grade were the most relevant factors for survival time. Calculating prognostic indices based on the results of the Cox analysis, MDR-1 could replace malignancy grade, resulting in a better prediction of survival and disease-free period (P < 0.001 vs 0.0031, P < 0.001 vs 0.021, respectively). MDR-1, an established predictor for chemo-resistance, may also be a potent prognostic factor for outcome in patients with locally confined RCC. Moreover, MDR-1 expression seems to correlate with the differentiation of the RCC and thus its value as an objective measure of the degree of differentiation should be further explored.

Epidermal growth factor family and renal cell carcinoma: expression and prognostic impact.

Expression and prognostic impact of some exponents of the epidermal growth factor (EGF) family in renal cell carcinoma (RCC) were examined. EGF, transforming growth factor-alpha (TGF-alpha), EGF receptor (EGF-R), and c-erb B-2 were determined immunohistochemically in formalin-fixed paraffin-embedded tumor samples of 30 patients with locally confined RCCs. The prognostic significance of these growth factors and their receptors as well as of tumor stage and malignancy grade was examined with respect to survival and tumor recurrence by following up the fate of the patients after nephrectomy (mean follow-up time 5.2 years). The members of the EGF family and their receptors studied were expressed to a variable degree in all RCCs investigated. However, using log-rank tests in Kaplan-Meier plots only tumor stage (p < 0.0007) and malignancy grade (p < 0.007) but none of the growth factors or receptors studied (p > 0.05, respectively) exhibited prognostic significance with respect to both survival and disease-free period. On the contrary, there was a significant correlation between EGF and TGF-alpha (p < 0.001), EGF and EGF-R (p = 0.028), EGF-R and c-erb B-2 (p = 0.0009), and-inversely related-between TGF-alpha and tumor stage (p = 0.047) and between EGF-R and malignancy grade (p = 0.03). The coexpression of the factors studied also showed no prognostic relevance. The expression of these members of the EGF family seems not to bear evaluable prognostic information for clinical use in the case of RCC.

Prognostic factors in malignant glioma: influence of the overexpression of oncogene and tumor-suppressor gene products on survival.

Despite the use of multimodal therapy, higher-grade glioma is still uniformly fatal in the adult population. There is a considerable difference between the length of survival in each given patient, even within the same tumor type and malignancy grade group, suggesting that there are factors that might differentially influence outcome. To identify such factors, 107 patients with anaplastic or malignant glioma were retrospectively investigated. Clinical parameters and paraclinical data on the p53, mdm2, and EGFR genes at the DNA or protein level were evaluated by univariate analysis and Cox proportional hazards regression modeling. Kaplan-Meier survival estimation demonstrated that immunohistochemical positivity for mdm2 protein in patients with anaplastic astrocytoma or with glioblastoma multiforme was associated with a shorter survival time (p = 0.02). P53 gene mutations and immunopositivity for the epidermal growth factor receptor (EGFR) protein were not significantly related to poor prognosis. The Cox proportional hazards model revealed immunohistochemical positivity for p53, mdm2, or for both of them, the presence of postoperative irradiation, and the extent of surgical resection of tumor to be variables significantly associated with prolonged survival. EGFR overexpression, age over 60 years, and Karnofsky performance score below 40 points did not significantly shorten survival time. In conclusion, the present study identified immunohistochemically detected mdm2-protein overexpression as a statistically significant negative prognostic parameter in patients bearing anaplastic or malignant glioma. Association analysis of variables revealed a possible correlation between mdm2 and p53, which is also consistent with the biological interaction mode of both proteins in vivo.