Prognosis In Human Cancer Research Articles

Elevated expression of valosin-containing protein (p97) is associated with poor prognosis of prostate cancer.

Valosin-containing protein (VCP) has been shown to be associated with metastasis and prognosis in human cancers. In the present study, the correlation of VCP with recurrence and prognosis in patients with prostate cancer (PCA) receiving conservative therapy was examined. VCP expression was analyzed immunohistochemically in 136 patients ranging from 46 to 92 years (median, 72 years), who received conservative therapy, including androgen deprivation, radiotherapy, or watchful waiting. Staining intensity of tumor cells was categorized as weaker (level 1) or equal to or stronger (level 2) than that in endothelial cells. The correlation of VCP expression between the mRNA and protein levels was examined in 10 patients. Thirty-two cases (23.5%) showed level 1 and 100 (76.5%) level 2 VCP expression. Quantitative reverse transcription-PCR analysis revealed greater VCPmRNA expression in level 2 (n = 5) than level 1 cases (n = 5; P < 0.05). A significant difference was observed between VCP level 1 and 2 patients in the positive rate for the digital rectal examination (P < 0.01), serum prostate-specific antigen level (P < 0.0001), cancer volume (P < 0.0001), Gleason score (P < 0.0001), stage (P < 0.0001), and progression-free and overall survival (P < 0.0001 for both). Multivariate analysis revealed VCP expression level, serum prostate-specific antigen level, and Gleason score to be independent prognosticators for progression-free and overall survival. Progression of PCA was found in 9.4% of level 1 but in 64% of level 2 patients. PCA with level 1 VCP expression could be treated conservatively.

Alteration of cell cycle regulators correlates with survival in epithelial ovarian cancer patients

The p16-cyclinD1/CDK4-pRb pathway (RB pathway) and p14ARF-MDM2-p53 pathway (p53 pathway) work at the G1-S checkpoint, and the ATM-chk2-CDC25-cyclinB1/cdk1 pathway works at the G2-M checkpoint. The disruption of these pathways is thought to be related to the prognosis of human cancer. In this study, we analyzed the status of these pathways in 107 epithelial ovarian cancer (EOC) patients by immunohistochemistry and evaluated the relationship of these results with chemotherapy response and the prognosis. Altered RB, p53, and G2 pathways were detected in 50.5% (54/107), 51.4% (55/107), and 33.6% (36/107) of cases, respectively. The overall survival (OS) of 77.3% for patients with a normal RB pathway was significantly higher than the OS of 50.0% for patients with an altered RB pathway (by Kaplan-Meier analysis, P = 0.0021). The OS of 66.2% for patients with a normal G2 pathway was significantly higher than the OS of 58.3% for patients with an altered G2 pathway ( P = 0.0416). However, the status of the p53 pathway was not related to OS. By univariate and multivariate analyses, advanced stage, high histological grade, altered RB pathway, and altered G2 pathway were significant predictors of poor OS. However, there was no significant relationship between pathway status and chemotherapy response. The status of the RB pathway and of the G2 pathway were independent prognostic factors of EOC.

Chk2 drives late G1/early S phase arrest of clonal myeloid progenitors expressing the p210 BCR-ABL tyrosine kinase in response to STI571.

STI571 is the most innovative drug for the cure of Chronic Myeloid Leukemia. It inhibits, in fact, the disease causative event, the p210 bcr-abl tyrosine kinase, and addresses clonal myeloid progenitors to apoptotic death. Here, we demonstrated that STI571 also induces growth arrest by activating the Chk2-Cdc25A-Cdk2 axis, a pathway complementary to p53 in the activation of G(1)/S cell cycle checkpoint. In vitro exposure to STI571 of 32D murine myeloid progenitor cell clones transducing a temperature-sensitive p210 bcr-abl construct was associated with Chk2 phosphorylation and activation, Cdc25A degradation and persistent Cdk2 inhibitory phosphorylation, preventing, in turn, cell transition to and progression throughout the S phase of cell cycle. Chk2 and Cdc25A are both components of a complex network that integrates signals involved in regulated cell cycle progression, DNA repair and cell decision between life or death. Chk2 gene mutations or decreased expression, leading to its protein loss of function on Cdc25A target, and Cdc25A overexpression have been linked to poor prognosis of human cancers. In CML, they might further enhance the proliferative advantage and genomic instability of clonal myeloid progenitors featuring a class of poor prognosis patients eventually resistant to STI571.

PROSTATIC LEVELS OF FATTY ACIDS AND THE HISTOPATHOLOGY OF LOCALIZED PROSTATE CANCER

The consumption of various fatty acids has been associated with advanced stage and fatal prostate cancer. While numerous mechanisms have been postulated, to our knowledge there physiological data linking exposure and prognosis in humans are lacking. We examined prostatic levels of individual fatty acids in relation to the prevalence of histopathological characteristics associated with invasiveness and the risk of progression in 49 men undergoing radical prostatectomy for localized prostate cancer. Fatty acids were measured using capillary gas chromatography in fresh nonmalignant prostate tissue collected at surgery. Markers of invasiveness and increased risk of progression (Gleason sum 7 or greater, perineural invasion, anatomical or surgical margin involvement, extracapsular extension, seminal vesical involvement and stage T3 tumor) were evaluated separately. Each marker was dichotomized into a yes (case) and no (control) level with patients grouped accordingly. Mean concentrations were compared using the Wilcoxon rank sum test. The percent of total prostatic polyunsaturated fat and polyunsaturated-to-saturated fat ratios were significantly lower in the presence of perineural invasion, seminal vesical involvement and stage T3 tumor (p = 0.02 to 0.049). alpha-Linolenic acid was significantly lower when tumor extended to an anatomical or surgical margin (p = 0.008). The omega-3 and omega-3-to-omega-6 fatty acid ratios were 1.5 to 3.3-fold lower in cases than in controls, reaching borderline significance in nearly all comparisons (p = 0.052 to 0.097). Saturated and monounsaturated fatty acids were not associated with the traits examined. These data suggest that polyunsaturated fatty acids and perhaps essential fatty acids in particular help to regulate prostate carcinogenesis in humans.

Downregulation and abnormal expression of E-cadherin and β-catenin in nasopharyngeal carcinoma: Close association with advanced disease stage and lymph node metastasis

Nasopharyngeal carcinoma (NPC) is predominantly of the undifferentiated histological subtype. Histological differentiation is of limited prognostic significance in NPC. Recent studies have suggested that downregulation of the cadherin-catenin cell adhesion complex may play a crucial role in the initial stage of cancer invasion and metastasis and is associated with poor prognosis in human cancers. Expression of E-cadherin has not been reported previously in NPC, and its prognostic value in NPC is unknown. The purpose of this study was to examine the expression pattern of E-cadherin and its associated partner, β-catenin, in NPC and their possible applications as prognostic markers to predict the clinical outcome of NPC. Expression of the E-cadherin and β-catenin was examined by immunohistochemical methods in 74 cases of primary NPC and 17 of their corresponding lymph node metastases. Normal nasopharyngeal epithelium showed strong and homogeneous immunocytochemical staining of E-cadherin and β-catenin at the cell membranes and intercellular junctions. In contrast, primary NPC showed variable and heterogeneous staining patterns of E-cadherin and β-catenin. Loss of membranous E-cadherin expression was significantly associated with advanced stages of diseases ( P < .001). Eighty percent to ninety percent of NPC in stages IV and V (Ho's staging), respectively, showed a reduced (<35%) membranous staining of E-cadherin compared with normal nasopharyngeal epithelium. Expression of β-catenin also was downregulated in advanced NPC. Ninety percent to one hundred percent of NPC in stages IV and V (Ho's staging) expressed a reduction (<35%) of immunocytochemical staining of β-catenin. The expression pattern of β-catenin staining was strongly associated with the expression of E-cadherin ( P < .001). Unlike E-cadherin, nuclear staining of β-catenin expression was observed in some of the primary NPC and lymph node metastasis. Reduced expression of E-cadherin and β-catenin expression was associated with a shorter survival of NPC patients ( P < .001). In advanced NPC patients (stages IV and V), a significant difference in survival was observed in tumors with higher or lower levels of E-cadherin expression ( P = .0224, log-rank test). These observations suggests that expression of E-cadherin and β-catenin may have prognostic values in NPC patients.

Syndrome approach for computer recognition of fuzzy systems and its application to immunological diagnostics and prognosis of human cancer

We propose a novel pattern recognition method for the processing of a great number of “fuzzy” features in small groups of objects with small differences of features among the groups and with the missing of some data. Our algorithm dealing with statistical weighted syndromes (SWS) is based on the three-level feedback processing of fuzzy sets: recasting procedures of continual features to the gradations, optimization procedures of selection of the informative subareas (syndromes) in the feature space, and statistically weighted calculation of these subareas for prognosis of the class number function. At the training phase of the SWS method, the special likelihood function for the distribution of objects on the subareas is constructed. At all algorithm steps for control of stabilization and reproducing of the results, the jackknife procedure is used. The SWS method has been applied to analysis of flow cytometry measurements of the lymphocyte subpopulations in blood before treatment of osteosarcoma patients. We selected the small sets of the features from among about 40 immunological features which allowed us to predict correctly the widespread metastases and to forecast successfully the outcome of preoperation chemotherapy of the patients with osteosarcoma. Thus, for the first time, the information about lymphocyte subpopulations in the blood is effectively used for individual diagnostics, staging and prognosis of patients with the low-immunogeneic solid human tumor.

L- myc allele polymorphism and prognosis for metastases in Russian gastric cancer patients

During recent years, several attempts have been made to use restriction fragment length polymorphism (RFLP) of protooncogenes, e.g. c-Ha-rus and L-myc, as a marker for prognosis in human cancers [I]. L-myc has L and S alleles, and the presence of two S-S alleles has been reported to be associated with metastases of lung [2] and stomach cancer [3] in Japanese patients, although another study of lung cancer in Caucasians showed no such association [4]. Stomach cancer is common among the Russian population and a good prognostic marker is greatly needed. We performed L-myc RFLP analysis of stomach cancer samples from 21 newly diagnosed patients in Russia. DNA from tumour samples and corresponding mucosa was amplified by polymerase chain reaction, before single strand conformation polymorphism analysis or EcoRI digestion [4]. 9 patients had metastases in regional lymphnodes. All the tumours contained the same L-myc genotypes as the corresponding normal mucosa. Among the 21 patients, the ratio of L-myc genotypes between L-L, L-S and S-S was 0.24:0.62:0.14, which is very close to that found for a healthy white Caucasian population [4]: 0.25:0.62:0.13 (P=O.9865, x2). Among the nine patients with metastases, only 1 patient was found to have the SS genotype, anddistribution ofL-mycalleles was 0.33:0.56:0.11. The distribution of alleles in patients without metastases was 0.17:0.66:0.17, which did not significantly differ from the patients with metastases (P=O.8137, x2). Thus, no excess prevalence of S-S L-myc allele genotype was found in these Russian patients with metastases. If the reported association between the S-S genotype and metastases in Japanese patients could be confirmed in future studies, such an association might be explained by the presence of some specific factor(s) (internal or external) modulating the metastatic process. Among such factors could be ethnic differences in genotypes in the L-myc gene and environmental risk factors. However, because loss of heterozygosity is infrequent in stomach cancer at the L-myc locus [S], the loss of putative metastasis suppressor gene near this locus is improbable. In addition, it appears that the L-myc gene itself is

Production of a monoclonal antibody (IND.64) identifying a cell cycle-associated antigen using spleen cells from nude mice bearing Ichikawa tumour.

Using spleen cells from athymic nude mice grafted with Ichikawa tumour, we have generated the monoclonal antibody IND.64, which detects a proliferation-associated nuclear antigen. Immunoblotting analysis with IND.64 showed a double band with apparent molecular weights of 395 and 345 kD. In normal human tissues, the antigen detected by IND.64 was expressed only by the nuclei of proliferating cells, such as germinal centre cells of reactive lymph nodes, cortical thymocytes, the basal layer of the skin, and proliferative compartments of the stomach, small intestine, and colon. IND.64 did not react with cells known to be non-proliferative or to show only a low turnover, such as cells of the kidney, liver, smooth muscle, cardiac muscle, and brain. The expression of this antigen during the cell cycle was determined using two approaches: IND.64 immunostaining of synchronized adult bovine aortic endothelial cells and flow cytometric analysis of double-labelled PHA-stimulated peripheral mononuclear blood leucocytes with a DNA marker and IND.64. The antigen recognized by IND.64 was found to appear in the late G1 phase, and persisted in phases S, G2, and M, but was absent in the G0 and early G1 phases. IND.64 was further investigated in different tumour types to evaluate the correlation between the percentage of IND.64-positive cells (IND.64 index) and the histological grade. In non-Hodgkin's lymphomas, an excellent correlation was found between the percentage of IND.64-positive cells and the cytomorphological grade. In nodular sclerosis and mixed cellularity Hodgkin's disease, a high number of Reed-Sternberg cells were positive with IND.64. The non-lymphoid neoplasms investigated showed a variable percentage of positive cells. IND.64 appears to be a promising tissue marker to complement the evaluation of prognosis in human cancer.

Two‐dimensional polyacrylamide gel electrophoresis of human lung cancer: Qualitative aspects of tissue preparation in relation to histopathology

It is of great importance to identify new objective markers significant for the diagnosis, treatment, and prognosis of human cancers. Cytometric assessment of the DNA content has been shown to be one parameter which correlates excellently with the clinical course of patients with solid cancers of the breast, prostate, and thyroid. However, additional specific marker polypeptides are needed in order to further improve the diagnostic and prognostic sensitivity. Two-dimensional polyacrylamide gel electrophoresis (2-DE) is a unique tool in this field of cancer research, but serious problems concerning intersample variations in the 2-DE pattern must be solved because quantitative variations of potential marker polypeptides are expected to occur at low levels. In this study we examined a modified preparation method for tumor tissues, focusing on the relation between histopathological properties and 2-DE gel quality. We selected a group of human lung cancers sharing similar prognosis; nevertheless, the 2-DE patterns showed significant intersample but low intrasample variations. It is concluded that histopathological features, such as a local homogeneity, and the amounts of connective tissue and serum proteins are critical factors for the successful preparation and high quality of 2-DE-gels.

Evaluation of ceruloplasmin concentration in prognosis of human cancer.

The serum ceruloplasmin concentration was determined in cancer patients before and after radiotherapy, and after relapse of cancer, The ceruloplasmin concentration in patients who responded to therapy, decreased to the range of normal controls. In patients who did not respond to treatment, the ceruloplasmin concentration was more or less elevated. In patients with relapse of cancer, the ceruloplasmin concentration was higher than before treatment.

Release of superoxide anion from resident and activated mouse peritoneal macrophages infected with Mycobacterium intracellulare.

Phagocytosis of Mycobacterium intracellulare triggered the release of superoxide anion (O-2) from mouse peritoneal macrophages; the amount release from BCG-activated cells was significantly greater than that from resident cells. Superoxide anion release was proportional to the number of phagocytes ingesting bacilli. An optimal phagocytic time course of 4 h was observed when estimating O-2 release consequent to bacterial challenge. Also, an inverse relationship between the amount of O-2 released and the virulence of M. intracellulare in mice was shown. Transparent and rough colony variants triggered the release of significantly lower amounts of O-2 as compared with the opaque and smooth colony variants. Serovars 4 and 8, which cause a disease with a poor prognosis in humans, triggered significantly less O-2 than did serovars 9, 12, 13, 14, 16, 18, and 19, which respond more favorably to chemotherapeutic regimens.

Symptoms as an index of biological behaviour and prognosis in human cancer.

Symptoms as an index of biological behaviour and prognosis in human cancer.