Estimating Time-Varying Effects of Prognostic Factors for Stomach Cancer Patients within a Dynamic Grouped Cox Model

We describe the identification of prognostic factors in the framework of a completely resected stomach cancer survival-study. For the analysis the dynamic grouped Cox-Model was used allowing for time-varying covariate effects. Therefore the hazard rate might be non-proportional. As estimation concept we applied the posterior mode, computed by iteratively weighted Kalman filtering and smoothing steps. The medical study and questions are described, the statistical method is illustrated, the results are given and interpreted and the method is discussed

Impact of cytokeratin-20 and carcinoembryonic antigen mRNA detection by RT-PCR in regional lymph nodes of patients with colorectal cancer

The reported rates for tumour cell involvement in the locoregional lymph nodes of colorectal cancer vary greatly, depending on the method used and case selection. In order to further evaluate the clinical value of molecular biologic detection of tumour cells we investigated 102 histologically tumour-free (pN0) regional lymph nodes from 51 consecutive, completely resected (UICC R0) colorectal carcinoma specimens for the presence of tumour cell mRNA by RT-PCR specific for carcinoembryonic antigen (CEA) and cytokeratin 20 (CK-20). Two lymph nodes located nearest to the primary tumour were investigated in each case. CK-20 mRNA was found in 31 of 51 patients (60.8%) and CEA mRNA in 30 of 51 patients (58.8%), respectively. Identical transcription patterns of CK-20 and CEA mRNA (both positive or both negative) were found in 38 of 51 patients (74.5%). There was a significantly higher proportion of cases with CEA positivity in the lymph nodes of tubulopapillary than of mucinous adenocarcinomas (P< 0.03). Detection of CK-20 and CEA mRNA correlated in nine of 12 cases (75.0%) with the risk of tumour recurrence (not significant) and showed a tendency towards shorter disease-free survival by univariate analysis (not significant). Our data indicate that CK-20 and CEA mRNA detection by RT-PCR may prove useful for the prediction of tumour recurrence of patients with pN0 colorectal carcinoma, although neither reach statistical significance in this series of patients. © 2000 Cancer Research Campaig

Transcriptional regulation of the urokinase receptor (u-PAR) - A central molecule of invasion and metastasis

The phenomenon of tumor-associated proteolysis has been acknowledged as a decisive step in the progression of cancer. This short review focuses on the urokinase receptor (u-PAR), a central molecule involved in tumor-associated invasion and metastasis, and summarizes the transcriptional regulation of u-PAR. The urokinase receptor (u-PAR) is a heavily glycosylated cell surface protein and binds the serine protease urokinase specifically and with high affinity. It consists of three similar cysteine-rich repeats and is anchored to the cell membrane via a GPI-anchor. The u-PAR gene comprises 7 exons and is located on chromosome 19q13. Transcriptional activation of the u-PAR promoter region can be induced by binding of transcription factors (Sp1, AP-1, AP-2, NF-kappaB). One current study gives an example for transcriptional downregulation of u-PAR through a PEA3/ets transcriptional silencing element. Knowledge of the molecular regulation of this molecule in tumor cells could be very important for diagnosis and therapy in the near future

Immunocytochemically detected free peritoneal tumour cells (FPTC) are a strong prognostic factor in gastric carcinoma

We prospectively investigated the prognostic significance of free peritoneal tumour cells (FPTC) in a series of 118 patients with completely resected gastric carcinoma. Immunocytochemistry with the monoclonal antibody Ber-Ep4 was performed on cytospins from intraoperative peritoneal lavage specimens. Twenty-three patients (20%) had FPTC which was significantly correlated with pT and pN categories, stage, tumour size, lymphatic invasion, Laurèn and WHO classifications and perigastric adipose tissue metastases. The median survival time for all FPTC positive compared with negative patients was significantly shorter (11 compared with > 72 months), with estimated 5-year survival rates of 8% vs. 60%. None of the patients with FPTC had an early gastric cancer. In advanced tumour subgroups without and with serosal invasion (n = 59 and 35), there were 19% and 34% with FPTC. Multivariate survival analysis showed nodal status, FPTC, mesenteric lymphangiosis, and lymph node metastasis to the compartment III to be independent prognostic factors with relative risks of 6.6, 4.5, 2.9 and 2.2 respectively. Recurrent disease occurred in 91% of FPTC-positive and in 38% of FPTC-negative patients. FPTC had a positive predictive value of 91% and a specificity of 97% for tumour recurrence. FPTC is a strong negative, independent prognostic indicator for survival in gastric carcinoma. © 1999 Cancer Research Campaig

Tumor marker utility and prognostic relevance of cathepsin B, cathepsin L, urokinase-type plasminogen activator, plasminogen activator inhibitor type-1, CEA and CA 19-9 in colorectal cancer

<p>Abstract</p> <p>Background</p> <p>Cathepsin B and L (CATB, CATL), urokinase-type plasminogen activator (uPA) and its inhibitor PAI-1 play an important role in colorectal cancer invasion. The tumor marker utility and prognostic relevance of these proteases have not been evaluated in the same experimental setting and compared with that of CEA and CA-19-9.</p> <p>Methods</p> <p>Protease, CEA and CA 19-9 serum or plasma levels were determined in 56 patients with colorectal cancer, 25 patients with ulcerative colitis, 26 patients with colorectal adenomas and 35 tumor-free control patients. Protease, CEA, CA 19-9 levels have been determined by ELISA and electrochemiluminescence immunoassay, respectively; their sensitivity, specificity, diagnostic accuracy have been calculated and correlated with clinicopathological staging.</p> <p>Results</p> <p>The protease antigen levels were significantly higher in colorectal cancer compared with other groups. Sensitivity of PAI-1 (94%), CATB (82%), uPA (69%), CATL (41%) were higher than those of CEA or CA 19-9 (30% and 18%, respectively). PAI-1, CATB and uPA demonstrated a better accuracy than CEA or CA 19-9. A combination of PAI-1 with CATB or uPA exhibited the highest sensitivity value (98%). High CATB, PAI-1, CEA and CA 19-9 levels correlated with advanced Dukes stages. CATB (<it>P </it>= 0.0004), CATL (<it>P </it>= 0.02), PAI-1 (<it>P </it>= 0.01) and CA 19-9 (<it>P </it>= 0.004) had a significant prognostic impact. PAI-1 (<it>P </it>= 0.001), CATB (<it>P </it>= 0.04) and CA 19-9 (<it>P </it>= 0.02) proved as independent prognostic variables.</p> <p>Conclusion</p> <p>At the time of clinical detection proteases are more sensitive indicators for colorectal cancer than the commonly used tumor markers. Determinations of CATB, CATL and PAI-1 have a major prognostic impact in patients with colorectal cancer.</p

Role of genetic polymorphisms in tumour angiogenesis

Angiogenesis plays a crucial role in the development, growth and spread of solid tumours. Pro- and anti-angiogenic factors are abnormally expressed in tumours, influencing tumour angiogenesis, growth and progression. Polymorphisms in genes encoding angiogenic factors or their receptors may alter protein expression and/or activity. This article reviews the literature to determine the possible role of angiogenesis-related polymorphisms in cancer. Further research studies in this potentially crucial area of tumour biology are proposed