Downregulation of ORP3 Correlates with Reduced Survival of Colon Cancer Patients with Advanced Nodal Metastasis and of Female Patients with Grade 3 Colon Cancer.

Genome instability is an essential hallmark in tumor development, including colorectal cancer. We have recently identified the oxysterol binding protein-related protein 3 (ORP3), also known as oxysterol binding protein-like 3 (OSBPL3), as a novel ploidy-control gene, whose knock-out leads to aneuploidy induction and promotes tumor formation, indicating that ORP3 is a bona fide tumor suppressor protein. Here we analyzed expression of ORP3 in a cohort (n = 206) of colon cancer patients in relation to patient survival. We show that low ORP3 mRNA levels correlate with reduced survival of patients with advanced nodal metastasis (N2). While patient survival does not associate with grading when the whole cohort is evaluated, importantly, low ORP3 mRNA levels associate with worse survival of female patients with grade 3 colon cancer. Similarly, low ORP3 mRNA levels associate with worse survival of grade 3 colon cancer patients 70 years of age and younger while low ORP3 mRNA levels seem to be beneficial for colon cancer patients with a T2 tumor size. Together, the data show that ORP3 expression is downregulated during colon cancer progression, which correlates with reduced patient survival. Thus, ORP3 mRNA levels may be a prognostic marker for better stratification of colon cancer patients.

Effects of altered expression and activity levels of CK1δ and ɛ on tumor growth and survival of colorectal cancer patients.

Colorectal cancer (CRC) is the fourth leading cause of cancer related death worldwide due to high apoptotic resistance and metastatic potential. Because mutations as well as deregulation of CK1 isoforms contribute to tumor development and tumor progression, CK1 has become an interesting drug target. In this study we show that CK1 isoforms are differently expressed in colon tumor cell lines and that growth of these cell lines can be inhibited by CK1-specific inhibitors. Furthermore, expression of CK1δ and ɛ is changed in colorectal tumors compared to normal bowel epithelium, and high CK1ɛ expression levels significantly correlate with prolonged patients' survival. In addition to changes in CK1δ and ɛ expression, mutations within exon 3 of CK1δ were detected in colorectal tumors. These mutations influence ATP binding resulting in changes in kinetic parameters of CK1δ. Overexpression of these mutants in HT29 cells alters their ability to grow anchorage independently. Consistent with these results, these CK1δ mutants lead to differences in proliferation rate and tumor size in xenografts due to changes in gene expression, especially in genes involved in regulation of cell proliferation, cell cycle, and apoptosis. In summary, our results provide evidence that changes in the expression levels of CK1 isoforms in colorectal tumors correlate with patients' survival. Furthermore, CK1 mutants affect growth and proliferation of tumor cells and induce tumor growth in xenografts, leading to the assumption that CK1 isoforms provide interesting targets for the development of novel effective therapeutic concepts to treat colorectal cancer.

Cyclin H expression is increased in GIST with very-high risk of malignancy.

BACKGROUND: Risk estimation of gastrointestinal stromal tumours (GIST) is based on tumour size and mitotic rate according to the National Institutes of Health consensus classification. The indication for adjuvant treatment of patients with high risk GIST after R0 resection with small molecule inhibitors is still a controversial issue, since these patients represent a highly heterogeneous population. Therefore, additional prognostic indicators are needed. Here, we evaluated the prognostic value of cyclin H expression in GIST. METHODS: In order to identify prognostic factors of GIST we evaluated a single centre cohort of ninety-five GIST patients. First, GISTs were classified with regard to tumour size, mitotic rate and localisation according to the NIH consensus and to three additional suggested risk classifications. Second, Cyclin H expression was analysed. RESULTS: Of ninety-five patients with GIST (53 female/42 male; median age: 66.78a; range 17-94a) risk classification revealed: 42% high risk, 20% intermediate risk, 23% low risk and 15% very low risk GIST. In patients with high risk GIST, the expression of cyclin H was highly predictive for reduced disease-specific survival (p = 0.038). A combination of cyclin H expression level and high risk classification yielded the strongest prognostic indicator for disease-specific and disease-free survival (p < or = 0.001). Moreover, in patients with tumour recurrence and/or metastases, cyclin H positivity was significantly associated with reduced disease-specific survival (p = 0.016) regardless of risk-classification. CONCLUSION: Our data suggest that, in addition to high risk classification, cyclin H expression might be an indicator for "very-high risk" GIST.

Circulating adipokine levels and prognostic value in septic patients.

BACKGROUND: Adipokines have a wide range of effects and are linked to sepsis and septic shock. The aim of the present study was to describe the changes in adipokine levels in septic patients in relation to patients' preseptic adipokine levels. Furthermore, we examined adipokines as prognostic markers. METHODS: Fourteen consecutive critically ill patients meeting the clinical criteria for severe sepsis or septic shock 3 days up to 1 month after major visceral surgery were enrolled prospectively. Plasma adipokines were measured preoperatively, 1 and 4 days after diagnosis of severe sepsis or septic shock following elective surgery. RESULTS: Median plasma adiponectin levels were lowered and resistin and leptin levels elevated in sepsis compared with preseptic plasma levels. MCP-1, C-reactive protein and white blood cell count were higher in septic compared with preseptic patients. Survivors had significantly higher preseptic adipokine levels than non-survivors. Adiponectin levels of survivors decreased significant (on average by 33 %) at day one after onset of sepsis compared with preseptic levels. In contrast, median adiponectin levels of patients dying during sepsis showed a slight increase (11 %). Median BMI of survivors was 30 kg/m(2), median BMI of non-survivors was 25, respectively. CONCLUSIONS: Adipokine levels change during the course of sepsis. Higher preseptic adiponectin levels and decreasing adiponectin levels after onset of sepsis are associated with survival of sepsis. Survival of overweight and obese patients was higher than in normal weight patients. Changes in adiponektin levels could be a prognostic marker for outcome of severe sepsis/septic shock following surgery.

Analysis of cell type-specific expression of CK1 epsilon in various tissues of young adult BALB/c Mice and in mammary tumors of SV40 T-Ag-transgenic mice.

Casein kinase 1 epsilon (CK1epsilon) is involved in various cellular processes, including cell growth, differentiation, and apoptosis, vesicle transport, and control of the circadian rhythm. Deregulation of CK1epsilon has been linked to neurodegenerative diseases and cancer. To better understand the cell type-specific functions of CK1epsilon, we determined its localization by immunhistochemistry in tissues of healthy, young adult BALB/c mice and in mammary tumors of SV40 T-antigen-transgenic mice. CK1epsilon expression was found to be highly regulated in normal tissues of endodermal, mesodermal, and ectodermal origin and in neoplastic tissue of mammary cancer. The data presented here give an overview of CK1epsilon reactivity in different organs under normal conditions and outline changes in its expression in mammary carcinomas. Our data suggest a cell/organ type-specific function of CK1epsilon and indicate that tumorigenic conversion of mammary glands in SV40 T-antigen-transgenic mice leads to downregulation of CK1epsilon. This manuscript contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials.

Surgery of colorectal cancer: surgical morbidity and five- and ten-year results in 2400 patients--monoinstitutional experience.

The objective of this study was to determine surgical morbidity and long-term outcome of colorectal cancer surgery for quality control reasons and as the basis for new treatment modalities. Surgically treated colorectal cancer patients (mean age 65 years) were followed prospectively in a university center (110 months mean follow-up, 1978-1999). Overall survival (OAS), radicality, extent of resection, recurrence, and morbidity were analyzed (log-rank test of survival, multivariate analysis). Altogether, 2452 colorectal cancers localized in the colon (CC, 44.6%), rectum (RC, 44.8%) or multicentric (CRC, 10.6%) were of UICC stages I (19%), II (30%), III (21%), IV (20%), or undetermined (10%). Radicality and stage but not tumor localization influenced the OAS (p <0.0001). The 5-year/10-year OASs were 50%/42% (all), 78%/66% (R0), 46%/36% (R1), 4%/0% (R2), 0% (unresected) and 86%/79% (I), 70%/58% (II), 42%/33% (III), 3%/0% (IV) or 21%/12% (undetermined), respectively (p <0.0001). Multivisceral resections (17%) resulted in morbidity and survival rates equal to those for standard resection. The overall tumor recurrence rate was 27%, mainly with both local and distant relapse (15%). Surgery-related complications occurred in 18% (all), 14% (CC), 21% (RC), or 20% (CRC). The perineal infection rate (RC) was 4%, overall anastomotic leakage 1%, and mortality rate 0.8%. A prospective, uniform follow-up used over two decades warrants quality control in colorectal cancer surgery, which was curative for half of the patients. The morbidity and mortality were low and were not increased by multivisceral resections.