Günter Daxenbichler

Significance of thrombocytosis in patients with epithelial ovarian cancer

Abstract OBJECTIVES: Our objective was to determine the relevance of a preoperative platelet count in ovarian cancer. Special interest was directed to a possible prognostic significance of thrombocytosis in this disease. STUDY DESIGN: Charts of 130 patients with epithelial ovarian cancer were reviewed retrospectively. Survival analyses were performed with the Kaplan-Meier method. Differences in survival were examined according to Mantel and Breslow. Platelet counts were furthermore correlated to other clinical parameters. For this purpose the Spearman rank test and a stepwise logistic regression model were used. Data comparison was accomplished with the Mann-Whitney U test and the χ 2 test. RESULTS: Prevalence of thrombocytosis was 38%. No differences in survival between patients with or without thrombocytosis was found. Volume of ascities and hemoglobin concentrations were independently associated with thrombocytosis (p = 0.002 and p = 0.004, respectively). CONCLUSIONS: Thrombocytosis is not a useful prognostic factor in ovarian cancer. Elevated platelets are predominately associated with the presence of ascites and marked anemia. (A M J O BSTET G YNECOL 1994;170:549-54.)

Metastatic lesions from prostate cancer do not express oestrogen and progesterone receptors

Oestrogen receptors (ER) and progesterone receptors (PR) have been reported by several authors in the stromal cells of the human prostate. Controversial results exist on the expression of ER and PR in epithelial cells of the prostate. Some recent publications, in contrast to previous findings, have suggested that these receptors are also present in human prostate cancer cell lines derived from metastatic lesions. The expression of ER and PR in these cell lines has been re‐examined to determine their presence in lymph node metastases from patients who did not receive any kind of endocrine therapy and in distant metastases obtained from patients who failed endocrine treatment. ER and PR expression in LNCaP, PC‐3, and DU‐145 cells was assessed by means of the reverse transcriptase‐polymerase chain reaction, ligand binding assays, and immunohistochemistry. With all the techniques applied, the three cell lines were found to be negative for both ER and PR. Immunohistochemical analyses were performed in four lymph node metastases obtained at radical prostatectomy from patients who did not receive endocrine therapy and in 17 distant metastases obtained at palliative surgery from patients who failed endocrine therapy. All 21 metastases were negative for ER and PR on immunohistochemistry. These results do not support the recently developed concept that receptors for oestrogenic and progestagenic steroids are present in metastases from human prostate cancer.

Clinical significance of serum and ascitic p53 autoantibodies in epithelial ovarian carcinoma

Accumulation of mutated p53 in malignant cells can lead to the generation of anti‐p53 autoantibodies in the serum and other body fluids of cancer patients. This retrospective study was performed to evaluate the prognostic significance of preoperative serum and ascitic anti‐p53 antibodies in advanced ovarian carcinoma.

Favorable prognostic value of SOCS2 and IGF-I in breast cancer

BackgroundSuppressor of cytokine signaling (SOCS) proteins comprise a protein family, which has initially been described as STAT induced inhibitors of the Jak/Stat pathway. Recent in vivo and in vitro studies suggest that SOCS proteins are also implicated in cancer. The STAT5 induced IGF-I acts as an endocrine and para/autocrine growth and differentiation factor in mammary gland development. Whereas high levels of circulating IGF-I have been associated with increased cancer risk, the role of autocrine acting IGF-I is less clear. The present study is aimed to elucidate the clinicopathological features associated with SOCS1, SOCS2, SOCS3, CIS and IGF-I expression in breast cancer.MethodsWe determined the mRNA expression levels of SOCS1, SOCS2, SOCS3, CIS and IGF-I in 89 primary breast cancers by reverse transcriptase PCR. SOCS2 protein expression was further evaluated by immuno-blot and immunohistochemistry.ResultsSOCS2 expression inversely correlated with histopathological grade and ER positive tumors exhibited higher SOCS2 levels. Patients with high SOCS2 expression lived significantly longer (108.7 vs. 77.7 months; P = 0.015) and high SOCS2 expression proved to be an independent predictor for good prognosis (HR = 0.45, 95% CI 0.23 – 0.91, P = 0.026). In analogy to SOCS2, high IGF-I expression was an independent predictor for good prognosis in the entire patient cohort. In the subgroup of patients with lymph-node negative disease, high IGF-I was a strong predictor for favorable outcome in terms of overall survival and relapse free survival (HR = 0.075, 95% CI 0.014 – 0.388, P = 0.002).ConclusionThis is the first report on the favorable prognostic value of high SOCS2 expression in primary mammary carcinomas. Furthermore a strong association of high IGF-I expression levels with good prognosis was observed especially in lymph-node negative patients. Our results suggest that high expression of the STAT5 target genes SOCS2 and IGF-I is a feature of differentiated and less malignant tumors.

Tumor marker CA-125 in tissues of the female reproductive tract and in serum during the normal menstrual cycle

OBJECTIVE To further elucidate the origin of the physiological CA-125 amounts that lead to cyclic changes in CA-125 serum levels in normally menstruating women. DESIGN Fifty-three normal endometria, 13 fallopian tubes, 25 ovaries, and nine isolated corpora lutea were prospectively investigated for their CA-125 content in a sandwich solid-phase RIA and by immunohistochemistry. In addition, endometrial CA-125 tissue content was compared with the actual CA-125 serum levels of the study patients. RESULTS Cytosolic CA-125 concentrations were 20-fold and twofold higher in the endometrium than those measured in the ovary and the fallopian tube, respectively. Moreover, only in the endometrium did CA-125 content show significant cyclic changes, with the highest concentrations during the early proliferative and middle secretory phase. The lowest tissue concentrations were measured during the early secretory phase. Furthermore, during the early and middle secretory phases cytosolic CA-125 was negatively associated with CA-125 serum levels. In immunohistochemistry, marked distributional changes in OC-125 reactivity were revealed in the basalis and the functionalis throughout the menstrual cycle and the postovulatory loss of CA-125 expression was found to be strongly connected with early secretory transformation of glandular epithelium. CONCLUSION Our findings indicate that the CA-125 amounts responsible for cyclic changes in serum levels in normally menstruating women seem to be a product of normal endometrium.

Prognostic value of CD44 splice variant expression in ovarian cancer

In 44 ovarian cancers, CD44 variant (CD44v) expression was investigated immunohistochemically using a variant-specific polyclonal antibody. Patients with CD44v-positive carcinomas had a significantly shorter disease-free survival than patients with CD44v-negative tumors. Overall survival was also significantly reduced for stages III and IV of the International Federation of Gynecology and Obstetrics. Furthermore, a highly significant inverse correlation was observed between CD44v expression and preoperative platelet count. Urinary neopterin concentration, a marker of cell-mediated immunostimulation, did not differ between CD44v-positive and -negative ovarian cancer patients. Moreover, in seven ovarian carcinoma cell lines, modulation of CD44v expression was analyzed by living cell radioimmunoassay. Interferon-alpha, interferon-gamma, tumor necrosis factor, transforming growth factor-beta, all-trans retinoic acid and cisplatin did not affect CD44v expression.

Effect of retinoic acid and 4-hydroxytamoxifen on human breast cancer cell lines

Using established breast cancer cell lines in a cell culture model we studied the growth effect of retinoic acid (RA) alone or in combination with the antiestrogen 4-hydroxytamoxifen (OHT). Cytoplasmic 3HRA binding sites were determined by sucrose density gradient centrifugation analysis. Of the three cell lines Hs578T, BT 20, and 734 B only the last showed a significant amount of specific RA binding (10(5) sites/cell). This cell line showed a dose dependent decrease in proliferation after a long-term incubation with RA whereas the 3H-thymidine uptake was highly significantly increased after incubation with 10(-6)M of RA for 20 hr. Growth inhibition was not further increased by the addition of OHT (10(-6) M), but the increase in thymidine incorporation due to RA was neutralized by OHT. Hs578T and BT 20 cells were not affected by any of the treatments. The different action of RA on proliferation and thymidine incorporation suggests a cell cycle specific mechanism.

Genome-Scale Screen for DNA Methylation-Based Detection Markers for Ovarian Cancer

Background The identification of sensitive biomarkers for the detection of ovarian cancer is of high clinical relevance for early detection and/or monitoring of disease recurrence. We developed a systematic multi-step biomarker discovery and verification strategy to identify candidate DNA methylation markers for the blood-based detection of ovarian cancer. Methodology/Principal Findings We used the Illumina Infinium platform to analyze the DNA methylation status of 27,578 CpG sites in 41 ovarian tumors. We employed a marker selection strategy that emphasized sensitivity by requiring consistency of methylation across tumors, while achieving specificity by excluding markers with methylation in control leukocyte or serum DNA. Our verification strategy involved testing the ability of identified markers to monitor disease burden in serially collected serum samples from ovarian cancer patients who had undergone surgical tumor resection compared to CA-125 levels. We identified one marker, IFFO1 promoter methylation (IFFO1-M), that is frequently methylated in ovarian tumors and that is rarely detected in the blood of normal controls. When tested in 127 serially collected sera from ovarian cancer patients, IFFO1-M showed post-resection kinetics significantly correlated with serum CA-125 measurements in six out of 16 patients. Conclusions/Significance We implemented an effective marker screening and verification strategy, leading to the identification of IFFO1-M as a blood-based candidate marker for sensitive detection of ovarian cancer. Serum levels of IFFO1-M displayed post-resection kinetics consistent with a reflection of disease burden. We anticipate that IFFO1-M and other candidate markers emerging from this marker development pipeline may provide disease detection capabilities that complement existing biomarkers.

Peritoneum and Tissues of the Female Reproductive Tract as Physiological Sources of CA-125

The origin of physiological CA-125 serum levels, which in normally menstruating women were shown to depend on their actual menstrual cycle phase, has not yet been completely elucidated. It is furthermore conceivable that physiological CA-125 sources may contribute to serum elevations in the various pathologies associated with increased circulating CA-125. The present review deals with menstrual cycle-dependent expression of CA-125 in normal tissues of the female reproductive tract in relation to the actual circulating CA-125 levels together with in vivo data concerning the inductive effect of medroxyprogesterone acetate on circulating CA-125 studied in 24 postmenopausal women. Furthermore, in vitro results on constitutive, steroid hormone- and cytokine-modulated CA-125 shedding from human peritoneal mesothelial and ovarian surface epithelial cells are summarized.

New insights into p53 regulation and gene therapy for cancer.

Due to its critical involvement in cell cycle control and apoptotic signaling, the transcription factor p53 has become the most important tumor suppressor currently under investigation. TP53 is the most frequently mutated gene in human cancers and is thought to play a crucial role in malignant transformation. Therefore, p53 appears to be an appealing target for gene therapy. Adenoviral-based p53 gene transfection is now being introduced in large clinical trials. Viral cell entry was found to be the rate-limiting step of gene delivery and thus of therapeutic efficiency. Attachment of adenoviruses to the target cell surface is mediated through the coxsackie-adenovirus receptor, and internalization is achieved via interactions with integrins of the alpha v beta(3) and alpha v beta(5) class. The assumption that the restitution of the p53-dependent apoptotic pathway results in a higher responsiveness of solid tumors to cytostatic agents remains a major matter of debate. Combinations of p53-based gene therapy with other components involved in apoptosis, such as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/APO2L, or agents neutralizing tumor-promoting antiapoptotic signals, such as humanized anti-growth factor antibodies, should further improve the effectiveness of cancer treatment in the future.