Christian Kainz

Interferon-gamma in the first-line therapy of ovarian cancer: a randomized phase III trial

Intraperitoneal treatment with interferon-γ (IFN-γ) has been shown to achieve surgically documented responses in the second-line therapy of ovarian cancer. To assess its efficacy in the first-line therapy, we conducted a randomized controlled trial with 148 patients who had undergone primary surgery for FIGO stage Ic–IIIc ovarian cancer. In the control arm women received 100 mg m–2cisplatin and 600 mg m–2cyclophosphamide, the experimental arm included the above regimen with IFN-γ 0.1 mg subcutaneously on days 1, 3, 5, 15, 17 and 19 of each 28-day cycle. Progression-free survival at 3 years was improved from 38% in controls to 51% in the treatment group corresponding to median times to progression of 17 and 48 months (P = 0.031, relative risk of progression 0.48, confidence interval 0.28–0.82). Three-year overall survival was 58% and 74% accordingly (n.s., median not yet reached). Complete clinical responses were observed in 68% with IFN-γ versus 56% in controls (n.s.). Toxicity was comparable in both groups except for a mild flu-like syndrome, experienced by most patients after administration of IFN-γ. Thus, with acceptable toxicity, the inclusion of IFN-γ in the first-line chemotherapy of ovarian cancer yielded a benefit in prolonging progression-free survival.

Vascular endothelial growth factor (VEGF) in human breast cancer : Correlation with disease-free survival

Studies have shown that microvessel density influences breast‐cancer prognosis. Since tumor angiogenesis is considered to be substantially affected by the excretion of vascular endothelial growth factor (VEGF) from tumor cells, we examined whether VEGF concentration is different in malignant and in non‐malignant breast tissue. It was also of interest to discover whether intratumoral VEGF concentration influences disease‐free survival (DFS) of breast‐cancer patients. Analysis is based on 120 tissue specimens taken from breast fibromas (n = 23), normal epithelial breast tissue adjacent to fibromas (n = 8) and invasive breast cancer (n = 89). VEGF concentration was quantified by using an immunoassay. Microvessel density was determined by immunostaining for factor‐VIII‐related antigen. Median VEGF concentration is given in pg/mg protein (25%‐quantile—75%‐quantile) and it was 0 (0–1.8) in normal breast tissue, 9.8 (0.52–43.0) in fibromas and 130.4 (50.8–362.2) in invasive carcinomas. A univariate Cox model revealed that node status, tumor size, estrogen‐receptor concentration, histological grading and microvessel density were prognostic factors for disease‐free survival in breast cancer. We found a significant correlation between VEGF concentration and microvessel count, but VEGF concentration did not significantly influence disease‐free survival. Although VEGF protein was found at a significantly higher concentration in malignant than in non‐malignant tissue, determination of intratumoral VEGF protein by an enzyme immunoassay was not prognostically relevant in our patient population. Int. J. Cancer 74:455–458, 1997.

Vascular endothelial growth factor serum concentrations in ovarian cancer

Objective To determine whether serum vascular endothelial growth factor is an independent prognostic factor in ovarian cancer patients. Methods We measured vascular endothelial growth factor in pretreatment serum samples of 60 women with International Federation of Gynecology and Obstetrics stages I to IV epithelial ovarian cancer, using an enzyme-linked immunosorbent assay. The results were correlated to clinical data. Results The median vascular endothelial growth factor serum level in ovarian cancer patients was 466.1 pg/mL (range 69.7-2835 pg/mL). The 75% quartile was defined as a cut-off level. Elevated vascular endothelial growth factor serum levels before therapy correlated significantly with a poorer disease-free (log-rank-test, P = .003) and overall survival (log-rank-test, P = .007). Multivariate analysis revealed serum vascular endothelial growth factor to be an independent prognostic factor of overall and disease-free survival. When median pretreatment levels of vascular endothelial growth factor were grouped by tumor stage, histologic grade of tumor cells, histologic type of the tumor, lymph node involvement, age of patient, and residual tumor mass, we found a statistically significant correlation between serum levels of vascular endothelial growth factor and histologic grade (Mann-Whitney U test, P = .03). Conclusion Vascular endothelial growth factor appears to be an additional factor for predicting the outcome of patients with epithelial ovarian cancer. Owing to its independence from established prognostic factors, vascular endothelial growth factor could be used for prognostic information in clinically relevant subsets such as early-stage or lymph node-negative ovarian cancers.

Monocyte chemoattractant protein-1 serum levels in ovarian cancer patients

The chemokine monocyte chemoattractant protein (MCP)-1 is an important mediator of monocyte infiltration in various solid tumours of epithelial origin. The aim of the present study was to evaluate the role of MCP-1 in the natural history of ovarian cancer and to determine its value as differentiation marker and prognostic marker regarding disease free and overall survival. This retrospective study comprises 86 patients with ovarian cancer, 48 with primary ovarian cancer and 38 with recurrent ovarian cancer, 67 patients with benign ovarian cysts and 42 healthy women. Median serum levels in patients with primary ovarian cancer, recurrent ovarian cancer, benign ovarian cysts and in healthy women were 535.6 (range 129.6–1200) pg ml–1, 427.3 (range 193.4–1101) pg ml–1, 371.2 (range 222–986.8) pg ml–1 and 318.7 (range 241.3–681.4) pg ml–1 respectively (Mann–Whitney U-test, P < 0.001). Univariate logistic regression models revealed a significant influence of MCP-1 serum levels on the odds of presenting with primary ovarian cancer versus benign cysts and versus healthy women respectively (univariate logistic regression, P < 0.001 and P < 0.001 respectively). In a multivariate logistic regression model considering MCP-1 and CA 125 serum levels simultaneously, both MCP-1 and CA 125 revealed statistical significance on the odds of presenting with primary ovarian cancer versus benign cysts (multivariate logistic regression, P = 0.05 and P < 0.001 respectively). In ovarian cancer patients, MCP-1 serum levels showed a statistically significant correlation with histological grade (Mann–Whitney U-test, P = 0.02) and age at the time of diagnosis (Mann–Whitney U-test, P = 0.03). Elevated MCP-1 serum levels prior to therapy were not associated with disease-free and overall survival (log-rank test, P = 0.2 and P = 0.7 respectively). In summary these data indicate that MCP-1 might play a functional role in the natural history of ovarian cancer and might serve as differentiation marker between benign ovarian cysts and ovarian cancer, providing additional information to the established tumour marker CA 125.

Preoperative CA 125: An independent prognostic factor in patients with stage I epithelial ovarian cancer

Objective To evaluate the prognostic importance of preoperative CA 125 levels in patients with International Federation of Gynecology and Obstetrics (FIGO) stage I epithelial ovarian cancer in comparison with the established prognostic factors: degree of differentiation, FIGO substage, and age. Methods In a retrospective analysis, the traditional prognostic factors and CA 125 levels (cutoff value 65 U/mL) were studied in 201 patients who were treated in five centers during 1984–1993. Patients with borderline tumors or nonepithelial ovarian carcinomas were excluded, as were women in whom CA 125 had not been determined preoperatively. Results In univariate analysis (Mantel test), overall survival decreased significantly in patients positive for CA 125 (P < .001). Substage (P = .004) and histologic grade (P = .01) also significantly influenced survival prognosis. When the effects of preoperative CA 125 levels were correlated with histologic grade, all three subgroups with CA 125 levels equal to or greater than 65 U/mL were associated with a decreased survival probability (grade 1, P = .04; grade 2, P = .003; grade 3, P = .01). Multivariate analysis (Cox model) identified preoperative CA 125 as the most powerful prognostic factor for survival (P < .001), the risk of dying of disease being 6.37 times higher (95% confidence interval 2.39–16.97) in CA 125-positive patients. Although FIGO substage retained its significant influence on survival (P = .03), histologic grade and age were not prognostically important. Conclusion Randomized trials investigating the efficacy of adjuvant treatment in patients with FIGO stage I epithelial ovarian cancer should also include stratification by preoperative CA 125 levels.

Prognostic value of CD44 splice variants in human stage III cervical cancer

The expression of specific cell adhesion molecule CD44 isoforms (splice variants) has been shown to be associated with poor prognosis in human malignancies, such as breast cancer. We used three different variant exon sequence-specific murine monoclonal antibodies to epitopes encoded by exons v5, v6 or v7-v8 of human variant CD44, to study the expression of CD44 splice variants by immunohistochemistry in human stage III cervical cancer. We investigated 40 pretreatment punch biopsies of cervical cancer FIGO stage III. CD44 splice variants CD44v5, CD44v6 and CD44v7-8 were detected by means of immunohistochemistry in 90%, 55% and 25%, respectively. CD44 epitopes encoded by exon v5 were not correlated with prognosis. Expression of CD44 splice variants containing epitopes encoded by exon v6 were correlated with significantly poorer prognosis (Mantel test, P = 0.008). Five-year survival rates with or without CD44v6 expression were 20% versus 71%, respectively. Expression of CD44v7-8 was also correlated with significantly poorer overall survival (Mantel test, P = 0.02). Expression of CD44 splice variants containing epitopes encoded by exons v7-v8 and especially exon v6 is associated with significantly poorer prognosis in stage III cervical cancer patients.

Concentration of vascular endothelial growth factor (VEGF) in the serum of patients with suspected ovarian cancer.

As a promoter of angiogenesis, vascular endothelial growth factor (VEGF) is believed to play a pivotal role in tumour growth and metastasis. The aim of this study was to determine the value of preoperative serum VEGF levels in the early diagnosis of ovarian cancer and in the differential diagnosis of adnexal masses. We examined preoperative serum VEGF levels in healthy women (n = 131), patients with benign ovarian cysts (n = 81) and in ovarian cancer patients (n = 44) by using an ELISA (R&D Systems, Minneapolis, MN, USA). A logistic regression model was carried out to determine the influence of VEGF and CA 125 on the probability of malignancy. VEGF revealed a significant influence on the odds of presenting with malignancy vs healthy women (P = 0.001). At 363.7 pg ml(-1), VEGF achieved a sensitivity of 54% and a specificity of 77%. With respect to the differentiation between benign cysts and ovarian cancer, CA 125 (P < 0.0001) but not VEGF (P = 0.229) predicts the presence of malignancy in a multivariate model. In conclusion, VEGF does not appear to be a useful tool in the early diagnosis of ovarian cancer or for indicating the absence or presence of malignancy in patients with an adnexal mass.

Serum soluble Fas levels in ovarian cancer.

Objective To determine the value of serum soluble Fas levels as a prognostic marker for survival of women with ovarian cancer and as a discriminator between benign and malignant adnexal masses. Methods Serum soluble Fas levels were measured with an enzyme-linked immunosorbent assay in 52 women with ovarian cancer, 30 women with benign ovarian cysts, and 35 healthy women. Results Median serum soluble Fas levels in women with ovarian cancer, women with benign ovarian cysts, and healthy women were 3.7 (range 1.6–14.5), 2.3 (range 1.3–4.1), and 1.5 ng/mL (range 0.1–5.6), respectively (P < .001). A univariate logistic regression model showed a significant influence of serum soluble Fas and CA 125 levels on the odds of presenting with ovarian cancer versus benign cysts (P < .001 and P = .001, respectively). In a multivariable logistic regression model for soluble Fas and CA 125, both markers showed a statistically significant influence on the odds of presenting with ovarian cancer versus benign cysts (P = .01 and P = .01, respectively). Increased pretreatment serum soluble Fas levels were associated with shortened disease-free and overall survival (P = .002 and P = .001, respectively). A multivariable Cox regression model identified serum soluble Fas levels as a significant prognostic factor for disease-free and overall survival, independent of tumor stage (P = .04 and P = .03, respectively). Conclusion Soluble Fas levels might be useful as a discriminator between benign ovarian cysts and ovarian cancer, adding to the information obtained with the use of the established tumor marker CA 125. Pretreatment serum soluble Fas levels also might be an independent prognostic factor for disease-free and overall survival.

Immunohistochemical and serological evaluation of CD44 splice variants in human ovarian cancer

The surface glycoprotein CD44 is widely distributed in different tissues. In contrast to healthy tissue, tumour samples show a more complex pattern of CD44 expression, indicating a loss of splice control. Beside cell-surface expression, the measurement of soluble CD44 in serum of cancer patients could be useful in early diagnosis and assessment of disease status. We evaluated the surface expression of CD44 isoforms in 22 ovarian cancer patients by means of immunohistochemistry. Additionally, we investigated 134 serological samples of these patients for the occurrence of CD44 isoform expression. For CD44 standard, CD44v5 and CF44v6 mean serum levels in patients with clinically detectable or non-detectable ovarian cancer were 422.4 +/- 143.8 ng ml-1 and 547.4 +/- 148.2 ng ml-1, 12.3 +/- 7.9 ng ml-1 and 21.9 +/- 12.2 ng ml-1 and 105.5 +/- 37.9 ng ml-1 and 144.9 +/- 50.9 ng ml-1 respectively (P-values not significant). CD44 surface proteins containing epitopes encoded by splice variants CD44v5, CD44v6 and CD44v7-8 were immunohistochemically detected in 9% (n = 2), 13% (n = 3) and 4% (n = 1) of the 22 tumour samples respectively. In the present study we showed that in ovarian cancer CD44 isoforms CD44v5 and CD44v6 are expressed in very low amounts by the tumours. In accordance with this, we found that the presence of tumour is not associated with higher serum levels of CD44standard, CD44v5 and CD44v6 in preoperative serum samples in ovarian cancer patients.

Tumor Anemia and Thrombocytosis in Patients with Vulvar Cancer

The aim of our study was to determine the prevalence of tumor anemia and thrombocytosis in patients with vulvar cancer, and to evaluate the prognostic value or pretreatment hemoglobin (Hb) and platelet count regarding disease-free and overall survival of patients with vulvar cancer. We measured pretreatment Hb and platelet count in 62 patients with squamous cell vulvar cancer. The results were correlated to clinical data. Median Hb and platelet count in patients with vulvar cancer were 13.1 g/dl (range 8.3–16.2) and 268,500/μl (range 88,000–778,000), respectively. Cut-off levels of 12 g/dl and 300,000/μl were selected for tumor anemia and tumor thrombocytosis, respectively according to published criteria. Tumor anemia and tumor thrombocytosis were present in 30.6 and 27.4% of patients with vulvar cancer, respectively. In a univariate analysis tumor stage and tumor thrombocytosis were significantly associated with a shortened disease-free (log-rank test, p < 0.001 and p = 0.003, respectively) and overall survival (log-rank test, p < 0.001 and p < 0.001, respectively). Tumor anemia was not associated with a shortened disease-free, but with a shortened overall survival of patients with vulvar cancer (log-rank test, p = 0.1 and p = 0.002, respectively). A multivariate Cox regression model considering tumor stage, tumor anemia, and tumor thrombocytosis showed, however, that pretreatment Hb and platelet count did not confer additional prognostic information to that already obtained by the established prognosticator tumor stage on disease free (multivariate Cox regression model, p = 0.8, p = 0.2, and p = 0.003, respectively) and overall survival (multivariate Cox regression model, p = 0.4, p = 0.5, and p = 0.04, respectively). Pretreatment tumor anemia and tumor thrombocytosis were associated with a poor prognosis, but were not an independent predictor of outcome in patients with vulvar cancer.