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Dirk O Bauerschlag,
Felix Hilpert,
Werner Meier,
Jörn Rau,
Ivo Meinhold-Heerlein,
Nicolai Maass,
Andreas Dubois,
Jalid Sehouli,
Norbert Arnold,
Christian Schem,
Hans-Heinrich Oberg,
Klaus Baumann
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ABSTRACT: In ovarian cancer, new therapeutic strategies are needed because the vast majority of patients develop a recurrence and resistance to platinum derivates. Attached to the AGO-OVAR2.11 study investigating the multityrosine kinase inhibitor sunitinib in recurrent platinum refractory ovarian cancers, this translational research project assesses the potential value of serum vascular endothelial growth factor (VEGF), soluble VEGF receptor-3 (sVEGFR-3), and angiopoietin-2 (Ang-2) levels for progression-free survival (PFS).
Longitudinal serum samples were taken while the patient was on study drugs. Serum concentration of VEGF, sVEGFR-3, and Ang-2 was determined by ELISA. The slope of the markers was correlated to the PFS.
Patients showing a decrease in VEGF concentration had a median PFS of 10.5 months [confidence interval (CI), 2.89-12.25] compared to 2.9 months (CI, 1.48-5.32) in the case of an increase (P = .17). The stratified log-rank test showed a trend for longer PFS if a decrease of Ang-2 was observed (P = .089). Dichotomized in absolute decrease or increase, the PFS was 8.4 months (CI, 2.89-12.26) versus 2.7 months (CI, 1.05-5.32), respectively. Patients with a reduction of the sVEGFR-3 concentration had a median PFS of 4.76 months (CI 2.86-10.65) versus 8.61 months (CI, 1.05-not estimable) in patients with an increase of sVEGFR-3. This observation was statistically not significant in the log-rank test (P = .81).
Ang-2 could potentially identify a patient population that might have a better PFS when under anti-angiogenic treatment, like the tyrosine kinase inhibitor sunitinib.
Translational oncology 06/2013; 6(3):305-10. · 3.40 Impact Factor
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Dirk Bauerschlag,
Karen Bräutigam,
Roland Moll,
Jalid Sehouli,
Alexander Mustea,
Darius Salehin,
Maryla Krajewska,
John C Reed,
Nicolai Maass,
Garret M Hampton,
Ivo Meinhold-Heerlein
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ABSTRACT: PURPOSE: Cancer of the ovary confers the worst prognosis among women with gynecological malignancies, primarily because most ovarian cancers are diagnosed at late stage. Hence, there is a substantial need to develop new diagnostic biomarkers to enable detection of ovarian cancer at earlier stages, which would confer better prognosis. In addition, the identification of druggable targets is of substantial interest to find new therapeutic strategies for ovarian cancer. METHODS: The expression of 22,500 genes in a series of 67 serous papillary carcinomas was compared with 9 crudely enriched normal ovarian tissue samples by RNA hybridization on oligonucleotide microarrays. Multiple genes with near-uniformly expression were elevated in carcinomas of varying grade and malignant potential, including several previously described genes (e.g., MUC-1, CD9, CD24, claudin 3, and mesothelin). We performed immunohistochemical staining with antibodies against several of the proteins encoded by differentially expressed genes in an independent cohort of 71 cases of paraffin-embedded ovarian cancer samples. RESULTS: We found striking differences in EpCAM (p < 0.005), CD9 (p < 0.001), MUC-1 (p < 0.001), and claudin 3 proteins (p < 0.001) but not for mesothelin (p > 0.05) using the Mann-Whitney U test. CONCLUSIONS: Protein expression of a majority of the differentially expressed genes tested was found to be elevated in ovarian carcinomas and, as such, define potential new biomarkers or targets.
Journal of Cancer Research and Clinical Oncology 10/2012; · 2.56 Impact Factor
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ABSTRACT: Ovarian cancer patients often suffer from malignant ascites and pleural effusion. Apart from worsening the outcome, this condition frequently impairs the quality of life in patients who are already distressed by ovarian cancer. This study investigated whether single intraperitoneal administration of the anti-VEGF antibody bevacizumab is capable of reducing the ascites-related body surface and prolonging survival. The study was performed in an orthotopic murine model of peritoneal disseminated platin-resistant ovarian cancer. Mice were treated with bevacizumab and/or paclitaxel or buffer (control). Reduction of body surface and increased survival rates were assessed as therapeutic success. Survival of mice in all treatment groups was significantly enhanced when compared to the non-treatment control group. The combination of paclitaxel plus bevacizumab significantly improved body surface as well as overall survival in comparison to a treatment with only one of the drugs. Treatment of malignant effusion with a single dose of bevacizumab as an intraperitoneal application, with or without cytostatic co-medication, may be a powerful alternative to systemic treatment.
Oncology letters 03/2012; 3(3):530-534. · 0.11 Impact Factor
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ABSTRACT: Targeted oncolytic adenoviruses capable of replication selectively in cancer cells are an appealing approach for the treatment of various cancer types refractory to conventional therapies. The aim of this study was to evaluate the effect of Ad5/3MDR1E1, a multidrug resistance gene 1 (MDR1)-targeted fiber-modified replication-competent adenovirus for the therapy of platinum-pretreated ovarian cancer in combination with cytostatic agents.
MDR1-specific tumor cell killing of Ad5/3MDR1E1 was systematically evaluated in chemotherapy naïve and pretreated ovarian cancer cells in vitro. Combinations of Ad5/3MDR1E1 and cytostatic agents were studied in vivo and in vitro. An in vivo hepatotoxicity model was used to evaluate liver toxicity.
We demonstrate efficient oncolysis of Ad5/3MDR1E1 in chemotherapy-resistant ovarian cancer cells as well as therapeutic efficacy in an orthotopic mouse model. Further, combining Ad5/3MDR1E1 with paclitaxel resulted in greater therapeutic benefit than either agent alone.
These preclinical data suggest that a fiber-modified adenovirus vector under the control of the MDR1 promoter represents a promising treatment strategy for platinum-pretreated ovarian cancer as a single agent or in combination with conventional anticancer drugs.
Journal of Cancer Research and Clinical Oncology 01/2012; 138(4):603-10. · 2.56 Impact Factor
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ABSTRACT: Objective. Case report of a 35-year-old gravida 3, para 2, at 40 + 6 weeks with massive respiratory dysfunction with need of oxygenation, requiring cesarean section. Case Report. Postpartum investigations revealed pathological cardiomegaly with left ventricular failure (NYHAIV). Cardiac biopsy diagnosed postpartum dilatative cardiomyopathy. Despite medication with bromocriptine and levosimendan, cardiac function continued to decrease, requiring surgical intervention and implantation of an intracorporal, left ventricular assist device. Following surgery, cardiac function progressively improved and stabilized. Objective. Peripartum cardiomyopathy (PPCM) is a rare, pregnancy-induced disease and requires an interdisciplinary approach for diagnostics and therapeutical treatment.
Hypertension in Pregnancy 01/2012; 31(4):451-3. · 1.69 Impact Factor
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ABSTRACT: To evaluate the oxidative state of lipoproteins in pregnancies complicated by intrauterine growth restriction (IUGR) in comparison to preeclampsia (PE) and healthy pregnant control subjects (CN).
Maternal serum of 20 PE, 29 IUGR, and 29 gestational age-matched CN were analyzed. Total cholesterol (TC), low-density lipoprotein (LDL)-bound cholesterol (LDL-C), and oxidized LDL (oxLDL) concentration were measured once between 25 and 34 weeks of gestation. Statistical estimates were performed by Student's t-test.
Serum concentrations of LDL-C and TC were significantly reduced in IUGR [LDL-C: CN - mean = 146 mg/dL, SD = ± 40.1; IUGR - mean = 102 mg/dL, SD = ± 27.3 (p < 0.0001); PE - mean = 130 mg/dL, SD = 38.8 mg/dL; TC: CN - mean = 259/dL, SD = ± 46.8; IUGR - mean = 218 mg/dL, SD = ± 35.0 (p < 0.001); PE - mean = 244 mg/dL, SD = 48.2]. There was no significant difference in oxLDL/LDL-C ratio within the three groups (CN: mean = 0.76, SD = 0.24; IUGR: mean = 0.74, SD = 0.12; PE: mean = 0.77, SD = 0.22).
Our results show a lower maternal LDL-C and TC concentration in IUGR pregnancies. These data contribute to the hypothesis of a decreased cholesterol supply to the fetus in IUGR. However, we could not confirm the hypothesis of an altered oxidative state in neither IUGR nor PE.
Hypertension in Pregnancy 01/2011; 31(1):156-65. · 1.69 Impact Factor
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ABSTRACT: Paraneoplastic syndromes (PNS) are a heterogeneous group of symptoms which are indirectly caused by primary or metastatic tumor. Paraneoplastic polyneuropathy (PNP) is mostly related to small cell lung cancer (5%), prostate, gastric, and breast cancer. Only sporadic cases have been reported to be associated with endometrial cancer. We present a case of a premenopausal woman with severe vasculitic, asymmetric sensorimotor polyneuropathy that developed in conjunction with an endometrial carcinoma responding to surgical therapy of primary tumor combined to steroid therapy. Neurological symptoms such as asymmetrical sensorimotor deficits and painful paresthesias are suspicious when they occur in otherwise healthy women with no medical history. The phenomenon of a paraneoplastic syndrome can point to an underlying malignancy and can be used as marker of progression or regression of the tumor. Due to the rarity of PNP, there is no standard treatment. Recommended therapy is stage-adjusted treatment of the primary tumor.
Case reports in obstetrics and gynecology. 01/2011; 2011:968756.
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ABSTRACT: BACKGROUND: Calpains (CAPN) are intracellular, non-lysosomal cytoplasmic cysteine endopeptidases and they are expressed ubiquitously. Their endogenous specific inhibitor is calpastatin. When calcium is present, calpastatin and calpain attach to each other, inhibiting the protease. The calpain system plays an important role in many processes including apoptosis, necrosis, ischaemia and exocytosis. The role of calpains in pathogenesis or further tumour progression has been proved in related studies. This study focused on the expression of the enzymes calpain 1, calpain 2 and the inhibitor calpastatin in normal and malignant endometrial tissue. MATERIALS AND METHODS: Immunohistochemical stainings were performed on paraffin slices and staining intensity, percentage of positive cells and international ratio score were evaluated. Results and conclusion: The endometrial carcinoma showed a higher expression of calpastatin than benign endometrial tissue.
Anticancer research 07/2010; 30(7):2837-43. · 1.73 Impact Factor
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ABSTRACT: In advanced ovarian cancers (OCs), p53 mutations are frequently observed. The objective of this study was to explore the value of the p53 mutational status, using four different techniques, in advanced OC patients as a predictive marker for responsiveness to platinum-based chemotherapy.
One hundred and four, mostly serous papillary OC specimens were analyzed, of which all received a platinum containing chemotherapy after optimal cyto-reductive surgery. To verify the p53 mutational status, immunohistochemical staining with monoclonal antibodies, functional yeast assay (FASAY), single-strand conformation polymorphism analysis (SSCP) and genomic sequencing was performed in parallel.
Out of ten OC patients [2 low malignant potential (LMP)/8 G1] only two had a mutant p53, whereas eight showed a wild-type p53. 40 out of 63 (G2/3) patients with G2/3 OC showed mutant p53 and 23 patients showed a wild-type pattern. p53 status was significantly different between these two groups (LMP/G1 vs. G2/3) (P = 0.015). A progressive disease after chemotherapy completion was noted in 35.6% of the patients (26 out of 73); in 69.2%, a mutated p53 and in 30.8%, a wild-type p53 was found. Nine (12.3%) patients showed a complete response at the end of the first-line chemotherapy. Out of these nine patients five had a mutated and four a wild-type p53. A partial response was observed in nine (12.3%) patients of whom four had a mutated p53. With respect to response to first-line chemotherapy (six cycles of platinum containing regimen), the p53 status was not predictive; no statistical significance regarding the p53 mutational status was observed when the two extreme groups PD versus PR/CR were compared (P > 0.05).
In this study, the p53 mutational status was not predictive for responsiveness to platinum-based chemotherapy; but p53 was significantly more frequently mutated in poorly differentiated OCs.
Journal of Cancer Research and Clinical Oncology 07/2009; 136(1):79-88. · 2.56 Impact Factor
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ABSTRACT: Leiomyomatosis peritonealis disseminata (LPD) is a rare disease occurring as intraabdominal benign tumors. The underlying mechanism of LPD development in premenopausal females is still unknown, but high levels of estrogen and progesterone seem to play a major role.
We present a case of a 29-year-old gravida 1, 22 6/7 weeks of gestation with symptoms of an acute abdomen. Abdominal ultrasound and MRI showed intraabdominal masses of uncertain origin most likely to be an extreme example of pseudomyxoma peritonei. Explorative laparotomy was performed, and histopathological analysis revealed benign tumors classified as leiomyomatosis. A cesarean section was performed due to increasing abdominal pain and excessive elevated inflammatory serum parameters. Postpartum, a spontaneous regression of the LPD was marked.
LPD is a rare disease of young women. Excessive hormonal exposure seems to play a major role. Diagnosis is often difficult and a histopathological analysis is needed.
Archives of Gynecology 05/2009; 281(1):123-7. · 0.91 Impact Factor
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ABSTRACT: Sentinel lymph node (SN) biopsy is part of the staging procedure in breast cancer patients. In this study, we compared an intraoperative tool named one-step nucleic acid amplification (OSNA) to our routine histological investigation. OSNA consists of a short homogenization step followed by amplification of cytokeratin (CK) 19 mRNA directly from the lysate. To evaluate the performance of OSNA in comparison to histology, analysis of 343 axillary lymph nodes (ALN) from 93 breast cancer patients was performed with both methods. Discordant samples were subjected to other methods. If these tests supported the OSNA results, these samples were excluded from the study. The concordance rate was 91.8%, sensitivity 98.1%, and specificity 90.8% before and 95.5%, 100%, and 95.6%, respectively, after discordant case investigation. Our results show that OSNA is an excellent method for the detection of metastases in lymph nodes and can be applied as an intraoperative diagnostic approach.
Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 01/2009; 454(2):203-10. · 2.49 Impact Factor
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ABSTRACT: Vital twin tubal gestation is a rare complication in pregnancy.
An asymptomatic gravida 1 female presented with increasing beta-HCG levels without an intrauterine gestation. Doppler sonography revealed cardiac motion of unilateral tubal twins. The patient was treated laparoscopically by partial tubectomy allowing a subsequent tubal re-anastomosis.
Doppler sonography may detect vital ectopic pregnancies early enabling fertility-conserving surgery.
Archives of Gynecology 06/2008; 279(1):87-90. · 0.91 Impact Factor
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ABSTRACT: Imatinib is a small molecule inhibiting the tyrosine kinases bcr-abl, c-kit, PDGFR-alpha and PDGFR-beta. Investigations were performed to screen ovarian cancer cell lines and tumor samples for target receptor expression. Effects of Imatinib on cell proliferation and apoptosis induction were measured with and without additional cytotoxic agents.
Expression patterns of abl, c-kit, PDGFR-alpha and PDGFR-beta (Imatinib targets) were studied in 5 cell lines and 111 tissue arrays by PCR and immunohistochemistry. Proliferation assays were performed with single agent Imatinib or combined with Paclitaxel and Carboplatin. Apoptosis was measured by DNA fragmentation.
All cell lines expressed abl and PDGFR-beta. C-kit was only expressed in 2/5 cell lines and PDGFR-alpha in 4/5. Imatinib reduced cell growth and lead to pro-apoptotic changes. Combination of Carboplatin, Paclitaxel and Imatinib showed synergistic activity.
Our results suggest that Imatinib may be useful for the specific treatment of ovarian cancer as an add-on to conventional chemotherapy.
Journal of Cancer Research and Clinical Oncology 06/2008; 134(12):1397-405. · 2.56 Impact Factor
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Ivo Meinhold-Heerlein, Dirk Bauerschlag,
Yingyao Zhou,
Lisa M Sapinoso,
Keith Ching,
Henry Frierson,
Karen Bräutigam,
Jalid Sehouli,
Elmar Stickeler,
Dominique Könsgen,
Felix Hilpert,
Constantin S von Kaisenberg,
Jacobus Pfisterer,
Thomas Bauknecht,
Walter Jonat,
Norbert Arnold,
Garret M Hampton
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ABSTRACT: Cancer of the ovary confers the worst prognosis among women with gynecologic malignancies, underscoring the need to develop new biomarkers for detection of early disease, particularly those that can be readily monitored in the blood.
We developed an algorithm to identify secreted proteins encoded among approximately 22,500 genes on commercial oligonucleotide arrays and applied it to gene expression profiles of 67 stage I to IV serous papillary carcinomas and 9 crudely enriched normal ovarian tissues, to identify putative diagnostic markers. ELISAs were used to validate increased levels of secreted proteins in patient sera encoded by genes with differentially high expression.
We identified 275 genes predicted to encode secreted proteins with increased/decreased expression in ovarian cancers (<0.5- or >2-fold, P < 0.001). The serum levels of four of these proteins (matrix metalloproteinase-7, osteopontin, secretory leukoprotease inhibitor, and kallikrein 10) were significantly elevated in a series of 67 independent patients with serous ovarian carcinomas compared with 67 healthy controls (P < 0.001, Wilcoxon rank sum test). Optimized support vector machine classifiers with as few as two of these markers (osteopontin or kallikrein 10/matrix metalloproteinase-7) in combination with CA-125 yielded sensitivity and specificity values ranging from 96% to 98.7% and 99.7% to 100%, respectively, with the ability to discern early-stage disease from normal, healthy controls.
Our data suggest that this assay combination warrants further investigation as a multi-analyte diagnostic test for serous ovarian adenocarcinoma.
Clinical Cancer Research 02/2007; 13(2 Pt 1):458-66. · 7.74 Impact Factor
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Ivo Meinhold-Heerlein, Dirk Bauerschlag,
Felix Hilpert,
Petre Dimitrov,
Lisa M Sapinoso,
Marzenna Orlowska-Volk,
Thomas Bauknecht,
Tjoung-Won Park,
Walter Jonat,
Anja Jacobsen,
Jalid Sehouli,
Jutta Luttges,
Maryla Krajewski,
Stan Krajewski,
John C Reed,
Norbert Arnold,
Garret M Hampton
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ABSTRACT: Profiles of gene transcription have begun to delineate the molecular basis of ovarian cancer, including distinctions between carcinomas of differing histology, tumor progression and patient outcome. However, the similarities and differences among the most commonly diagnosed noninvasive borderline (low malignant potential, LMP) lesions and invasive serous carcinomas of varying grade (G1, G2 and G3) have not yet been explored. Here, we used oligonucleotide arrays to profile the expression of 12,500 genes in a series of 57 predominantly stage III serous ovarian adenocarcinomas from 52 patients, eight with borderline tumors and 44 with adenocarcinomas of varying grade. Unsupervised and supervised analyses showed that LMP lesions were distinct from high-grade serous adenocarcinomas, as might be expected; however, well-differentiated (G1) invasive adenocarcinomas showed a strikingly similar profile to LMP tumors as compared to cancers with moderate (G2) or poor (G3) cellular differentiation, which were also highly similar. Comparative genomic hybridization of an independent cohort of five LMP and 63 invasive carcinomas of varying grade demonstrated LMP and G1 were again similar, exhibiting significantly less chromosomal aberration than G2/G3 carcinomas. A majority of LMP and G1 tumors were characterized by high levels of p21/WAF1, with concomitant expression of cell growth suppressors, gadd34 and BTG-2. In contrast, G2/G3 cancers were characterized by the expression of genes associated with the cell cycle and by STAT-1-, STAT-3/JAK-1/2-induced gene expression. The distinction between the LMP-G1 and G2-G3 groups of tumors was highly correlated to patient outcome (chi(2) for equivalence of death rates=7.681189; P=0.0056, log-rank test). Our results are consistent with the recent demonstration of a poor differentiation molecular 'meta-signature' in human cancer, and underscore a number of cell-cycle- and STAT-associated targets that may prove useful as points of therapeutic intervention for those patients with aggressive disease.
Oncogene 03/2005; 24(6):1053-65. · 6.37 Impact Factor
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ABSTRACT: Oncogenesis occurs through the acquisition and selection of multiple somatic mutations--each contributing to the growth, survival and spread of the cancer. Key attributes of the malignant phenotype, such as unchecked proliferation and cell survival, can often be "reversed" by the selective diminution of dominant oncogenes by chemical or genetic means (e.g. beta-catenin in colorectal carcinomas; bcr-abl in chronic myelogenous leukemias (CMLs)). These observations suggest that the products of oncogenes, or of secondary genes that mediate and maintain tumor phenotypes, might be revealed through the systematic disruption of each and every gene in tumor-derived cells. Some of these genes may encode proteins amenable to therapeutic intervention, thus fueling the cancer drug discovery process. However, a functional assessment of each known or predicted gene in mammalian cells is a daunting task and represents the rate-limiting step in drug target identification and validation. In this regard, RNA interference (RNAi) by small interfering RNAs (siRNA) holds great promise as the "tool of choice" to mediate the selective attenuation of mammalian gene expression and protein function. Here, we review strategies by which RNAi might be used to determine the genetic alterations that contribute to malignant transformation via large-scale cell-based screens, and propose how this information can be used in conjunction with small molecule screens to identify pathways critical to cancer cell survival.
Seminars in Cancer Biology 09/2003; 13(4):293-300. · 6.47 Impact Factor
