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Background We evaluated the efficacy and safety of the aromatase inhibitor exemestane in patients with advanced, persistent or recurrent endometrial carcinoma. Methods We performed an open-label one-arm, two-stage, phase II study of 25 mg of oral exemestane in 51 patients with advanced (FIGO stage III-IV) or relapsed endometrioid endometrial cancer. Patients were stratified into subsets of estrogen receptor (ER) positive and ER negative patients. Results Recruitment to the ER negative group was stopped prematurely after 12 patients due to slow accrual. In the ER positive patients, we observed an overall response rate of 10%, and a lack of progression after 6 months in 35% of the patients. No responses were registered in the ER negative patients, and all had progressive disease within 6 months. For the total group of patients, the median progression free survival (PFS) was 3.1 months (95% CI: 2.0-4.1). In the ER positive patients the median PFS was 3.8 months (95% CI: 0.7-6.9) and in the ER negative patients it was 2.6 months (95% CI: 2.1-3-1). In the ER positive patients the median overall survival (OS) time was 13.3 months (95% CI: 7.7-18.9), in the ER negative patients the corresponding numbers were 6.1 months (95% CI: 4.1-8.2). Treatment with exemestane was well tolerated. Conclusion Treatment of estrogen positive advanced or recurrent endometrial cancer with exemestane, an aromatase inhibitor, resulted in a response rate of 10% and lack of progression after 6 months in 35% of the patients. Trial registration Trial identification number (Clinical Trials.gov): NCT01965080. Nordic Society of Gynecological Oncology: NSGO-EC-0302. EudraCT number: 2004-001103-35. [ABSTRACT FROM AUTHOR]

Background: High-resolution magic angle proton magnetic resonance spectroscopy (HR 1H MAS MRS) provides a broad metabolic mapping of intact tumor samples and allows for microscopy investigations of the samples after spectra acquisition. Experimental studies have suggested that the method can be used for detection of apoptosis, but this has not been investigated in a clinical setting so far. We have explored this hypothesis in cervical cancers by searching for metabolites associated with apoptosis that were not influenced by other histopathological parameters like tumor load and tumor cell density. Methods: Biopsies (n = 44) taken before and during radiotherapy in 23 patients were subjected to HR MAS MRS. A standard pulse-acquire spectrum provided information about lipids, and a spin-echo spectrum enabled detection of non-lipid metabolites in the lipid region of the spectra. Apoptotic cell density, tumor cell fraction, and tumor cell density were determined by histopathological analysis after spectra acquisition. Results: The apoptotic cell density correlated with the standard pulse-acquire spectra (p <0.001), but not with the spin-echo spectra, showing that the lipid metabolites were most important. The combined information of all lipids contributed to the correlation, with a major contribution from the ratio of fatty acid -CH2 to CH3 (p =0.02). In contrast, the spin-echo spectra contained the main information on tumor cell fraction and tumor cell density (p < 0.001), for which cholines, creatine, taurine, glucose, and lactate were most important. Significant correlations were found between tumor cell fraction and glucose concentration (p = 0.001) and between tumor cell density and glycerophosphocholine (GPC) concentration (p = 0.024) and ratio of GPC to choline (p < 0.001). Conclusion: Our findings indicate that the apoptotic activity of cervical cancers can be assessed from the lipid metabolites in HR MAS MR spectra and that the HR MAS data may reveal novel information on the metabolic changes characteristic of apoptosis. These changes differed from those associated with tumor load and tumor cell density, suggesting an application of the method to explore the role of apoptosis in the course of the disease. [ABSTRACT FROM AUTHOR]

Background: A better understanding of the development of metastatic disease and the identification of molecular markers for cancer spread would be useful for the design of improved treatment strategies. This study was conducted to identify gene expressions associated with metastatic phenotypes of locally advanced cervical carcinomas and investigate whether gains or losses of these genes could play a role in regulation of the transcripts. Gene expressions and copy number changes were determined in primary tumors from 29 patients with and 19 without diagnosed lymph node metastases by use of cDNA and genomic microarray techniques, respectively. Results: Thirty-one genes that differed in expression between the node positive and negative tumors were identified. Expressions of eight of these genes (MRPL11, CKS2, PDK2, MRPS23, MSN, TBX3, KLF3, LSM3) correlated with progression free survival in univariate analysis and were therefore more strongly associated with metastatic phenotypes than the others. Immunohistochemistry data of CKS2 and MSN showed similar relationships to survival. The prognostic genes clustered into two groups, suggesting two major metastatic phenotypes. One group was associated with rapid proliferation, oxidative phosphorylation, invasiveness, and tumor size (MRPS23, MRPL11, CKS2, LSM3, TBX3, MSN) and another with hypoxia tolerance, anaerobic metabolism, and high lactate content (PDK2, KLF3). Multivariate analysis identified tumor volume and PDK2 expression as independent prognostic variables. Gene copy number changes of the differentially expressed genes were not frequent, but correlated with the expression level for seven genes, including MRPS23, MSN, and LSM3. Conclusion: Gene expressions associated with known metastatic phenotypes of cervical cancers were identified. Our findings may indicate molecular mechanisms underlying development of these phenotypes and be useful as markers of cancer spread. Gains or losses of the genes may be involved in development of the metastatic phenotypes in some cases, but other mechanisms for transcriptional regulation are probably important in the majority of tumors. [ABSTRACT FROM AUTHOR]

Background: The taxanes paclitaxel and docetaxel have traditionally been used in high doses every third week in the treatment of cancer. Lately there has been a trend towards giving weekly low doses to improve the therapeutic index. This article describes the development of high performance liquid chromatographic (HPLC) methods suitable for monitoring taxane levels in patients, focusing on patients receiving low-dose therapy. Methods: Paclitaxel and docetaxel were extracted from human plasma by solid phase extraction, and detected by absorbance at 227 nm after separation by reversed phase high performance liquid chromatography. The methods were validated and their performance were tested using samples from patients receiving paclitaxel or docetaxel. Results: The limits of quantitation were 1 nM for docetaxel and 1.2 nM for paclitaxel. For both compounds linearity was confirmed from the limit of quantitation up to 1000 nM in plasma. The recoveries ranged between 92% and 118% for docetaxel and between 76% and 104% for paclitaxel. Accuracy and precision were within international acceptance criteria, that is within ± 15%, except at the limit of quantitation where values within ± 20% are acceptable. Low-dose patients included in an on going clinical trial had a median docetaxel concentration of 2.8 nM at 72 hours post infusion. Patients receiving 100 mg/m2 of paclitaxel had a mean paclitaxel concentration of 21 nM 48 hours after the end of infusion. Conclusion: We have developed an HPLC method using UV detection capable of quantifying 1 nM of docetaxel in plasma samples. The method should be useful for pharmacokinetic determinations at all relevant doses of docetaxel. Using a similar methodology paclitaxel can be quantified down to a concentration of 1.2 nM in plasma with acceptable accuracy and precision. We further demonstrate that the previously reported negative influence of Cremophor EL on assay performance may be overcome by degradation of the detergent by incubation with lipase. [ABSTRACT FROM AUTHOR]

Background: While numerous studies have characterized primary ovarian tumors, little information is available regarding expression patterns of metastatic sites of this cancer. To define sets of genes that distinguish primary and metastatic ovarian tumors, we used cDNA microarrays to characterize global gene expression patterns in 38 effusions (28 peritoneal, 10 pleural) and 8 corresponding primary ovarian tumors, and searched for associations between expression patterns and clinical parameters. Results: We observed multidimensional variation in expression patterns among the cancers. Coordinate variation in expression of genes from two chromosomal regions, 8q and 19q, was seen in subsets of the cancers indicating possible amplifications in these regions. A set of 112 unique genes of known function was differentially expressed between primary tumors and effusions using supervised analysis. Relatively few differences were seen between effusions isolated from the pleural and peritoneal cavities or between effusions from patients diagnosed with stage III and stage IV cancers. A set of 84 unique genes was identified that distinguished high from lower grade ovarian cancers. The results were corroborated using immunocytochemistry, mRNA in situ hybridization, and immunoblotting. Conclusion: The extensive variation in expression patterns observed underscores the molecular heterogeneity of ovarian cancer, but suggests a similar molecular profile for ovarian carcinoma cells in serosal cavities. [ABSTRACT FROM AUTHOR]

Background: High-resolution magic angle proton magnetic resonance spectroscopy (HR 1H MAS MRS) provides a broad metabolic mapping of intact tumor samples and allows for microscopy investigations of the samples after spectra acquisition. Experimental studies have suggested that the method can be used for detection of apoptosis, but this has not been investigated in a clinical setting so far. We have explored this hypothesis in cervical cancers by searching for metabolites associated with apoptosis that were not influenced by other histopathological parameters like tumor load and tumor cell density., Methods: Biopsies (n = 44) taken before and during radiotherapy in 23 patients were subjected to HR MAS MRS. A standard pulse-acquire spectrum provided information about lipids, and a spin-echo spectrum enabled detection of non-lipid metabolites in the lipid region of the spectra. Apoptotic cell density, tumor cell fraction, and tumor cell density were determined by histopathological analysis after spectra acquisition., Results: The apoptotic cell density correlated with the standard pulse-acquire spectra (p < 0.001), but not with the spin-echo spectra, showing that the lipid metabolites were most important. The combined information of all lipids contributed to the correlation, with a major contribution from the ratio of fatty acid -CH2 to CH3 (p = 0.02). In contrast, the spin-echo spectra contained the main information on tumor cell fraction and tumor cell density (p < 0.001), for which cholines, creatine, taurine, glucose, and lactate were most important. Significant correlations were found between tumor cell fraction and glucose concentration (p = 0.001) and between tumor cell density and glycerophosphocholine (GPC) concentration (p = 0.024) and ratio of GPC to choline (p < 0.001)., Conclusion: Our findings indicate that the apoptotic activity of cervical cancers can be assessed from the lipid metabolites in HR MAS MR spectra and that the HR MAS data may reveal novel information on the metabolic changes characteristic of apoptosis. These changes differed from those associated with tumor load and tumor cell density, suggesting an application of the method to explore the role of apoptosis in the course of the disease.