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Simple Summary: Cancer antigen 125 (CA-125) is a protein found at a high concentration in the blood of patients with specific types of cancer, mainly ovarian cancer. In 2004, the Gynecologic Cancer Intergroup (GCIG) proposed criteria defining response to treatment, as well as disease progression, based on the CA-125 concentration. Ever since, for the follow-up of ovarian cancer patients, the CA-125 concentration and/or CT-scans are used. This paper aims to compare different summaries of CA-125 evolution in the 3 to 6 months following treatment initiation in newly diagnosed advanced ovarian cancer and explore their prognostic capacity to predict overall survival. Based on individual patient data from the GCIG meta-analysis, we propose the most appropriate timeframe between follow-up and the prediction horizon in order to obtain robust, dynamic, individual predictions. (1) Background: Cancer antigen 125 (CA-125) is a protein produced by ovarian cancer cells that is used for patients' monitoring. However, the best ways to analyze its decline and prognostic role are poorly quantified. (2) Methods: We leveraged individual patient data from the Gynecologic Cancer Intergroup (GCIG) meta-analysis (N = 5573) to compare different approaches summarizing the early trajectory of CA-125 before the prediction time (called the landmark time) at 3 or 6 months after treatment initiation in order to predict overall survival. These summaries included observed and estimated measures obtained by a linear mixed model (LMM). Their performances were evaluated by 10-fold cross-validation with the Brier score and the area under the ROC (AUC). (3) Results: The estimated value and the last observed value at 3 months were the best measures used to predict overall survival, with an AUC of 0.75 CI 95% [0.70; 0.80] at 24 and 36 months and 0.74 [0.69; 0.80] and 0.75 [0.69; 0.80] at 48 months, respectively, considering that CA-125 over 6 months did not improve the AUC, with 0.74 [0.68; 0.78] at 24 months and 0.71 [0.65; 0.76] at 36 and 48 months. (4) Conclusions: A 3-month surveillance provided reliable individual information on overall survival until 48 months for patients receiving first-line chemotherapy. [ABSTRACT FROM AUTHOR]

The study attempts to evaluate and compare the efficacy of neoadjuvant chemotherapy followed by interval debunking surgery as a treatment option in stage IIIC or IV ovarian cancer as against debunking surgery followed by chemotherapy. The results indicate that both forms of treatment had similar outcomes.

Many patients with locally advanced cervical cancer experience recurrence within the radiation field after chemoradiotherapy. Biomarkers of tumor radioresistance are required to identify patients in need of intensified treatment. Here, the biomarker potential of miR-200 family members was investigated in this disease. Also, involvement of tumor hypoxia in the radioresistance mechanism was determined, using a previously defined 6-gene hypoxia classifier. miR-200 expression was measured in pretreatment tumor biopsies of an explorative cohort (n = 90) and validation cohort 1 (n = 110) by RNA sequencing. Publicly available miR-200 data of 79 patients were included for the validation of prognostic significance. A score based on expression of the miR-200a/b/-429 (miR-200a, miR-200b, and miR-429) cluster showed prognostic significance in all cohorts. The score was significant in multivariate analysis of central pelvic recurrence. No association with distant recurrence or hypoxia status was found. Potential miRNA target genes were identified from gene expression profiles and showed enrichment of genes in extracellular matrix organization and cell adhesion. miR-200a/b/-429 overexpression had a pronounced radiosensitizing effect in tumor xenografts, whereas the effect was minor in vitro. In conclusion, miR-200a/b/-429 downregulation is a candidate biomarker of central pelvic recurrence and seems to predict cell adhesion-mediated tumor radioresistance independent of clinical markers and hypoxia. [ABSTRACT FROM AUTHOR]

Abstract 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 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 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.

Background: There is significant evidence that DCE-MRI may have the potential to provide clinically useful biomarkers of the outcome of locally advanced cervical carcinoma. However, there is no consensus on how to analyze DCE-MRI data to arrive at the most powerful biomarkers. The purpose of this study was to analyze DCE-MRI data of cervical cancer patients by using the Brix pharmacokinetic model and to compare the biomarkers derived from the Brix analysis with biomarkers determined by non-model-based analysis [i.e., low-enhancing tumor volume (LETV) and tumor volume with increasing signal (TVIS)] of the same patient cohort. Material and methods: DCE-MRI recordings of 80 patients (FIGO stage IB–IVA) treated with concurrent cisplatin-based chemoradiotherapy were analyzed voxel-by-voxel, and frequency distributions of the three parameters of the Brix model (ABrix, kep, and kel) were determined. Moreover, risk volumes were calculated from the Brix parameters and termed RV-ABrix, RV-kep, and RV-kel, where the RVs represent the tumor volume with voxel values below a threshold value determined by ROC analysis. Disease-free survival (DFS) and overall survival (OS) were used as measures of treatment outcome. Results: Significant associations between the median value or any other percentile value of ABrix, kep, or kel and treatment outcome were not found. However, RV-ABrix, RV-kep, and RV-kel correlated with DFS and OS. Multivariate analysis revealed that the prognostic power of RV-ABrix, RV-kep, and RV-kel was independent of well-established clinical prognostic factors. RV-ABrix, RV-kep, and RV-kel correlated with each other as well as with LETV and TVIS. Conclusion: Strong biomarkers of the outcome of locally advanced cervical carcinoma can be provided by subjecting DCE-MRI series to pharmacokinetic analysis using the Brix model. The prognostic power of these biomarkers is not necessarily superior to that of biomarkers identified by non-model-based analyses. [ABSTRACT FROM AUTHOR]

Background:Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) may provide prognostic biomarkers for cervix carcinoma. We have shown previously that the early phase of the signal intensity-versus-time curve (SITC) may have significant prognostic power. The purpose of the present investigation was to explore the prognostic value of the late phase of the SITC. Material and methods:DCE-MRI data of 80 patients (FIGO stage IB–IVA) treated with concurrent chemoradiotherapy were examined. Four parameters were calculated from the late-phase SITC: tumor volume with decreasing signal, tumor fraction with decreasing signal, tumor volume with increasing signal (TVIS), and tumor fraction with increasing signal. Results:Multivariate analysis involving clinical parameters and late-phase SITC parameters suggested that TVIS is a strong independent prognostic factor for both disease-free and overall survival. When early-phase SITC parameters were included in the multivariate analysis, the early-phase SITC, but not the late-phase SITC, was found to have independent prognostic value. Conclusion:The late-phase SITC can provide prognostic factors for the outcome of cervix carcinoma, that is, a large tumor volume with increasing late-phase SITCs is associated with poor outcome. However, the prognostic power of the late-phase SITC is not as strong as that of the early-phase SITC. [ABSTRACT FROM AUTHOR]

Background: There is a critical need for predictive/resistance biomarkers for VEGF inhibitors to optimise their use.Methods: Blood samples were collected during and following treatment and, where appropriate, upon progression from ovarian cancer patients in ICON7, a randomised phase III trial of carboplatin and paclitaxel with or without bevacizumab. Plasma concentrations of 15 circulating angio-biomarkers were measured using a validated multiplex ELISA, analysed through a novel network analysis and their relevance to the PFS then determined.Results: Samples (n=650) were analysed from 92 patients. Bevacizumab induced correlative relationships between Ang1 and Tie2 plasma concentrations, which reduced after initiation of treatment and remained decreased until progressive disease occurred. A 50% increase from the nadir in the concentration of circulating Tie2 (or the product of circulating Ang1 and Tie2) predicted tumour progression. Combining Tie2 with GCIG-defined Ca125 data yielded a significant improvement in the prediction of progressive disease in patients receiving bevacizumab in comparison with Ca125 alone (74.1% vs 47.3%, P<1 × 10(-9)).Conclusions: Tie2 is a vascular progression marker for bevacizumab-treated ovarian cancer patients. Tie2 in combination with Ca125 provides superior information to clinicians on progressive disease in patients with VEGFi-treated ovarian cancers. [ABSTRACT FROM AUTHOR]

Hypoxia is an adverse factor in cervical cancer, and hypoxia-related gene expression could be a powerful biomarker for identifying the aggressive hypoxic tumors. Reverse transcription quantitative PCR (RT-qPCR) is a valuable method for gene expression studies, but suitable reference genes for data normalization that are independent of hypoxia status and clinical parameters of cervical tumors are lacking. In the present work, we aimed to identify reference genes for RT-qPCR studies of hypoxia in squamous cervical cancer. From 422 candidate reference genes selected from the literature, we used Illumina array-based expression profiles to identify 182 genes not affected by hypoxia in cervical cancer, i.e. genes regulated by hypoxia in eight cervical cancer cell lines or correlating with the hypoxia-associated dynamic contrast-enhanced magnetic resonance imaging parameter ABrix in 42 patients, were excluded. Among the 182 genes, nine candidates (CHCHD1, GNB2L1, IPO8, LASP1, RPL27A, RPS12, SOD1, SRSF9, TMBIM6) that were not associated with tumor volume, stage, lymph node involvement or disease progression in array data of 150 patients, were selected for further testing by RT-qPCR. geNorm and NormFinder analyses of RT-qPCR data of 74 patients identified CHCHD1, SRSF9 and TMBIM6 as the optimal set of reference genes, with stable expression both overall and across patient subgroups with different hypoxia status (ABrix) and clinical parameters. The suitability of the three reference genes were validated in studies of the hypoxia-induced genes DDIT3, ERO1A, and STC2. After normalization, the RT-qPCR data of these genes showed a significant correlation with Illumina expression (P<0.001, n = 74) and ABrix (P<0.05, n = 32), and the STC2 data were associated with clinical outcome, in accordance with the Illumina data. Thus, CHCHD1, SRSF9 and TMBIM6 seem to be suitable reference genes for studying hypoxia-related gene expression in squamous cervical cancer samples by RT-qPCR. Moreover, STC2 is a promising prognostic hypoxia biomarker in cervical cancer. [ABSTRACT FROM AUTHOR]