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BACKGROUND: After transfusion of senescent red blood cells (RBCs) a considerable fraction is rapidly cleared from the recipients' circulation. Thus, transfusion of senescent RBCs may be less effective in terms of increasing hemoglobin concentration (cHb) after transfusion. STUDY DESIGN AND METHODS: Data were retrospectively obtained in patients who underwent major abdominal surgery between 2006 and 2012. Patients were eligible if they received RBCs during surgery and had at least two arterial blood gas analyses performed. The primary endpoint was the increase of recipients' cHb related to the transfusion of 1 unit of RBCs with respect to different storage periods. Four storage periods were defined according to the distribution of RBC storage of the study population. General estimating equation was used for calculation of the primary endpoint and to adjust for confounding variables. RESULTS: A total of 598 arterial blood gas samples from 120 patients, receiving 429 RBC units, were analyzed. Mean (±SD) RBC storage was 21 (±9) days. RBC storage duration and the increase in recipients' cHb were inversely and gradually related; that is, the older the RBCs, the lower the increase in the recipients' cHb after transfusion (storage

Epithelial ovarian cancer (EOC) is the most frequent cause of death from all gynecological malignancies because of its late diagnosis. As N-glycosylation is modified in the course of ovarian cancer, it is a promising source of tumor biomarkers. In this work, serum glycoproteins, depleted from albumin and IgG, were separated by 2DE. Protein spots of acute-phase proteins were identified by peptide mapping and their corresponding glycan moieties were released enzymatically, fluorescently labeled and analyzed by CE-LIF. In the positive acute-phase proteins, haptoglobin, α1-antitrypsin, and α1-antichymotrypsin, an increase of antennarity and Lewis(X) motif could be measured in EOC patients on tri- and/or tetraantennary N-glycans. Tetraantennary N-glycans containing three Lewis(X) epitopes and triantennary N-glycans containing a β(1-6) branch and a Lewis(X) epitope were only present in EOC patients. We also showed for the first time that the core-fucosylated biantennary digalactosylated N-glycan of α1-acid glycoprotein is a potential biomarker for EOC. To conclude, core-fucosylated biantennary N-glycans on α1-acid glycoprotein as well as higher antennarity and increased amounts of Lewis(X) motif on haptoglobin, α1-antitrypsin, and α1-antichymotrypsin are promising biomarkers for EOC. Nevertheless, their specificity and selectivity for the early detection of EOC should be evaluated in a larger study.

Tumor recurrence, following initial response to adjuvant chemotherapy, is a major problem in women with high-grade serous ovarian cancer (HGSOC). Microarray analysis of primary tumors has identified genes that may be useful in risk stratification/overall survival, but are of limited value in predicting the >70% rate for tumor recurrence. In this study, we performed RNA-Seq analysis of primary and recurrent HGSOC to first identify unique differentially expressed genes. From this dataset, we selected 21 archetypical coding genes and one noncoding RNA, based on statistically significant differences in their expression profile between tumors, for validation by qPCR in a larger cohort of 110 ovarian tumors (71 primary and 39 recurrent) and for testing association of specific genes with time-to-recurrence (TTR). Kaplan-Meier tests revealed that high expression of collagen type II, alpha 1 (COL2A1) was associated with delayed TTR (HR = 0.47, 95% CI: 0.27-0.82, p = 0.008), whereas low expression of the pseudogene, solute carrier family 6 member 10 (SLC6A10P), was associated with longer TTR (HR = 0.53, 95% CI: 0.30-0.93, p = 0.027). Notably, TTR was significantly delayed for tumors that simultaneously highly expressed COL2A1 and lowly expressed SLC6A10P (HR = 0.21, 95% CI: 0.082-0.54, p = 0.0011), an estimated median of 95 months as compared to an estimated median of 16 months for subjects expressing other levels of COL2A1 and SLC6A10P. Thus, evaluating expression levels of COL2A1 and SLC6A10P at primary surgery could be beneficial for clinically managing recurrence of HGSOC.

Aim Despite promising preclinical findings regarding clinical utility of farnesyltransferase inhibitors (FTI), such as lonafarnib, success of clinical trials is limited. A multicentre AGO-OVAR-15 phase II trial reported an unfavourable effect of lonafarnib on the outcome of patients with advanced ovarian cancer. This study was performed as a genetic subgroup analysis of the AGO-OVAR-15 trial, and investigated the utility of the promoter polymorphism rs11623866 of the farnesyltransferase s-subunit gene (FNTB) in predicting the clinical effectiveness of lonafarnib. Methods The influence of rs11623866 (c.-609G > C) on FNTB promoter activity was investigated by electrophoretic-mobility-shift assay, luciferase-reporter assay and RT-qPCR. A total of 57 out of 105 patients from the AGO-OVAR-15 trial, treated with carboplatin and paclitaxel ± lonafarnib, was genotyped for rs11623866 by restriction fragment length polymorphism analysis. Genotype-dependent survival analysis was performed by Kaplan–Meier analysis. Results The presence of the G allele was associated with increased FNTB promoter activity compared with the C allele. An unfavourable effect of lonafarnib was limited to patients carrying a GG genotype (HRPFS 6.2, 95%CI = 2.01, 19.41, P = 0.002; HROS 9.6, 95%CI = 1.89, 48.54, P = 0.006). Median progression free survival (PFS) for patients with the GG genotype in the lonafarnib treated arm was 10 months, whereas median PFS without FTI-treatment was 40 months. Median overall survival (OS) in the lonafarnib-treated group was 19 months, whereas median OS was not reached in the untreated group. Conclusions Discrepancies between preclinical success and clinical failure may be due to the patients' genetic variability of FNTB. Therefore, our results may encourage retrospective evaluation of FNTB polymorphisms in previous FTI studies, especially those reporting positive FTI response.

Alterations in IgG N-glycosylation coincide with the development of a number of diseases including cancer and could potentially be used as diagnostic markers. CE-LIF of 8-aminopyrene-1,3,6-trisulfonic acid labeled N-glycans is a well-established rapid method to characterize IgG N-glycans that needs only low amounts of starting material. However,sialylated N-glycans have short migration times due to their negative charge. As a result,some of them are not well resolved and co-migrate with neutral glycans. In this work, we neutralized the negative charge of sialic acids by methylation and optimized the protocol using the commercially available disialylated biantennary oligosaccharide (A2G2S2). IgGN-glycans isolated from healthy human serum were then analyzed using this method. We could demonstrate that co-migration of A2, FA2G2S1, and FA2B[3]G1S1 was prevented,which allowed an accurate quantification of these N-glycans. Finally, we investigated the IgG N-glycan profiles of patients suffering from ovarian cancer using the conventional and methylation methods.With both methods, we observed an increase of agalactosylated structures that was accompanied by a decrease in digalactosylated structures. Finally, using the methylation protocol, we could further demonstrate an increase of A2, which was technically impossible with the conventional method.

FGFR4 has been shown to play an important role in the etiology and progression of solid tumors. A single nucleotide polymorphism (SNP) within the FGFR4 gene has previously been linked to prognosis and response to chemotherapy in breast cancer and other malignancies. This study evaluates the relevance of this SNP in advanced ovarian cancer. FGFR4-genotype was analyzed in 236 patients recruited as part of the OVCAD project. Genotyping was performed on germ-line DNA using a TaqMan based genotyping assay. Results were correlated with clinicopathological variables and survival. The FGFR4 388Arg genotype was significantly associated with prolonged progression-free and overall survival (univariate: HR 0.68, p = 0.017; HR 0.49, p = 0.005; multivariate: HR 0.69, p = 0.025; HR 0.49, p = 0.006) though the positive prognostic value was restricted to patients without postoperative residual tumor. Indeed, there was a significant interaction between FGFR4 genotype and residual tumor for overall survival. Furthermore, the FGFR4 388Arg genotype significantly correlated with platinum sensitivity in the same subgroup (multivariate OR 3.81 p = 0.004). FGFR4 Arg388Gly genotype is an independent and strong context specific prognostic factor in patients with advanced ovarian cancer and could be used to predict platinum-sensitivity.

Sinn B V, Darb-Esfahani S, Wirtz R M, Budczies J, Sehouli J, Chekerov R, Dietel M & Denkert C (2011) Histopathology 59, 918–927 Evaluation of a hormone receptor-positive ovarian carcinoma subtype with a favourable prognosis by determination of progesterone receptor and oestrogen receptor 1 mRNA expression in formalin-fixed paraffin-embedded tissue Aims: In vitro and epidemiological studies indicate an essential role for progesterone in the aetiology and progression of ovarian carcinoma. The aim of this study was to examine the prognostic role of progesterone receptor (PR) protein and mRNA expression. Methods and results: PR expression was examined by immunohistochemistry (n = 143) and kinetic reverse transcription–polymerase chain reaction (RT–PCR) from formalin-fixed and paraffin-embedded tissue (n = 55). PR mRNA and protein expression correlated (P

Background and Objectives In contrast to primary ovarian cancer, the value of surgery in relapsed-OC (ROC) remains unclear. We evaluated surgical and clinical outcome of secondary cytoreduction in ROC. Methods All consecutive ROC patients who underwent secondary tumor-debulking surgery were systematically analyzed as based on a validated intraoperative documentation tool. Tumor dissemination pattern, operative and clinical outcome were evaluated. Cox-regression analysis was performed to identify independent predictors of mortality. Results Between 09/2000 and 10/2008, 240 operations were evaluated; 184 patients (81.1%) were platinum-sensitive and 43 (20%) platinum-resistant. 47.5% of the patients had ascites, while 85.8% presented a multifocal tumor dissemination pattern. In 53.8% a complete tumor resection was achieved; in another 24.2%, postoperative tumor residuals were 500 ml (HR: 6.76; 95% CI: 3.77–12.1), platinum resistance (HR: 3.1; 95% CI: 1.26–7.7), and initial FIGO stage IV (HR: 2.86; 95% CI: 1.16–7) were the most significant risk factors for mortality. Median OS was 42.3 months (95% CI: 24.37–60.2); 17.7 months (95% CI: 12.27–23.13); and 7.7 months (95% CI: 3.1–12.3) for patients with complete tumor resection, tumor residuals ≤1 and >1 cm, respectively (trend P-value

Darb-Esfahani S, Sinn B V, Weichert W, Budczies J, Lehmann A, Noske A, Buckendahl A-C, Muller B M, Sehouli J, Koensgen D, Gyorffy B, Dietel M & Denkert C (2010) Histopathology 56. 727–739 Expression of classical NF-κB pathway effectors in human ovarian carcinoma Aims: Functional studies have demonstrated that nuclear factor (NF)-κB promotes tumour progression in ovarian cancer cells. However, surprisingly little is known of the expression of effectors of the NF-κB pathway in human ovarian cancer in vivo. Methods and results: Immunohistochemistry and in situ hybridization revealed that in a cohort of 85 primary ovarian carcinomas, total p65 expression was inversely correlated to nuclear and cytoplasmic phospho-IκBα (P = 0.002 and P = 0.05, respectively), and IκBα mRNA expression (P = 0.032). In contrast, phospho-p65 expression was paralleled by the expression of nuclear (P = 0.027) and cytoplasmic phospho-IκBα (P = 0.01). Total p65 expression was an adverse prognostic factor for overall survival (P = 0.018). In contrast, total IκBα and phosphorylated nuclear and cytoplasmic IκBα expression were favourable prognostic markers (P = 0.001, P = 0.031, P = 0.001, respectively). Cytoplasmic phospho-IκBα expression remained a significant prognostic factor on multivariate analysis (P = 0.010). In cultured, stimulated OVCAR-3 ovarian cancer cells the cytoplasmic retranslocation of p65 was delayed by inhibition of the nuclear membrane transporter chromosomal region maintenance/exportin1 protein (CRM1). A positive association of p65 and CRM1 expression was demonstrated in ovarian cancer tissue (P

MicroRNA (miRNA) deregulation is a hallmark of human cancer. However, the mechanisms underlying miRNA alteration and the specific role of proteins involved in miRNA processing remains to be elucidated. Dicer is a key enzyme in the miRNA processing pathway that is essential for the production of mature miRNAs from their precursors. We tested the hypothesis that Dicer has biological and clinical relevance in ovarian cancer, using a range of methods including in vitro manipulation of Dicer expression. We observed down-regulation of Dicer in a subgroup of ovarian carcinomas, and found that decreased Dicer expression correlates significantly with reduced patient survival in serous cancers and advanced disease stages. Moreover, microarray and functional analysis suggest that reduced Dicer expression is connected with a global down-regulation of the microRNAome and with gene expression changes, particularly reduced expression of oestrogen receptor (ER) mRNA and protein in tumour tissue and in cell culture. Our data suggest a common mechanism for miRNAs changes by alterations in the basic machinery controlling miRNA biogenesis, of which Dicer is a central enzyme. These alterations of miRNA processing are of prognostic value and may play a role in the molecular pathogenesis of ovarian carcinoma and, possibly, other tumours. Knowledge of these molecular pathways may help toward new targeted therapeutic approaches for ovarian cancer.

Evidence indicates that acquired resistance of cancers to chemotherapeutic agents can occur via epigenetic mechanisms. Down-regulation of expression of argininosuccinate synthetase (ASS1), the rate-limiting enzyme in the biosynthesis of arginine, has been associated with the development of platinum resistance in ovarian cancer treated with platinum-based chemotherapy. The aim of the present study was to analyse epigenetic regulation of ASS1 in ovarian cancer tissue taken at diagnosis and relapse and determine its significance as a predictor of clinical outcome in patients treated with platinum-based chemotherapy. In addition, expression and epigenetic regulation of ASS1 were analysed in human ovarian cancer cell lines, and ASS1 expression correlated with the ability of the lines to grow in media containing cisplatin, carboplatin or taxol or in arginine-depleted media. Our results show that aberrant methylation in the ASS1 promoter correlated with transcriptional silencing in ovarian cancer cell lines. ASS1 silencing conferred selective resistance to platinum-based drugs and conferred arginine auxotrophy and sensitivity to arginine deprivation. In ovarian cancer, ASS1 methylation at diagnosis was associated with significantly reduced overall survival (p = 0.01) and relapse-free survival (p = 0.01). In patients who relapse, ASS1 methylation was significantly more frequent at relapse (p = 0.008). These data establish epigenetic inactivation of ASS1 as a determinant of response to platinum chemotherapy and imply that transcriptional silencing of ASS1 contributes to treatment failure and clinical relapse in ovarian cancer. The collateral sensitivity of cells lacking endogenous ASS1 to arginine depletion suggests novel therapeutic strategies for the management of relapsed ovarian cancer.

Ovarian carcinoma has the highest mortality rate among gynaecological malignancies. In this project, we investigated the hypothesis that molecular markers are able to predict outcome of ovarian cancer independently of classical clinical predictors, and that these molecular markers can be validated using independent data sets. We applied a semi-supervised method for prediction of patient survival. Microarrays from a cohort of 80 ovarian carcinomas (TOC cohort) were used for the development of a predictive model, which was then evaluated in an entirely independent cohort of 118 carcinomas (Duke cohort). A 300-gene ovarian prognostic index (OPI) was generated and validated in a leave-one-out approach in the TOC cohort (Kaplan-Meier analysis, p = 0.0087). In a second validation step, the prognostic power of the OPI was confirmed in an independent data set (Duke cohort, p = 0.0063). In multivariate analysis, the OPI was independent of the post-operative residual tumour, the main clinico-pathological prognostic parameter with an adjusted hazard ratio of 6.4 (TOC cohort, CI 1.8-23.5, p = 0.0049) and 1.9 (Duke cohort, CI 1.2-3.0, p = 0.0068). We constructed a combined score of molecular data (OPI) and clinical parameters (residual tumour), which was able to define patient groups with highly significant differences in survival. The integrated analysis of gene expression data as well as residual tumour can be used for optimized assessment of the prognosis of platinum-taxol-treated ovarian cancer. As traditional treatment options are limited, this analysis may be able to optimize clinical management and to identify those patients who would be candidates for new therapeutic strategies.

Aims: Multidrug resistance is a major impediment in chemotherapeutic treatment of ovarian carcinoma patients. The aim of this study was to investigate the expression of multidrug resistance-associated protein 1 (MRP1) and to assess the possible associations with clinicopathological variables and patient outcome in primary ovarian carcinoma. Methods and results: Tumour specimens from 129 patients were obtained before chemotherapy and analysed by immunohistochemistry on tissue microarrays, and by real-time reverse transcriptase-polymerase chain reaction on RNA extracted from formalin-fixed paraffin-embedded tissue specimens using a new technique. Significantly increased MRP1 protein expression was observed in high-grade tumours (P = 0.005) and advanced International Federation of Gynaecology and Obstetrics stages (P = 0.036). On univariate Kaplan–Meier analysis, patients with higher expression of MRP1 protein had significantly decreased overall survival (P = 0.006). On multivariate Cox regression analysis, MRP1 protein expression retained its significance as an independent negative prognostic marker for overall survival (hazard ratio = 6.52, P = 0.003). Furthermore, MRP1 expression correlated with topoisomerase IIα expression both at mRNA and protein level (P

Introduction We performed a systematic evaluation of tumor pattern and surgical outcome in 214 consecutive patients with primary ovarian cancer. Methods Based on the surgical and histological reports we retrospectively analyzed tumor localizations, surgical and clinical outcome. Cox-regression analysis was performed to identify independent predictors of complete tumor resection and mortality. Results Median age was 57.7 years (range: 20–88). FIGO-stage-I was classified in 8.4% and IV in 16.4% of all patients. The peritoneum was the structure most affected (76%) followed by the colon (52%) and diaphragm (44%). Upper abdominal tumor involvement was associated with a significantly higher rate of lymph node metastasis and a significantly lower rate of complete surgical tumor resection, when compared to patients with tumor limited to the lower abdomen. Median overall survival was 56; 61 and 27 months for patients with tumor load in the upper, lower and whole abdomen respectively (P

Background and Objectives The value of liver resection for metastases from breast cancer is still controversial. This study was conducted to clarify safety and effectiveness of hepatectomy in this conditions and to identify selection criteria for patients suitable for liver resection. Methods From January 1988 to December 2006, 39 patients underwent liver resection for metastases from breast cancer. The outcome of these 39 patients was retrospectively reviewed using a prospective database. Prognostic factors for patient survival were determined by univariate and multivariate analysis. Results None of the patients died perioperatively and the morbidity rate was 13% (n = 5). The overall 1-, 3-, and 5-year survival rates were 77%, 50%, and 42%, respectively. In the univariate analysis, metastatic manifestation prior to hepatectomy, vascular invasion and resection margin revealed statistically significant influence on survival. The multivariate analysis identified only resection margin as an independent prognostic factor for survival. Conclusions Liver resection should be considered in the multimodal treatment approach of patients with metastatic breast cancer. Hepatic resection can be performed with low risk and offers a chance of long-term survival. Achievement of a curative resection and less important absence of previous metastatic manifestation represent suitable criteria to select patients for liver resection. J. Surg. Oncol. 2008;97:25–29. © 2007 Wiley-Liss, Inc.

Background: The goal of this study was to determine whether multivisceral surgery for advanced primary or recurrent gynaecological malignancies has prognostic implications with regard to operative features, morbidity, quality of life, and survival. Methods: Between January 1991 and January 2000, we treated 48 patients suffering from advanced gynaecological tumours (except ovarian cancer) with 60 ultraradical surgical procedures. The most common indication for operation was recurrent cervical cancer (75%). Results: Macroscopically tumour-free situation (29%) after surgery represents the most important prognostic parameter. In our study, these patients and those with residual tumours of less than 2 cm in diameter (34%) had a median survival time of 12 months; those with a larger lesion (32%), only 5.5 months. The postoperative complications are representative of those associated with any major cancer operation. Two patients died within 30 days postoperatively. Half of the patients reported a better quality of life. Conclusions: Radical multivisceral surgery is feasible, safe and efficient for primary as well as for recurrent advanced gynaecological malignancies. It is justified also for complications of nonoperative therapy. The survival benefit for those patients in whom optimal surgical cytoreduction has been achieved is evident. Careful patient selection and complete interdisciplinary management are mandatory.

We report a 58-year-old female patient with the suspected diagnosis of ovarian cancer. Upon surgical exploration, examination of the appendix revealed the histological diagnosis of primary mucinous adenocarcinoma. This is an unusual consideration in the differential diagnosis of the ovarian cancer. We discuss the diagnosis, classification and treatment of the cancer of the appendix in relation to ovarian cancer.