A case-control study on the effect of rhythmic masticatory muscle activity (RMMA) clusters on sleep fragmentation and severity of orofacial muscle pain in sleep bruxism.

Rhythmic masticatory muscle activity (RMMA) is a periodic muscle activity that characterises sleep bruxism (SB) events. These can occur as a single event, in pairs, or in clusters. Since RMMA episodes often occur in clusters and the relevance of this occurrence is unknown, we conducted a study to investigate the effect of RMMA clusters on sleep fragmentation and the severity of orofacial muscle pain. This study involved a secondary analysis using data from 184 adult subjects with orofacial muscle pain who underwent definitive polysomnography (PSG) for sleep bruxism diagnosis. Self-reported orofacial muscle pain (OFMP) was assessed using the numeric rating scale, and additional evaluation of side-to-side equivalence (symmetry) was described using a binary system. Among the 184 participants, 60.8% (n = 112) did not exhibit clusters and among the 72 participants with clusters, 36.1% (n = 26) and 63.9% (n = 46) were in the high and low RMMA frequency groups, respectively. The high SB group had significantly three times more phasic RMMA events than the noncluster group. A total of 89.67% (n = 165) of subjects reported orofacial muscle pain. While there was no difference in the severity of OFMP among groups, a significant decrease in symmetry between the severity of temporal muscle pain on the left and right sides was noted in the cluster group compared with the noncluster group. Clustering of RMMA events is associated with sleep fragmentation. The asymmetry of temporal muscle pain is related to the presence of RMMA clusters in sleep bruxism.

COX-2 expression pattern is related to ovarian cancer differentiation and prognosis, but is not consistent with new model of pathogenesis.

OBJECTIVE: Numerous studies suggest that cyclooxygenase-2 (COX-2) is overexpressed in cancer. Our objective was to investigate the relationship between COX-2 expression in ovarian carcinoma and clinicopathological factors. An emphasis was put on the association with the new pattern of tumorigenesis that divides tumors into type I--less aggressive, and type II--more aggressive one. The prognostic significance of COX-2 expression was evaluated. METHODS: Ovarian cancer tissues were obtained from 65 patients in FIGO III stage (23 with type I and 42 with type II ovarian cancer). COX-2 expression was evaluated by immunohistochemistry. The statistical analysis was performed in order to assess the connection between COX-2 expression and characteristic factors of ovarian cancer patients as well as the new division for type I and type II ovarian cancer RESULTS: COX-2 expression was detected in 91% of tissue samples. It was markedly elevated in well differentiated tumors (p = 0.0041). The platinum-resistant tumors had significantly higher expression of COX-2 (p = 0.0337). There was no difference between COX-2 expression in type I and type II ovarian cancer (p = 0.6720). The COX-2 staining was not associated to age, CA125 level, the presence of ascites or any special histological type. An increased expression of COX-2 was an unfavorable prognostic factor for overall survival (p = 0.0369) and progression-free survival (p = 0.0218). Multivariate analysis confirmed that COX-2 overexpression is an independent unfavorable prognostic factor of shorter progression-free survival (p = 0.048). CONCLUSIONS: COX-2 expression is an unfavorable prognostic factor for progression-free survival and overall survival in ovarian cancer There is no relationship between COX-2 expression in ovarian cancer tissue and the examined model of ovarian cancer pathogenesis.

YB-1 dependent oncolytic adenovirus efficiently inhibits tumor growth of glioma cancer stem like cells.

BACKGROUND: The brain cancer stem cell (CSC) model describes a small subset of glioma cells as being responsible for tumor initiation, conferring therapy resistance and tumor recurrence. In brain CSC, the PI3-K/AKT and the RAS/mitogen activated protein kinase (MAPK) pathways are found to be activated. In consequence, the human transcription factor YB-1, knowing to be responsible for the emergence of drug resistance and driving adenoviral replication, is phosphorylated and activated. With this knowledge, YB-1 was established in the past as a biomarker for disease progression and prognosis. This study determines the expression of YB-1 in glioblastoma (GBM) specimen in vivo and in brain CSC lines. In addition, the capacity of Ad-Delo3-RGD, an YB-1 dependent oncolytic adenovirus, to eradicate CSC was evaluated both in vitro and in vivo. METHODS: YB-1 expression was investigated by immunoblot and immuno-histochemistry. In vitro, viral replication as well as the capacity of Ad-Delo3-RGD to replicate in and, in consequence, to kill CSC was determined by real-time PCR and clonogenic dilution assays. In vivo, Ad-Delo3-RGD-mediated tumor growth inhibition was evaluated in an orthotopic mouse GBM model. Safety and specificity of Ad-Delo3-RGD were investigated in immortalized human astrocytes and by siRNA-mediated downregulation of YB-1. RESULTS: YB-1 is highly expressed in brain CSC lines and in GBM specimen. Efficient viral replication in and virus-mediated lysis of CSC was observed in vitro. Experiments addressing safety aspects of Ad-Delo3-RGD showed that (i) virus production in human astrocytes was significantly reduced compared to wild type adenovirus (Ad-WT) and (ii) knockdown of YB-1 significantly reduced virus replication. Mice harboring othotopic GBM developed from a temozolomide (TMZ)-resistant GBM derived CSC line which was intratumorally injected with Ad-Delo3-RGD survived significantly longer than mice receiving PBS-injections or TMZ treatment. CONCLUSION: The results of this study supported YB-1 based virotherapy as an attractive therapeutic strategy for GBM treatment which will be exploited further in multimodal treatment concepts.

MRP2 (ABCC2, cMOAT) expression in nuclear envelope of primary fallopian tube cancer cells is a new unfavorable prognostic factor.

OBJECTIVE: To determine the prognostic value of the immunohistochemical evaluation of the multidrug resistance-associated protein 2 (MRP2) expression, together with its subcellular localization in primary fallopian tube carcinomas (PFTCs). METHODS: The immunohistochemical analysis was performed using samples originating from 70 patients with PFTCs. RESULTS: (1) We documented that MRP2 can be localized in the plasma membrane (MRP2c), as well as in the nuclear envelope (MRP2n) of the PFTC cells. (2) Patients with more advanced stage, with progression of the disease and patients who died, showed significantly higher expression of the MRP2n. (3) Univariate and multivariate analyses showed that MRP2n is an unfavorable prognostic factor in PFTCs. (4) The analysis of the classic clinicopathological data revealed that only the FIGO stage had prognostic value, both in the univariate, as well as in multivariate analysis. CONCLUSIONS: (1) This study suggests that MRP2n is a new disadvantageous prognostic factor in PFTCs and (2) that expression in nuclear envelope can be associated with lower differentiation of cancer cells and their resistance to the cisplatin. (3) We have also confirmed independent prognostic value of FIGO stage in PFTCs.

Quercetin inhibits proliferation and increases sensitivity of ovarian cancer cells to cisplatin and paclitaxel.

INTRODUCTION: Due to frequent diagnosis of ovarian cancer at an advanced clinical stage, in most cases surgical debulking is followed by chemotherapy. The principal cause of therapeutic failure involves incomplete surgery and resistance of neoplastic cells to chemotherapy. A search continues for substances which would overcome resistance to treatment and, as a result, would increase efficacy of the applied treatment. Quercetin represents one of more interesting compounds, which at present in subjected to several tests. MATERIAL AND METHODS: Studies were performed on in vitro sensitivity of human ovarian cancer cell lines, SKOV-3, EFO27, OVCAR-3 and A278OP to low doses of quercetin and on the effect exerted by quercetin on sensitivity of the cell lines to cisplatin and pactitaxel. RESULTS: The experiments proved that the studied cells of ovarian cancer manifest a similar sensitivity to quercetin. Following incubation of the cells with two distinct concentrations of quercetin and the studied cytostatic agents all the cells lines were found to significantly increase their sensitivity to pactitaxel in cases of two cell lines, OVCAR-2 and A278OP, they also significantly increased their sensitivity to cisplatin. DISCUSSION: Our results demonstrated suitability of low quercetin doses (achievable using oral administration) as a substance which increases sensitivity of ovarian cancer cells to cisplatin and paclitaxel. The value of quercetin include its wide accessibility efficacy and a broad range of activity but also its low toxicity as compared to other examined compounds. CONCLUSIONS: Used in low doses, quercetin increases chemosensitivity of ovarian cancer cells examined compounds.

Platelet-rich Plasma Stimulates Collagen Type I Synthesis in the Human Skin: A Placebo-controlledin vivo Study.

Platelet-rich plasma (PRP) is used in medicine as a source of autologous growth factors in different indications. At present, PRP is applied increasingly frequently in aesthetic medicine with the aim of skin revitalization. Until now, the mechanisms of PRP effects in healthy human skin treated with aesthetic goals have not been identified in detail. This study aimed to examine PRP effects on the synthesis of procollagen type I in human skin. This study was a prospective, single-center, single-dose, open-label, non-randomized controlled clinical study. The study was conducted on a group of 10 volunteers in whom forearm skin was injected with PRP, while the placebo control group received injections of 0.9% NaCl. Expression of procollagen type I was examined after 21 days using immunohistochemistry. The study demonstrated that skin fragments subjected therapy using PRP demonstrated a significantly higher expression of procollagen than that which was observed in placebo controls. The study demonstrated that PRP stimulated collagen expression in healthy human skin.

[Analysis of BCRP expression in breast cancer patients]. / Analiza ekspresji BCRP u pacjentek z rakiem piersi.

UNLABELLED: Breast cancer resistance protein (BCRP, ABCG2) is a xenobiotic half-transporter protein. It is a member of the ATP-binding cassette protein family and functions as an energy-dependent efflux pump. BCRP is involved in multidrug resistance. The study aimed at examining BCRP expression in breast cancers and at defining a relationship between activity of this protein and clinical course of the cancer. MATERIALS AND METHODS: We analyzed the expression of BCRP in 101 stage II breast cancer patients. All the patients were diagnosed and treated at the Lower Silesia Oncology Centre (LSOC) between January 1993 and June 1994. After the treatment the patients remained under constant control at LSOC. Mean duration of the observation was 14.2 years (ranging between 9.1 and 16.5 years). Data related to relapse of the disease and deaths were obtained from medical documentation stored in LSOC. The immunohistochemical reactions were performed on paraffin sections of primary tumours, using monoclonal antibodies against BCRP. The intensity of immunohistochemical reactions with BCRP antibody was evaluated using the semi-quantitative IRS (ImmunoReactive Score) scale, which took into account the intensity of the colour reaction and percentage of positive cells. Results of the immunohistochemical reactions, pathological and of clinical observations were subjected to statistical analysis. Correlations between these factors and BCRP were analyzed using Spearman and Chi2 tests. In order to estimate the survival rate, we used Kaplan Meier statistics, log-rank tests and Cox proportional hazard regression. RESULTS: In our analysis we observed a positive correlation between the expression of the BCRP protein and grade of tumour advancement (r = 0.2 p = 0.03). We found also a negative correlation between the expression of BCRP and the estrogen (r = 0.24 p = 0.02) and progesteron (r = 0.28 p = 0.02) receptors. In a univariate analysis a significantly shorter disease free survival (DFS) and disease specific survival (DSS) was noted in patients with metastases to the lymph nodes (p = 0.003 and p = 0.0006), over the age of 50 years old ((p = 0.02 and p = 0.04) and clearly statistically significant in patients with a high expression of BCRP (p = 0.00044 and p = 0.00005). Overall survival (OS) was shorter in patients over the age of 50 (p = 0.01), with higher stage of the disease - IIB (p = 0.025), with metastases to the lymph nodes (p = 0.003) and also clearly statistically significant in patients with a high expression of BCRP (p = 0.00004). A multivariate analysis allowed to reveal that only higher expression of BCRP and metastases to lymph nodes were typical for cases of DFS (p = 0.,028 and p = 0.00015), DSS (p = 0.00052 and 0.000017) and OS (p = 0.0018 and p = 0.000007) time. CONCLUSIONS: We demonstrated that high BCRP expression level is associated with poor survival in early stage breast cancer patients.

Barbed PDO Thread Face Lift: A Case Study of Bacterial Complication.

Procedures with polydioxanone (PDO) threads are increasingly used for aesthetic indications. To date, eight cases of serious complications following the use of PDO threads have been published. In this case report, we present a case of a serious bacterial complication after a procedure with four PDO threads. A 52-year-old female patient presented to our center 1 month after undergoing the procedure at another center. Despite early symptoms, no treatment had previously been implemented. Perforating abscesses were found along the course of the threads. After 5 days of antibiotic therapy (amoxicillin 875 mg and clavulanic acid 125 mg p.o. every 12 hours), the threads were surgically removed due to skin rippling. During the procedure, the threads were found to be fragile, and several incisions were necessary to remove them. After 1 month, no signs of inflammation were reported. However, persistent deformities occurred due to delayed treatment implementation. Bacterial complications seem to be a typical complication following the procedure with PDO threads. PDO threads can be difficult to remove due their fragility. The possible need for surgical removal of the threads should be considered when selecting areas for application.

Influence of tamoxifen on cisplatin-sensitivity and estrogen receptors expression in ovarian carcinoma cell lines.

BACKGROUND: Tamoxifen, used in breast cancer treatment, competitively inhibits estrogen receptor (ER) and also demonstrates direct antiproliferative effect on cancer cells even in ER lacking cancer tissue. However its molecular mechanism of action is still unclear MATERIAL AND METHODS: We exposed on tamoxifen 11 ovarian cancer cell lines, including well-documented platinum-sensitive and platinum-resistant ones, and studied tamoxifen-, cisplatin-sensitivity and expression of ERalpha and beta. RESULTS: We observed: no correlation between TAM-sensitivity and ERalpha and ERbeta expressions, no correlation between TAM influence on cisplatin-sensitivity and ERalpha and ERbeta expressions, increase of ERbeta expression after TAM-exposure in 3 cell lines; decrease in the 1 line, no TAM-exposure influence on ERalpha expression and increase of 1050 for cisplatin after TAM-exposure in 5 (45%) cell lines. These results show ovarian cancer cells being affected by TAM have different platinum sensitivity CONCLUSIONS: Our data suggests that ovarian cancer cells platinum-sensitivity are not linked with ER expressions. We claim the necessity of seeking some TAM predicting factors, using DNA microarrays.

Effect of diallyl disulfide and garlic oil on different human astrocytoma cell lines.

Gliomas are a group of malignant brain tumors. Despite significant efforts to optimize treatment options for patients with high-grade glioma, the prognosis of the overwhelming majority of patients remain poor. This bleak prognosis despite treatment of the glioma, is partly due to the tendency of therapeutics to diffusely penetrate into the neighboring brain tissues, but also due to the innate resistance of these tumors to chemotherapy and radiation. Garlic contains water-soluble and oil-soluble sulfur compounds. The oil-soluble compounds, including diallyl sulfide, diallyl disulfide (DADS), diallyl trisulfide and ajoene, are more effective potential anti-cancer treatments than the water-soluble compounds. There are several studies examining the effects of oil-soluble compounds on various types of cancer cells, although, to the best of our knowledge, there are no studies examining the effects of these compounds on glioma cells. The aim of the present study was to investigate the potential anti-glioma properties of DAD and garlic oil on proliferation and induction of apoptosis in four different types of glioma cell lines representative of different grades of the disease. The results showed that garlic oil exhibits favorable anti-cancer potential towards gliomas of various degrees of differentiation.

Esters of betulin and betulinic acid with amino acids have improved water solubility and are selectively cytotoxic toward cancer cells.

Betulin and betulinic acid are naturally occurring pentacyclic triterpenes showing cytotoxicity towards a number of cancer cell lines. Unfortunately they are practically insoluble in aqueous media and therefore their overall absorption index is not satisfactory. We have modified structures of both compounds by simple transformation to mono- and disubstituted esters of l-amino acids. This allowed us to achieve better water solubility without loss of the observed earlier anticancer properties. Comet assay on various cancer cell lines demonstrate that these compounds act via an apoptotic mechanism.

Comparision of the cytotoxic effects of birch bark extract, betulin and betulinic acid towards human gastric carcinoma and pancreatic carcinoma drug-sensitive and drug-resistant cell lines.

Betulin and betulinic acid are naturally occurring pentacyclic triterpenes showing cytotoxicity towards a number of cancer cell lines. These compounds can be found in the bark of the many plants. In this report we have compared the cytotoxic activity of crude birch bark extract and purified betulin and betulinic acid towards human gastric carcinoma (EPG85-257) and human pancreatic carcinoma (EPP85-181) drug-sensitive and drug-resistant (daunorubicin and mitoxantrone) cell lines. Our results show significant differences in sensitivity between cell lines depending on the compound used, and suggest that both betulin and betulinic acid can be considered as a promising leads in the treatment of cancer.

Prognostic significance of Ki-67 antigen expression in non-Hodgkin's lymphomas.

BACKGROUND: Non-Hodgkin's lymphomas (NHLs) are malignant tumours of the lymphoid system. Various risk factors have been described which are helpful in diagnosing, monitoring of the clinical course and predicting survival time of the patients. Proliferative activity of the tumour, measured by expression of Ki-67 antigen, is linked to the tumour proliferation rate and represents a recognised prognostic index in various tumours. In this study, the prognostic and predictive value of Ki-67 expression in NHL was evaluated. PATIENTS AND METHODS: Expression of Ki-67 was examined using an immunohistochemical technique in archival paraffin-embedded sections taken from 56 previously untreated patients with diagnosed primary NHL. An attempt was made to test correlation between Ki-67 expression on one hand and clinical parameters of the patients and their survival on the other. RESULTS: Expression of Ki-67 antigen was noted in 75% of the tumour cases. In the group manifesting higher Ki-67 indices, survival of the patients was significantly shorter (p = 0.03). No significant correlation could be detected between Ki-67 antigen expression and clinical or pathological parameters of the patients. CONCLUSION: The results demonstrate that the most cases of NHL display the expression of Ki-67. Moreover, shortened survival was noted in patients with high expression of Ki-67.

Positive correlation between cyclooxygenase 2 and the expression of ABC transporters in non-small cell lung cancer.

BACKGROUND: The primary method of treatment of non-small cell lung cancer (NSCLC) in stage IIIB and IV is chemotherapy. Previous data suggested a correlation between cyclooxygenase-2 (COX-2) expression and the multidrug-resistant phenotype of cancer cells. MATERIALS AND METHODS: In this prospective study, 32 patients with NSCLC in stage IIIB and IV from 1,078 patients were included. The expression of COX-2 as well as the expression of the ABC transporters MDR1/P-glycoprotein (MDR1/P-gp), BCRP and MRP1 were detected immunohistochemically. RESULTS: Univariate and multivariate analyses demonstrated no prognostic or predictive significance of these proteins. It was merely demonstrated that complete or partial response are favourable factors for prediction of longer progression-free survival time. However, a strong positive correlation between the expression of COX-2, MDR1/P-gp and BCRP was found in NSCLC. CONCLUSION: These data suggest no clinical impact for the expression of MDR1/P-gp, MRP1, BCRP or COX-2 in NSCLC, but a putative coregulation of COX-2 and MDRI/P-gp and BCRP in NSCLC.

Analysis of hMLH1 and hMSH2 expression in cisplatin-treated ovarian cancer patients.

BACKGROUND: Loss of DNA mismatch repair may result in resistance to platinum- based anticancer drugs. The hMLH1 and hMSH2 proteins play a critical role in the maintenance of genome integrity and are involved in resistance to platinum-based therapy in colorectal cancer, which is deficient in hMLH1 protein and endometrial cancer, as well as in hMSH2 protein. However, the predictive value of MLH1 and MSH2 expression in ovarian cancer cisplatin-resistance is still to be determined. OBJECTIVE: The aim of this study was to investigate the expression of hMLH1 and hMSH2 proteins in ovarian carcinoma specimens and to evaluate their prognostic significance by means of overall survival (OS) and progression-free survival rates (PSF). MATERIAL: Ovarian cancer tissues were obtained from 61 patients: 45 platinum-sensitive and 16 platinum-resistant. hMLH1 and hMSH2 proteins expression was evaluated by immunohistochemistry, with the use of mouse monoclonal antibodies clone 14 for hMLH1 and clone FE11 for hMSH2. The log-rank test and Kaplan-Meier statistics were used to analyze the relationship between proteins expression and progression free survival, as well as the overall survival. RESULT: No significant correlation was found between hMLH1 and hMSH2 expression and overall survival and progression free survival in the group of patients sensitive and resistant to cisplatin. No significant difference was found in proteins expression intensity between the two compared groups of patients. Age of patients, type of cancer histology, FIGO staging, grading, clinical response and CA 125 did not reveal correlation with the expression of the analyzed proteins. CONCLUSION: The immunohistochemical expression of hMLH1 and hMSH2 proteins in ovarian cancer has no predictive value in resistance to cisplatin.

Taxol-resistance-associated gene-3 (TRAG-3/CSAG2) expression is predictive for clinical outcome in ovarian carcinoma patients.

An obstacle in chemotherapy of ovarian cancer is the development of drug resistance. Taxol (paclitaxel)-resistance-associated gene-3 (TRAG-3/CSAG2) was found to be overexpressed in a paclitaxel-resistant ovarian carcinoma cell line. However, clinical impact of TRAG-3 in ovarian carcinoma has not been demonstrated previously. For demonstration of potential clinical impact of TRAG-3, immunohistochemistry was applied to determine TRAG-3 protein expression in specimens obtained from ovarian carcinoma patients (n=37) who received a paclitaxel-based chemotherapy at two different time points, initial laparotomy before chemotherapy, and secondary cytoreduction after chemotherapy. The TRAG-3-specific immunohistochemical staining was correlated with clinical outcome. In ovarian carcinoma specimens obtained at the initial laparotomy, an advantage in overall (P < 0.001) and progression-free (P = 0.003) survival for patients with weak TRAG-3 expression could be demonstrated. Tumor specimens excised at secondary cytoreduction procedure were not predictive for clinical outcome. In summary, TRAG-3 was found to be a prognostic factor for the prediction of clinical outcome after the application of paclitaxel-based chemotherapy.

Nuclear metallothionein expression correlates with cisplatin resistance of ovarian cancer cells and poor clinical outcome.

Elevated metallothionein (MT) expression in ovarian cancers treated with cisplatin-based schemes represents an unfavorable prognostic index. MT expression is significantly higher in tumor samples obtained after chemotherapy. The present study aimed at examining MT expression in ovarian carcinoma cells sensitive (A2780) or resistant (A2780RCIS) against platinum drug treatment as well as examining effects of exposure to cisplatin on MT expression. Subcellular expression of MT was evaluated also in samples originating from 73 ovarian tumors. Cisplatin-resistant A2780RCIS cells were exposed to increasing cisplatin concentrations, and the subcellular expression of MT was determined by immunocytochemistry. The studies demonstrated that cisplatin-resistant A2780RCIS cells exposed to cisplatin typically manifested a nuclear MT expression. The study demonstrated also that exposure to cisplatin was paralleled by growing MT expression in cell nuclei. The nuclear expression of MT was also found to be specific for ovarian cancers of poor clinical outcome. No relationship could be demonstrated between cytoplasmic expression of MT and clinical variables. Nuclear MT expression is induced by cisplatin and seems to protect DNA in the cells from toxic effects of the drug.

Expression of factors involved in regulation of DNA mismatch repair- and apoptosis pathways in ovarian cancer patients.

A major obstacle in treatment of ovarian cancer is intrinsic or acquired drug resistance causing failure of chemotherapy followed by a poor clinical outcome. Drug resistance of ovarian carcinoma can be caused by dysregulation of cellular factors involved in regulation of apoptosis and DNA repair pathways. In this study, 73 ovarian carcinoma specimens obtained before and after chemotherapy were analysed by immunohistochemistry for expression of seven proteins playing an important role in regulation of DNA mismatch repair and apoptosis. The prognostic significance of these proteins in the meaning of overall and progression-free survival was evaluated in univariate and multivariate analysis. Bcl-xL, hMSH2, caspase-3, p21 and p53 displayed prognostic importance in univariate analysis. Furthermore, it was demonstrated that caspase-3 and p21 were also independent prognostic markers for both, overall and progression-free survival. In conclusion, these data indicate that analysis of proteins involved in DNA mismatch repair and apoptosis can be useful for prediction of clinical outcome in ovarian carcinoma patients.

Occurence of stromal myofibroblasts in the invasive ductal breast cancer tissue is an unfavourable prognostic factor.

BACKGROUND: Numerous experimental studies have described the capacity of myofibroblasts to stimulate mammary cancer cells in a paracrine manner. Until now, the prognostic significance of myofibroblasts present in breast cancer has not been examined. PATIENTS AND METHODS: In paraffin sections, originating from 45 patients with primary invasive breast cancer, immunohistochemical reactions were performed using antibodies directed against smooth muscle actin, Ki-67, VEGF, bFGF and UPA. RESULTS: The cases with higher content of myofibroblasts in the tumour tissue manifested higher grade, more pronounced expression of Ki-67, VEGF and bFGF and shorter overall survival and relapse-free survival. CONCLUSION: The present study for the first time documents the unfavourable prognostic significance of myofibroblasts in tissues of invasive ductal mammary carcinomas.

ABCC2 (MRP2, cMOAT) can be localized in the nuclear membrane of ovarian carcinomas and correlates with resistance to cisplatin and clinical outcome.

PURPOSE: Cisplatin resistance is a major obstacle in the treatment of ovarian carcinoma. ABCC2 is commonly localized in apical cell membranes and could confer cisplatin resistance. Here, we show that ABCC2 can be localized in the cytoplasmic membrane as well as in the nuclear membrane of various human tissues including ovarian carcinoma cells. EXPERIMENTAL DESIGN: For the subcellular detection of ABCC2, immunohistochemistry was done using 41 Federation Internationale des Gynaecologistes et Obstetristes stage III ovarian carcinoma specimens prepared before treatment with cisplatin-based schemes and 35 specimens from the same group after chemotherapy. Furthermore, 11 ovarian carcinoma cell lines as well as tissue microarrays consisting of various human tissues were analyzed. RESULTS: Nuclear membranous localization of ABCC2 was associated with response to first-line chemotherapy at primary (P = 0.0013) and secondary surgery (P = 0.0060). Cases with relapse showed higher nuclear membrane expression at primary (P = 0.0003) and secondary surgery (P = 0.0024). Kaplan-Meier analyses showed that weak nuclear membrane ABCC2 expression before treatment was associated with significantly longer overall (P = 0.04) and progression-free survival (P = 0.001); following chemotherapy, it correlated with significantly longer progression-free survival (P = 0.038). Tissue microarrays confirmed nuclear membranous localization of ABCC2, in particular, in poorly differentiated cells. In ovarian carcinoma cells, it correlated with resistance against cisplatin, whereas localization in the cytoplasmic membrane did not. CONCLUSIONS: ABCC2 confers resistance to cisplatin of ovarian carcinoma in cell culture systems and in clinics when expressed in the nuclear membrane. Thus, ABCC2 localization can predict platinum therapy outcome. Furthermore, expression of ABCC2 in nuclear membranes in human tissues is specific for poorly differentiated cells including stem cells.