Expression of multidrug resistance marker MDR1 in patients with ovarian cancer and its possible predictive significance.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e17530-e17530
Author(s):  
Elena P. Ulianova ◽  
Darya Yu. Yakubova ◽  
Aleksandr B. Sagakyants ◽  
Galina V. Zhukova ◽  
Evgeniya M. Nepomnyashchaya ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Multidrug Resistance ◽  
Tumor Cells ◽  
Detection System ◽  
Chemotherapeutic Agents ◽  
Platinum Resistance ◽  
Mdr1 Expression ◽  
Analysis Of Results ◽  
Group 2 ◽  
Group 1

e17530 Background: Despite the progress made in diagnosis and treatment, ovarian cancer (OC) is still the third most common genital cancer. Poor results of therapy for various forms of OC stimulate the search for fundamentally new approaches to the treatment. One of the main reasons for resistance to chemotherapeutic agents includes multidrug resistance (MDR) of tumor cells. The most characterized of its various mechanisms is the elevated activity of the ABC family protein - ABCB1 (Pgp or MDR1). The purpose of the study was evaluation of the expression of this ABC transporter as a predictive factor in platinum-containing chemotherapy in OC patients. Methods: 100 patients aged 29-79 years with advanced stage IIIC - IV OC with/without ascites were recruited between 2016 and 2020. Depending on the treatment results, patients were divided into 2 groups: group 1 (n = 59) - patients with platinum sensitivity; group 2 (n = 41) - patients with platinum resistance during the treatment or within 6 months after its completion. IHC analysis was performed using rabbit polyclonal anti-MDR1 antibodies (Affinity Biosciences) diluted 1:600 and the Reveal Polyvalent HRP-DAB Detection System. The percentage and the intensity of staining were assessed: 0, 1+ weak, 2+ moderate, 3+ strong. MDR1 expression was considered positive when staining was detected in more than 10% (cut-off) tumor cells with intensities of 2+ and 3+. Statistical analysis of results was performed in the Statistica 13.0 program (StatSoftInc., USA). Results: Patients with MDR1+ prevailed in group 2 (98%), and patients with MDR1- in group 1 (32%). The average expression of MDR1 in tumor cells in group 2 (64.0±7.0) was statistically significantly higher by 1.7 times (p = 0.003) than in group 1 (37.2±6.8) by the Mann-Whitney U-test. When distributed according to Pearson's χ2 criterion, positive MDR1 as a risk factor in the platinum-resistant group increased the risks of refractory to platinum therapy by 19 times (95% CI 2.4-148.8). Conclusions: The study demonstrated predictive significance of the MDR1 biomarker in platinum treatment in patients with ovarian cancer.

scholarly journals The impact of the early tenotomy of Achilles tendon on the length and results of congenital clubfoot severe forms treatment

2019 ◽  
Vol 76 (8) ◽  
pp. 795-801
Author(s):  
Zoran Rakonjac
Keyword(s):  
Achilles Tendon ◽  
Negative Impact ◽  
Ponseti Method ◽  
Congenital Clubfoot ◽  
Results Of Treatment ◽  
Analysis Of Results ◽  
Group 2 ◽  
The Impact ◽  
Group 1 ◽  
Female Subjects

Background/Aim. In this paper we present our modification of the Ponseti method which we have been using for the treatment of severe forms of congenital clubfoot since 2007. The aim of this paper was to determine, on the basis of the analysis of results, the impact of the early tenotomy of the Achilles tendon on the length and results of treatment of severe forms of congenital clubfoot. Methods. The study was prospective and lasted from 2007 to 2016 year. It was implemented in the Clinic for Children's Surgery Banjaluka. The Group 1 consisted of the subjects treated by the modified Ponseti method in the period of 9 years (2007?2016). There were a total of 30 subjects (52 feet). There were 20 (67%) of male and 10 (33%) of female subjects. There were 22 (77%) subjects with bilateral and 8 (27%) with unilateral deformity. The Group 2 consisted of the subjects treated by the classic Ponseti method in the period of 9 years (2007?2016). There were a total of 32 subjects (52 feet). There were 26 (81%) of male and 6 (19%) of female subjects. There were 20 (63%) of subjects with bilateral and 12 (37%) with unilateral deformity. We used the Pirani score for: classification of deformity according to the severity, monitoring of results of the correction, determination of indication for tenotomy of the Achilles tendon and for the analysis of results of the treatment. Results. The total length of treatment in the Group 1 was from 6 to 9 weeks (mean = 6.71 ? 0.871), and in the Group 2 from 9 to 12 weeks (mean = 9.92 ? 0.882) (r = 0.86; p = 0.001). There was no difference in the results of the treatment (?2 = 2.372 df = 2 n = 52 p = 0.936. Conclusion. Applying early tenotomy of Achilles tendon in the treatment of severe forms of congenital club foot significantly shortens the duration of treatment and has no negative impact on the results of treatment.

Dual-responsive TPGS crosslinked nanocarriers to overcome multidrug resistance

2020 ◽  
Vol 8 (36) ◽  
pp. 8383-8394
Author(s):  
Li Li ◽  
Tao Liu ◽  
Jia-Xin Liao ◽  
Zhe-Yi Zhang ◽  
Dai-Bo Song ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Cancer Therapy ◽  
Tumor Cells ◽  
Chemotherapeutic Agents ◽  
Dual Responsive ◽  
Efficient Delivery

Efficient delivery of chemotherapeutic agents into tumor cells and reversal of chemoresistance are crucially important to enhance cancer therapy.

scholarly journals Ubiquitination-mediated degradation of TRDMT1 regulates homologous recombination and therapeutic response

NAR Cancer ◽  
2021 ◽  
Vol 3 (1) ◽  
Author(s):  
Xiaolan Zhu ◽  
Xiangyu Wang ◽  
Wei Yan ◽  
Haibo Yang ◽  
Yufei Xiang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Homologous Recombination ◽  
Tumor Cells ◽  
Therapeutic Response ◽  
3D Structure ◽  
Platinum Resistance ◽  
Promising Therapeutic Target

Abstract The RNA methyltransferase TRDMT1 has recently emerged as a key regulator of homologous recombination (HR) in the transcribed regions of the genome, but how it is regulated and its relevance in cancer remain unknown. Here, we identified that TRDMT1 is poly-ubiquitinated at K251 by the E3 ligase TRIM28, removing TRDMT1 from DNA damage sites and allowing completion of HR. Interestingly, K251 is adjacent to G155 in the 3D structure, and the G155V mutation leads to hyper ubiquitination of TRDMT1, reduced TRDMT1 levels and impaired HR. Accordingly, a TRDMT1 G155V mutation in an ovarian cancer super responder to platinum treatment. Cells expressing TRDMT1-G155V are sensitive to cisplatin in vitro and in vivo. In contrast, high expression of TRDMT1 in patients with ovarian cancer correlates with platinum resistance. A potent TRDMT1 inhibitor resensitizes TRDMT1-high tumor cells to cisplatin. These results suggest that TRDMT1 is a promising therapeutic target to sensitize ovarian tumors to platinum therapy.

scholarly journals ERCC1-Positive Circulating Tumor Cells in the Blood of Ovarian Cancer Patients as a Predictive Biomarker for Platinum Resistance

2014 ◽  
Vol 60 (10) ◽  
pp. 1282-1289 ◽  
Author(s):  
Jan Dominik Kuhlmann ◽  
Pauline Wimberger ◽  
Agnes Bankfalvi ◽  
Thomas Keller ◽  
Sarah Schöler ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Surface ◽  
Cancer Patients ◽  
Independent Predictor ◽  
Excision Repair ◽  
Complementation Group ◽  
Primary Diagnosis ◽  
Platinum Resistance ◽  
Ercc1 Expression ◽  
Group 1

Abstract BACKGROUND Platinum resistance constitutes one of the most recognized clinical challenges for ovarian cancer. Notably, the detection of the primary tumor-based excision repair cross-complementation group 1 (ERCC1) protein by immunohistochemistry was recently shown to be inaccurate for the prediction of platinum resistance. On the basis of the previous finding that circulating tumor cells (CTC) in the blood of ovarian cancer patients are prognostically significant, and given our hypothesis that the negative prognostic impact of CTC may arise from a cellular phenotype associated with platinum resistance, we asked whether expression of the excision repair cross-complementation group 1 (ERCC1) gene in the form of the ERCC1 transcript in CTC may be a suitable blood-based biomarker for platinum resistance. METHODS The presence of CTC was analyzed by immunomagnetic CTC enrichment (n = 143 patients) targeting the epithelial epitopes epithelial cell adhesion molecule (EPCAM) (also known as GA733-2) and mucin 1, cell surface associated (MUC1), followed by multiplex reverse-transcription PCR to detect the transcripts EPCAM, MUC1, and mucin 16, cell surface associated (MUC16) (also known as CA125), including ERCC1 transcripts in a separate approach. ERCC1 expression in primary tumors was comparatively assessed by immunohistochemistry, using the antibody 8F1. RESULTS At primary diagnosis, the presence of CTC was observed in 14% of patients and constituted an independent predictor of overall survival (OS) (P = 0.041). ERCC1-positive CTC (ERCC1+CTC) were observed in 8% of patients and constituted an independent predictor, not only for OS but also for progression-free survival (PFS) (P = 0.026 and P = 0.009, respectively). More interestingly, we discovered the presence of ERCC1+CTC at primary diagnosis to be likewise an independent predictor of platinum resistance (P = 0.010), whereas ERCC1 expression in corresponding primary tumor tissue predicted neither platinum resistance nor prognosis. CONCLUSIONS The presence of ERCC1+CTC can serve as a blood-based diagnostic biomarker for predicting platinum resistance at primary diagnosis of ovarian cancer.

Effect of introduction of paclitaxel on survival among women with stage III and IV ovarian cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 5536-5536
Author(s):  
S. S. Dawood ◽  
C. Albaracin ◽  
A. Gonzalez-Angulo ◽  
M. Markman ◽  
B. Hennessy
Keyword(s):  
Ovarian Cancer ◽  
Stage Iv ◽  
Stage Iii ◽  
First Line ◽  
Fda Approval ◽  
Significant Difference ◽  
Stage Iv Disease ◽  
Group 3 ◽  
Group 2 ◽  
Group 1

5536 Background: The objective of this study was to evaluate survival over time in relation to FDA approval of paclitaxel (P) for second- and first-line treatment in a population-based cohort of women with stage III and de novo stage IV ovarian cancer. Methods: The Surveillance, Epidemiology, and End Results (SEER) program was searched to identify 8,267 and 10,746 women with stage III and stage IV epithelial ovarian cancer diagnosed between 1988–2004. Women were divided according to their year of diagnosis and year of FDA approval of P for second- (1992) and first-line(1998) treatment of ovarian cancer: Group1 (1988–1991; before P approval); Group2 (1992–1997; P approved for second-line); Group3 (1998–2003; P approved for first-line). Overall (OS) and ovarian-cancer-specific survival (OCS) were estimated using Kaplan-Meier product method and compared across groups with log rank statistic. Cox-proportional hazards models were fitted to determine the association of group year of diagnosis and survival after adjusting for patient/tumor characteristics. Results: Median age was 66 years. Median OCS was 44 and 18 months among women with stages III and IV disease, respectively. With stage III disease, 2-year OCS was 64%, 68%, and 70% for groups 1, 2, and 3, respectively (p < 0.0001). With stage IV disease, 2-year OCS was 39%, 41%, and 42% for groups 1, 2, and 3, respectively (p = 0.19). In the multivariable model for stage III disease, women in group 1 (HR = 1.4, 95% CI 1.2–1.5, p < 0.0001) and group 2 (HR = 1.2, 95% CI 1.1–1.3, p = 0.0003) had an increased hazard of ovarian-cancer-specific death vs. group 3. For stage IV disease, women in group 1 (HR = 1.2, 95% CI 1.12–1.3, p < 0.0001) had a significantly increased hazard of ovarian cancer-specific death, but no significant difference in group 2 (HR = 1.0, 95% CI 0.9–1.1, p = 0.88) vs. group 3. Similar trends were observed for OS. Conclusions: The survival of women with stages III and IV ovarian cancer has significantly improved with the introduction of P over the last two decades. However, the incremental improvement in survival with stage IV disease is clinically minimal and indeed not significant in the univariable analysis in the SEER patient cohort analyzed, suggesting a desperate need for new and more active drugs in these patients. No significant financial relationships to disclose.

Association of ERCC1 protein expression to platinum resistance in epithelial ovarian cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 5530-5530
Author(s):  
K. D. Steffensen ◽  
M. Waldstrøm ◽  
A. Jakobsen
Keyword(s):  
Ovarian Cancer ◽  
Protein Expression ◽  
Tumor Cells ◽  
Excision Repair ◽  
Positive Association ◽  
Platinum Resistance ◽  
Newly Diagnosed ◽  
Platinum Based Chemotherapy ◽  
Clinical Resistance ◽  
Significant Difference

5530 Background: Although platinum-based chemotherapy remains the cornerstone for treatment of ovarian cancer, some patients are resistant to the treatment and will therefore not benefit from the standard platinum-based chemotherapy. Preclinical and clinical data have suggested a potential use of ERCC1 (excision repair cross-complementation group 1 enzyme) as a molecular predictor of clinical resistance to platinum-based chemotherapy. ERCC1 is a key enzyme in the nucleotide excision repair pathway which is involved in the DNA repair mechanisms in tumor cells. The primary aim of the present study was to investigate if immunohistochemical expression of ERCC1 protein was associated with resistance to standard combination carboplatin and paclitaxel chemotherapy in newly diagnosed ovarian cancer patients. Methods: Formalin-fixed, paraffin-embedded tissue sections from 101 patients with newly diagnosed ovarian cancer were used for immunohistochemical staining for the ERCC1 protein. The percentage of positive tumor cells in each slide were scored as 0 if 0 % of the tumor cells were positive, 0.1 if 1 %-9 %; 0.5 if 10 %-49 %; and 1.0 if 50 % or more were positive. A semi quantitative H-score was calculated by multiplying the staining intensity (0–3) with the percentage score. The tumor was considered positive when the H-score was > 1.0. All patients received carboplatin-paclitaxel combination chemotherapy. Results: ERCC1 protein overexpression was found in 13.9 % of the tumors. Platinum resistance were found in 75 % of the tumors with positive ERCC1 protein expression compared to 27 % among the patients with negative tumor staining for ERCC1 (p = 0.0013). These findings translated into a significant difference in progression free survival in both univariate (p = 0.0012) and in multivariate analysis (p = 0.006). Conclusions: The data presented suggests a positive association between positive ERCC1 protein expression and clinical resistance to platinum-based chemotherapy. No significant financial relationships to disclose.

Correlation of PR and ER expression in tumors in various growth patterns of cervical cancer as a prognostic factor.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e18031-e18031
Author(s):  
Elena P. Ulianova ◽  
Diana A. Spiridonova ◽  
Vera P. Nikitina ◽  
Inna A. Novikova ◽  
Aleksandr B. Sagakyants ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Prognostic Factor ◽  
Tumor Growth ◽  
Detection System ◽  
Rank Correlation ◽  
Growth Patterns ◽  
Eligibility Criteria ◽  
Group 2 ◽  
Er Expression ◽  
Group 1

e18031 Background: Cervical cancer is the fourth leading cause of cancer deaths among women worldwide. Since the uterus has receptors through which hormonal effects are realized, studies on the tissue receptor apparatus for estrogen and progesterone are relevant. The purpose of the study was to evaluate the correlation of PR and ER expression as a prognostic factor in cervical cancer. Methods: The study included 60 patients aged 28-65 years diagnosed with cervical cancer. Patients were divided into two groups: group 1 – endophytic pattern of tumor growth (n = 30), group 2 – exophytic pattern (n = 30). Eligibility criteria included morphologically confirmed squamous cell carcinoma of the cervix T1b-2aN0M0, stage I-II. Rabbit monoclonal antibodies for ER (Thermo scientific) and PR (Cell Marque) with the Reveal Polyvalent HRP-DAB Detection System were used for the IHC analysis. Statisical analysis of the results was performed with the Statistica 10 program (StatSoft Inc., USA). Results: The average expression of the ER marker was 5.4±3.03% for group 1 (endophytic tumors) and 13.9±8.2% for group 2 (exophytic tumors). The average PR expression was 0.5±0.3% and 1.6±1.1%, respectively. The maximal accumulation of both PR and ER in the nuclei of tumor cells was registered in patients of group 2, being 3.2 times (p = 0.931) and 2.6 times (p = 0.815) higher than in group 1, respectively. However, the difference was not statistically significant (the Mann-Whitney test, p > 0.05). The Spearman rank correlation test did not show statistically significant correlation between the groups and the markers (r = -0.218, p = 0.338). Statistically significant correlation was observed only in the group with exophytic pattern of tumor growth (r = 0.786, p < 0.01). Conclusions: The IHC analysis revealed a tendency to an increase in the expression of PR and ER in patients with exophytic tumors. However, the correlation between the expression of these indicators cannot be considered as a predictive factor in cervical cancer.

Factors of angiogenesis (VEGF and CD34) in primary and recurrent soft tissue sarcomas.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e23545-e23545
Author(s):  
Evgeniya M. Nepomnyashchaya ◽  
Elena P. Ulianova ◽  
Aleksandr B. Sagakyants ◽  
Inna A. Novikova ◽  
Larisa N. Vashchenko ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Blood Vessels ◽  
Molecular Mechanisms ◽  
Detection System ◽  
Dynamic Balance ◽  
Soft Tissue Sarcomas ◽  
Field Of View ◽  
Primary Tumors ◽  
Group 2 ◽  
Group 1

e23545 Background: The tumor ability to induce and maintain angiogenesis is one of the main stages of its development. Studies of molecular mechanisms of angiogenesis showed that the dynamic balance that ensures the formation and development of new vessels inside the tumor depends on pro- and anti-angiogenic factors. VEGF and the CD34 endothelial cell marker are considered among the main activators of angiogenesis. Our purpose was to study characteristics of angiogenesis in primary and recurrent soft tissue sarcomas. Methods: The study included 30 patients with primary sarcomas (group 1) and 26 patients with recurrent sarcomas (group 2). Sections of tissues embedded in paraffin blocks were studied by immunohistochemistry using the Thermo Scientific 480S automated stainer. The Reveal Polyvalent HRP-DAB Detection System was used for the visualization. The density of blood vessels stained with antibodies against VEGF and CD34 was determined. The statistical analysis of results was performed in the STATISTICA 10.0 program (StatSoftInc., USA). Results: The numbers of blood vessels ranged: CD34 in group 1 – 7-16 blood vessels in one field of view; in group 2 – 2-18 vessels. VEGF in group 1 – 2-20 vessels, with up to 40 vessels in 3 cases (11.5%) only; in group 2 – 5-11 vessels, with up to 20 vessels in 2 cases (7.7%). The average numbers of microcirculatory vessels stained with antibodies against VEGF and CD34 were: CD34 –12.2±1.04 and 8.4±1.4 (p = 0.0247) in groups 1 and 2, respectively; VEGF – 12.8±4.06 and 8.4±11.6 (p = 0.3074) in groups 1 and 2, respectively. Conclusions: The IHC analysis showed the minimal numbers of microcirculatory vessels in one field of view in patients with recurrent soft tissue sarcomas. The value was 1.5 times lower for both CD34 and VEGF, compared to patients with primary tumors. However, only CD34 value was statistically significant (the Mann–Whitney U-test). Probably, a certain decrease in angiogenesis factors in recurrent tumors can be explained by adjuvant chemotherapy suppressing tumor growth.

Correlation of the survival of ovarian cancer patients with mRNA expression of the 60-kD heat-shock protein HSP-60.

1993 ◽  
Vol 11 (5) ◽  
pp. 891-898 ◽  
Author(s):  
E Kimura ◽  
R E Enns ◽  
J E Alcaraz ◽  
J Arboleda ◽  
D J Slamon ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Epithelial Ovarian Cancer ◽  
Mrna Expression ◽  
Southern Blot ◽  
Ovarian Carcinomas ◽  
Kaplan Meier ◽  
Group 2 ◽  
Group 1

PURPOSE Ovarian carcinomas express the 60-kD heat-shock protein HSP-60 at widely varying levels in different tumors. The aim of this study was to determine whether there was a relationship between expression of HSP-60 and survival in patients with ovarian carcinoma. MATERIALS AND METHODS Total RNA and DNA were prepared from 51 epithelial ovarian cancer tissue samples. The expression and structure of the HSP-60 gene were examined by Northern and Southern blot analyses using the carboxyl-terminal portion of this gene as a probe (0.89 kilobases [kb]). HSP-60 expression was correlated with overall survival by the Kaplan-Meier method. RESULTS The 2.3-kb HSP-60 message was detected in all samples, but there was marked variation from tumor to tumor. Patients were classified into two groups on the basis of HSP-60 expression: group 1 (n = 25) included patients with low expression, and group 2 (n = 26) consisted of patients with high expression. There were no significant differences between the groups with respect to age, cell type, pathologic grade, clinical stage, and previous treatment. After a median follow-up period of 17 months, Kaplan-Meier plots demonstrated a much better survival for group 1 (median, 46.8 months; 41% at 4 years) than group 2 (median, 22.1 months; 16% at 3.9 years), a difference that was highly significant by the Mantel-Haenszel test (P = .00183). Southern blot analysis of these samples showed no amplification or rearrangement of the gene. CONCLUSION The level of HSP-60 mRNA expression is a valuable prognostic factor in epithelial ovarian cancer. Variation in the level of expression is not due to amplification of this gene.

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