A systematic review of platinum and taxane resistance from bench to clinic: an inverse relationship

We undertook a systematic review of the pre-clinical and clinical literature for studies investigating the relationship between platinum and taxane resistance. Medline was searched for 1) cell models of acquired drug resistance reporting platinum and taxane sensitivities and 2) clinical trials of platinum or taxane salvage therapy in ovarian cancer. 137 models of acquired drug resistance were identified. 68.1% of cisplatin-resistant cells were sensitive to paclitaxel and 66.7% of paclitaxel-resistant cells were sensitive to cisplatin. A similar inverse pattern was observed for cisplatin vs docetaxel, carboplatin vs paclitaxel and carboplatin vs docetaxel. These associations were independent of cancer type, agents used to develop resistance and reported mechanisms of resistance. 65 eligible clinical trials of paclitaxel-based salvage after platinum therapy were identified. Studies of single agent paclitaxel in platinum-resistant ovarian cancer where patients had previously recieved paclitaxel had a pooled response rate of 35.3% n=232, compared to 22% in paclitaxel naïve patients n=1918 (p<0.01 Chi-squared). Suggesting that pre-treatment with paclitaxel may improve the response of salvage paclitaxel therapy. The response rate to paclitaxel/platinum combination regimens in platinum-sensitive ovarian cancer was 79.5% n=88 compared to 49.4% n=85 for paclitaxel combined with other agents (p<0.001 Chi-squared), suggesting a positive interaction between taxanes and platinum. Therefore the inverse relationship between platinum and taxanes resistance seen in cell models is mirrored in the clinical response to these agents in ovarian cancer. An understanding of the cellular and molecular mechanisms responsible would be valuable in predicting response to salvage chemotherapy and may identify new therapeutic targets

A systematic review of platinum and taxane resistance from bench to clinic: an inverse relationship

We undertook a systematic review of the pre-clinical and clinical literature for studies investigating the relationship between platinum and taxane resistance. Medline was searched for (1) cell models of acquired drug resistance reporting platinum and taxane sensitivities and (2) clinical trials of platinum or taxane salvage therapy in ovarian cancer. One hundred and thirty-seven models of acquired drug resistance were identified. 68.1% of cisplatin-resistant cells were sensitive to paclitaxel and 66.7% of paclitaxel-resistant cells were sensitive to cisplatin. A similar inverse pattern was observed for cisplatin vs. docetaxel, carboplatin vs. paclitaxel and carboplatin vs. docetaxel. These associations were independent of cancer type, agents used to develop resistance and reported mechanisms of resistance. Sixty-five eligible clinical trials of paclitaxel-based salvage after platinum therapy were identified. Studies of single agent paclitaxel in platinum-resistant ovarian cancer where patients had previously recieved paclitaxel had a pooled response rate of 35.3%, n=232, compared to 22% in paclitaxel naïve patients n=1918 (p<0.01, Chi-squared). Suggesting that pre-treatment with paclitaxel may improve the response of salvage paclitaxel therapy. The response rate to paclitaxel/platinum combination regimens in platinum-sensitive ovarian cancer was 79.5%, n=88 compared to 49.4%, n=85 for paclitaxel combined with other agents (p<0.001, Chi-squared), suggesting a positive interaction between taxanes and platinum. Therefore, the inverse relationship between platinum and taxanes resistance seen in cell models is mirrored in the clinical response to these agents in ovarian cancer. An understanding of the cellular and molecular mechanisms responsible would be valuable in predicting response to salvage chemotherapy and may identify new therapeutic targets

A systematic review of platinum and taxane resistance from bench to clinic: an inverse relationship

We undertook a systematic review of the pre-clinical and clinical literature for studies investigating the relationship between platinum and taxane resistance. Medline was searched for (1) cell models of acquired drug resistance reporting platinum and taxane sensitivities and (2) clinical trials of platinum or taxane salvage therapy in ovarian cancer. One hundred and thirty-seven models of acquired drug resistance were identified. 68.1% of cisplatin-resistant cells were sensitive to paclitaxel and 66.7% of paclitaxel-resistant cells were sensitive to cisplatin. A similar inverse pattern was observed for cisplatin vs. docetaxel, carboplatin vs. paclitaxel and carboplatin vs. docetaxel. These associations were independent of cancer type, agents used to develop resistance and reported mechanisms of resistance. Sixty-five eligible clinical trials of paclitaxel-based salvage after platinum therapy were identified. Studies of single agent paclitaxel in platinum-resistant ovarian cancer where patients had previously recieved paclitaxel had a pooled response rate of 35.3%, n=232, compared to 22% in paclitaxel naïve patients n=1918 (p<0.01, Chi-squared). Suggesting that pre-treatment with paclitaxel may improve the response of salvage paclitaxel therapy. The response rate to paclitaxel/platinum combination regimens in platinum-sensitive ovarian cancer was 79.5%, n=88 compared to 49.4%, n=85 for paclitaxel combined with other agents (p<0.001, Chi-squared), suggesting a positive interaction between taxanes and platinum. Therefore, the inverse relationship between platinum and taxanes resistance seen in cell models is mirrored in the clinical response to these agents in ovarian cancer. An understanding of the cellular and molecular mechanisms responsible would be valuable in predicting response to salvage chemotherapy and may identify new therapeutic targets

Cyclin B1 mediates the effect of UCHL1 in promoting cell cycle progression in uterine papillary serous carcinoma

Uterine papillary serous carcinoma (UPSC) is an aggressive form of endometrial cancer with poor survival rates and a high risk of recurrence. The rarity of UPSC poses challenges to the discovery of novel targeted therapies. Therefore, the purpose of this dissertation was to identify novel therapeutic targets that could aid in the management of UPSC. To do so, we began with the relatively large cohort of UPSC cases in the TCGA data set, which was used to identify differentially expressed genes between UPSC and low-grade endometrioid endometrial carcinoma (EEC) and normal tissue. We identified Ubiquitin Carboxyl-Terminal Hydrolase L1 (UCHL1) to be a gene of interest, as it was significantly upregulated in UPSC and correlated with poorer overall survival. These findings were validated through immunohistochemical analysis of an independent cohort of tumor samples. Due to its role as a deubiquitinating enzyme, we hypothesized that UCHL1 contributes to UPSC tumor progression by modulating the protein stability of target genes. To test this hypothesis, we first examined the functional role of UCHL1 in UPSC progression. Subsequently, we found that UCHL1 silencing reduced cell proliferation in vitro and in vivo. The treatment of UPSC-bearing mice with the UCHL1-specific inhibitor LDN-57444 via intraperitoneal injection also reduced tumor growth and increased overall survival times. Next, we found that the effect of UCHL1 on increased cell proliferation was due to its ability to stabilize cyclin B1 protein, an essential protein in mitotic progression. Specifically, we demonstrated that UCHL1 and cyclin B1 interact with each other in both the cytoplasm and nuclear space prior to mitosis. UCHL1 silencing increased the deubiquitination of cyclin B1, suggesting that UCHL1 counteracts the ubiquitination of cyclin B1 by the anaphase-promoting complex. Accordingly, UCHL1 silencing slowed the progression of cells into mitosis. Taken together, our findings indicate that UCHL1 impairs the degradation of cyclin B1, leading to uncontrolled cell cycle progression. In summary, we have identified UCHL1 as a prognostic marker for UPSC and a viable therapeutic target

Valutazione dell´endothelin axis (ET-1, ETAR, ETBR) come markers prognostici per il carcinoma invasivo della vulva mediante tecnica immunoistochimica su microarray tissutale

Background: Vulvar carcinoma is a rare gynecologic malignancy (incidence rate 3-5% of all female genital tract neoplasias) and mainly affects elderly women. Squamous cell carcinoma represent the vast majority of vulvar carcinomas (90-95%). TNM staging, deep of stromal invasion and presence of lymph node metastasis are the most important prognostic factors. Surgery is the standard treatment for primary vulvar carcinoma, followed by post operative radiotherapy when is neccesary. After primary treatment a high rate of patients develop recurrences, and a routine follow-up is necessary. Purpose: The ET-axis (Endothelin-1 and its receptors ETAR and ETBR) is overexpressed in various human tumors. We analyzed the ET-axis expression in vulva cancer, and its prognostic value. Methods: Samples were obtained from local excision and radical vulvectomy patients. ET-axis expression was investigated immunohistochemistry on tissue microarrays of 68 vulva cancer patients. Results: Elevated ET-1 expression of tumour cells is correlated high significantly to early stages pT1-T2 (P=0,004), and presence of metastasis (P=0,04). High staining levels ETBR within tumour tissue was related significantly to tumour progression (P=0,01), relapse-free survival (P=0,019), delayed metastasis (P=0,09 as a trend) and lymph node involvement (P=0,059 as a trend). A significant reduced overall survival could be shown concerning the low stages (pT1-2) (log rank P=0,036) and the patients without radiotherapy (log rank P=0,0539) as well as for the pM1 stage (log rank P= 0,0019). A significant reduced disease free survival could be shown concerning the low stages (pT1-T2) (long rank P=0,0206) with high ETBR expression. A correlation of both receptors was related significantly with tumour progression (P=0,022) and with local recurrence (P=0,005). Conclusions: These results suggest that, in addition to known histological risk factors and TNM classification criteria, measurement of ET-R expression with a simple immunohistochemical analysis might further help in predicting the prognosis of patients with vulva squamous cell carcinoma

Molecular Research of Endometrial Pathophysiology

The endometrium has been the subject of intense research in a variety of clinical settings, because of its importance in the reproductive process and its role in women’s health. In the past 15 years, significant efforts have been invested in defining the molecular phenotype of the receptive phase endometrium as well as of various endometrial pathologies. Although this has generated a wealth of information on the molecular landscape of human endometrium, there is a need to complement this information in light of the novel methodologies and innovative technical approaches. The focus of this International Journal of Molecular Sciences Special Issue is on molecular and cellular mechanisms of endometrium and endometrium-related disorders. The progress made in the molecular actions of steroids, in the metabolism of steroids and intracrinology, in endometrial intracellular pathways, in stem cells biology, as well as in the molecular alterations underlying endometrium-related pathologies has been the focus of the reviews and papers included

Manager’s and citizen’s perspective of positive and negative risks for small probabilities

So far „risk‟ has been mostly defined as the expected value of a loss, mathematically PL, being P the probability of an adverse event and L the loss incurred as a consequence of the event. The so called risk matrix is based on this definition. Also for favorable events one usually refers to the expected gain PG, being G the gain incurred as a consequence of the positive event. These “measures” are generally violated in practice. The case of insurances (on the side of losses, negative risk) and the case of lotteries (on the side of gains, positive risk) are the most obvious. In these cases a single person is available to pay a higher price than that stated by the mathematical expected value, according to (more or less theoretically justified) measures. The higher the risk, the higher the unfair accepted price. The definition of risk as expected value is justified in a long term “manager‟s” perspective, in which it is conceivable to distribute the effects of an adverse event on a large number of subjects or a large number of recurrences. In other words, this definition is mostly justified on frequentist terms. Moreover, according to this definition, in two extreme situations (high-probability/low-consequence and low-probability/high-consequence), the estimated risk is low. This logic is against the principles of sustainability and continuous improvement, which should impose instead both a continuous search for lower probabilities of adverse events (higher and higher reliability) and a continuous search for lower impact of adverse events (in accordance with the fail-safe principle). In this work a different definition of risk is proposed, which stems from the idea of safeguard: (1Risk)=(1P)(1L). According to this definition, the risk levels can be considered low only when both the probability of the adverse event and the loss are small. Such perspective, in which the calculation of safeguard is privileged to the calculation of risk, would possibly avoid exposing the Society to catastrophic consequences, sometimes due to wrong or oversimplified use of probabilistic models. Therefore, it can be seen as the citizen‟s perspective to the definition of risk