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Minnelide: A promising new therapy for ovarian cancer
Abstracts
36 cervix, 248 endometrial and 316 ovarian carcinomas. We used integrative genomic analyses of publicly available mutational and DNA copy number data to identify hypermutated cancers and to infer underlying mutational processes driving hypermutation. Results: We identified 395 hypermutated tumors in 16 diverse tumor types representing ~3.6% of all cancers. Of these, 47% of patient tumors possessed somatic hypermutation that could not be explained by an established exogenous mutagen, environmental exposure, or known defect in DNA repair. Hypermutation was most common in endometrial cancer and was observed in 69% of samples. Defects in DNA polymerase episilon and/or in mismatch repair drives hypermutation in endometrial cancers. Colorectal and stomach carcinomas also had hypermutation as a recurring mutational subtype observed in 26% and 24% of samples, respectively. Despite the identification of hypermutation in disparate tumor types, ovarian and cervical carcinomas did not have any samples with this phenotype (p b 0.0001). We used allelic abundance data to help determine the temporal sequence of somatic events in endometrial cancers with multiple defects potentially contributing to the observed hypermutation. Conclusion: Somatic hypermutation is most commonly found in endometrial, colorectal and stomach carcinomas but absent in ovarian and cervix carcinomas. We exploit big data to explore uncommon cancer phenotypes like somatic hypermutation across cancer types, bridging the gap between complex mutational landscapes to help inform clinical decisions.
doi:10.1016/j.ygyno.2014.07.020
Minnelide: A promising new therapy for ovarian cancer C. Rivard, M. Geller, R. Isaksson Vogel, E. Schnettler, M. Saluja, A. Saluja, S. Ramakrishnan. Objectives: Minnelide (Minn) is a novel, water soluble prodrug of triptolide. The goal of this study was to evaluate the effectiveness of Minn on ovarian cancer using in vitro and in vivo models. Methods: The effect of Minn on ovarian cancer cell proliferation was assessed by real time growth inhibition assays by determining electrical impedance using the xCELLigence system. A synergistic relationship between carboplatin (C) and Minn was determined in proliferation assays. Platinum sensitive (A2780) and resistant (C200) epithelial ovarian cancer xenograft models using 6 week old athymic (nu/nu) mice were used to assess the efficacy of Minn alone or in combination with C and paclitaxel (T). Tumors were evaluated for apoptosis, proliferation and vessel density by immunohistochemistry (IHC). Overall survival was calculated from treatment initiation to death/censorship at 100 days. Kaplan–Meier methods and log rank tests were used for comparisons by treatment; median survival and 95% confidence intervals are presented. Results: Minn treatment showed concentration dependent inhibition of both platinum sensitive and resistant ovarian cancer cell growth at nM concentrations. At 500 nM both cell types were completely inhibited and stopped proliferating after 12 h of exposure to Minn. The addition of 25 nM of Minn to C led C200 cells to cease proliferation after 21 h while those treated with C alone continued to proliferate. Minn significantly increased survival of mice bearing established ovarian cancers. In the A2780 model, median survival in the control arm was 26 (19–28) days and in the Minn arm was 46 (30–46) days (p b 0.0001). In the C200 model, median survival in the control arm was 32.6 (27–46) days and for the Minn arm was 51.5 (40–66) days (p = 0.0001). Mice receiving the combination of Minn and C + T had improved survival compared to those receiving Minn alone (p b 0.0001); Graphic 1. Minn led to increased apoptosis of tumor cells (120 cells/hpf) and the combination of Minn and C + T showed additive effects with N250 apoptotic cells/hpf.
387
Conclusion: Minn shows cytotoxicity against platinum sensitive and resistant ovarian cancer cells in vitro and in vivo. The additional killing observed when Minn is combined with C + T suggests that this is a promising agent for further investigation.
doi:10.1016/j.ygyno.2014.07.021
2012 cervical cancer screening guidelines: Are we following the new recommendations and have we improved over time? L. Howell, M. Dodson, M. Adelman, K. Pena, B. Mize, A. Soisson. Objectives: To determine current provider compliance with the most recent cervical cancer screening guidelines and to evaluate performance during the past decade. Methods: In this retrospective chart review, pap tests and Human Papilloma Virus (HPV) tests performed from January 1, 2013 to December 1, 2013 were identified and categorized into age groups (under 21 years, 21–29 years, and 30–65 years). The charts were reviewed to assess the date of prior pap. The screening tests were marked either appropriate or inappropriate according to the age appropriate guidelines. The percentage of inappropriate pap tests and HPV tests were calculated according to the 2012 guidelines. This procedure was then completed with pap and HPV tests performed from 2004 to 2012 and the percentages of appropriate and inappropriate testing were calculated based on updated guidelines published in 2003 and 2009. Secondarily, the average cost of pap and HPV tests in the US was identified and the total cost of inappropriate pap and HPV testing calculated. Results: In 2013, 82,098 pap tests were performed. In women under 21 years, 2032 pap tests were performed (100% inappropriate). In the 21–29 age group 25,528 pap tests were performed and 11,789 (46%) were inappropriate. In the 30–65 age group 52,566 pap tests were performed and 28,754 (54%) were inappropriate. A total of 42,626(52%) inappropriate pap tests were performed in 2013. In 2013, 25,402 HPV tests were performed and 7595(30%) were inappropriate. By age (under 21, 21–29, 30–65) the number of inappropriate tests were 325 (100%), 1343 (47%), and 5920 (21%), respectively. From 2010 to 2012 (Table 1), there were 43,271(15%) unnecessary pap tests and 12,864 (24%) unnecessary HPV tests performed. From 2004 to 2009 (Table 1), there were 45,082 (8%) inappropriate pap tests and 22,753 (39%) unnecessary HPV tests performed. The average cost of a pap test and HPV test in the United States is $30 each. When applied to the above results, over $1 million was spent on inappropriate pap tests and $700,000 on inappropriate HPV tests in 2013. Conclusion: Health care providers continue to perform an excessive number of pap and HPV tests at inappropriate time intervals. Adherence to national guidelines has significantly deteriorated in the past decade. Inappropriate pap and HPV tests cost our local healthcare system nearly
36 cervix, 248 endometrial and 316 ovarian carcinomas. We used integrative genomic analyses of publicly available mutational and DNA copy number data to identify hypermutated cancers and to infer underlying mutational processes driving hypermutation. Results: We identified 395 hypermutated tumors in 16 diverse tumor types representing ~3.6% of all cancers. Of these, 47% of patient tumors possessed somatic hypermutation that could not be explained by an established exogenous mutagen, environmental exposure, or known defect in DNA repair. Hypermutation was most common in endometrial cancer and was observed in 69% of samples. Defects in DNA polymerase episilon and/or in mismatch repair drives hypermutation in endometrial cancers. Colorectal and stomach carcinomas also had hypermutation as a recurring mutational subtype observed in 26% and 24% of samples, respectively. Despite the identification of hypermutation in disparate tumor types, ovarian and cervical carcinomas did not have any samples with this phenotype (p b 0.0001). We used allelic abundance data to help determine the temporal sequence of somatic events in endometrial cancers with multiple defects potentially contributing to the observed hypermutation. Conclusion: Somatic hypermutation is most commonly found in endometrial, colorectal and stomach carcinomas but absent in ovarian and cervix carcinomas. We exploit big data to explore uncommon cancer phenotypes like somatic hypermutation across cancer types, bridging the gap between complex mutational landscapes to help inform clinical decisions.
doi:10.1016/j.ygyno.2014.07.020
Minnelide: A promising new therapy for ovarian cancer C. Rivard, M. Geller, R. Isaksson Vogel, E. Schnettler, M. Saluja, A. Saluja, S. Ramakrishnan. Objectives: Minnelide (Minn) is a novel, water soluble prodrug of triptolide. The goal of this study was to evaluate the effectiveness of Minn on ovarian cancer using in vitro and in vivo models. Methods: The effect of Minn on ovarian cancer cell proliferation was assessed by real time growth inhibition assays by determining electrical impedance using the xCELLigence system. A synergistic relationship between carboplatin (C) and Minn was determined in proliferation assays. Platinum sensitive (A2780) and resistant (C200) epithelial ovarian cancer xenograft models using 6 week old athymic (nu/nu) mice were used to assess the efficacy of Minn alone or in combination with C and paclitaxel (T). Tumors were evaluated for apoptosis, proliferation and vessel density by immunohistochemistry (IHC). Overall survival was calculated from treatment initiation to death/censorship at 100 days. Kaplan–Meier methods and log rank tests were used for comparisons by treatment; median survival and 95% confidence intervals are presented. Results: Minn treatment showed concentration dependent inhibition of both platinum sensitive and resistant ovarian cancer cell growth at nM concentrations. At 500 nM both cell types were completely inhibited and stopped proliferating after 12 h of exposure to Minn. The addition of 25 nM of Minn to C led C200 cells to cease proliferation after 21 h while those treated with C alone continued to proliferate. Minn significantly increased survival of mice bearing established ovarian cancers. In the A2780 model, median survival in the control arm was 26 (19–28) days and in the Minn arm was 46 (30–46) days (p b 0.0001). In the C200 model, median survival in the control arm was 32.6 (27–46) days and for the Minn arm was 51.5 (40–66) days (p = 0.0001). Mice receiving the combination of Minn and C + T had improved survival compared to those receiving Minn alone (p b 0.0001); Graphic 1. Minn led to increased apoptosis of tumor cells (120 cells/hpf) and the combination of Minn and C + T showed additive effects with N250 apoptotic cells/hpf.
387
Conclusion: Minn shows cytotoxicity against platinum sensitive and resistant ovarian cancer cells in vitro and in vivo. The additional killing observed when Minn is combined with C + T suggests that this is a promising agent for further investigation.
doi:10.1016/j.ygyno.2014.07.021
2012 cervical cancer screening guidelines: Are we following the new recommendations and have we improved over time? L. Howell, M. Dodson, M. Adelman, K. Pena, B. Mize, A. Soisson. Objectives: To determine current provider compliance with the most recent cervical cancer screening guidelines and to evaluate performance during the past decade. Methods: In this retrospective chart review, pap tests and Human Papilloma Virus (HPV) tests performed from January 1, 2013 to December 1, 2013 were identified and categorized into age groups (under 21 years, 21–29 years, and 30–65 years). The charts were reviewed to assess the date of prior pap. The screening tests were marked either appropriate or inappropriate according to the age appropriate guidelines. The percentage of inappropriate pap tests and HPV tests were calculated according to the 2012 guidelines. This procedure was then completed with pap and HPV tests performed from 2004 to 2012 and the percentages of appropriate and inappropriate testing were calculated based on updated guidelines published in 2003 and 2009. Secondarily, the average cost of pap and HPV tests in the US was identified and the total cost of inappropriate pap and HPV testing calculated. Results: In 2013, 82,098 pap tests were performed. In women under 21 years, 2032 pap tests were performed (100% inappropriate). In the 21–29 age group 25,528 pap tests were performed and 11,789 (46%) were inappropriate. In the 30–65 age group 52,566 pap tests were performed and 28,754 (54%) were inappropriate. A total of 42,626(52%) inappropriate pap tests were performed in 2013. In 2013, 25,402 HPV tests were performed and 7595(30%) were inappropriate. By age (under 21, 21–29, 30–65) the number of inappropriate tests were 325 (100%), 1343 (47%), and 5920 (21%), respectively. From 2010 to 2012 (Table 1), there were 43,271(15%) unnecessary pap tests and 12,864 (24%) unnecessary HPV tests performed. From 2004 to 2009 (Table 1), there were 45,082 (8%) inappropriate pap tests and 22,753 (39%) unnecessary HPV tests performed. The average cost of a pap test and HPV test in the United States is $30 each. When applied to the above results, over $1 million was spent on inappropriate pap tests and $700,000 on inappropriate HPV tests in 2013. Conclusion: Health care providers continue to perform an excessive number of pap and HPV tests at inappropriate time intervals. Adherence to national guidelines has significantly deteriorated in the past decade. Inappropriate pap and HPV tests cost our local healthcare system nearly