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Instrumental variable estimation in functional linear models
Gynecologic Oncology 137 (2015) 591–599
Contents lists available at ScienceDirect
Gynecologic Oncology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / y g y n o
Abstract 1: Gynecologic oncologists as benign gynecologic surgeons W. Baker, E. Chang, E. Pelkofski, L. Duska. University of Virginia Health System, Charlottesville, VA, United States
DP
Objectives: The 2010 Society of Gynecologic Oncologists (SGO) Practice Survey revealed that up to one third of operations performed by gynecologic oncologists are for benign indications. This evolving practice pattern may have significant workforce implications and is a topic not well studied. The aim of this study was to characterize the benign gynecologic surgical practices of SGO members and identify attitudes toward noncancer gynecologic surgery. Methods: In November 2013, SGO members were invited to complete a 23-question online survey regarding surgical practice patterns. Descriptive statistics were used to analyze responses as well as chi square and t-test banalyses.
Abstract 2: Prognostic significance of POLE exonuclease domain mutations in high grade endometrioid endometrial cancer on survival and recurrence C. C. Billingsleya, E. M. Hadeb, D. E. Cohna, D. G. Mutchc, P. J. Goodfellowa. aThe Ohio State University, Department of Obstetrics and Gynecology, Division of Gynecology Oncology, Columbus, OH, United States, bThe Ohio State University, Department of Obstetrics and Gynecology, Biostatistics, Columbus, OH, United States, cWashington University, Department of Obstetrics and Gynecology, Division of Gynecology Oncology, St. Louis, MO, United States
RO
Poster Presentations
OF
SGO 2015 Winter Meeting Abstracts
TE
Objectives: POLE exonuclease domain mutations have previously been described to occur in the tumors of endometrial cancer (EC) patients, and result in the inability to repair mismatched bases during DNA replication. The prognostic impact of these mutations is controversial. We sought to investigate the prevalence of POLE mutation tumor status and its prognostic significance on survival and recurrence outcomes in women with high grade endometrioid EC.
Methods: Polymerase chain reaction amplification and Sanger sequencing were previously used to test for POLE mutations in 72 grade 3, endometrioid tumors. Associations between demographics, survival, clinicopathologic, and molecular features were investigated. P-values were calculated by Fisher’s exact test and by Wilcoxon rank-sum test as appropriate. Cox proportional hazard models were used to estimate the adjusted associations between POLE mutation status and recurrence free survival (RFS).
CO
RR
EC
Results: Responses were received from 234 of 1154 SGO members (20%). Overall, respondents reported that 50% of patients were referred with known malignant disease, 30% with suspected malignant disease, and 20% with known benign disease. Minimally invasive surgery (MIS) was used in 66% of overall surgical volume but 78% of benign surgeries (P = b0.0001). The most common noncancer referrals were: adnexal masses without features concerning for malignancy, benign vulvar disease, and patients with medical comorbidities. More than half of respondents (65%) reported increased frequency of benign surgical referrals due to ability to offer MIS. Most (67%) felt benign surgery to have neutral or no impact on their ability to care for women with cancer. Gynecologic oncologists in private practice were more likely to report that benign gynecology positively affected their practice's finances than academic clinicians (61% versus 39%, P = 0.004). These clinicians were also more likely to encourage referral of patients with benign disease (45% versus 29%, P = 0.027).
UN
Conclusions: Benign gynecologic surgery accounts for approximately 20% of gynecologic oncologists' surgical volume. Most gynecologic oncologists have a neutral view on the impact of benign gynecologic surgery on their ability to care for cancer patients, professional satisfaction, and practice finances. Subspecialty expertise in minimally invasive techniques is likely to foster continued referrals for benign surgical procedures and management of benign pelvic masses. doi:10.1016/j.ygyno.2015.03.018
0090-8258/$ – see front matter.
Results: POLE mutations were identified in 7 of 72 (9.7%) grade 3 endometrioid ECs. There were no significant differences in the clinicopathologic features between those with POLE mutations compared to those without (wildtype). There was one recurrence among the 7 women with POLE mutant tumors (14.3%) compared to 26 of 65 women (40%) with wildtype tumors. A decreased risk of recurrence was suggested in those patients with a POLE mutation, even after adjusting for age (aHR = 0.37, 95%CI 0.09–1.55), as well as considerable decreased risk of death in women with a POLE mutation. This risk of death was approximately 1/5 of that of patients without a tumor POLE mutation, after adjusting for age (aHR = 0.19, 95% CI: 0.03–1.42). Conclusions: The prognostic role of POLE tumor mutation in endometrioid EC has previously been investigated with uncertain significance. However, in the subset of women with grade 3, endometrioid EC, there is a strong suggestion of a trend towards significantly better RFS and overall survival. These findings suggest that the risk of recurrence is 1/3, and the risk of death is decreased by 80% in women with POLE mutations compared to those without mutations. These findings may contribute to the existing literature of POLE mutations, and serve as a
Abstracts / Gynecologic Oncology 137 (2015) 591–599
doi:10.1016/j.ygyno.2015.03.019
Abstract 3: Inhibition of STAT3 in ovarian clear cell carcinoma results in decreased cell proliferation and induction of apoptosis K. Bixel, U. Saini, J. Fowler, S. Rajendiran, R. Wanner, K. Hideg, D.E. Cohn, S. Karuppaiyah. Ohio State University, Columbus, OH, United States Objectives: Advanced ovarian clear cell carcinoma (OCCC) is most often resistant to standard platinum and taxane chemotherapy making prognosis poor. STAT3 expression and activation have been shown to regulate tumor progression in various human cancers though has not been well studied in OCCC. In this study, we aim to characterize the expression of the STAT family of proteins in OCCC and examine the efficacy of HO-3867, a novel STAT3 inhibitor.
Results: Three hundred and fifty nine women were included in the final analysis. The mean patient age was 64.2 years. PMS2 and MLH1 were expressed less frequently in patients greater than 61 years of age (p b 0.05). In the older-age group, only 45.5% of those screened expressed the PMS2 gene compared to 76.8% of patients in the younger-age group. Similarly, the MLH1 gene was expressed in only 45.5% of patients in the older-age group compared to 73.9% in the younger-age group. No significant differences in gene expression were found between the two age groups for either the PMS1 and MLH2. Conclusions: Diminished expression of the PMS1 and MLH2 genes was noted in patients greater than 60 years of age with endometrial adenocarcinoma. Future large scale population-based studies are needed to confirm our findings. Should diminished gene expression be confirmed in patients over 60 years of age, consideration may be given to the modification of Lynch syndrome screening in patients with endometrial adenocarcinoma.
doi:10.1016/j.ygyno.2015.03.021
Abstract 5: Evaluation of universal immunohistochemistry screening for diagnosing Lynch syndrome in endometrial cancer patients at a tertiary care center E.G. Hartnetta, A. Stuckeya, C. McCourtb. aWomen & Infants Hospital/ Brown University, Providence, RI, United States, bWashington University in St. Louis, St. Louis, MO, United States
DP
Methods: OCCC tumor tissue was obtained from the tissue bank after IRB approval. Drug resistant OCCC cell lines used include JHOC, OVISE, OVTOKO, and RMGV. Cell lines were treated with cisplatin and HO-3867 alone and in combination. Protein expression in tumor tissues and cell lines were determined by western blotting (WB). Cell viability was determined by MTT assays, cell proliferation measured by BrdU assay, and ANNEXIN V kit was used to quantify apoptosis.
expression was compared in patients less than and older than 60 years of age. Data were analyzed using the chi square test.
OF
positive prognostic marker and may provide guidance in the treatment of women with grade 3 endometrioid tumors.
RO
592
Objectives: The aim of this study was to compare genetic counseling referrals and rates of Lynch syndrome (LS) detection during the initial year of universal screening (2013–2014) of endometrial cancers to those in the previous year when screenings and referrals were performed solely at physicians' discretion.
TE
Results: Activated STAT3 (pSTAT3 Tyr705 or Ser727) was consistently expressed in all 7 OCCC tumor samples evaluated. Additionally, OCCC cell lines constitutively expressed pSTAT3 whereas other forms of activated STAT were not present (pSTAT1, 2, 6). All cell lines treated were cisplatin resistant and treatment resulted in increased expression of pSTAT3 as well as FAS suggesting these pathways as possible mechanisms for resistance. Treatment with HO-3867 selectively decreased expression of pSTAT3 while total STAT3 remained constant. HO-3867 decreased cell proliferation by 50% to 60% in multiple OCCC cell lines. The inhibitory effect of HO-3867 on cell viability is associated with induction of apoptosis (28% to 43%) as confirmed by ANNEXIN V staining. Further, we have observed a decrease in BCL2 and cleavage of caspase 3, caspase 7 and PARP confirming induction of apoptosis.
EC
Methods: Universal screening for LS in all endometrial cancers treated at our institution was implemented in September 2013. Uterine specimens underwent immunohistochemistry (IHC) for mismatch repair protein markers MLH1, MSH2, MSH6 and PMS2 with reflex methylation testing when indicated. A genetic counselor contacted patients with abnormal screens to offer genetic counseling appointments. IHC results were collected for the initial year of universal screening. Additionally, a retrospective analysis was performed tracking molecular screens and referrals to genetics for all endometrial cancers treated in the year prior to universal screening. Results: Two hundred and five endometrial cancers were screened in the initial 12 months of universal screening and 230 endometrial cancers were tracked during the year without screening. During the universal screening period, 43 patients (21%) had abnormal IHC results: 1 lacked expression of MSH6/PMS2, 5 lacked MSH6 and 37 lacked MLH1/PMS2. Of the 37 patients who lacked MLH1/PMS2 expression, 36 had MLH1 promoter methylation and were assumed to have sporadic cancers. The 7 patients with confirmed abnormal screens were referred to genetics; 6 patients underwent genetic counseling and pursued genetic testing. Three women were diagnosed with LS and none of these patients met traditional criteria for screening. There were also 10 patients with negative IHC screens who were referred to genetic counseling based on family history alone. Between 2012 and 2013, 8 patients (3.5%) met traditional screening guidelines (Amsterdam II or revised Bethesda guidelines); none of these were screened. However, IHC was requested on 16 other patients, and a total of 6 patients were referred for genetic counseling. No cases of LS were diagnosed in the pre-screening year. Conclusions: Universal screening of endometrial cancers is critical
CO
RR
Conclusions: pSTAT3 is constitutively activated in OCCC tumor tissues and cell lines. Inhibition of pSTAT3 by HO-3867results in decreased cell viability and proliferation as well as induction of apoptosis in platinum resistant OCCC cell lines. These findings warrant future investigation into the mechanism by which HO-3867 targets the STAT3 pathway as well as its therapeutic efficacy in vivo. doi:10.1016/j.ygyno.2015.03.020
UN
Abstract 4: Differential gene expression associated with Lynch syndrome in patients less than and over 60 years of age with endometrial adenocarcinoma O. Dziadek, B. Shoup, K. Williams. UMKC School of Medicine, Kansas City, MO, United States Objectives: The purpose of the study was to determine trends in Lynch syndrome gene expression in patients less than 60 years of age compared to those greater than 60 years of age. Methods: A retrospective case control study was performed. Gene expression was determined for MSH1, MSH2, MSH6 and PMS2 via immunohistochemistry on all patients diagnosed with endometrial adenocarcinoma between December 2011 and December 2013. Gene
Contents lists available at ScienceDirect
Gynecologic Oncology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / y g y n o
Abstract 1: Gynecologic oncologists as benign gynecologic surgeons W. Baker, E. Chang, E. Pelkofski, L. Duska. University of Virginia Health System, Charlottesville, VA, United States
DP
Objectives: The 2010 Society of Gynecologic Oncologists (SGO) Practice Survey revealed that up to one third of operations performed by gynecologic oncologists are for benign indications. This evolving practice pattern may have significant workforce implications and is a topic not well studied. The aim of this study was to characterize the benign gynecologic surgical practices of SGO members and identify attitudes toward noncancer gynecologic surgery. Methods: In November 2013, SGO members were invited to complete a 23-question online survey regarding surgical practice patterns. Descriptive statistics were used to analyze responses as well as chi square and t-test banalyses.
Abstract 2: Prognostic significance of POLE exonuclease domain mutations in high grade endometrioid endometrial cancer on survival and recurrence C. C. Billingsleya, E. M. Hadeb, D. E. Cohna, D. G. Mutchc, P. J. Goodfellowa. aThe Ohio State University, Department of Obstetrics and Gynecology, Division of Gynecology Oncology, Columbus, OH, United States, bThe Ohio State University, Department of Obstetrics and Gynecology, Biostatistics, Columbus, OH, United States, cWashington University, Department of Obstetrics and Gynecology, Division of Gynecology Oncology, St. Louis, MO, United States
RO
Poster Presentations
OF
SGO 2015 Winter Meeting Abstracts
TE
Objectives: POLE exonuclease domain mutations have previously been described to occur in the tumors of endometrial cancer (EC) patients, and result in the inability to repair mismatched bases during DNA replication. The prognostic impact of these mutations is controversial. We sought to investigate the prevalence of POLE mutation tumor status and its prognostic significance on survival and recurrence outcomes in women with high grade endometrioid EC.
Methods: Polymerase chain reaction amplification and Sanger sequencing were previously used to test for POLE mutations in 72 grade 3, endometrioid tumors. Associations between demographics, survival, clinicopathologic, and molecular features were investigated. P-values were calculated by Fisher’s exact test and by Wilcoxon rank-sum test as appropriate. Cox proportional hazard models were used to estimate the adjusted associations between POLE mutation status and recurrence free survival (RFS).
CO
RR
EC
Results: Responses were received from 234 of 1154 SGO members (20%). Overall, respondents reported that 50% of patients were referred with known malignant disease, 30% with suspected malignant disease, and 20% with known benign disease. Minimally invasive surgery (MIS) was used in 66% of overall surgical volume but 78% of benign surgeries (P = b0.0001). The most common noncancer referrals were: adnexal masses without features concerning for malignancy, benign vulvar disease, and patients with medical comorbidities. More than half of respondents (65%) reported increased frequency of benign surgical referrals due to ability to offer MIS. Most (67%) felt benign surgery to have neutral or no impact on their ability to care for women with cancer. Gynecologic oncologists in private practice were more likely to report that benign gynecology positively affected their practice's finances than academic clinicians (61% versus 39%, P = 0.004). These clinicians were also more likely to encourage referral of patients with benign disease (45% versus 29%, P = 0.027).
UN
Conclusions: Benign gynecologic surgery accounts for approximately 20% of gynecologic oncologists' surgical volume. Most gynecologic oncologists have a neutral view on the impact of benign gynecologic surgery on their ability to care for cancer patients, professional satisfaction, and practice finances. Subspecialty expertise in minimally invasive techniques is likely to foster continued referrals for benign surgical procedures and management of benign pelvic masses. doi:10.1016/j.ygyno.2015.03.018
0090-8258/$ – see front matter.
Results: POLE mutations were identified in 7 of 72 (9.7%) grade 3 endometrioid ECs. There were no significant differences in the clinicopathologic features between those with POLE mutations compared to those without (wildtype). There was one recurrence among the 7 women with POLE mutant tumors (14.3%) compared to 26 of 65 women (40%) with wildtype tumors. A decreased risk of recurrence was suggested in those patients with a POLE mutation, even after adjusting for age (aHR = 0.37, 95%CI 0.09–1.55), as well as considerable decreased risk of death in women with a POLE mutation. This risk of death was approximately 1/5 of that of patients without a tumor POLE mutation, after adjusting for age (aHR = 0.19, 95% CI: 0.03–1.42). Conclusions: The prognostic role of POLE tumor mutation in endometrioid EC has previously been investigated with uncertain significance. However, in the subset of women with grade 3, endometrioid EC, there is a strong suggestion of a trend towards significantly better RFS and overall survival. These findings suggest that the risk of recurrence is 1/3, and the risk of death is decreased by 80% in women with POLE mutations compared to those without mutations. These findings may contribute to the existing literature of POLE mutations, and serve as a
Abstracts / Gynecologic Oncology 137 (2015) 591–599
doi:10.1016/j.ygyno.2015.03.019
Abstract 3: Inhibition of STAT3 in ovarian clear cell carcinoma results in decreased cell proliferation and induction of apoptosis K. Bixel, U. Saini, J. Fowler, S. Rajendiran, R. Wanner, K. Hideg, D.E. Cohn, S. Karuppaiyah. Ohio State University, Columbus, OH, United States Objectives: Advanced ovarian clear cell carcinoma (OCCC) is most often resistant to standard platinum and taxane chemotherapy making prognosis poor. STAT3 expression and activation have been shown to regulate tumor progression in various human cancers though has not been well studied in OCCC. In this study, we aim to characterize the expression of the STAT family of proteins in OCCC and examine the efficacy of HO-3867, a novel STAT3 inhibitor.
Results: Three hundred and fifty nine women were included in the final analysis. The mean patient age was 64.2 years. PMS2 and MLH1 were expressed less frequently in patients greater than 61 years of age (p b 0.05). In the older-age group, only 45.5% of those screened expressed the PMS2 gene compared to 76.8% of patients in the younger-age group. Similarly, the MLH1 gene was expressed in only 45.5% of patients in the older-age group compared to 73.9% in the younger-age group. No significant differences in gene expression were found between the two age groups for either the PMS1 and MLH2. Conclusions: Diminished expression of the PMS1 and MLH2 genes was noted in patients greater than 60 years of age with endometrial adenocarcinoma. Future large scale population-based studies are needed to confirm our findings. Should diminished gene expression be confirmed in patients over 60 years of age, consideration may be given to the modification of Lynch syndrome screening in patients with endometrial adenocarcinoma.
doi:10.1016/j.ygyno.2015.03.021
Abstract 5: Evaluation of universal immunohistochemistry screening for diagnosing Lynch syndrome in endometrial cancer patients at a tertiary care center E.G. Hartnetta, A. Stuckeya, C. McCourtb. aWomen & Infants Hospital/ Brown University, Providence, RI, United States, bWashington University in St. Louis, St. Louis, MO, United States
DP
Methods: OCCC tumor tissue was obtained from the tissue bank after IRB approval. Drug resistant OCCC cell lines used include JHOC, OVISE, OVTOKO, and RMGV. Cell lines were treated with cisplatin and HO-3867 alone and in combination. Protein expression in tumor tissues and cell lines were determined by western blotting (WB). Cell viability was determined by MTT assays, cell proliferation measured by BrdU assay, and ANNEXIN V kit was used to quantify apoptosis.
expression was compared in patients less than and older than 60 years of age. Data were analyzed using the chi square test.
OF
positive prognostic marker and may provide guidance in the treatment of women with grade 3 endometrioid tumors.
RO
592
Objectives: The aim of this study was to compare genetic counseling referrals and rates of Lynch syndrome (LS) detection during the initial year of universal screening (2013–2014) of endometrial cancers to those in the previous year when screenings and referrals were performed solely at physicians' discretion.
TE
Results: Activated STAT3 (pSTAT3 Tyr705 or Ser727) was consistently expressed in all 7 OCCC tumor samples evaluated. Additionally, OCCC cell lines constitutively expressed pSTAT3 whereas other forms of activated STAT were not present (pSTAT1, 2, 6). All cell lines treated were cisplatin resistant and treatment resulted in increased expression of pSTAT3 as well as FAS suggesting these pathways as possible mechanisms for resistance. Treatment with HO-3867 selectively decreased expression of pSTAT3 while total STAT3 remained constant. HO-3867 decreased cell proliferation by 50% to 60% in multiple OCCC cell lines. The inhibitory effect of HO-3867 on cell viability is associated with induction of apoptosis (28% to 43%) as confirmed by ANNEXIN V staining. Further, we have observed a decrease in BCL2 and cleavage of caspase 3, caspase 7 and PARP confirming induction of apoptosis.
EC
Methods: Universal screening for LS in all endometrial cancers treated at our institution was implemented in September 2013. Uterine specimens underwent immunohistochemistry (IHC) for mismatch repair protein markers MLH1, MSH2, MSH6 and PMS2 with reflex methylation testing when indicated. A genetic counselor contacted patients with abnormal screens to offer genetic counseling appointments. IHC results were collected for the initial year of universal screening. Additionally, a retrospective analysis was performed tracking molecular screens and referrals to genetics for all endometrial cancers treated in the year prior to universal screening. Results: Two hundred and five endometrial cancers were screened in the initial 12 months of universal screening and 230 endometrial cancers were tracked during the year without screening. During the universal screening period, 43 patients (21%) had abnormal IHC results: 1 lacked expression of MSH6/PMS2, 5 lacked MSH6 and 37 lacked MLH1/PMS2. Of the 37 patients who lacked MLH1/PMS2 expression, 36 had MLH1 promoter methylation and were assumed to have sporadic cancers. The 7 patients with confirmed abnormal screens were referred to genetics; 6 patients underwent genetic counseling and pursued genetic testing. Three women were diagnosed with LS and none of these patients met traditional criteria for screening. There were also 10 patients with negative IHC screens who were referred to genetic counseling based on family history alone. Between 2012 and 2013, 8 patients (3.5%) met traditional screening guidelines (Amsterdam II or revised Bethesda guidelines); none of these were screened. However, IHC was requested on 16 other patients, and a total of 6 patients were referred for genetic counseling. No cases of LS were diagnosed in the pre-screening year. Conclusions: Universal screening of endometrial cancers is critical
CO
RR
Conclusions: pSTAT3 is constitutively activated in OCCC tumor tissues and cell lines. Inhibition of pSTAT3 by HO-3867results in decreased cell viability and proliferation as well as induction of apoptosis in platinum resistant OCCC cell lines. These findings warrant future investigation into the mechanism by which HO-3867 targets the STAT3 pathway as well as its therapeutic efficacy in vivo. doi:10.1016/j.ygyno.2015.03.020
UN
Abstract 4: Differential gene expression associated with Lynch syndrome in patients less than and over 60 years of age with endometrial adenocarcinoma O. Dziadek, B. Shoup, K. Williams. UMKC School of Medicine, Kansas City, MO, United States Objectives: The purpose of the study was to determine trends in Lynch syndrome gene expression in patients less than 60 years of age compared to those greater than 60 years of age. Methods: A retrospective case control study was performed. Gene expression was determined for MSH1, MSH2, MSH6 and PMS2 via immunohistochemistry on all patients diagnosed with endometrial adenocarcinoma between December 2011 and December 2013. Gene