Enzyme-promoted kinetic resolution of acetoxymethyl aryl sulfoxides

Article abstract of DOI:10.1016/j.molcatb.2015.04.016

A simple and efficient method of the synthesis of enantiomerically enriched, unknown acetoxymethyl aryl sulfoxides has been developed which is based on an enzyme-catalyzed hydrolysis of racemic substrates under the kinetic resolution conditions. The hydro

Full text of DOI:10.1016/j.molcatb.2015.04.016

Gynecologic Oncology 137 (2015) 591–599
Contents lists available at ScienceDirect
Gynecologic Oncology
journal homepage: www.elsevier.com/locate/ygyno
SGO 2015 Winter Meeting Abstracts
Poster Presentations
Abstract 2: Prognostic significance of POLE exonuclease domain
mutations in high grade endometrioid endometrial cancer on
survival and recurrence
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
a
b
a
c
C. C. Billingsley , E. M. Hade , D. E. Cohn , D. G. Mutch , P. J.
a
a
Goodfellow . The Ohio State University, Department of Obstetrics and
Gynecology, Division of Gynecology Oncology, Columbus, OH, United
b
States, The Ohio State University, Department of Obstetrics and
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.
c
Gynecology, Biostatistics, Columbus, OH, United States, Washington
University, Department of Obstetrics and Gynecology, Division of
Gynecology Oncology, St. Louis, MO, United States
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: In November 2013, SGO members were invited to complete a
2
3-question online survey regarding surgical practice patterns. De-
scriptive statistics were used to analyze responses as well as chi square
and t-test banalyses.
Results: Responses were received from 234 of 1154 SGO members
Methods: Polymerase chain reaction amplification and Sanger se-
quencing 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).
(
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 non-
cancer 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 academ-
ic clinicians (61% versus 39%, P = 0.004). These clinicians were also
more likely to encourage referral of patients with benign disease
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 com-
pared 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).
(
45% versus 29%, P = 0.027).
Conclusions: Benign gynecologic surgery accounts for approximately
0% of gynecologic oncologists' surgical volume. Most gynecologic
2
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 mini-
mally invasive techniques is likely to foster continued referrals for
benign surgical procedures and management of benign pelvic
masses.
Conclusions: The prognostic role of POLE tumor mutation in endo-
metrioid EC has previously been investigated with uncertain signifi-
cance. 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
doi:10.1016/j.ygyno.2015.03.018
mutations compared to those without mutations. These findings may
contribute to the existing literature of POLE mutations, and serve as a
0
090-8258/$ – see front matter.

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Abstracts / Gynecologic Oncology 137 (2015) 591–599
positive prognostic marker and may provide guidance in the treatment
of women with grade 3 endometrioid tumors.
expression was compared in patients less than and older than
60 years of age. Data were analyzed using the chi square test.
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
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
4
5.5% 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.
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.
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.
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
doi:10.1016/j.ygyno.2015.03.021
Abstract 5: Evaluation of universal immunohistochemistry screen-
ing for diagnosing Lynch syndrome in endometrial cancer patients
at a tertiary care center
(
WB). Cell viability was determined by MTT assays, cell prolifera-
tion measured by BrdU assay, and ANNEXIN V kit was used to
quantify apoptosis.
a
a
b a
E.G. Hartnett , A. Stuckey , C. McCourt . Women & Infants Hospital/
Results: Activated STAT3 (pSTAT3 Tyr705 or Ser727) was consis-
tently expressed in all 7 OCCC tumor samples evaluated. Addition-
ally, 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
b
Brown University, Providence, RI, United States, Washington University in
St. Louis, St. Louis, MO, United States
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.
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 appoint-
ments. 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.
6
0% 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.
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.
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 diag-
nosed 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
doi:10.1016/j.ygyno.2015.03.020
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