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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 identied 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 endometrialcancer and was observed in 69% of samples. Defects in DNA polymerase

episilon and/or in mismatch repair drives hypermutation in endome-

trial cancers. Colorectal and stomach carcinomas also had hyper-

mutation as a recurring mutational subtype observed in 26% and 24% of 

samples, respectively. Despite the identication 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 proliferationwas 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 ef cacy of Minn alone

or in combination with C and paclitaxel (T). Tumors were evaluated

for apoptosis, proliferation and vessel density by immunohistochemis-

try (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%

condence intervals are presented.

Results: Minntreatment showed concentration dependentinhibitionof 

both platinum sensitive and resistant ovarian cancer cell growth at nMconcentrations. At 500 nM both cell types were completely inhibited

and stopped proliferating after 12 h of exposureto Minn. Theadditionof 

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 signicantly

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 combina-

tion of Minn and C + T showed additive effects with  N 250 apoptotic

cells/hpf.

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 perfor-

mance during the past decade.

Methods:   In this retrospective chart review, pap tests and Human

Papilloma Virus (HPV) tests performedfrom January1, 2013 to December

1, 2013 were identied 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 orinappropriate accordingto theage appropriateguidelines. Thepercentage

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 identied 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

performedand 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

numberof papand HPV tests at inappropriatetime intervals. Adherence

to national guidelines has signicantly deteriorated in the past decade.

Inappropriate pap and HPV tests cost our local healthcare system nearly

 Abstracts   387

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$2 million yearly which extrapolates to over $1 billion annually in

the US.

doi:10.1016/j.ygyno.2014.07.022

Discrepant cervical cytology and colposcopic directed biopsies:

Clinical predictive factors

A. Ramzana

, T. Menesesb

, Y. Linc

, P. Faucegliab

. a

Department of Obstetricsand Gynecology at University of Southern California, Los Angeles, CA, USA,bDepartment of Pathology at University of Southern California, Los Angeles,

CA, USA,   c Department of Gynecologic Oncology at University of Southern

California, Los Angeles, CA, USA.

Objectives:  Discrepancies between cervical cytology (CC) and subse-

quent cervical biopsy (CB) results are problematic for clinicians and

patients. This study aims to identify clinical variables to account for

discrepancies between CC and corresponding CB to help inform future

management.

Methods: This is a retrospective cohort study as part of an institutional

QA program. All cases of CC and their corresponding CB from 2010

to 2013 were identied from pathology archives. Clinical data were

retrieved from a chart review of the medical record. Diagnoses for all

discrepant cases were conrmed by an expert cytologistand a pathologist

blinded to the original diagnosis. Discrepant cases were classied as

(1) major and (2) minor. A major discrepancy is a case with high-grade

cytologic AGC, ASC-H or HSIL and histologicbenign epithelium or CIN1. A

minor discrepancy is a case with low-grade cytologic ASC-US or LSIL and

histologic CIN-2 or -3. Uni- and multivariate analyses were performed to

identify clinical variables associated with CC/CB discrepancy.

Results:   Of 304 identied cases, 114 were discrepant; 190 were

concordant (controls). The median ages for patients with high-grade

andlow-grade cytologicabnormalities were 43 years (range 20–73) and

38 years (range 14–72), respectively. The study population comprised

of 174 (57%) Hispanic, 74 (24%) white, and 56 (19%) other racial

groups. Major discrepancies were 8 times more likely to occur among

CC collected by mid-level practitioners compared to CC collected by

physicians (p = 0.008). Furthermore, a time lapseN60 daysbetween CC

and CB, as well as an immune compromised status showed a trend

towards signicance for major discrepancies (p = 0.061 each). High-

risk HPV positivity was associated with a 3.6 fold increase in observing a

minor discrepancy among CC and CB (p = 0.005). Surprisingly, the

training level of the colposcopist did not signicantly impact the rate of 

CC/CB discrepancy.

Conclusion: Thisstudy identies several variables associatedwithCC/CB

discrepancies that are important for a rigorous multi-disciplinary quality

assurance effort. The clinical signicance of the higher discrepancy rate

among CC collected by non-physicians is unclear, but represents an

opportunity to critically examine CC collection practices among all

providers. The association of high-risk HPV with minor discrepancy

between CC and CB supports the 2012 ASCCP guidelines recommending

that those with detectable high-risk HPV undergo immediate colposcopyand biopsy.

doi:10.1016/j.ygyno.2014.07.023

Negative loop electrosurgical excision procedure biopsies following 

high grade dysplasia: Good news or bad?

Shireen De Sam Lazaro, Colin Newbill, Michelle Berlin, Terry Morgan.

Objectives:   Loop electrosurgical excision procedure (LEEP) is fre-

quently used to evaluate and treat high grade cervical intraepithelial

neoplasia (CIN2 or 3). Absence of dysplasia on LEEP specimens

presents a dilemma for clinicians, as the implications of negative

LEEPs are uncertain. Our study sought to determine the proportion

of LEEP procedures with no evidence of dysplasia (“negative” LEEPs)

and proportion with dysplasia at follow-up at our institution. Addi-

tionally, we wanted to evaluate if increased use of p16 immuno-

staining on colposcopic directed biopsy prior to the LEEP reduces

frequency of negative LEEPs.

Methods:  A retrospective clinicopathologic review of all 955 cervical

LEEPs performed from 2000 to 2012 was performed. Colposcopic

biopsies and LEEP specimens were reviewed to con

rm high-gradedysplasia with p16 immunostaining if indicated. Data obtained from

chart review included age, colposcopic biopsy diagnosis, Pap smear

diagnosis and history, birth control method, STI, and smoking history.

Data were analyzed comparing the frequency of conrmed negative

LEEPs in the period before p16 use (2002–2005) to the period after

initiation (2006–2012) by Chi squared and logistic regression. Descrip-

tive statistics were utilized for clinical characteristic variables, which

were then compared using Chi squared and logistic regression.

Results:   The frequency of negative LEEPs before 2006 was 12/126

(10%), which then dropped to a frequency of 23/447 (5%) from 2006 to

2012. From 2006 to 2012, p16 use by our pathologists rose to a peak

frequency of 37%. The odds ratio of having a negative LEEP following a

CIN2+ biopsy without p16 support was 1.9 [1.0–4.0] (p = 0.05).

Conclusion: We observed a signicant reduction in the frequency of 

negative follow-up LEEPs after our practice began using p16 to assist

with CIN2+ classication. This is signicant because fewer unnec-

essary LEEPs will improve patient care and cost-effectiveness.

doi:10.1016/j.ygyno.2014.07.024

Following the gynecologic health of women living in New Orleans

 with both HIV and cervical dysplasia

L. Miller, K. Kjellsson, W. Robinson III.   Tulane Cancer Center and

School of Medicine, USA.

Objectives:   The purpose of this report is to assess the long-term

outcomes of Cervical Intraepithelial Neoplasia (CIN) and generalgynecologic status in a cohort of HIV-infected women enrolled in

cooperative group randomized clinical trials and followed over a

time period of up to 20 years.

Methods:  218 women were enrolled between 1994 and 1998 in two

international cooperative group sponsored randomized clinical trials

ACTG 200 and 293. 32 were enrolled from a single site. The current

study compares health outcomes in this population against historical

data. The normal theory test, Fisher's exact test, and chi-squared test

with Yates' correction were applied to evaluate incidence of recurrence

and progression of dysplasia, incidence of cervical cancer, hysterecto-

mies, and adherence to HAART therapy.

Results: The risk of recurrence or progression of cervical neoplasia in

this well-documented cohort of HIV-infected women is similar to that

seen in the general US population. No new cases of cervical cancerwere diagnosed. Thestudycohort wasfoundto have a lower incidence

of hysterectomy and other gynecologic surgeries. The study cohort

also displayed betteradherence to HAART therapy, higherCD4 counts,

and fewer co-infections or neoplasms than HIV-infected women not

diagnosed with cervical neoplasia in the same community.

Conclusion:  Very little data exists on long-term follow up of HIV-

infected women with cervical neoplasia. In this population, the long-

term risk of recurrence or progression of cervical neoplasia in HIV-

infected women who use HAART and have stable HIV-related disease

is similar to that seen in the general population. Also, HIV-infected

women with CIN who enrolled in clinical trials have fewer gyne-

cologic surgeries and better adherence to HAART. The long-term risk

of cervical neoplasia appears to be directly correlated to control of 

the HIV-disease process in infected women. Enrollment in clinical

 Abstracts388

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