Publications by authors named "Floor J Backes"

69 Publications

Endometrial cancer: A society of gynecologic oncology evidence-based review and recommendations.

Gynecol Oncol 2021 Mar 27;160(3):817-826. Epub 2021 Jan 27.

Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Medicine, Stony Brook University Cancer Center, Stony Brook, NY, United States of America.

Introduction: In 2014, the Society of Gynecologic Oncology's Clinical Practice Committee published a clinical update reviewing the treatment of women with endometrial cancer. At that time, there had been significant advances in the diagnosis, work-up, surgical management, and available treatment options allowing for more optimal care of affected women. Despite these advances, the incidence of endometrial cancer as well as the deaths attributable to the disease have continued to rise; from 1987 to 2014 there has been a 75% increase in cases and almost 300% increase in endometrial cancer deaths. Fortunately, since then, there has been progress in the treatment of patients with endometrial cancer with increased utilization of molecular pathology, greater understanding of genetic predisposition, enhanced methods for lymph node assessment, a broader understanding of the efficacy of radiation and chemotherapy, and a more efficient approach to survivorship and surveillance. The purpose of this document is to present a comprehensive review of this progress.

Manuscript Development Process: The authors reviewed the available evidence, contributed to the development of this manuscript, provided critical review of the guidelines, and finalized the manuscript recommendations. The review was also presented to and approved by the Society of Gynecologic Oncology (SGO) Clinical Practice Committee, SGO Publications Committee, and the SGO board members prior to submission for publication. The recommendations for this manuscript were developed by a panel of gynecologic oncologists who were members of the SGO Clinical Practice and Education Committees. Panelists reviewed and considered evidence from current uterine cancer literature. The terminology used in these guidelines was adopted from the ASCCP management guidelines [1] using a two-part rating system to grade the strength of recommendation and quality of evidence (Table 1). The rating for each recommendation is given in parentheses.
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http://dx.doi.org/10.1016/j.ygyno.2020.12.021DOI Listing
March 2021

Endometrial cancer: A society of gynecologic oncology evidence-based review and recommendations, part II.

Gynecol Oncol 2021 Mar 13;160(3):827-834. Epub 2021 Jan 13.

Department of Obstetrics, Gynecology and Reproductive Medicine, Stony Brook University Cancer Center, Stony Brook, NY, United States of America.

In 2014, the Society of Gynecologic Oncology's Clinical Practice Committee published a clinical update reviewing the treatment of women with endometrial cancer. At that time, there had been significant advances in the diagnosis, work-up, surgical management, and available treatment options allowing for more optimal care of affected women. This manuscript, Part II in a two-part series, includes specific recommendations on treatment of recurrent disease, post treatment surveillance and survivorship, considerations for younger women, and special situations. Part I covered histopathology and molecular pathology, risk factors, presentation and diagnostic approach, surgical approach and adjuvant therapy.
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http://dx.doi.org/10.1016/j.ygyno.2020.12.024DOI Listing
March 2021

Pathologic chemotherapy response score in epithelial ovarian cancer: Surgical, genetic, and survival considerations.

Surg Oncol 2020 Sep 11;34:40-45. Epub 2020 Mar 11.

Department of Obstetrics and Gynecology, The Ohio State University Wexner Medical Center, Columbus, United States. Electronic address:

Objective: A pathologic chemotherapy response score (CRS) is used to grade ovarian cancer response to neoadjuvant chemotherapy (NACT). We evaluated the prognostic significance of the CRS in a single institution cohort.

Methods: A retrospective review of all consecutive epithelial ovarian cancer patients undergoing interval debulking surgery (IDS) after NACT from 2016 to 2017 were included. Clinical, pathologic, surgical, outcomes, and genetic data were abstracted from medical records. CRS was assigned by pathology based on a section of omentum as follows: 1 = minimal response, 2 = moderate response, and 3 = near complete response.

Results: Among the 50 subjects, 14 (28%) were classified as CRS1, 29 (58%) as CRS2, and 7 (14%) as CRS3. The majority of patients were diagnosed with high grade serous histology (94%). Most women in this cohort underwent either an optimal or complete cytoreduction to no gross residual disease (96%). Women in the CRS2 group were most likely to have a pathogenic variant (51.7%) while those in the CRS1 were least likely (7.1%). Most women recurred regardless of CRS. CRS was not associated with progression-free survival (log-rank p = 0.82) or overall survival (log-rank p = 0.30).

Conclusions: Though previous data support the use of CRS as a prognostic indicator, we failed to show a correlation between CRS and survival in our continuous single institution cohort. The high rate of optimal debulking across all CRS groups in this study may mitigate the prognostic significance of the scoring system. Nevertheless, tumors that respond poorly to traditional chemotherapy should remain of avid interest for potential novel therapies.
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http://dx.doi.org/10.1016/j.suronc.2020.03.001DOI Listing
September 2020

Evaluating the efficacy of enzalutamide and the development of resistance in a preclinical mouse model of type-I endometrial carcinoma.

Neoplasia 2020 10 17;22(10):484-496. Epub 2020 Aug 17.

Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA. Electronic address:

Androgen Receptor (AR) signaling is a critical driver of hormone-dependent prostate cancer and has also been proposed to have biological activity in female hormone-dependent cancers, including type I endometrial carcinoma (EMC). In this study, we evaluated the preclinical efficacy of a third-generation AR antagonist, enzalutamide, in a genetic mouse model of EMC, Sprr2f-Cre;Pten. In this model, ablation of Pten in the uterine epithelium leads to localized and distant malignant disease as observed in human EMC. We hypothesized that administering enzalutamide through the diet would temporarily decrease the incidence of invasive and metastatic carcinoma, while prolonged administration would result in development of resistance and loss of efficacy. Short-term treatment with enzalutamide reduced overall tumor burden through increased apoptosis but failed to prevent progression of invasive and metastatic disease. These results suggest that AR signaling may have biphasic, oncogenic and tumor suppressive roles in EMC that are dependent on disease stage. Enzalutamide treatment increased Progesterone Receptor (PR) expression within both stromal and tumor cell compartments. Prolonged administration of enzalutamide decreased apoptosis, increased tumor burden and resulted in the clonal expansion of tumor cells expressing high levels of p53 protein, suggestive of acquired Trp53 mutations. In conclusion, we show that enzalutamide induces apoptosis in EMC but has limited efficacy overall as a single agent. Induction of PR, a negative regulator of endometrial proliferation, suggests that adding progestin therapy to enzalutamide administration may further decrease tumor burden and result in a prolonged response.
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http://dx.doi.org/10.1016/j.neo.2020.07.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7452078PMC
October 2020

Randomized Phase II Trial of Carboplatin-Paclitaxel Compared with Carboplatin-Paclitaxel-Trastuzumab in Advanced (Stage III-IV) or Recurrent Uterine Serous Carcinomas that Overexpress Her2/Neu (NCT01367002): Updated Overall Survival Analysis.

Clin Cancer Res 2020 08 29;26(15):3928-3935. Epub 2020 Jun 29.

Yale University, New Haven, Connecticut.

Purpose: Uterine-serous-carcinoma (USC) is an aggressive variant of endometrial cancer. On the basis of preliminary results of a multicenter, randomized phase II trial, trastuzumab (T), a humanized-mAb targeting Her2/Neu, in combination with carboplatin/paclitaxel (C/P), is recognized as an alternative in treating advanced/recurrent HER2/Neu-positive USC. We report the updated survival analysis of NCT01367002.

Patients And Methods: Eligible patients had stage III to IV or recurrent disease. Participants were randomized 1:1 to receive C/P for six cycles ± T followed by maintenance T until progression or toxicity. Progression-free survival (PFS) was the primary endpoint; overall survival (OS) and toxicity were secondary endpoints.

Results: Sixty-one patients were randomized. After a median-follow-up of 25.9 months, 43 progressions and 38 deaths occurred among 58 evaluable patients. Updated median-PFS continued to favor the T-arm, with medians of 8.0 months versus 12.9 months in the control and T-arms (HR = 0.46; 90% CI, 0.28-0.76; = 0.005). Median-PFS was 9.3 months versus 17.7 months among 41 patients with stage III to IV disease undergoing primary treatment (HR = 0.44; 90% CI, 0.23-0.83; = 0.015), and 7.0 months versus 9.2 months among 17 patients with recurrent disease (HR = 0.12; 90% CI, 0.03-0.48; = 0.004). OS was higher in the T compared with the control arm, with medians of 29.6 months versus 24.4 months (HR = 0.58; 90% CI, 0.34-0.99; = 0.046). The benefit was most notable in those with stage III to IV disease, with survival median not reached in the T-arm versus 24.4 months in the control arm (HR = 0.49; 90% CI, 0.25-0.97; = 0.041). Toxicity was not different between arms.

Conclusions: Addition of T to C/P increased PFS and OS in women with advanced/recurrent HER2/Neu-positive USC, with the greatest benefit seen for the treatment of stage III to IV disease.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0953DOI Listing
August 2020

ALDH1A1 Contributes to PARP Inhibitor Resistance via Enhancing DNA Repair in BRCA2 Ovarian Cancer Cells.

Mol Cancer Ther 2020 01 18;19(1):199-210. Epub 2019 Sep 18.

Department of Radiation Oncology, College of Medicine, The Ohio State University, Columbus, Ohio.

Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are approved to treat recurrent ovarian cancer with or mutations, and as maintenance therapy for recurrent platinum-sensitive ovarian cancer (BRCA wild-type or mutated) after treatment with platinum. However, the acquired resistance against PARPi remains a clinical hurdle. Here, we demonstrated that PARP inhibitor (olaparib)-resistant epithelial ovarian cancer (EOC) cells exhibited an elevated aldehyde dehydrogenase (ALDH) activity, mainly contributed by increased expression of ALDH1A1 due to olaparib-induced expression of BRD4, a member of bromodomain and extraterminal (BET) family protein. We also revealed that ALDH1A1 enhanced microhomology-mediated end joining (MMEJ) activity in EOC cells with inactivated BRCA2, a key protein that promotes homologous recombination (HR) by using an intrachromosomal MMEJ reporter. Moreover, NCT-501, an ALDH1A1-selective inhibitor, can synergize with olaparib in killing EOC cells carrying BRCA2 mutation in both cell culture and the xenograft animal model. Given that MMEJ activity has been reported to be responsible for PARPi resistance in HR-deficient cells, we conclude that ALDH1A1 contributes to the resistance to PARP inhibitors via enhancing MMEJ in BRCA2 ovarian cancer cells. Our findings provide a novel mechanism underlying PARPi resistance in BRCA2-mutated EOC cells and suggest that inhibition of ALDH1A1 could be exploited for preventing and overcoming PARPi resistance in EOC patients carrying BRCA2 mutation.
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http://dx.doi.org/10.1158/1535-7163.MCT-19-0242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946874PMC
January 2020

Preoperative predictors of endometrial cancer at time of hysterectomy for endometrial intraepithelial neoplasia or complex atypical hyperplasia.

Am J Obstet Gynecol 2020 01 8;222(1):60.e1-60.e7. Epub 2019 Aug 8.

Division of Gynecologic Oncology, Department of Obstetrics/Gynecology, The Ohio State University College of Medicine, Columbus, OH. Electronic address:

Background: Endometrial intraepithelial neoplasia, also known as complex atypical hyperplasia, is a precancerous lesion of the endometrium associated with a 40% risk of concurrent endometrial cancer at the time of hysterectomy. Although a majority of endometrial cancers diagnosed at the time of hysterectomy for endometrial intraepithelial neoplasia are low risk and low stage, approximately 10% of patients ultimately diagnosed with endometrial cancers will have high-risk disease that would warrant lymph node assessment to guide adjuvant therapy decisions. Given these risks, some physicians choose to refer patients to a gynecologic oncologist for definitive management. Currently, few data exist regarding preoperative factors that can predict the presence of concurrent endometrial cancer in patients with endometrial intraepithelial neoplasia. Identification of these factors may assist in the preoperative triaging of patients to general gynecology or gynecologic oncology.

Objective: To determine whether preoperative factors can predict the presence of concurrent endometrial cancer at the time of hysterectomy in patients with endometrial intraepithelial neoplasia; and to describe the ability of preoperative characteristics to predict which patients may be at a higher risk for lymph node involvement requiring lymph node assessment at the time of hysterectomy.

Materials And Methods: We conducted a retrospective cohort study of women undergoing hysterectomy for pathologically confirmed endometrial intraepithelial neoplasia from January 2004 to December 2015. Patient demographics, imaging, pathology, and outcomes were recorded. The "Mayo criteria" were used to determine patients requiring lymphadenectomy. Unadjusted associations between covariates and progression to endometrial cancer were estimated by 2-sample t-tests for continuous covariates and by logistic regression for categorical covariates. A multivariable model for endometrial cancer at the time of hysterectomy was developed using logistic regression with 5-fold cross-validation.

Results: Of the 1055 charts reviewed, 169 patients were eligible and included. Of these patients, 87 (51.5%) had a final diagnosis of endometrial intraepithelial neoplasia/other benign disease, whereas 82 (48.5%) were ultimately diagnosed with endometrial cancer. No medical comorbidities were found to be strongly associated with concurrent endometrial cancer. Patients with endometrial cancer had a thicker average endometrial stripe compared to the patients with no endometrial cancer at the time of hysterectomy (15.7 mm; standard deviation, 9.5) versus 12.5 mm; standard deviation, 6.4; P = .01). An endometrial stripe of ≥2 cm was associated with 4.0 times the odds of concurrent endometrial cancer (95% confidence interval, 1.5-10.0), controlling for age. In all, 87% of endometrial cancer cases were stage T1a (Nx or N0). Approximately 44% of patients diagnosed with endometrial cancer and an endometrial stripe of ≥2 cm met the "Mayo criteria" for indicated lymphadenectomy compared to 22% of endometrial cancer patients with an endometrial stripe of <2 cm.

Conclusion: Endometrial stripe thickness and age were the strongest predictors of concurrent endometrial cancer at time of hysterectomy for endometrial intraepithelial neoplasia. Referral to a gynecologic oncologist may be especially warranted in endometrial intraepithelial neoplasia patients with an endometrial stripe of ≥2 cm given the increased rate of concurrent cancer and potential need for lymph node assessment.
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http://dx.doi.org/10.1016/j.ajog.2019.08.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7201377PMC
January 2020

Prospective clinical trial of robotic sentinel lymph node assessment with isosulfane blue (ISB) and indocyanine green (ICG) in endometrial cancer and the impact of ultrastaging (NCT01818739).

Gynecol Oncol 2019 06 4;153(3):496-499. Epub 2019 Apr 4.

Division of Gynecologic Oncology, The Ohio State University Wexner Medical Center, James Cancer Hospital, Columbus, OH, USA.

Objectives: To assess the performance sentinel lymph node (SLN) biopsy and effect of ultrastaging in clinically early stage endometrial cancer.

Methods: Patients with endometrial cancer prospectively enrolled after informed consent was obtained. The cervix was injected superficially with 1 mL of ISB and 1 mL of ICG (diluted 1:25) at 3 and 9 o'clock each. SLN biopsy was followed by complete pelvic lymphadenectomy (aortic lymphadenectomy at the discretion of the surgeon). Lymph nodes (LNs) were analyzed by standard sectioning with H&E; ultrastaging of SLN was done retrospectively and blinded to treating physicians.

Results: 204 patients received dye injections. In 184 (90.2%) patients at least one SLN was identified. Of all patients, 138 (68%) had bilateral mapping. In the patients with successful mapping of a hemipelvis, ICG detected SLNs in 83% and ISB in 64% of cases (p < 0.0001). Median BMI (kg/m) for patients with successful mapping was 35.7 compared to 40.1 for those who did not map (p = 0.01). Twenty-three (11.3%) patients had positive LNs. Applying the SLN algorithm, positive nodes were detected in 21/23 (91.3%). The negative predictive value (NPV) was 98.9% (95% CI: 96.01% to 99.71%). Eleven patients had positive SLN with isolated tumor cells (ITCs) or micrometastases detected on ultrastaging. Including these patients, 34 (17%) had positive LNs, increasing the NPV to 99% and sensitivity to 94%. There were no recurrences in patients with ITCs only.

Conclusions: SLN assessment in endometrial cancer is feasible and safe with high NPV (99%). ICG was more effective in detecting SLN compared to ISB. Although ultrastaging detected additional positive LNs, treatment based on standard sectioning appears reasonable but further research is needed.
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http://dx.doi.org/10.1016/j.ygyno.2019.03.252DOI Listing
June 2019

Conization pathologic features as a predictor of intermediate and high risk features on radical hysterectomy specimens in early stage cervical cancer.

Gynecol Oncol 2019 05 2;153(2):255-258. Epub 2019 Feb 2.

The Ohio State University, James Cancer Hospital, Division of Gynecologic Oncology, 320 West 10(th) Avenue, Columbus, OH 43210, USA. Electronic address:

Objective: The impact of pathologic features of a cone biopsy on the management of women with early stage cervical cancer is understudied. Our objective was to evaluate the additive value of pathologic features of a cone biopsy toward identifying patients with high risk tumors for which adjuvant therapy may be indicated.

Methods: Patients with early stage cervical cancer undergoing a conization followed by radical hysterectomy from 1995 to 2016 were retrospectively identified. Clinical and pathologic data were abstracted from patient medical records.

Results: A total of 115 patients were identified. Based on final pathology, 70.5% were low risk, 10.4% intermediate risk, and 19.1% were high risk. The additive pathologic features of the conization specimen would have reclassified five patients from low into the intermediate risk group. Though depth of invasion did not correlate with final pathology results, when lymphovascular space invasion (LVSI) was present in the conization specimen, 51.2% of patients were noted to meet intermediate/high risk; compared to only 9.5% without LVSI.

Conclusions: In women with early stage cervical cancer, additive pathology of the conization and hysterectomy specimen did not significantly impact risk stratification, only affecting 4.3% of patients. However, presence of LVSI in the conization was associated with intermediate risk criteria in 60% of cases and high risk criteria in 37% of cases. As patients with intermediate/high risk criteria would meet recommendations for adjuvant therapy, the evaluation of LVSI in conization specimens may influence the selection of primary treatment for women with cervical cancer.
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http://dx.doi.org/10.1016/j.ygyno.2019.01.026DOI Listing
May 2019

Mismatch repair deficiency identifies patients with high-intermediate-risk (HIR) endometrioid endometrial cancer at the highest risk of recurrence: A prognostic biomarker.

Cancer 2019 02 18;125(3):398-405. Epub 2018 Dec 18.

Division of Gynecologic Oncology, Ohio State University Comprehensive Cancer Center, Columbus, Ohio.

Background: The objective of this study was to assess the correlation between mismatch repair (MMR) status, disease recurrence patterns, and recurrence-free survival (RFS) in patients with high-intermediate-risk (HIR) endometrioid endometrial cancer (EEC).

Methods: A single-institution chart review for consecutive patients who were diagnosed with ECC between 2007 and 2016 was undertaken. Tumor MMR status was determined for all patients based on reported findings for mutL homolog 1 (MLH1), postmeiotic segregation (PMS2), mutS homolog 2 (MSH2), and MSH6 immunohistochemistry; and defective MMR (dMMR) status was defined as the lack of expression of at least 1 of these proteins. Patients were classified with HIR EEC according to criteria used for Gynecologic Oncology Group study 249. The factors associated with recurrence were assessed by logistic regression. RFS and associated factors were assessed by Kaplan-Meier survival analysis and Cox proportional-hazards models.

Results: In total, 197 patients who had HIR EEC (64 with dMMR and 133 with intact MMR [iMMR]) were identified, of whom 32 (16.2%) developed recurrent disease. The median follow-up was 54 months. The recurrence rate for women who had dMMR was 28% compared with 10.5% for those who had iMMR (P = .002), independent of the type of adjuvant therapy they received. The increase in distant recurrences among patients who had dMMR was even more pronounced (14.1% vs 3%; P = .003). The estimated 5-year RFS was 66% for women who had dMMR compared with 89% for those who had iMMR (P = .001). Excluding isolated vaginal recurrences, the difference in 5-year RFS was 73.5% versus 95%, respectively (P = .0004).

Conclusions: Patients who had HIR EEC with dMMR had increased rates of recurrence and decreased RFS compared with those who had HIR EEC with iMMR, despite the receipt of similar adjuvant treatment. The current findings highlight the need for alternative treatment options and the importance of MMR status as a biomarker for patients with HIR EEC.
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http://dx.doi.org/10.1002/cncr.31901DOI Listing
February 2019

Outpatient desensitization of patients with moderate (high-risk) to severe platinum hypersensitivity reactions.

Gynecol Oncol 2019 02 29;152(2):316-321. Epub 2018 Nov 29.

Division of Gynecologic Oncology, Department of Obstetrics/Gynecology, The Ohio State University College of Medicine, Columbus, OH 43220, USA. Electronic address:

Objectives: Platinum hypersensitivity reactions (HSR) affect approximately 5% of the general oncologic population. Here we report the efficacy and safety of outpatient platinum desensitization protocol (PD) in gynecologic oncology patients with moderate (high-risk) to severe platinum HSR.

Methods: This is a retrospective report of patients with gynecologic malignancies undergoing an outpatient PD for moderate (high-risk) to severe platinum HSR from 2011 to 2017. Patient demographics, chemotherapy histories, and PD outcomes were collected. Descriptive statistics were performed given the exploratory nature of the study.

Results: Forty-eight patients meeting inclusion criteria were identified. Most patients were being treated for ovarian cancer (56.3%) and were receiving carboplatin during their initial platinum HSR (75.0%). Patients received a mean of 10.3 platinum doses prior to their initial HSR. Transient hypertension was the most common sign of moderate (high-risk) HSR while persistent tachycardia was the most common sign of severe HSR. A total of 295 PD cycles were attempted with a successful completion rate of 96.6%. The mean number of PD cycles received by patients was 5.1. Almost 65% of patients experienced breakthrough reactions but over 58% of these breakthrough reactions were isolated to the first PD cycle. Only 8.3% of patients had severe breakthrough reactions, all of whom initially underwent shortened desensitization. Of these 4 patients, 2 successfully underwent desensitization with a prolonged protocol.

Conclusion: Outpatient PD is safe and effective in patients with gynecologic malignancies. This may present a feasible option for institutions with multi-disciplinary teams experienced with the management of platinum HSR.
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http://dx.doi.org/10.1016/j.ygyno.2018.10.037DOI Listing
February 2019

The Adrenal Gland as a Sanctuary Site of Metastases After Pembrolizumab Treatment: A Case Series.

J Natl Compr Canc Netw 2018 11;16(11):1279-1283

Therapeutic agents targeting the PD-1/PD-L1 axis have shown durable clinical responses in patients with various cancer types. Although objective responses are common, intrapatient heterogeneous responses have been described, and the mechanism for the different organ responses remains unknown. We present a series of patients in whom a lack of response was noted solely in the adrenal glands. This is the first case series describing 3 patients with heterogeneous patterns of response to pembrolizumab with progression of adrenal metastatic disease despite objective response (complete or partial response) in all other sites of metastatic disease. Two patients, one with melanoma and one with uterine carcinosarcoma, underwent robotic adrenalectomy for enlarging adrenal metastases. An additional patient with melanoma underwent laparotomy with attempted resection, but infiltration of the adrenal tumor into the inferior vena cava prohibited safe excision. This report provides additional insight into the heterogeneous patterns of disease response to anti-PD-1 therapy, highlighting the adrenal gland as a potential sanctuary site for this immunotherapy. These cases display the potential benefit of early surgical resection in this scenario and the pitfalls of delaying referral to a surgeon for assessment of operative intervention.
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http://dx.doi.org/10.6004/jnccn.2018.7059DOI Listing
November 2018

Time to chemotherapy in ovarian cancer: Compliance with ovarian cancer quality indicators at a National Cancer Institute-designated Comprehensive Cancer Center.

Gynecol Oncol 2018 12 30;151(3):501-505. Epub 2018 Sep 30.

Division of Gynecologic Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, United States of America.

Objective: To assess compliance with, and outcomes related to, the Society of Gynecologic Oncology quality measure in ovarian cancer to administer chemotherapy within 42 days of cytoreductive surgery in patients with epithelial ovarian/fallopian tube/peritoneal cancer.

Methods: Institutional ovarian cancer database was evaluated for compliance with the quality measure to administer chemotherapy within 42 days of cytoreductive surgery. The influence of chemotherapy timing on the risk of death was evaluated, and factors related to the timing of chemotherapy after surgery was assessed.

Results: Of 668 patients with epithelial ovarian/fallopian tube/peritoneal cancer who underwent surgical treatment for their disease (primary or interval), 635 met criteria for administration of adjuvant chemotherapy (with stages IA/IB, grade 2 or 3 disease; stage IC or more advanced stage disease). Compliance to administer chemotherapy within 42 days was 59.1%. The adjusted risk of death was not strongly associated with time to chemotherapy within 42 days (aHR: 0.80; 0.61, 1.05) and this did not differ by primary or interval debulking surgery.

Conclusions: In this prospectively maintained database, 59.1% of patients received chemotherapy within 42 days of surgery. The time to chemotherapy interval of within 42 days was not strongly associated with improved survival, particularly when age, stage of disease, insurance enrollment and surgical characteristics were taken into account. Further, the relationship between time to chemotherapy interval of within 42 days and survival did not vary by patients who received primary versus interval debulking surgery or had no residual disease.
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http://dx.doi.org/10.1016/j.ygyno.2018.09.014DOI Listing
December 2018

Functional characterization of recurrent FOXA2 mutations seen in endometrial cancers.

Int J Cancer 2018 12 29;143(11):2955-2961. Epub 2018 Sep 29.

Division of Gynecologic Oncology, James Comprehensive Cancer Center at The Ohio State University, Columbus, OH.

FOXA2, a member of the forkhead family of DNA-binding proteins, is frequently mutated in uterine cancers. Most of the mutations observed in uterine cancers are frameshifts and stops. FOXA2 is considered to be a driver gene in uterine cancers, functioning as a haploinsufficient tumor suppressor. The functional consequences of FOXA2 mutations, however, have not yet been determined. We evaluated the effects that frameshift mutations and a recurrent missense mutation have on FOXA2 transcriptional activity. Recurrent N-terminal frameshifts resulted in truncated proteins that failed to translocate to the nucleus and have no transcriptional activity using an E-cadherin/luciferase reporter assay. Protein abundance was reduced for the recurrent p.S169 W mutation, as was transcriptional activity. A C-terminal frameshift mutation had increased FOXA2 levels evidenced by both Western blot and immunofluorescence. Given that FOXA2 is a recognized activator of E-cadherin (CDH1) expression and E-cadherin's potential role in epithelial-to-mesenchymal transition in a wide range of cancer types, we tested the hypothesis that FOXA2 mutations in primary uterine cancer specimens would be associated with reduced CDH1 transcript levels. qRT-PCR revealed significantly lower levels of CDH1 expression in primary tumors with FOXA2 mutations. Our findings in vitro and in vivo suggest that reduced transcriptional activity associated with FOXA2 mutations in uterine cancers is likely to contribute to protumorigenic changes in gene expression.
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http://dx.doi.org/10.1002/ijc.31784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235715PMC
December 2018

Detection of endometrial cancer cells in the fallopian tube lumen is associated with adverse prognostic factors and reduced survival.

Gynecol Oncol 2018 07 10;150(1):38-43. Epub 2018 May 10.

Division of Pathology, The Ohio State University College of Medicine, Columbus, OH, United States.

Objective: Stage is a critical determinant of prognosis and treatment for endometrial cancer (EC) patients. Women who have had a tubal ligation for sterilization have improved EC survival, secondary to lower stage at presentation, suggesting that transtubal spread may represent an important route of metastasis. We evaluated detection of intraluminal tumor cells (ILTCs) in relation to tumor characteristics and survival.

Methods: One pathologist retrospectively evaluated hematoxylin and eosin sections of routinely collected fallopian tubes for ILTCs from 295 EC patients, masked to outcome. We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between demographic (age, race) and clinical [FIGO 2009 stage, lymphovascular space invasion (LVSI), histological subtype] characteristics and ILTCs. Cox regression was used to estimate hazard ratios (HRs) and 95% CIs for associations between ILTCs and recurrence-free survival (RFS) and EC-specific survival, overall and stratified by histological subtype or stage.

Results: In univariable logistic regression models, age (55-64 vs. ≥65: OR = 3.41, 95% CI = 1.48-7.84), stage (stage IV vs. stage I OR = 14.58, 95% CI = 5.27-40.35), LVSI (OR = 2.93, 95% CI = 1.42-6.04), and histological subtype (serous vs. low-grade endometrioid OR = 3.21, 95% CI = 1.08-9.58), were associated with ILTCs. Only age and stage remained significantly associated with ILTCs in adjusted models. ILTCs were significantly associated with lower EC-specific survival among women with serous EC or stage I disease; however, adjustment for age, stage, and histology attenuated these associations.

Conclusion: Our findings suggest that ILTCs are associated with adverse EC prognostic features and reduced survival in cases of early stage or serous histology.
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http://dx.doi.org/10.1016/j.ygyno.2018.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6400270PMC
July 2018

An NRG Oncology/GOG study of molecular classification for risk prediction in endometrioid endometrial cancer.

Gynecol Oncol 2018 01 11;148(1):174-180. Epub 2017 Nov 11.

The Ohio State University, Columbus, OH, United States. Electronic address:

Objectives: The purpose of this study was to assess the prognostic significance of a simplified, clinically accessible classification system for endometrioid endometrial cancers combining Lynch syndrome screening and molecular risk stratification.

Methods: Tumors from NRG/GOG GOG210 were evaluated for mismatch repair defects (MSI, MMR IHC, and MLH1 methylation), POLE mutations, and loss of heterozygosity. TP53 was evaluated in a subset of cases. Tumors were assigned to four molecular classes. Relationships between molecular classes and clinicopathologic variables were assessed using contingency tests and Cox proportional methods.

Results: Molecular classification was successful for 982 tumors. Based on the NCI consensus MSI panel assessing MSI and loss of heterozygosity combined with POLE testing, 49% of tumors were classified copy number stable (CNS), 39% MMR deficient, 8% copy number altered (CNA) and 4% POLE mutant. Cancer-specific mortality occurred in 5% of patients with CNS tumors; 2.6% with POLE tumors; 7.6% with MMR deficient tumors and 19% with CNA tumors. The CNA group had worse progression-free (HR 2.31, 95%CI 1.53-3.49) and cancer-specific survival (HR 3.95; 95%CI 2.10-7.44). The POLE group had improved outcomes, but the differences were not statistically significant. CNA class remained significant for cancer-specific survival (HR 2.11; 95%CI 1.04-4.26) in multivariable analysis. The CNA molecular class was associated with TP53 mutation and expression status.

Conclusions: A simple molecular classification for endometrioid endometrial cancers that can be easily combined with Lynch syndrome screening provides important prognostic information. These findings support prospective clinical validation and further studies on the predictive value of a simplified molecular classification system.
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http://dx.doi.org/10.1016/j.ygyno.2017.10.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5756518PMC
January 2018

Programmed Death Ligand 1 Expression Among 700 Consecutive Endometrial Cancers: Strong Association With Mismatch Repair Protein Deficiency.

Int J Gynecol Cancer 2018 01;28(1):59-68

Objective: This study aims to determine the prevalence of programmed death ligand 1 (PD-L1) expression in endometrial carcinoma (EC) and determine clinical and pathological associations.

Methods: Immunohistochemistry for PD-L1 was performed on sections of a triple-core tissue microarray of 700 ECs. Positive PD-L1 expression, defined as 1% of cells staining positive, was evaluated in tumor and stromal compartments. Using age-adjusted logistic regression, we estimated odds ratios and 95% confidence intervals for associations between PD-L1 expression (overall and by staining compartment) with clinical and tumor characteristics. Kaplan-Meier plots and log-rank tests were used to evaluate associations between PD-L1 expression and EC-specific survival.

Results: PD-L1 expression was observed in 100 cases (14.3%), including 27 (3.9%) with expression in tumor cells only, 35 (5.0%) with expression in both tumor cells and stroma, and 38 (5.4%) with expression in stroma only. Expression was observed in ECs of different histologic types. Tumors characterized by loss of mismatch repair proteins were significantly associated with tumoral PD-L1 expression (P < 0.0001), but not with stromal PD-L1 expression. Both tumoral and stromal PD-L1 expressions were associated with high-grade endometrioid histology, nonendometrioid histology, and lymphovascular space invasion. We observed no significant associations between PD-L1 expression and EC-specific survival.

Conclusions: PD-L1 is expressed in a significant proportion of EC and is associated with mismatch repair deficiency, potentially representing a mechanism of tumor immune evasion and a therapeutic target in EC.
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http://dx.doi.org/10.1097/IGC.0000000000001120DOI Listing
January 2018

Genome-wide association study evaluating single-nucleotide polymorphisms and outcomes in patients with advanced stage serous ovarian or primary peritoneal cancer: An NRG Oncology/Gynecologic Oncology Group study.

Gynecol Oncol 2017 11 19;147(2):396-401. Epub 2017 Sep 19.

Gynecological Oncology, Massachusetts General Hospital, Department of Medicine, Boston, MA, USA. Electronic address:

Objective: This study evaluated single nucleotide polymorphisms (SNPs) associated with progression free (PFS) and overall survival (OS) in patients with advanced stage serous EOC.

Methods: Patients enrolled in GOG-172 and 182 who provided specimens for translational research and consent were included. Germline DNA was evaluated with the Illumina's HumanOMNI1-Quad beadchips and scanned using Illumina's iScan optical imaging system. SNPs with allele frequency>0.05 and genotyping rate>0.98 were included. Analysis of SNPs for PFS and OS was done using Cox regression. Statistical significance was determined using Bonferroni corrected p-values with genomic control adjustment.

Results: The initial GWAS analysis included 1,124,677 markers in 396 patients. To obtain the final data set, quality control checks were performed and limited to serous tumors and self-identified Caucasian race. In total 636,555 SNPs and 289 patients passed all the filters. The pre-specified statistical level of significance was 7.855e. No SNPs met this criteria for PFS or OS, however, two SNPs were close to significance (rs10899426 p-2.144e) (rs6256 p-9.774e) for PFS and 2 different SNPs were identified (rs295315 p-7.536e; rs17693104 p-7.734e) which were close to significance for OS.

Conclusions: Using the pre-specified level of significance of 1×10, we did not identify any SNPs of statistical significance for OS or PFS, however several were close. The SNP's identified in this GWAS study will require validation and these preliminary findings may lead to identification of novel pathways and biomarkers.
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http://dx.doi.org/10.1016/j.ygyno.2017.08.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5706110PMC
November 2017

Genetic consultation embedded in a gynecologic oncology clinic improves compliance with guideline-based care.

Gynecol Oncol 2017 10 8;147(1):110-114. Epub 2017 Aug 8.

Division of Gynecologic Oncology, Ohio State University College of Medicine, Columbus, OH, United States.

Objective: Analyze the impact of embedding genetic counseling services in gynecologic oncology on clinician referral and patient uptake of cancer genetics services.

Methods: Data were reviewed for a total of 737 newly diagnosed epithelial ovarian cancer patients seen in gynecologic oncology at a large academic medical center including 401 from 11/2011-7/2014 (a time when cancer genetics services were provided as an off-site consultation). These data were compared to data from 8/2014-9/2016 (n=336), when the model changed to the genetics embedded model (GEM), incorporating a cancer genetic counselor on-site in the gynecologic oncology clinic.

Results: A statistically significant difference in proportion of patients referred pre- and post-GEM was observed (21% vs. 44%, p<0.0001). Pre-GEM, only 38% of referred patients were actually scheduled for genetics consultation and post-GEM 82% were scheduled (p<0.00001). The difference in the time from referral to scheduling in genetics was also statistically significant (3.92months pre-GEM vs. 0.79months post-GEM, p<0.00001) as was the time from referral to completion of genetics consultation (2.52months pre-GEM vs. 1.67months post-GEM, p<0.01). Twenty-five percent of patients referred post GEM were seen by the genetic counselor on the same day as the referral.

Conclusions: Providing cancer genetics services on-site in gynecologic oncology and modifying the process by which patients are referred and scheduled significantly increases referral to cancer genetics and timely completion of genetics consultation, improving compliance with guideline-based care. Practice changes are critical given the impact of genetic test results on treatment and familial cancer risks.
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http://dx.doi.org/10.1016/j.ygyno.2017.07.141DOI Listing
October 2017

Epigenetic silencing of MLH1 in endometrial cancers is associated with larger tumor volume, increased rate of lymph node positivity and reduced recurrence-free survival.

Gynecol Oncol 2017 09 11;146(3):588-595. Epub 2017 Jul 11.

Department of Obstetrics and Gynecology, The Ohio State University Wexner Medical Center, Columbus, United States.

Objectives: To determine the relationship between mismatch repair (MMR) classification and clinicopathologic features including tumor volume, and explore outcomes by MMR class in a contemporary cohort.

Methods: Single institution cohort evaluating MMR classification for endometrial cancers (EC). MMR immunohistochemistry (IHC)±microsatellite instability (MSI) testing and reflex MLH1 methylation testing was performed. Tumors with MMR abnormalities by IHC or MSI and MLH1 methylation were classified as epigenetic MMR deficiency while those without MLH1 methylation were classified as probable MMR mutations. Clinicopathologic characteristics were analyzed.

Results: 466 endometrial cancers were classified; 75% as MMR proficient, 20% epigenetic MMR defects, and 5% as probable MMR mutations. Epigenetic MMR defects were associated with advanced stage, higher grade, presence of lymphovascular space invasion, and older age. MMR class was significantly associated with tumor volume, an association not previously reported. The epigenetic MMR defect tumors median volume was 10,220mm compared to 3321mm and 2,846mm, for MMR proficient and probable MMR mutations respectively (P<0.0001). Higher tumor volume was associated with lymph node involvement. Endometrioid EC cases with epigenetic MMR defects had significantly reduced recurrence-free survival (RFS). Among advanced stage (III/IV) endometrioid EC the epigenetic MMR defect group was more likely to recur compared to the MMR proficient group (47.7% vs 3.4%) despite receiving similar adjuvant therapy. In contrast, there was no difference in the number of early stage recurrences for the different MMR classes.

Conclusions: MMR testing that includes MLH1 methylation analysis defines a subset of tumors that have worse prognostic features and reduced RFS.
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http://dx.doi.org/10.1016/j.ygyno.2017.07.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5601318PMC
September 2017

Sentinel lymph node mapping and staging in endometrial cancer: A Society of Gynecologic Oncology literature review with consensus recommendations.

Gynecol Oncol 2017 08 28;146(2):405-415. Epub 2017 May 28.

University of California at San Francisco, San Francisco, CA, USA.

The emphasis in contemporary medical oncology has been "precision" or "personalized" medicine, terms that imply a strategy to improve efficacy through targeted therapies. Similar attempts at precision are occurring in surgical oncology. Sentinel lymph node (SLN) mapping has recently been introduced into the surgical staging of endometrial cancer with the goal to reduce morbidity associated with comprehensive lymphadenectomy, yet obtain prognostic information from lymph node status. The Society of Gynecologic Oncology's (SGO) Clinical Practice Committee and SLN Working Group reviewed the current literature for preparation of this document. Literature-based recommendations for the inclusion of SLN assessment in the treatment of patients with endometrial cancer are presented. This article examines.
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http://dx.doi.org/10.1016/j.ygyno.2017.05.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6075736PMC
August 2017

Surgical-pathological findings in type 1 and 2 endometrial cancer: An NRG Oncology/Gynecologic Oncology Group study on GOG-210 protocol.

Gynecol Oncol 2017 06 6;145(3):519-525. Epub 2017 Apr 6.

Department of Obstetrics & Gynecology, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States. Electronic address:

Objective: To report clinical and pathologic relationships with disease spread in endometrial cancer patients.

Methods: Surgical candidates with uterine cancer (adenocarcinoma or carcinosarcoma) who were eligible to participate in a surgical pathological study to create a clinically annotated tissue biorepository to support translational and clinical research studies. All patients were to undergo a hysterectomy, bilateral salpingo-oophorectomy, and bilateral pelvic and para-aortic lymphadenectomy. From 2003-2007, open eligibility enrollment was conducted, and from 2007-2011, eligibility was restricted to enrich underrepresented patients or those at high risk.

Results: This report details clinical pathological relationships associated with extra uterine disease spread of 5866 evaluable patients including those with endometrioid histology as well as papillary serous, clear cell and carcinosarcoma histologies. Review of unrestricted enrollment was constructed in an effort to capture a cross-section population representative of endometrial cancers seen by the GOG participating members. Evaluation of this group of patients suggested the more natural incidence of different surgical pathological findings as well as demographic information. The addition of 2151 patients enrolled during the restricted time interval allowed a total of 1630 poor histotype patients available for further analysis. As expected, endometrioid (E) cancers represented the largest enrollment and particularly E grade 1 and 2 (G1 and 2) were more frequently confined to the uterus. Grade 3 (G3) endometrioid cancers as well as the poor histotype (papillary serous, clear cell and carcinosarcoma) had a much greater propensity for extant disease.

Conclusions: This study confirms the previously reported surgical pathological findings for endometrioid cancers but in addition, using a large database of papillary serous, clear cell and carcinosarcoma, surgical pathological findings substantiate the categorization of poor histotypes for these cancers.
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http://dx.doi.org/10.1016/j.ygyno.2017.03.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5702929PMC
June 2017

Sparse feature selection for classification and prediction of metastasis in endometrial cancer.

BMC Genomics 2017 03 27;18(Suppl 3):233. Epub 2017 Mar 27.

The University of Texas at Dallas, Richardson, TX, USA.

Background: Metastasis via pelvic and/or para-aortic lymph nodes is a major risk factor for endometrial cancer. Lymph-node resection ameliorates risk but is associated with significant co-morbidities. Incidence in patients with stage I disease is 4-22% but no mechanism exists to accurately predict it. Therefore, national guidelines for primary staging surgery include pelvic and para-aortic lymph node dissection for all patients whose tumor exceeds 2cm in diameter. We sought to identify a robust molecular signature that can accurately classify risk of lymph node metastasis in endometrial cancer patients. 86 tumors matched for age and race, and evenly distributed between lymph node-positive and lymph node-negative cases, were selected as a training cohort. Genomic micro-RNA expression was profiled for each sample to serve as the predictive feature matrix. An independent set of 28 tumor samples was collected and similarly characterized to serve as a test cohort.

Results: A feature selection algorithm was designed for applications where the number of samples is far smaller than the number of measured features per sample. A predictive miRNA expression signature was developed using this algorithm, which was then used to predict the metastatic status of the independent test cohort. A weighted classifier, using 18 micro-RNAs, achieved 100% accuracy on the training cohort. When applied to the testing cohort, the classifier correctly predicted 90% of node-positive cases, and 80% of node-negative cases (FDR = 6.25%).

Conclusion: Results indicate that the evaluation of the quantitative sparse-feature classifier proposed here in clinical trials may lead to significant improvement in the prediction of lymphatic metastases in endometrial cancer patients.
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http://dx.doi.org/10.1186/s12864-017-3604-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5374706PMC
March 2017

Recurrent low grade serous ovarian cancer in a 20 year old woman: A case from the Ohio State University College of Medicine.

Gynecol Oncol 2017 03 1;144(3):451-455. Epub 2017 Feb 1.

Department of Pathology, Ohio State University College of Medicine, Columbus, OH, United States.

A 20 year old with recurrent low-grade serous carcinoma (LGSC) is discussed. The differential diagnosis, pathology, epidemiology, treatment options are discussed. Focus on the molecular pathways of LGSC and the implications of the diagnosis on fertility are highlighted.
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http://dx.doi.org/10.1016/j.ygyno.2017.01.023DOI Listing
March 2017

Synuclein-γ in uterine serous carcinoma impacts survival: An NRG Oncology/Gynecologic Oncology Group study.

Cancer 2017 04 7;123(7):1144-1155. Epub 2016 Dec 7.

Division of Reproductive Science in Medicine, Department of Obstetrics and Gynecology, Northwestern University, Chicago, Illinois.

Background: Synuclein-γ (SNCG) is highly expressed in advanced solid tumors, including uterine serous carcinoma (USC). The objective of the current study was to determine whether SNCG protein was associated with survival and clinical covariates using the largest existing collection of USCs from the Gynecologic Oncology Group (GOG-8023).

Methods: High-density tissue microarrays (TMAs) of tumor tissues from 313 patients with USC were stained by immunohistochemistry for SNCG, p53, p16, FOLR1, pERK, pAKT, ER, PR, and HER2/neu. Associations of SNCG and other tumor markers with overall and progression-free survival were assessed using log-rank tests and Cox proportional-hazards models, which also were adjusted for age, race, and stage.

Results: The overall survival at 5 years was 46% for women with high SNCG expression and 62% for those with low SNCG expression (log-rank P = .021; hazard ratio [HR], 1.31; 95% confidence interval [CI], 0.91-1.9 in adjusted Cox model). The progression-free survival rate at 5 years was worse for women who had high SNCG expression, at 40%, compared with 56% for those who had low SNCG expression (log-rank P = .0081; HR, 1.36; 95% CI, 0.96-1.92 in adjusted Cox model). High levels of both p53 and p16 were significantly associated with worse overall survival (p53: HR, 4.20 [95% CI, 1.54-11.45]; p16: HR, 1.95 [95% CI, 1.01-3.75]) and progression-free survival (p53: HR, 2.16 [95% CI, 1.09-4.27]; p16: HR, 1.53 [95% CI, 0.87-2.69]) compared with low levels.

Conclusions: This largest collection of USCs to date demonstrates that SNCG was associated with poor survival in univariate analyses. SNCG does not predict survival outcome independent of p53 and p16 in models that jointly consider multiple markers. Cancer 2017;123:1144-1155. © 2016 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5360512PMC
April 2017

Less radical surgery for early-stage cervical cancer: Can conization specimens help identify patients at low risk for parametrial involvement?

Gynecol Oncol 2017 Feb 21;144(2):290-293. Epub 2016 Nov 21.

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, The Ohio State University, Columbus, OH, United States. Electronic address:

Objective: Radical hysterectomy for cervical cancer is associated with increased morbidity over an extrafascial hysterectomy. The goal of this study was to determine incidence of and risk factors for parametrial involvement (PI) based on conization specimen (CS) and to potentially identify candidates for less radical surgery.

Methods: Patients with FIGO IA2-IIA cervical cancer treated with radical hysterectomy and pelvic lymph node dissection (RH) from 2000 to 2010 were retrospectively identified. Data was extracted from operative and pathology reports. Statistical analyses were performed using Fisher's exact test, t-test, and asymptotic logistic regression.

Results: Of 267 RH patients identified, 118 (44%) had conization prior to RH. The incidence of PI was 15.7% overall and 7.5% in patients treated with conization prior to RH. There was no association between PI and histology, stage, grade, or tumor size. Conization patients with PI were more likely to have LVSI on CS (77.8% vs. 29.4%) and positive lymph nodes (LNP) (66.7% vs. 8.3%). Of patients with positive endocervical curettage, a modest 12% had PI, which was not statistically significant. Tumor size, depth of invasion, and margin status on CS were not statistically associated with PI. In logistic regression analysis, LNP alone or LNP+LVSI were predictive of PI.

Conclusions: The incidence of PI in early-stage cervical cancer is significant. Only LVSI on CS and LNP were predictors of PI in the current study. While there may be select patients with early stage cervical cancer who can be spared parametrectomy, additional research is warranted.
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http://dx.doi.org/10.1016/j.ygyno.2016.11.029DOI Listing
February 2017

What is the role of retroperitoneal exploration in optimally debulked stage IIIC epithelial ovarian cancer? An NRG Oncology/Gynecologic Oncology Group ancillary data study.

Cancer 2017 May 16;123(6):985-993. Epub 2016 Nov 16.

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Drexel University College of Medicine, Philadelphia, Pennsylvania.

Background: The purpose of this study was to determine the effect of retroperitoneal (RP) exploration on progression-free survival (PFS) and overall survival (OS) in epithelial ovarian cancer (EOC) patients with stage IIIC disease who underwent optimal debulking surgery.

Methods: Data were collected from records of the Gynecologic Oncology Group 182 (GOG-182) study of stage IIIC EOC patients cytoreduced to no gross residual disease (R0) or minimal gross residual (<1 cm) disease (MGRD) at primary surgery. Patients with stage IIIC disease by intraperitoneal (IP) tumor were included and divided into 3 groups: 1) > 2 cm IP tumor without lymph node involvement (IP/RP-), 2) > 2 cm IP tumor with lymph node involvement (IP/RP+), and 3) > 2 cm IP tumor with no RP exploration (IP/RP?). The effects of disease distribution and RP exploration on PFS and OS were assessed using Kaplan-Meier and proportional hazards methods.

Results: There were 1871 stage IIIC patients in GOG-182 who underwent optimal primary debulking surgery. Of these, 689 (36.8%) underwent RP exploration with removal of lymph nodes from at least 1 para-aortic site, and 1182 (63.2%) did not. There were 269 patients in the IP/RP- group, 420 patients in the IP/RP + group, and 1182 patients in the IP/RP? group. Improved PFS (18.5 vs 16.0 months; P < .0001) and OS (53.3 vs 42.8 months; P < .0001) were associated with RP exploration versus no exploration. Patients with MGRD had improved PFS (16.8 vs 15.1 months, P = 0.0108) and OS (44.9 vs 40.5 months, P = 0.0076) versus no exploration.

Conclusions: RP exploration at the time of primary surgery in patients with optimally debulked stage IIIC EOC is associated with a survival benefit. Cancer 2017;123:985-93. © 2016 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5339038PMC
May 2017

Perioperative Outcomes for Laparotomy Compared to Robotic Surgical Staging of Endometrial Cancer in the Elderly: A Retrospective Cohort.

Int J Gynecol Cancer 2016 11;26(9):1717-1721

*Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, The Ohio State University Wexner Medical Center, Columbus, OH; and †Florida Hospital Gynecologic Oncology, Florida Hospital Cancer Institute, Orlando, FL.

Objective: This study aimed to compare outcomes of endometrial cancer (EMCA) staging in elderly patients performed either robotically or via laparotomy.

Methods: A retrospective, multi-institutional chart review was conducted of all robotic and laparotomy staging surgeries for EMCA between 2003 and 2009. Charts were reviewed for intraoperative and postoperative complications and morbidities.

Results: Seven hundred forty-six women were identified who had undergone EMCA staging either robotically or via laparotomy; 89 and 93 patients 70 years or older underwent staging for EMCA via robotic and laparotomy, respectively. Both groups had similar age and body mass index. Among elderly patients being staged robotically, a higher incidence of pelvic lymphadenectomy, and decreased blood loss, incidence of blood transfusion, and overall complications were seen compared to laparotomy. Postoperatively, elderly patients staged robotically had a shorter median hospital stay (1 vs 4 days, P < 0.001), with no increase in readmission or return to the operating theater. No vessel, bowel, or genitourinary injuries occurred. Vaginal cuff dehiscence after robotic surgery was not significantly different, but wound and fascial complications were significantly increased in patients undergoing laparotomy. Thromboembolism rates were similar between both groups.

Conclusions: Elderly patients can safely undergo robotic EMCA staging with improved outcomes compared to laparotomy. The benefits of robotic staging include higher incidence of completion of lymphadenectomy, decreased hospital stay (without an increase in readmissions or reoperations), decreased transfusions, and decreased wound and fascial complications.
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http://dx.doi.org/10.1097/IGC.0000000000000822DOI Listing
November 2016

The Microcystic, Elongated, and Fragmented (MELF) Pattern of Invasion: A Single Institution Report of 464 Consecutive FIGO Grade 1 Endometrial Endometrioid Adenocarcinomas.

Am J Surg Pathol 2017 01;41(1):49-55

*Department of Pathology †Center for Biostatistics ‡Department of Obstetrics and Gynecology, The Ohio State University Wexner Medical Center, Columbus, OH.

MELF invasion has been associated with nonvaginal recurrences and lymph node (LN) metastases in multi-institutional case control studies but has not been well examined in large single-institution cohorts. Hysterectomy specimens with FIGO 1 endometrioid endometrial carcinoma and lymphadenectomies from 2007 to 2012 were identified. Electronic medical records and histologic slides were reviewed. Of 464 identified cases, 163 (35.1%) were noninvasive, 60 (12.9%) had MELF, 222 (47.8%) had a component of the infiltrative invasion pattern without MELF, 13 (2.8%) had pure pushing borders of invasion, 5 (1.1%) had pure adenomyosis-like invasion, and 1 (0.2%) had pure adenoma malignum-like invasion. Sixteen cases had LN metastases. Significantly more MELF cases had positive LNs than non-MELF cases overall (18.3% vs. 1.2%, P<0.001). The results were almost identical when invasive infiltrative cases with and without MELF were compared (18.3% vs. 1.8%, P<0.001). The maximum number of MELF glands per slide did not differ between cases with and without LN metastases, P=0.137. A majority of positive LNs, even in MELF cases, demonstrated nonhistiocyte-like metastases. Only 5 cases (all with MELF invasion) demonstrated micrometastatic lesions or isolated tumor cells only. MELF cases demonstrated a nonsignificant decrease in time to extravaginal recurrence (P=0.082, log-rank test), for which analysis was limited by low recurrence rates. In summary, MELF is associated with LN metastases, even when compared with other infiltrative cases and shows multiple patterns of growth in positive LNs. MELF cases additionally trended toward decreased time to extravaginal recurrence.
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http://dx.doi.org/10.1097/PAS.0000000000000754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5159271PMC
January 2017

Clinicopathologic Significance of Mismatch Repair Defects in Endometrial Cancer: An NRG Oncology/Gynecologic Oncology Group Study.

J Clin Oncol 2016 09 20;34(25):3062-8. Epub 2016 Jun 20.

D. Scott McMeekin and Lisa M. Landrum, University of Oklahoma Health Sciences Center, Oklahoma City, OK; David L. Tritchler, Heather A. Lankes, and Shamshad Ali, NRG Oncology Statistics and Data Management Center; Shashikant B. Lele, Roswell Park Cancer Institute, Buffalo; Michael L. Pearl, Stony Brook University Hospital, Stony Brook, NY; David E. Cohn, Floor J. Backes, and Paul J. Goodfellow, The Ohio State University; Nilsa Ramirez, Research Institute at Nationwide Children's Hospital, Columbus, OH; David G. Mutch, Matthew A. Powell, and Feng Gao, Washington University School of Medicine, St. Louis, MO; Melissa A. Geller, University of Minnesota, Minneapolis, MN; Richard Zaino, Penn State Milton S. Hersey Medical Center, Hershey, PA; Russell D. Broaddus, The University of Texas MD Anderson Cancer Center, Houston, TX; Kathleen M. Darcy, Women's Health Integrated Research Collective, Annandale, VA; and Paul A. DiSilvestro, Women and Infants Hospital of Rhode Island, Providence, RI.

Purpose: The clinicopathologic significance of mismatch repair (MMR) defects in endometrioid endometrial cancer (EEC) has not been definitively established. We undertook tumor typing to classify MMR defects to determine if MMR status is prognostic or predictive.

Methods: Primary EECs from NRG/GOG0210 patients were assessed for microsatellite instability (MSI), MLH1 methylation, and MMR protein expression. Each tumor was assigned to one of four MMR classes: normal, epigenetic defect, probable mutation (MMR defect not attributable to MLH1 methylation), or MSI-low. The relationships between MMR classes and clinicopathologic variables were assessed using contingency table tests and Cox proportional hazard models.

Results: A total of 1,024 tumors were assigned to MMR classes. Epigenetic and probable mutations in MMR were significantly associated with higher grade and more frequent lymphovascular space invasion. Epigenetic defects were more common in patients with higher International Federation of Gynecology and Obstetrics stage. Overall, there were no differences in outcomes. Progression-free survival was, however, worse for women whose tumors had epigenetic MMR defects compared with the MMR normal group (hazard ratio, 1.37; P < .05; 95% CI, 1.00 to 1.86). An exploratory analysis of interaction between MMR status and adjuvant therapy showed a trend toward improved progression-free survival for probable MMR mutation cases.

Conclusion: MMR defects in EECs are associated with a number of well-established poor prognostic indicators. Women with tumors that had MMR defects were likely to have higher-grade cancers and more frequent lymphovascular space invasion. Surprisingly, outcomes in these patients were similar to patients with MMR normal tumors, suggesting that MMR defects may counteract the effects of negative prognostic factors. Altered immune surveillance of MMR-deficient tumors, and other host/tumor interactions, is likely to determine outcomes for patients with MMR-deficient tumors.
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http://dx.doi.org/10.1200/JCO.2016.67.8722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5012715PMC
September 2016