Publications by authors named "Adrian A Suarez"

32 Publications

Double somatic mismatch repair gene pathogenic variants as common as Lynch syndrome among endometrial cancer patients.

Gynecol Oncol 2021 Jan 21;160(1):161-168. Epub 2020 Oct 21.

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, The Ohio State University Comprehensive Cancer Center, OH, United States of America.

Objective: Lynch syndrome is the most common cause of inherited endometrial cancer, attributable to germline pathogenic variants (PV) in mismatch repair (MMR) genes. Tumor microsatellite instability (MSI-high) and MMR IHC abnormalities are characteristics of Lynch syndrome. Double somatic MMR gene PV also cause MSI-high endometrial cancers. The aim of this study was to determine the relative frequency of Lynch syndrome and double somatic MMR PV.

Methods: 341 endometrial cancer patients enrolled in the Ohio Colorectal Cancer Prevention Initiative at The Ohio State University Comprehensive Cancer Center from 1/1/13-12/31/16. All tumors underwent immunohistochemical (IHC) staining for the four MMR proteins, MSI testing, and MLH1 methylation testing if the tumor was MMR-deficient (dMMR). Germline genetic testing for Lynch syndrome was undertaken for all cases with dMMR tumors lacking MLH1 methylation. Tumor sequencing followed if a germline MMR gene PV was not identified.

Results: Twenty-seven percent (91/341) of tumors were either MSI-high or had abnormal IHC indicating dMMR. As expected, most dMMR tumors had MLH1 methylation; (69, 75.8% of the dMMR cases; 20.2% of total). Among the 22 (6.5%) cases with dMMR not explained by methylation, 10 (2.9% of total) were found to have Lynch syndrome (6 MSH6, 3 MSH2, 1 PMS2). Double somatic MMR PV accounted for the remaining 12 dMMR cases (3.5% of total).

Conclusions: Since double somatic MMR gene PV are as common as Lynch syndrome among endometrial cancer patients, paired tumor and germline testing for patients with non-methylated dMMR tumor may be the most efficient approach for LS screening.
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http://dx.doi.org/10.1016/j.ygyno.2020.10.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783191PMC
January 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

Intentional weight loss, weight cycling, and endometrial cancer risk: a systematic review and meta-analysis.

Int J Gynecol Cancer 2019 11 26;29(9):1361-1371. Epub 2019 Aug 26.

Division of Epidemiology, The Ohio State University College of Public Health, Columbus, OH, USA

Purpose: Weight cycling, defined as intentional weight loss followed by unintentional weight regain, may attenuate the benefit of intentional weight loss on endometrial cancer risk. We summarized the literature on intentional weight loss, weight cycling after intentional weight loss, bariatric surgery, and endometrial cancer risk.

Methods: A systematic search was conducted using MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases published between January 2000 and November 2018. We followed Preferred Reporting Items of Systematic Reviews and Meta-analysis (PRISMA) guidelines. We qualitatively summarized studies related to intentional weight loss and weight cycling due to the inconsistent definition, and quantitatively summarized studies when bariatric surgery was the mechanism of intentional weight loss.

Results: A total of 127 full-text articles were reviewed, and 13 were included (bariatric surgery n=7, self-reported intentional weight loss n=2, self-reported weight cycling n=4). Qualitative synthesis suggested that, compared with stable weight, self-reported intentional weight loss was associated with lower endometrial cancer risk (RR range 0.61-0.96), whereas self-reported weight cycling was associated with higher endometrial cancer risk (OR range 1.07-2.33). The meta-analysis yielded a 59% lower risk of endometrial cancer following bariatric surgery (OR 0.41, 95% CI 0.22 to 0.74).

Conclusions: Our findings support the notion that intentional weight loss and maintenance of a stable, healthy weight can lower endometrial cancer risk. Strategies to improve awareness and maintenance of weight loss among women with obesity are needed to reduce endometrial cancer risk.
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http://dx.doi.org/10.1136/ijgc-2019-000728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832748PMC
November 2019

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

Ovarian insufficiency and CTNNB1 mutations drive malignant transformation of endometrial hyperplasia with altered PTEN/PI3K activities.

Proc Natl Acad Sci U S A 2019 03 19;116(10):4528-4537. Epub 2019 Feb 19.

Department of Cancer Biology and Genetics, Ohio State University, Columbus, OH 43210;

Endometrioid endometrial carcinomas (EECs) carry multiple driver mutations even when they are low grade. However, the biological significance of these concurrent mutations is unknown. We explored the interactions among three signature EEC mutations: loss-of-function (LOF) mutations in , gain-of-function (GOF) mutations of phosphoinositide 3-kinase (PI3K), and exon 3 mutations, utilizing in vivo mutagenesis of the mouse uterine epithelium. While epithelial cells with a monoallelic mutation in any one of three genes failed to propagate in the endometrium, any combination of two or more mutant alleles promoted the growth of epithelium, causing simple hyperplasia, in a dose-dependent manner. Notably, exon 3 deletion significantly increased the size of hyperplastic lesions by promoting the growth of PTEN LOF and/or PI3K GOF mutant cells through the activation of neoadenogenesis pathways. Although these three mutations were insufficient to cause EEC in intact female mice, castration triggered malignant transformation, leading to myometrial invasion and serosal metastasis. Treatment of castrated mice with progesterone or estradiol attenuated the neoplastic transformation. This study demonstrates that multiple driver mutations are required for premalignant cells to break the growth-repressing field effect of normal endometrium maintained by ovarian steroids and that exon 3 mutations play critical roles in the growth of preneoplastic cells within the endometrium of premenopausal women and in the myometrial invasion of EECs in menopausal women.
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http://dx.doi.org/10.1073/pnas.1814506116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6410785PMC
March 2019

Clinicopathologic characteristics, tumor infiltrating lymphocytes and programed cell death ligand-1 expression in 162 endometrial carcinomas with deficient mismatch repair function.

Int J Gynecol Cancer 2019 01;29(1):113-118

Department of Pathology, Wexner Medical Center at The Ohio State University, Columbus, Ohio, USA

Objective: Endometrial carcinoma (EC) with deficient mismatch repair (dMMR) protein has been reported to have increased tumor infiltrating lymphocytes (TILs) and programed cell death ligand-1 (PD-L1) expression. TILs and PD-L1 expression are compared between two main types of dMMR ECs (epigenetic dMMR due to MLH1 promoter methylation vs mutated dMMR due to genetic mutation).

Methods: Immunohistochemistry for PD-L1 was performed in triplicate on tissue microarray sections. TILs were semi-quantitatively evaluated on whole-slide images of whole histologic sections. The clinicopathologic characteristics together with PD-L1 expression and TILs were analyzed between mutated and epigenetic dMMR ECs.

Results: Of the 162 dMMR ECs identified, 126 had epigenetic dMMR and 36 had mutated dMMR. Univariate analysis demonstrated mutated dMMR ECs showed younger age, less myometrium invasion of >50%, less lymphovascular invasion, and more TILs than epigenetic dMMR ECs. Multivariate analysis demonstrated significantly younger age and more TILs in mutated dMMR ECs than in epigenetic ECs. PD-L1 expression did not show any significant difference between these two groups. Seventeen (13.5%) patients with epigenetic dMMR EC had recurrence and 13 (10.3%) patients died of disease. In contrast, only one patient with mutated dMMR EC had recurrence (3%) and died of disease (3%).

Conclusion: ECs with mutated dMMR demonstrated significantly increased TILs than ECs with epigenetic dMMR, suggesting a stronger immune reaction and potential response to immunotherapy in these tumors.
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http://dx.doi.org/10.1136/ijgc-2018-000042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6724202PMC
January 2019

Postmenopausal Squamous Atypia: Cytologic Features, Hybrid Capture 2 Tests and Contribution to the ASCUS Pool.

Acta Cytol 2018 25;62(5-6):418-422. Epub 2018 Jul 25.

Department of Pathology, Ohio State University Wexner Medical Center, Columbus, Ohio,

Objective: Postmenopausal squamous atypia (PSA) mimics squamous intraepithelial lesion (SIL). We investigate the PSA contribution to the atypical squamous cells of undetermined significance (ASCUS) pool, its cytologic features and Hybrid Capture 2 (HC2) relative light unit/cutoff (RLU/CO) values.

Study Design: 658 ASCUS Pap tests in women ≥55 years were reviewed to select those with koilocyte-like cells and/or atypical parakeratosis. Follow-up was positive when a biopsy showed SIL or carcinoma or a later HC2 test was positive.

Results: Sixty-nine cases (10.5%) were selected. Forty-two (60.9%) were HC2 negative, and 27 (39.1%) were HC2 positive. Follow-up was available for 23 (54.7%) HC2-negative and 19 (70.3%) HC2-positive cases. No HC2-negative (0%) and 8 HC2-positive (42.1%) cases were positive on follow-up. Within cases negative on follow-up, 3 were PSA on biopsy. PSA was characterized by perinuclear halos, mild nuclear enlargement, smooth nuclear contours, and smooth chromatin. PSA-associated RLU/CO values were 0.25-2.95. Cases with SIL or carcinoma had RLU/CO values from 3.78 to 1,241.59.

Conclusions: PSA contributes 0.5-2.3% to the ASCUS pool in women ≥55 years old. HC2 testing with RLU/CO of ≥1 may result in PSA occasionally testing positive. A different cutoff is not recommended but awareness of this caveat is important.
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http://dx.doi.org/10.1159/000490691DOI Listing
January 2019

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

Hypoxia-induced exosomes contribute to a more aggressive and chemoresistant ovarian cancer phenotype: a novel mechanism linking STAT3/Rab proteins.

Oncogene 2018 07 11;37(28):3806-3821. Epub 2018 Apr 11.

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

Hypoxia-mediated tumor progression, metastasis, and drug resistance are major clinical challenges in ovarian cancer. Exosomes released in the hypoxic tumor microenvironment may contribute to these challenges by transferring signaling proteins between cancer cells and normal cells. We observed that ovarian cancer cells exposed to hypoxia significantly increased their exosome release by upregulating Rab27a, downregulating Rab7, LAMP1/2, NEU-1, and also by promoting a more secretory lysosomal phenotype. STAT3 knockdown in ovarian cancer cells reduced exosome release by altering the Rab family proteins Rab7 and Rab27a under hypoxic conditions. We also found that exosomes from patient-derived ascites ovarian cancer cell lines cultured under hypoxic conditions carried more potent oncogenic proteins-STAT3 and FAS that are capable of significantly increasing cell migration/invasion and chemo-resistance in vitro and tumor progression/metastasis in vivo. Hypoxic ovarian cancer cells derived exosomes (HEx) are proficient in re-programming the immortalized fallopian tube secretory epithelial cells (FT) to become pro-tumorigenic in mouse fallopian tubes. In addition, cisplatin efflux via exosomes was significantly increased in ovarian cancer cells under hypoxic conditions. Co-culture of HEx with tumor cells led to significantly decreased dsDNA damage and increased cell survival in response to cisplatin treatment. Blocking exosome release by known inhibitor Amiloride or STAT3 inhibitor and treating with cisplatin resulted in a significant increase in apoptosis, decreased colony formation, and proliferation. Our results demonstrate that HEx are more potent in augmenting metastasis/chemotherapy resistance in ovarian cancer and may serve as a novel mechanism for tumor metastasis, chemo-resistance, and a point of intervention for improving clinical outcomes.
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http://dx.doi.org/10.1038/s41388-018-0189-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6043362PMC
July 2018

Radiation-associated Angiosarcoma Mimicking Fallopian Tube High-grade Serous Carcinoma in a Woman With De Novo Li-Fraumeni Syndrome.

Int J Gynecol Pathol 2019 May;38(3):258-262

Department of Obstetrics & Gynecology, Division of Gynecologic Oncology (S.M.C., L.J.C.) Department of Internal Medicine, Division of Human Genetics (L.S.-J.) Department of Internal Medicine, Division of Medical Oncology (J.L.C.) Department of Pathology (A.A.S.), The Ohio State University James Cancer Hospital and Solove Research Institute, Columbus, OH.

We present a case study of a woman with history of rectal adenocarcinoma, and a new diagnosis of radiation-associated angiosarcoma mimicking fallopian tube high-grade serous carcinoma who was subsequently found to have de novo Li-Fraumeni syndrome. Our objective is to highlight angiosarcoma as a potential pitfall in the diagnosis of high-grade serous carcinoma.
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http://dx.doi.org/10.1097/PGP.0000000000000502DOI Listing
May 2019

Levels Serve as "Early Signature" Genes in the Development of High-Grade Serous Carcinoma from the Fallopian Tube.

Cancer Res 2018 04 16;78(7):1739-1750. Epub 2018 Jan 16.

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Comprehensive Cancer Center, the Ohio State University Wexner Medical Center, Columbus, Ohio.

The initial molecular events that lead to malignant transformation of the fimbria of the fallopian tube (FT) through high-grade serous ovarian carcinoma (HGSC) remain poorly understood. In this study, we report that increased expression of signal transducer and activator of transcription 3 () and suppression or loss of protein inhibitor of activated STAT3 () in FT likely drive HGSC. We evaluated human tissues-benign normal FT, tubal-peritoneal junction (TPJ), p53 signature FT tissue, tubal intraepithelial lesion in transition (TILT), serous tubal intraepithelial carcinoma (STIC) without ovarian cancer, and HGSC for expression of (compared with their known signature) and their target proliferation genes. We observed constitutive activation of and low levels or loss of in the TPJ, p53 signature, TILT, and STIC through advanced stage IV (HGSC) tissues. Elevated expression of and decreased levels of appeared as early as TPJ and the trend continued until very advanced stage HGSC (compared with high and low expression in normal benign FT). Exogenous expression of in FT cells mediated translocation of and into the nucleus. experiments demonstrated that overexpression of in FT secretory epithelial cells promoted tumor progression and metastasis, mimicking the clinical disease observed in patients with HGSC. Thus, we conclude that the pathway plays a role in the development and progression of HGSC from its earliest premalignant states. Concomitant gain of pSTAT3 Tyr705 and loss of PIAS3 appear critical for initiation and development of high-grade serous carcinoma. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-1671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5907493PMC
April 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

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

In Reply.

Am J Surg Pathol 2017 08;41(8):1150-1151

*Department of Pathology, The Ohio State University, Columbus, OH †Department of Pathology, University of California San Francisco San Francisco, CA.

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http://dx.doi.org/10.1097/PAS.0000000000000880DOI Listing
August 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

Bokhman Redux: Endometrial cancer "types" in the 21st century.

Gynecol Oncol 2017 Feb 16;144(2):243-249. Epub 2016 Dec 16.

Department of Obstetrics and Gynecology, College of Medicine, The Ohio State University, United States.

In 1983 Jan V. Bokhman, M.D. published a landmark paper entitled "Two Pathogenetic Types of Endometrial Carcinoma" in which an enduring dualistic view of endometrial cancer was first proposed. "Type I" cancers are thought to represent estrogen driven mostly low grade endometrioid tumors strongly associated with obesity and other components of the metabolic syndrome. "Type II" cancers represent higher grade non-endometrioid tumors for which the latter associations are less significant. Basic tenets of this dichotomy including significant prognostic differences have been abundantly confirmed by later literature. The construct has in turn contributed a useful framework for decades of teaching and scientific advancement across disciplines. However, recent large epidemiologic studies indicate a more complex web of risk factors with obesity and hormones likely playing an important role across the entire endometrial cancer histologic and clinical spectrum. Moreover, high quality molecular data and refinements in pathologic classification challenge any simplistic classification of endometrial cancer. For example, the Cancer Genome Atlas (TCGA) recently defined four clinically distinct endometrial cancer types based on their overall mutational burden, specific p53, POLE and PTEN mutations, microsatellite instability and histology. Additionally, new histologic categories with clear prognostic implications have been accepted and it is becoming evident from an epidemiologic point of view that metabolic factors may play an important role in endometrial cancer overall. While Bokhman's intuitive dualistic model remains relevant when working with large registries and databases lacking granular information; most other efforts should integrate clinical, pathological and molecular specifics into more nuanced classifications.
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http://dx.doi.org/10.1016/j.ygyno.2016.12.010DOI Listing
February 2017

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

Elevated STAT3 expression in ovarian cancer ascites promotes invasion and metastasis: a potential therapeutic target.

Oncogene 2017 01 13;36(2):168-181. Epub 2016 Jun 13.

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

Although activation of the STAT3 pathway has been associated with tumor progression in a wide variety of cancer types (including ovarian cancer), the precise mechanism of invasion and metastasis due to STAT3 are not fully delineated in ovarian cancer. We found that pSTAT3 Tyr705 is constitutively activated in patient ascites and ascites-derived ovarian cancer cells (ADOCCs), and the range of STAT3 expression could be very high to low. In vivo transplantation of ADOCCs with high pSTAT3 expression into the ovarian bursa of mice resulted in a large primary tumor and widespread peritoneal metastases. In contrast, ADOCCs with low STAT3 expression or ADOCCs with STAT3 expression knockdown, led to reduced tumor growth and an absence of metastases in vivo. Cytokines derived from the ADOCC culture medium activate the interleukin (IL)-6/STAT pathway in the STAT3 knockout (KO) cells, compensating for the absence of inherent STAT3 in the cells. Treatment with HO-3867 (a novel STAT3 inhibitor at 100 p.p.m. in an orthotopic murine model) significantly suppressed ovarian tumor growth, angiogenesis and metastasis by targeting STAT3 and its downstream proteins. HO-3867 was found to have cytotoxic effects in ex vivo cultures of freshly collected human ovarian cancers, including those resistant to platinum-based chemotherapy. Our results show that STAT3 is necessary for ovarian tumor progression/metastasis and highlight the potential for targeting STAT3 by HO-3867 as a therapeutic strategy for ovarian cancer.
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http://dx.doi.org/10.1038/onc.2016.197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5338638PMC
January 2017

Constitutive Activation of PI3K in Oocyte Induces Ovarian Granulosa Cell Tumors.

Cancer Res 2016 07 9;76(13):3851-61. Epub 2016 May 9.

Department of Molecular Virology, Immunology and Medical Genetics, The Comprehensive Cancer Center, Ohio State University, Columbus, Ohio.

Cell-cell interactions play crucial roles in the maintenance of tissue homeostasis, a loss of which often leads to varying diseases, including cancer. Here, we report that uncontrolled PI3K activity within oocytes irreversibly transforms granulosa cells (GC), causing GC tumors (GCT) through perturbed local cell communication. Previously, we reported reproductive phenotypes of transgenic mice, in which expression of constitutively active mutant PI3K was induced in primordial oocytes by Gdf9-iCre. The transgenic mice (Cre(+)) demonstrated severe ovarian phenotypes, including the overgrowth of excess ovarian follicles and anovulation. Surprisingly, the Cre(+) mice became cachectic by postnatal day 80 due to bilateral GCT. Although GCT cells proliferated independently of oocytes, local interactions with mutant PI3K-positive oocytes during early folliculogenesis were essential for the GC transformation. Growing GCT cells expressed high levels of inhibin βA and nuclear SMAD3, and the proliferation rate was positively correlated with a high activin A to inhibin A ratio. These results suggested that the tumor cells stimulated their growth through an activin A autocrine signaling pathway, a hypothesis confirmed by activin A secretion in cultured GCT cells, which proliferated in response. Although communication between the oocyte and surrounding somatic cells is critical for the normal development of ovarian follicles, perturbations in oocyte-GC communication during early folliculogenesis can induce GCT by activating an autocrine growth circuit program in GC. Cancer Res; 76(13); 3851-61. ©2016 AACR.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5081136PMC
http://dx.doi.org/10.1158/0008-5472.CAN-15-3358DOI Listing
July 2016

Estrogen receptor-alpha as a predictive biomarker in endometrioid endometrial cancer.

Gynecol Oncol 2016 05 10;141(2):312-317. Epub 2016 Mar 10.

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

Background: We sought to validate the prognostic significance of estrogen receptor alpha (ERα) expression and to investigate the relationship between ESR1 mutation status and outcomes in a large cohort of patients with endometrial cancer. We also investigated the predictive value of ERα for lymph node involvement in a large surgically staged cohort.

Methods: A tumor microarray (TMA) was constructed including only pure endometrioid adenocarcinomas, stained with ER50 monoclonal antibody, and assessed using digital image analysis. For mutation analysis, somatic DNA was extracted and sequenced for ESR1 gene hotspot regions. Differences in patient and tumor characteristics, recurrence and survival between ERα positive and negative, mutated and wild-type tumors were evaluated.

Results: Sixty (18.6%) tumors were negative for ERα. Absence of ERα was significantly associated with stage and grade, but not with disease-free or overall survival. ERα was a strong predictor of lymph node involvement (RR: 2.37, 95% CI: 1.12-5.02). Nineteen of 1034 tumors (1.8%) had an ESR1 hotspot mutation; twelve in hotspot 537Y, four in 538D and three in 536L. Patients with an ESR1 mutation had a significantly lower BMI, but were comparable in age, stage and grade, and progression-free survival.

Conclusion: Patients with ERα negative endometrioid endometrial cancer are more often diagnosed with higher grade and advanced stage disease. Lymph node involvement is more common with lack of ERα expression, and may be able to help triage which patients should undergo lymphadenectomy. Mutations in ESR1 might explain why some low risk women with low BMI develop endometrial cancer.
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http://dx.doi.org/10.1016/j.ygyno.2016.03.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878441PMC
May 2016

Endometrial Cancer Insulin-Like Growth Factor 1 Receptor (IGF1R) Expression Increases with Body Mass Index and Is Associated with Pathologic Extent and Prognosis.

Cancer Epidemiol Biomarkers Prev 2016 Mar 18;25(3):438-45. Epub 2015 Dec 18.

Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, Ohio.

Background: Obesity is a main risk factor for endometrial carcinoma (EC). Insulin-like growth factor 1 receptor (IGF1R) expression may influence this association.

Methods: IGF1R IHC was performed on a tissue microarray with 894 EC and scored according to the percentage and intensity of staining to create immunoreactivity scores, which were dichotomized into low and high IGF1R expression groups. Logistic regression modeling assessed associations with body mass index (BMI), age, histology, pathologic extent of disease (pT), and lymph node metastasis (pN). Overall survival (OS) and disease-free survival (DFS) were compared between IGF1R expression groups using Kaplan-Meier curves and log-rank tests.

Results: The proportion of patients with high IGF1R expression increased as BMI (<30, 30-39, and 40+ kg/m(2)) increased (P = 0.002). The adjusted odds of having high IGF1R expression was 1.49 [95% confidence interval (CI), 1.05-2.10, P = 0.024] for patients with BMI 30 to 39 kg/m(2) compared with <30 kg/m(2) and 1.62 (95% CI, 1.13-2.33, P = 0.009) for patients with BMI 40+ kg/m(2) compared with <30 kg/m(2). High IGF1R expression was associated with pT and pN univariately and with pT after adjusting for BMI, pN, age, and histologic subtype. DFS and OS were better with high IGF1R expression, P = 0.020 and P = 0.002, respectively, but DFS was not significant after adjusting for pT, pN, and histologic subtype of the tumor.

Conclusions: There is an association between BMI and EC IGF1R expression. Higher IGF1R expression is associated with lower pT and better DFS and OS.

Impact: These findings suggest a link between IGF1R EC expression and obesity, as well as IGF1R expression and survival.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5075967PMC
http://dx.doi.org/10.1158/1055-9965.EPI-15-1145DOI Listing
March 2016

Noncatalytic PTEN missense mutation predisposes to organ-selective cancer development in vivo.

Genes Dev 2015 Aug;29(16):1707-20

Solid Tumor Biology Program, James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Department of Molecular Genetics, College of Arts and Sciences, The Ohio State University, Columbus, Ohio 43210, USA; Department of Molecular Virology, Immunology, and Medical Genetics, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA;

Inactivation of phosphatase and tensin homology deleted on chromosome 10 (PTEN) is linked to increased PI3K-AKT signaling, enhanced organismal growth, and cancer development. Here we generated and analyzed Pten knock-in mice harboring a C2 domain missense mutation at phenylalanine 341 (Pten(FV)), found in human cancer. Despite having reduced levels of PTEN protein, homozygous Pten(FV/FV) embryos have intact AKT signaling, develop normally, and are carried to term. Heterozygous Pten(FV/+) mice develop carcinoma in the thymus, stomach, adrenal medulla, and mammary gland but not in other organs typically sensitive to Pten deficiency, including the thyroid, prostate, and uterus. Progression to carcinoma in sensitive organs ensues in the absence of overt AKT activation. Carcinoma in the uterus, a cancer-resistant organ, requires a second clonal event associated with the spontaneous activation of AKT and downstream signaling. In summary, this PTEN noncatalytic missense mutation exposes a core tumor suppressor function distinct from inhibition of canonical AKT signaling that predisposes to organ-selective cancer development in vivo.
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http://dx.doi.org/10.1101/gad.262568.115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4561480PMC
August 2015

Mass spectrometry identification of potential mediators of progestin-only contraceptive-induced abnormal uterine bleeding in human endometrial stromal cells.

Contraception 2015 Mar 21;91(3):253-60. Epub 2014 Nov 21.

Department of Obstetrics and Gynecology, The University of South Florida, Tampa, FL 33606, USA.

Objective: Thrombin and hypoxia each target human endometrial stromal cells (HESCs) to mediate long-acting progestin-only contraceptive (LAPC)-induced abnormal uterine bleeding (AUB). Thus, the secretome resulting from treatment of primary cultures of HESCs with thrombin or hypoxia was screened by mass spectrometry (MS) to detect potential protein mediators that lead to AUB.

Study Design: Cultured HESCs were primed with estradiol±medroxyprogesterone acetate (MPA) or etonogestrel (ETO), the respective progestins in MPA-injected and ETO-implanted LAPCs, and then treated by incubation with thrombin or under hypoxia. Collected conditioned medium supernatants were used for protein identification and quantitation of potential AUB mediators by liquid chromatography combined with tandem mass spectrometry analysis. Microarray analysis of parallel cultures and immunostaining of endometrial biopsies of LAPC users vs. nonusers corroborated MS results.

Results: MS identified several proteins displaying changes in expression levels from either thrombin or hypoxia treatments that are integral to angiogenesis or extracellular matrix formation. Several MS-identified proteins were confirmed by mRNA microarray analysis. Overexpressed stanniocalcin-1 (STC-1) was observed in endometrium of LAPC users. Unlike controls, all LAPC users displayed endometrial tubal metaplasia (ETM).

Conclusions: MS analysis identified many proteins that can affect angiogenesis or vessel integrity, thereby contributing to AUB. Confirmation of STC-1 overexpression in LAPC users and microarray data supports the validity of the MS data and suggests STC-1 involvement in AUB. The discovery of ETM in LAPC users indicates that LAPC-related side effects extend beyond AUB. The results presented here demonstrate a complex biological response to LAPC use.

Implications: MS identified several HESC secreted proteins deregulated by thrombin and hypoxia that may mediate LAPC-induced AUB. The revelation of overexpressed STC-1 by combined in vivo and in vitro observations identifies a potential target for future studies to prevent or minimize LAPC-induced AUB.
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http://dx.doi.org/10.1016/j.contraception.2014.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4395468PMC
March 2015

Comprehensive evaluation of caspase-14 in vulvar neoplasia: an opportunity for treatment with black raspberry extract.

Gynecol Oncol 2014 Dec 23;135(3):503-9. Epub 2014 Sep 23.

Department of Pathology, The Ohio State University Wexner Medical Center, 410 W 10th Ave, Columbus, OH 43210, USA. Electronic address:

Objective: The aim of this study is to determine the expression of caspase-14, a key protein in maturation of squamous epithelia, in archival malignant and premalignant vulvar squamous lesions and examine in-vitro effects of a black raspberry extract (BRB-E) on a vulvar squamous cell carcinoma (VSCC) cell line.

Methods: VSCC cell cultures were exposed to different BRB-E concentrations and used to create cell blocks. Immunohistochemistry for caspase-14 was performed on cell block sections, whole tissue sections, and a tissue microarray consisting of normal vulvar skin, lichen sclerosus (LS), classic and differentiated vulvar intraepithelial neoplasia (cVIN and dVIN respectively), and VSCC.

Results: LS demonstrated abnormal full thickness (5/11) or absent (1/11) caspase-14 staining. dVIN often showed markedly reduced expression (4/7), and cVIN occasionally demonstrated either absent or reduced caspase-14 (6/22). VSCC predominantly had absent or markedly reduced caspase-14 (26/28). VSCC cell cultures demonstrated a significant increase in caspase-14 (p=0.013) after BRB-E treatment: 7.3% (±2.0%) of untreated cells showed caspase-14 positivity, while 21.3% (±8.9%), 21.7% (±4.8%), and 22.6% (±5.3%) of cells were positive for caspase-14 after treatment with 200, 400, and 800 μg/mL BRB-E, respectively. Pair-wise comparisons between the treatment groups and the control demonstrated significant differences between no treatment with BRB-E and each of these treatment concentrations (Dunnett's adjusted p-values: 0.024, 0.021, and 0.014, respectively).

Conclusions: Caspase-14 is frequently decreased in premalignant and malignant vulvar squamous lesions, and is upregulated in VSCC cell culture by BRB-E. BRB-E should be further explored and may ultimately be incorporated in topical preparations.
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http://dx.doi.org/10.1016/j.ygyno.2014.09.012DOI Listing
December 2014

Polymerase ɛ (POLE) mutations in endometrial cancer: clinical outcomes and implications for Lynch syndrome testing.

Cancer 2015 Feb 15;121(3):386-94. Epub 2014 Sep 15.

Department of Obstetrics and Gynecology, Division of Gynecology Oncology, The Ohio State University, College of Medicine, Columbus, Ohio.

Background: DNA polymerase ɛ (POLE) exonuclease domain mutations characterize a subtype of endometrial cancer (EC) with a markedly increased somatic mutational burden. POLE-mutant tumors were described as a molecular subtype with improved progression-free survival by The Cancer Genome Atlas. In this study, the frequency, spectrum, prognostic significance, and potential clinical application of POLE mutations were investigated in patients with endometrioid EC.

Methods: Polymerase chain reaction amplification and Sanger sequencing were used to test for POLE mutations in 544 tumors. Correlations between demographic, survival, clinicopathologic, and molecular features were investigated. Statistical tests were 2-sided.

Results: Thirty POLE mutations (5.6%) were identified. Mutations were associated with younger age (<60 years; P=.001). POLE mutations were detected in tumors with microsatellite stability (MSS) and microsatellite instability (MSI) at similar frequencies (5.9% and 5.2%, respectively) and were most common in tumors with MSI that lacked mutL homolog 1 (MLH1) methylation (P<.001). There was no association with progression-free survival (hazard ratio, 0.22; P=.127).

Conclusions: The discovery that mutations occur with equal frequency in MSS and MSI tumors and are most frequent in MSI tumors lacking MLH1 methylation has implications for Lynch syndrome screening and mutation testing. The current results indicate that POLE mutations are associated with somatic mutation in DNA mismatch repair genes in a subset of tumors. The absence of an association between POLE mutation and progression-free survival indicates that POLE mutation status is unlikely to be a clinically useful prognostic marker. However, POLE testing in MSI ECs could serve as a marker of somatic disease origin. Therefore, POLE tumor testing may be a valuable exclusionary criterion for Lynch syndrome gene testing.
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http://dx.doi.org/10.1002/cncr.29046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4304930PMC
February 2015

Mismatch repair protein expression in 1049 endometrial carcinomas, associations with body mass index, and other clinicopathologic variables.

Gynecol Oncol 2014 Apr 17;133(1):43-7. Epub 2014 Jan 17.

Department of Pathology, The Ohio State University College of Medicine, Columbus, OH, USA. Electronic address:

Objective: Links between obesity, with its attendant estrogen abnormalities, and the endometrial carcinoma (EC) DNA Mismatch Repair Protein (MMR) system have recently been proposed. We investigated relationships between body mass index (BMI) and clinicopathological correlates including MMR expression in a large single institution EC cohort.

Methods: Clinical and pathological databases from 2007 to 2012 were used to identify consecutive hysterectomy specimens with EC. Univariate and multivariate analyses were used to explore relationships between BMI, age, stage, tumor type and immunohistochemical results for MLH1, PMS2, MSH2 and MSH6.

Results: 1049 EC were identified. Overall, BMI was higher amongst women with normal MMR (p=0.002). However, when stratified by age and specific MMR, statistically significant differences localized exclusively to women <50years old with loss of MSH2 and/or MSH6 (p=0.003 and p=0.005 respectively). Higher BMI correlated with endometrioid FIGO 1 and 2 tumors (p<0.001) and with stage 1a (p<0.001). Conversely, MMR abnormalities did not show significant associations with stage (p=0.302) or histologic grade (p=0.097).

Conclusions: BMI showed statistically significant associations with MMR expression, tumor grade and stage amongst 1049 consecutive EC. Obesity correlates with lower grade and stage EC. A link between BMI and maintenance of the MMR system is not supported by our data because the only statistically significant association occurred in women <50years old with MSH2 and/or MSH6 abnormalities where Lynch syndrome related cases are expected to cluster.
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http://dx.doi.org/10.1016/j.ygyno.2014.01.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4127575PMC
April 2014

Hybrid capture 2 test results after an initial equivocal RLU/CO value are dependent on age.

Am J Clin Pathol 2013 May;139(5):605-10

Department of Pathology, The Ohio State University Medical Center, Columbus, OH 43210, USA.

The effect of age on Hybrid Capture 2 (HC2) tests initially falling within the equivocal range has not been determined. We identified 359 cervicovaginal liquid cytology specimens with initial equivocal values. First and second retest relative light units/cutoff (RLU/CO) values were compared for women of 3 different age groups (15-29, 30-49, and ≥50 years). The proportion of first retests with an RLU/CO of less than 1 increased with age (P < .001). Of the 56 second retests performed, only 4 had an RLU/CO of 1 or more. The proportion of "positive" HC2 results following the current HC2 algorithm decreased with increasing age (P < .001), showing that HC2 test results after an initial equivocal value are dependent on age. Follow-up demonstrated cervical intraepithelial neoplasia grade 2 or worse (CIN2+) in 6 (5.9%) women 15 to 29 years old and in 5 (6.3%) women 30 to 49 years old. No CIN2+ was found on follow-up of 34 of 57 women 50 years and older. These results likely reflect human papillomavirus infection prevalence and question the use of identical cutoff values regardless of age for detection of CIN2+.
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http://dx.doi.org/10.1309/AJCPARHTB40DTVFVDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3869231PMC
May 2013

[Study of diaphragmatic muscle function during abdominal weight in normal subjects].

Medicina (B Aires) 2012 ;72(2):98-102

Instituto de Investigaciones Médicas Alfredo Lanari, Universidad de Buenos Aires, Argentina.

The effects of the abdominal weight with the intention of producing training of the diaphragm, have not been sufficiently evaluated. We studied the function of the diaphragm during the abdominal weight training and during associated changes in the respiratory pattern. Six normal volunteers were studied. Flow at the mouth at functional residual capacity (FRC) was obtained as well as gastric pressure (Pga), esophageal pressure (Pes), thoracic and abdominal movements, maximal inspiratory pressure and mean and maximal transdiaphragmatic pressure (Pdi and Pdi max). Pdi/Pdimax and the diaphragm tension-time index (TTdi) were calculated. Studied steps: normal pattern (NP), abdominal pattern (AP) and weight of 1, 2, 4 and 6 kg with NP and AP as well. We found 1) The AP was facilitated by the abdominal weight, 2) Only with 6 kg (NP and AP) the Pga at FRC increased significantly (p 0.001), 3) the Pdi followed the variations of the Pga and increased with all the AP (p < 0.001), 4) The index TTdi load reached a value of 0.05 ± 0.02 (p < 0.001). The charges did not increase this rate more than did the AP alone. Our findings suggest abdominal weight increases propioception related to the respiratory movements and descent of the diaphragm. The loads on the abdomen produce minor changes in mechanics of the diaphragm (1/3 of the load required to develop fatigue in normal subjects). Al least in normal subjects these changes appear to be insufficient to produce respiratory muscle training.
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November 2014

The use of full-setting non-invasive ventilation in the home care of people with amyotrophic lateral sclerosis-motor neuron disease with end-stage respiratory muscle failure: a case series.

J Med Case Rep 2012 Jan 30;6:42. Epub 2012 Jan 30.

Laboratorio Pulmonar de Enfermedades Neuromusculares, Instituto de Investigaciones Médicas Alfredo Lanari, Universidad de Buenos Aires, CONICET Combatientes de Malvinas 3150, CP 1427, Buenos Aires, Argentina.

Introduction: Little has been written about the use of non-invasive ventilation in the home care of amyotrophic lateral sclerosis-motor neuron disease patients with end-stage respiratory muscle failure. Nocturnal use of non-invasive ventilation has been reported to improve daytime blood gases but continuous non-invasive ventilation dependence has not been studied in this regard. There continues to be great variation by country, economics, physician interest and experience, local concepts of palliation, hospice requirements, and resources available for home care. We report a case series of home-based amyotrophic lateral sclerosis-motor neuron disease patients who refused tracheostomy and advanced non-invasive ventilation to full-setting, while maintaining normal alveolar ventilation and oxygenation in the course of the disease. Since this topic has been presented in only one center in the United States and nowhere else, it is appropriate to demonstrate that this can be done in other countries as well.

Case Presentation: We present here the cases of three Caucasian patients (a 51-year-old Caucasian man, a 45-year-old Caucasian woman and a 57-year-old Caucasian woman) with amyotrophic lateral sclerosis who developed continuous non-invasive ventilation dependence for 15 to 27 months without major complications and were able to maintain normal CO2 and pulse oxyhemoglobin saturation despite a non-measurable vital capacity. All patients were wheelchair-dependent and receiving riluzole 50 mg twice a day. Patient one developed mild-to-moderate bulbar-innervated muscle weakness. He refused tracheostomy but accepted percutaneous gastrostomy. Patient two had two lung infections, acute bronchitis and pneumonia, which were treated with antibiotics and cough assistance at home. Patient three had three chest infections (bronchitis and pneumonias) and asthmatic episodes treated with antibiotics, bronchodilators and cough assistance at home. All patients had normal speech while receiving positive pressure; they died suddenly and with normal oxygen saturation.

Conclusions: Although warned that prognosis was poor as vital capacity diminished, our patients survived without invasive airway tubes and despite non-measurable vital capacity. No patient opted for tracheostomy. Our patients demonstrate the feasibility of resorting to full-setting non-invasive management to prolong survival, optimizing wellness and management at home, and the chance to die peacefully.
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http://dx.doi.org/10.1186/1752-1947-6-42DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3295643PMC
January 2012