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PTEN is known to be frequently mutated in uterine cancer and also dephosphorylates FAK. Here, we examined the impact of PTEN alterations on the response to treatment with a FAK inhibitor (GSK2256098). In vitro and in vivo therapeutic experiments were carried out using PTEN-mutated and PTEN-wild-type models of uterine cancer alone and in combination with chemotherapy. Treatment with GSK2256098 resulted in greater inhibition of pFAKY397 in PTEN-mutated (Ishikawa) than in PTEN-wild-type (Hec1A) cells. Ishikawa cells were more sensitive to GSK2256098 than the treated Hec1A cells. Ishikawa cells were transfected with a wild-type PTEN construct and pFAKY397 expression was unchanged after treatment with GSK2256098. Decreased cell viability and enhanced sensitivity to chemotherapy (paclitaxel and topotecan) in combination with GSK2256098 was observed in Ishikawa cells as compared with Hec1a cells. In the Ishikawa orthoptopic murine model, treatment with GSK2256098 resulted in lower tumor weights and fewer metastases than mice inoculated with Hec1A cells. Tumors treated with GSK2256098 had lower microvessel density (CD31), less cellular proliferation (Ki67), and higher apoptosis (TUNEL) rates in the Ishikawa model when compared with the Hec1a model. From a large cohort of evaluable patients, increased FAK and pFAKY397 expression levels were significantly related to poor overall survival. Moreover, PTEN levels were inversely related to pFAKY397 expression. These preclinical data demonstrate that PTEN-mutated uterine cancer responds better to FAK inhibition than does PTEN wild-type cancer. Therefore, PTEN could be a biomarker for predicting response to FAK-targeted therapy during clinical development. Mol Cancer Ther; 14(6); 1466–75. ©2015 AACR.

Mean mouse weights in orthotopic mouse models of uterine cancer.

Background: In contrast with the decreasing incidence seen for most cancers, endometrial cancer has been increasing in the United States. We examined whether the increasing incidence and mortality from endometrial cancer are equally distributed by race/ethnicity and tumor histologic subtype.Methods: Surveillance, Epidemiology, and End Results (SEER) endometrial cancer incidence and mortality data were obtained from 2000 to 2011. Age-adjusted incidence and incidence-based mortality rates, 95% confidence intervals, and annual percent changes (APC) were calculated. Rate ratios were calculated to compare racial/ethnic groups. Five-year relative survival rates were presented to explore survival by stage at diagnosis.Results: Incidence rates for endometrial cancers are rising across all racial/ethnic groups, with the greatest APC seen among non-Hispanic black (NHB) and Asian women (APC, 2.5 for both). NHB women have significantly higher incidence rates of aggressive endometrial cancers (clear cell, serous, high-grade endometrioid, and malignant mixed Mullerian tumors) compared with non-Hispanic white (NHW) women. Hispanic and Asian women have incidence rates equal to or lower than NHW women for all tumor subtypes. For nearly every stage and subtype, the 5-year relative survival for NHB women is significantly less than NHW women, whereas Hispanic and Asian women have the same or better survival.Conclusions: Endometrial cancer incidence is increasing for all women, particularly the aggressive subtypes. The disparity associated with excess incidence for these aggressive histologic subtypes and poorer survival is limited to NHB women.Impact: Increasing rates of aggressive endometrial cancers may widen the survival disparity between NHW and NHB women. Cancer Epidemiol Biomarkers Prev; 24(9); 1407–15. ©2015 AACR.

Supplementary Table S1: Annual percent change by subtype and race and ethnicity for endometrial cancers diagnosed 2000-2007, Surveillance, Epidemiology and End Results. Supplementary Table S2: 5 year relative survival by subtype, race and ethnicity, and stage for endometrial cancers diagnosed 2000-2007, Surveillance, Epidemiology and End Results.

Human and Mouse osteoclast precursor cells express Gal-3.

Management of bone metastasis remains clinically challenging and requires the identification of new molecular target(s) that can be therapeutically exploited to improve patient outcome. Galectin-3 (Gal-3) has been implicated as a secreted factor that alters the bone microenvironment. Proteolytic cleavage of Gal-3 may also contribute to malignant cellular behaviors, but has not been addressed in cancer metastasis. Here, we report that Gal-3 modulates the osteolytic bone tumor microenvironment in the presence of RANKL. Gal-3 was localized on the osteoclast cell surface, and its suppression by RNAi or a specific antagonist markedly inhibited osteoclast differentiation markers, including tartrate-resistant acid phosphatase, and reduced the number of mature osteoclasts. Structurally, the 158–175 amino acid sequence in the carbohydrate recognition domain (CRD) of Gal-3 was responsible for augmented osteoclastogenesis. During osteoclast maturation, Gal-3 interacted and colocalized with myosin-2A along the surface of cell–cell fusion. Pathologically, bone metastatic cancers expressed and released an intact form of Gal-3, mainly detected in breast cancer bone metastases, as well as a cleaved form, more abundant in prostate cancer bone metastases. Secreted intact Gal-3 interacted with myosin-2A, leading to osteoclastogenesis, whereas a shift to cleaved Gal-3 attenuated the enhancement in osteoclast differentiation. Thus, our studies demonstrate that Gal-3 shapes the bone tumor microenvironment through distinct roles contingent on its cleavage status, and highlight Gal-3 targeting through the CRD as a potential therapeutic strategy for mitigating osteolytic bone remodeling in the metastatic niche. Cancer Res; 76(6); 1391–402. ©2016 AACR.

Mouse osteoclast precursor expresses and secretes endogenous Gal-3.

Results of immunohistochemistry in breast and prostate cancer patients with metastasis.

Anti-CRD of Gal-3 inhibits osteoclast cell fusion.

Myosin-2A is a candidate for binding partner of Gal-3.

Gal-3 is involved in osteoclastogenesis in bone tumor microenvironment.

A noninvasive screening test would significantly facilitate early detection of epithelial ovarian cancer. This study used a combination of high-throughput selection and array-based serologic detection of many antigens indicative of the presence of cancer, thereby using the immune system as a biosensor. This high-throughput selection involved biopanning of an ovarian cancer phage display library using serum immunoglobulins from an ovarian cancer patient as bait. Protein macroarrays containing 480 of these selected antigen clones revealed 65 clones that interacted with immunoglobulins in sera from 32 ovarian cancer patients but not with sera from 25 healthy women or 14 patients having other benign or malignant gynecologic diseases. Sequence analysis data of these 65 clones revealed 62 different antigens. Among the markers, we identified some known antigens, including RCAS1, signal recognition protein-19, AHNAK-related sequence, nuclear autoantogenic sperm protein, Nijmegen breakage syndrome 1 (Nibrin), ribosomal protein L4, Homo sapiens KIAA0419 gene product, eukaryotic initiation factor 5A, and casein kinase II, as well as many previously uncharacterized antigenic gene products. Using these 65 antigens on protein microarrays, we trained neural networks on two-color fluorescent detection of serum IgG binding and found an average sensitivity and specificity of 55% and 98%, respectively. In addition, the top 6 of the most specific clones resulted in an average sensitivity and specificity of 32% and 94%, respectively. This global approach to antigenic profiling, epitomics, has applications to cancer and autoimmune diseases for diagnostic and therapeutic studies. Further work with larger panels of antigens should provide a comprehensive set of markers with sufficient sensitivity and specificity suitable for clinical testing in high-risk populations. (Cancer Res 2006; 66(2): 1181-90)

Supplementary Tables 1-4 from Diagnostic Markers of Ovarian Cancer by High-Throughput Antigen Cloning and Detection on Arrays

Materials and Methods for Tissue microarray, Immunofluorescence, Quantitative Real-Time PCR, Proteomics analysis, Co-immunoprecipitation, Co-culture.

Context.— Intraoperative consultation—frozen section diagnosis (FSD)—determines tumor pathology and guides the optimal surgical management of ovarian neoplasms intraoperatively. Objective.— To evaluate the diagnostic accuracy of the FSD and analyze the discrepancy between the FSD and final diagnosis. Design.— This is a retrospective study of 618 ovarian neoplasm FSDs from 2009 to 2018 at a tertiary health care center. The discrepant cases were reviewed and reevaluated by gynecologic and general surgical pathologists. The outcomes of interest were performing unnecessary procedure, returning for a second surgery, and 30-day postoperative mortality. Results.— The sensitivity and the positive predictive value of the FSD were lower in borderline tumors than in benign and malignant epithelial ovarian tumors. Major and minor discrepancies were identified in 5.3% (33 of 618) and 12.3% of (76 of 618) cases, respectively. A root cause analysis of the major discrepant cases showed that sampling error accounted for 43% (14 of 33). The discrepancy distributions of gynecologic and general surgical pathologists were statistically similar in the overall cohort (P = .65). The overall κ for diagnostic agreement among gynecologic pathologists, general surgical pathologists, and final diagnosis was 0.18 (0.10–0.26, P < .001), implying only a slight overall agreement. Of the major discrepant cases, only 3 had a clinical implication. One overdiagnosed patient underwent an unecessary procedure, and 2 underdiagnosed patients were recommended to return for a second surgery. No patient had 30-day postoperative mortality. Conclusions.— Frozen section diagnosis remains a definitive diagnostic tool in ovarian neoplasms and plays a crucial role in guiding intraoperative surgical management.

Background: With limited health data on Arab Americans (AAs), we sought to describe the health-seeking behaviors, prevalence of abnormal cervical cytology and high-risk human papillomavirus (HPV) serotypes, and the relationship with socioeconomic factors among a subset of AA women. Methods: Retrospective observational cohort study of women undergoing routine cancer screening at the Arab-American Center for Economic and Social Services clinic. Data collected included demographics, tobacco use, gross monthly income, prior Papanicolaou (Pap) smear history, and results of cervical cytology and high-risk HPV testing. Results: Of 430 women, 74 (17%) reported that they had never had a Pap smear. Three hundred eighty-eight (90%) women had cervical cytology interpreted as “negative for intraepithelial lesion,” the remaining 42 (10%) women had abnormal results. Thirteen (3%) women reported prior abnormal Pap smear, which was significantly associated with additional abnormal Pap smear on multivariable analyses (odds ratio 65.46; 95% confidence interval [CI] 17.01–338.62; p

Context.— Metaplastic breast carcinoma is an aggressive form of breast cancer that accounts for 0.5% to 3% of all breast cancers. Objective.— To study the clinicopathologic characteristics and outcomes of this rare disease. Design.— Retrospective study of patients with a diagnosis of metaplastic breast carcinoma between 2000 and 2019. Hematoxylin-eosin–stained slides were reviewed and additional clinical data were obtained from electronic medical records. Univariable and multivariable Cox proportional hazard regression analyses were used to determine associations between overall survival and several clinicopathologic variables. Results.— Of the 125 patients with metaplastic breast carcinoma identified, only patients with high-grade disease (N = 115) were included in the data analysis. A total of 38 participants (33%) were white, 66 (57%) were African American, and 11 (10%) belonged to other ethnicities. The median age at diagnosis was 57 years. The median tumor size was 3 cm. Heterologous histology was seen in 30% of cases. Multivariable analyses showed that patients with a larger tumor size had worse overall survival (hazard ratio [HR], 1.25; 95% CI, 1.10–1.44; P < .001). Distant metastatic disease was also associated with worse overall survival on multivariable analysis (HR, 10.27; 95% CI, 2.03–55.54; P = .005). In addition to treatment with either partial or complete mastectomies, 84 patients (73%) received chemotherapy. Multivariable analyses showed that chemotherapy had no effect on overall survival (HR, 0.53; 95% CI, 0.09–6.05; P = .55). Conclusions.— A larger tumor size and distant metastatic disease are associated with worse overall survival in patients with metaplastic breast carcinoma. Additional studies are needed to further characterize our findings.

Background: Vaccine hesitancy is the next great barrier for public health. Arab Americans are a rapidly growing demographic in the United States with limited information on the prevalence of vaccine hesitancy. We therefore sought to study the attitudes towards the coronavirus disease 2019 (COVID-19) vaccine amongst Arab American health professionals living in the United States. Methods: This was a cross sectional study utilizing an anonymous online survey. The survey was distributed via e-mail to National Arab American Medical Association members and Arab-American Center for Economic and Social Services healthcare employees. Respondents were considered vaccine hesitant if they selected responses other than a willingness to receive the COVID-19 vaccine. Results: A total of 4000 surveys were sent via e-mail from 28 December 2020 to 31 January 2021, and 513 responses were received. The highest group of respondents were between the ages of 18–29 years and physicians constituted 48% of the respondents. On multivariable analysis, we found that respondents who had declined an influenza vaccine in the preceding 5 years (p &lt, 0.001) and allied health professionals (medical assistants, hospital administrators, case managers, researchers, scribes, pharmacists, dieticians and social workers) were more likely to be vaccine hesitant (p = 0.025). In addition, respondents earning over $150,000 US dollars annually were less likely to be vaccine hesitant and this finding was significant on multivariable analysis (p = 0.011). Conclusions: Vaccine hesitancy among health care providers could have substantial impact on vaccine attitudes of the general population, and such data may help inform vaccine advocacy efforts.

To assess the role of serial FLT-PET scans during early neoadjuvant treatment as a prognostic marker of response to treatment and survival. This study is a prospective cohort study which draws from a larger original study which examined the utility of FLT-PET imaging across multiple cancers. Our cohort consisted of patients who had biopsy-confirmed breast cancer amenable to surgical resection. These patients underwent serial FLT-PET scans: the first scan prior to starting neoadjuvant chemotherapy (NAC), and a second scan shortly after starting NAC. SUVmean was derived using an isocontour ROI drawn approximately half way between the SUVmax and background on three planes for each scan. The change in mean standardized uptake value (SUVmean) for the primary tumor between these two scans was then calculated, and patients were stratified into “responder” and “non-responder” groups based on a cut-off of 20% arithmetic decrease in SUVmean between the two scans. The rates of pathologic complete response (pCR) on subsequent surgical excision, overall survival (OS), and progression-free survival (PFS) were then compared between the two groups to assess for significant difference between responders and non-responders. 16 patients (n = 16) met criteria for inclusion and successfully underwent FLT-PET scans in the prescribed sequence of events. Seven of these patients had a decrease of 20% or larger between the two serial PET scans, making them “responders”. The remaining nine patients were “non-responders” to NAC based on PET imaging. Between responders and non-responders, there was no significant difference in median PFS (7.9 years versus 3.7 years; p = 0.425) and median OS (7.5 years versus 5.0 years; p = 0.944). In the 14 patients who underwent surgical resection (n = 14), there was no significant difference in the rate of achieving pCR (33% vs. 14%; p = 0.5846) between responders and non-responders. Further study of a larger sample size is needed to examine the potential role for FLT-PET in predicting response to neoadjuvant treatment, particularly in correlating with long-term overall and progression-free survival. Our study is limited by small sample size, but does suggest that FLT-PET has a role in the long-term prognosis of breast cancer treated with NAC and surgical resection which is worthy of further study.

Background: Uterine serous carcinomas (USC) comprise 10-15% of all uterine cancers, but are responsible for approximately 40% of all deaths due to the disease. African American women have the highest incidence of and mortality from USC of any racial or ethnic group. Assessment of racial differences in driver mutation frequency may partially explain the survival disparity, and identification of novel alterations may provide avenues for targeted treatment. Methods: Two academic hospitals in Detroit, Michigan identified 125 women who had surgical treatment for USC and formalin fixed, paraffin-embedded tissue available for whole exome sequencing (WES). Detailed clinical and pathological data were also available, including long-term follow up. WES was performed using Illumina’s NovaSeq 6000 platform and data were processed via the Genome Analysis Toolkit (GATK), with additional filtering to account for excess artifacts resulting from formalin fixation. Functional mutations were determined by ANNOVAR and the ClinVar database, while putative driver mutations were identified via the IntOGen pipeline. Percentages were used to describe the proportion of tumors harboring a gene mutation, and the Fisher’s exact test was used to test for statistically significant differences in African American (AA) versus non-Hispanic white (NHW) mutation frequencies. Results: The majority of tumors were from AA women (n=87, 69.6%), with the remaining from NHW women (n=38, 30.4%). The overall mutational burden in tumors from AA women was similar to tumors from NHW women (median=122 and 166.5, respectively, p-value=0.12).TP53 was the most frequently mutated, with 77% of tumors from AA women and 65.8% of tumors from NHW women harboring a mutation (p-value=0.20), followed by PPP2R1A (AA=19.5%, NHW=28.9%, p-value=0.25) and PIK3CA (AA=13.8%, NHW=23.7%, p-value=0.20). Of the 66 driver genes in uterine cancer identified from IntOGen, only 3 differed significantly by race: ARID1A (AA=5.7%, NHW=28.9%; p-value=0.001), PTEN (AA=1.1%, NHW=15.8%; p-value=0.003) and FGFR2 (AA=0%, NHW=7.9%, p-value=0.02). Examination of genes with mutational frequencies ≥10% in AA or NHW tumors and with significant differences in mutation distribution by race (n=96) identified an additional 10 genes with mutations that are considered drivers in other cancer types that have not been described in uterine cancers. Conclusions: There are potential driver mutations undescribed in USC that are clinically important in other cancers. Additionally, we noted several differences in the mutation frequency by race which highlights the importance of including racially diverse samples in research, particularly AA women who have the largest burden of USC. Defining the somatic landscape of USC will lead to identification of actionable molecular targets, which will ultimately improve the prognosis of this aggressive subtype. Citation Format: Michele L. Cote, Greg Dyson, Douglas Craig, Julie J. Ruterbusch, Julie Boerner, Mohamed A. Elshaikh, Thomas P. Conrads, Nicholas W. Bateman, George L. Maxwell, Kathleen M. Darcy, Sasha Makohon-Moores, Timothy D. O'Connor, Hassan Abdallah, Logan Corey, Mira Kheil, Rouba Ali-Fehmi. Whole exome sequencing of uterine serous carcinomas reveals racial differences in known and novel driver mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 750.

Background Arab-Americans constitute ~ 5% of Michigan’s population. Estimates of obesity in Arab-Americans are not up-to-date. Here we describe the distribution of, and factors associated with obesity in an Arab-American population.Methods Arab-American patients, ages 18–98 years, from Arab Community Center for Economic and Social Services (ACCESS) clinic located in Dearborn, Michigan were identified from medical records. Retrospective chart review abstracted age, sex, marital status, employment, body mass index (BMI), hypertension (HTN), diabetes mellitus (DM), hyperlipidemia (HLD), employment status, tobacco use and alcohol consumption. This cohort was compared to Michigan’s Behavioral Risk Factor Surveillance System (BRFSS) data from 2018 and to a cohort seeking care between 2013–2019 from a free clinic in Ferndale, Michigan.Results Of the 2,363 Arab-American patients from the ACCESS clinic, 67% (n = 1591) were female and 33% (n = 772) were male. Among Arab-Americans, patients who were older or with HTN, DM or HLD had a higher prevalence of obesity than patients who were younger or without these comorbidities (all p-value Conclusion Obesity rates in Arab-Americans were comparable to their BRFSS counterparts, and lower than their FCFC counterparts. Further studies are required to understand the impact of obesity and the association of comorbidities in Arab-Americans residing in the US.

The Pap smear is a well-known screening tool for squamous lesions of the uterine cervix. However, its screening role in glandular lesions is less effective. The incidence of squamous cell carcinoma of the cervix has dramatically decreased with the advent of Pap smear and recent understanding related to HPV carcinogenesis of cervical cancers including the advent of HPV vaccines. However, in recent years, the incidence of glandular abnormalities, diagnosed on Pap smears, has increased with greater sensitivity and precision. The incidence of atypical glandular cells (AGC) is approximately 0.18–0.74% of all cervical smears with a reported prevalence of 2.5% among all Pap smears. A high degree of suspicion, good clinical history, and the presence of diagnostic cytomorphological findings are essential for the proper interpretation of glandular cell abnormalities. A methodical approach to evaluate Pap smear greatly helps interpretation and avoids the diagnostic pitfalls. The Bethesda System for reporting cervical cytology has categorized glandular cell abnormalities into various categories as follows: Endocervical adenocarcinoma in situ (AIS) Atypical glandular cells (AGCs) Endocervical cells: a1 NOS or specify in comments; a2 Favor neoplastic Endometrial cells: NOS or specify in comments Adenocarcinoma (AdCa) Endocervical Endometrial Extrauterine NOS Subtle differences in quantitative and qualitative cytologic features are essential for distinguishing one category from another. In this chapter, we highlight an organized approach for the interpretation of glandular abnormalities in Pap smear for our readers. This is an overview of the Bethesda categories, the reason for classification, and differential diagnosis with key characteristic features. An approach to the methodical evaluation of hyperchromatic crowded groups is discussed with key cytomorphologic differences. An algorithmic approach is suggested to facilitate the interpretation of various AGC categories.

INTRODUCTION: There is mounting evidence supporting the role of tryptophan metabolism via the kynurenine pathway (KP) in the pathogenesis of primary brain tumors. Under normal physiological conditions, the KP is the major catabolic pathway for the essential amino acid tryptophan. However, in cancer cells, the KP becomes dysregulated, depletes local tryptophan, and contributes to an immunosuppressive tumor microenvironment. METHODS: We examined the protein expression levels (in 73 gliomas and 48 meningiomas) of the KP rate-limiting enzymes indoleamine 2,3-dioxygenase (IDO) 1, IDO2, and tryptophan 2,3-dioxygenase (TDO2), as well as, the aryl hydrocarbon receptor (AhR), a carcinogenic transcription factor activated by KP metabolites. In addition, we utilized commercially available small-molecules to pharmacologically modulate IDO1, IDO2, TDO2, and AhR in patient-derived glioma and meningioma cell lines (n = 9 each). RESULTS: We observed a positive trend between the grade of the tumor and the average immunohistochemical staining score for IDO1, IDO2, and TDO2, with TDO2 displaying the strongest immunostaining. AhR immunostaining was present in all grades of gliomas and meningiomas, with the greatest staining intensity noted in glioblastomas. Immunocytochemical staining showed a positive trend between nuclear localization of AhR and histologic grade in both gliomas and meningiomas, suggesting increased AhR activation with higher tumor grade. Unlike enzyme inhibition, AhR antagonism markedly diminished patient-derived tumor cell viability, regardless of tumor type or grade, following in vitro drug treatments. CONCLUSIONS: Collectively, these results suggest that AhR may offer a novel and robust therapeutic target for a patient population with highly limited treatment options.

Meningiomas are the most common primary brain tumor. Grade I meningiomas are slow growing with a good prognosis following surgical resection. High grade meningiomas (II and III) are more aggressive with greater rates of recurrence and poor prognosis despite surgical resection and radiotherapy. This study sought to identify key pathways and genes that contribute to the molecular mechanisms that separate these distinct meningioma phenotypes. FFPE specimens were evaluated and graded by a pathologist. Total RNA was extracted from tissue curls and RNA samples were measured with the Illumina DASL whole genome gene expression assay (n = 29,374 probes). A log2 transformation was applied to all of the data and quantile normalization using 21 samples. A t-test of the log2 expression of the 10 grade III samples and 11 grade I samples resulted in 1505 differentially expressed genes. The GeneCard Suite’s GeneAnalytics tool was used to perform pathway enrichment analysis. Similar to other comparable data sets, DNA Damage, Cell Cycle, EGF/EGFR Signaling, TGF-Beta Signaling, and PI3K-AKT Signaling pathways were among the 20 enriched pathways. Notably, matrix metalloprotease 28 (MMP28, also known as epilysin) was down regulated in grade III meningiomas compared to grade I (III/I expression ratio 0.315; P=0.015). MMP28 is expressed in numerous tissues including the nervous system during development and regeneration. In cancer, MMP28 is thought to enhance epithelial to mesenchymal transition by altering the TGF-B signaling pathways. MMP28 is an indicator of poor prognosis for pancreatic, lung, gastric and hepatic cancers as well as glioblastoma. However, MMP28 has also been reported as down regulated during malignant transformation in colon cancer. Our data suggest that MMP28 may have an alternative role in meningioma and serve as a positive prognostic indicator.

Objectives Clear cell carcinoma (CCC) comprises a rare yet an aggressive subtype, accounting for less than 5% of all uterine carcinomas. Several clinicopathologic features have been predictive of poor prognosis; however, data remain controversial. The aim of this study was to evaluate the clinicopathologic features of a multi-institutional cohort of endometrial CCC in order to identify which, if any, have prognostic significance. Methods Retrospective review of endometrial CCC diagnosed between 1995 and 2012 at 3 institutions was conducted to evaluate clinicopathologic parameters: age, race, tumor size, stage, myometrial invasion (MI), lymphovascular invasion, lymph node and adnexal involvement, adjuvant therapy, and outcomes. Data were analyzed using Fisher exact, Cox regression, and Kaplan-Meier analyses. Results Patients’ ages ranged from 36 to 90 years (median, 67 years). The median tumor size was 3.6 cm. Inner-half MI was present in 44%, lymphovascular invasion in 34%, adnexal involvement in 16%, and lymph node metastasis in 30% of cases. Fifty-eight percent of the patients presented with early-stage disease. The 5-year overall survival (OS) was 58%. Shorter disease-free interval (DFI) was significantly associated with older age at diagnosis (>70 years), advanced-stage disease, adnexal involvement, and deep MI (P = 0.005, P = 0.001, P = 0.001, and P = 0.003, respectively). Patients who received adjuvant chemotherapy had a significantly worse DFI and 5-year OS (P = 0.001 and P = 0.001, respectively). A significantly shorter 5-year OS was noted with advanced stage (III–IV) and presence of adnexal involvement (P = 0.001 and P = 0.021, respectively). On Cox regression analysis, advanced-stage disease, older age, and adnexal involvement were significant independent predictors of worse DFI (P = 0.001, P = 0.005, and P = 0.019, respectively), whereas inner-half MI was a significant independent predictor of longer DFI (P = 0.004). Adjuvant radiotherapy alone was a significant independent predictor of better 5-year OS (P = 0.012). Conclusions In our series of endometrial CCC, older age at diagnosis, advanced stage, deep MI, and adnexal involvement were independent poor prognostic factors. Adjuvant radiotherapy had a significant positive impact on 5-year OS.

Background and Objectives To examine association of lympho-vascular space invasion (LVSI) with clinico-pathological factors and to evaluate survival of women with low-grade serous ovarian carcinoma containing areas of LVSI. Methods This is a multicenter retrospective study examining consecutive cases of surgically treated stage I-IV low-grade serous ovarian carcinoma (n = 178). Archived histopathology slides for the ovarian tumors were reviewed, and LVSI was scored as present or absent. LVSI status was correlated to clinico-pathological findings and survival outcome. Results LVSI was seen in 79 cases (44.4%, 95% confidence interval [CI] 37.1-51.7). LVSI was associated with increased risk of omental metastasis (87.0% vs 64.9%, odds ratio [OR] 3.62, P = 0.001), high pelvic lymph node ratio (median 12.9% vs 0%, P = 0.012), and malignant ascites (49.3% vs 32.6%, OR 2.01, P = 0.035). On multivariable analysis, controlling for age, stage, and cytoreductive status, presence of LVSI in the ovarian tumor remained an independent predictor for decreased progression-free survival (5-year rates 21.0% vs 35.7%, adjusted-hazard ratio 1.57, 95%CI 1.06-2.34, P = 0.026). LVSI was significantly associated with increased risk of recurrence in lymph nodes (OR 2.62, 95%CI 1.08-6.35, P = 0.047). Conclusion LVSI in the ovarian tumor is associated with adverse clinico-pathological characteristics and decreased progression-free survival in women with low-grade serous ovarian carcinoma.

// Young-Suk Jung 1, 7, * , Abdo J. Najy 1, * , Wei Huang 1 , Seema Sethi 1 , Michael Snyder 2, 3 , Wael Sakr 1 , Gregory Dyson 2 , Maik Huttemann 4 , Icksoo Lee 4, 8 , Rouba Ali-Fehmi 1 , Silvia Franceschi 5 , Linda Struijk 6 , Harold E. Kim 2, 3 , Ikuko Kato 2, 1 and Hyeong-Reh Choi Kim 1 1 Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA 2 Department of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA 3 Division of Radiation Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA 4 Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, USA 5 International Agency for Research on Cancer, Lyon, France 6 DDL Diagnostic Laboratory, Rijswijk, The Netherlands 7 Current Address: Pusan National University College of Pharmacy, Geumjeong-gu, Busan, Republic of Korea 8 Current Address: College of Medicine, Dankook University, Cheonan-si, Chungcheongnam-do, Republic of Korea * These authors have contributed equally to this work Correspondence to: Hyeong-Reh Choi Kim, email: hrckim@med.wayne.edu Keywords: head and neck squamous cell carcinoma, human papillomavirus, radiation, glucose metabolism, mitochondrial respiration Received: November 04, 2016 Accepted: April 05, 2017 Published: May 16, 2017 ABSTRACT HPV-positive oropharyngeal cancer patients experience significantly lower locoregional recurrence and higher overall survival in comparison with HPV-negative patients, especially among those who received radiation therapy. The goal of the present study is to investigate the molecular mechanisms underlying the differential radiation sensitivity between HPV-negative and HPV-positive head and neck squamous cell carcinoma (HNSCC). Here, we show that HPV-negative HNSCC cells exhibit increased glucose metabolism as evidenced by increased production of lactate, while HPV-positive HNSCC cells effectively utilize mitochondrial respiration as evidenced by increased oxygen consumption. HPV-negative cells express HIF1α and its downstream mediators of glucose metabolism such as hexokinase II (HKII) and carbonic anhydrase IX (CAIX) at higher levels, while the expression level of cytochrome c oxidase (COX) was noticeably higher in HPV-positive HNSCC. In addition, the expression levels of pyruvate dehydrogenase kinases (PDKs), which inhibit pyruvate dehydrogenase activity, thereby preventing entry of pyruvate into the mitochondrial tricarboxylic acid (TCA) cycle, were much higher in HPV-negative HNSCC compared to those in HPV-positive cells. Importantly, a PDK inhibitor, dichloroacetate, effectively sensitized HPV-negative cells to irradiation. Lastly, we found positive interactions between tonsil location and HPV positivity for COX intensity and COX/HKII index ratio as determined by immunohistochemical analysis. Overall survival of patients with HNSCC at the tonsil was significantly improved with an increased COX expression. Taken together, the present study provides molecular insights into the mechanistic basis for the differential responses to radiotherapy between HPV-driven vs . spontaneous or chemically induced oropharyngeal cancer.

Granulosa cell tumors (GCTs) comprise 2% to 5% of ovarian neoplasms, with unpredictable patterns of recurrence. The HER family, GATA4, and SMAD3 genes are reportedly involved in GCT proliferation and apoptosis and may serve as new predictors of recurrence. The aim of the study was to evaluate novel predictors of recurrence in GCT from a large single institution cohort. Patients diagnosed with GCTs (n = 125) between 1975 and 2014 were identified. Clinicopathologic parameters were obtained and immunohistochemical evaluation was performed of calretinin, inhibin, HER2, CD56, SMAD3, and GATA4. Statistical analyses were conducted using Fisher exact test and Kaplan-Meier survival curves and Cox regression analysis. The median follow-up period was 120 months (range, 1–465 mo). Recurrence was noted in 12/125 (9.6%) patients. Kaplan-Meier analysis showed a shorter mean disease-free interval in whites versus blacks (P = 0.001), stage III-IV versus stage I-II (P = 0.0001), patients treated with surgery+chemotherapy versus surgery (P = 0.0001), mitotic rate ≥4 (P = 0.005), severe nuclear pleomorphism (P = 0.013), high HER2 expression (P = 0.001), high CD56 expression (P = 0.001), and high SMAD3 expression (P = 0.001). On Cox regression analysis, SMAD3 and type of treatment received were the only 2 independent prognostic factors for disease-free interval (P = 0.03 and P = 0.007, respectively). On subanalysis for early-stage (stage I) GCTs, the need for adjuvant chemotherapy and high expression of SMAD3 continued to be independent predictors of recurrence (HR = 10.2, P = 0.01 and HR = 8.9, P = 0.001, respectively).

Ventricular Septal Defect (VSD), the most common congenital heart defect, is characterized by a hole in the septum between the right and left ventricles. The pathogenesis of VSD is unknown in most clinical cases. There is a paucity of data relevant to epigenetic changes in VSD. The placenta is a fetal tissue crucial in cardiac development and a potentially useful surrogate for evaluating the development of heart tissue. To understand epigenetic mechanisms that may play a role in the development of VSD, genome-wide DNA methylation assay on placentas of 8 term subjects with isolated VSD and no known or suspected genetic syndromes and 10 unaffected controls was performed using the Illumina HumanMethylation450 BeadChip assay. We identified a total of 80 highly accurate potential CpGs in 80 genes for detection of VSD; area under the receiver operating characteristic curve (AUC ROC) 1.0 with significant 95% CI (FDR) p-values < 0.05 for each individual locus. The biological processes and functions for many of these differentially methylated genes are previously known to be associated with heart development or disease, including cardiac ventricle development (HEY2, ISL1), heart looping (SRF), cardiac muscle cell differentiation (ACTC1, HEY2), cardiac septum development (ISL1), heart morphogenesis (SRF, HEY2, ISL1, HEYL), Notch signaling pathway (HEY2, HEYL), cardiac chamber development (ISL1), and cardiac muscle tissue development (ACTC1, ISL1). In addition, we identified 8 microRNAs that have the potential to be biomarkers for the detection of VSD including: miR-191, miR-548F1, miR-148A, miR-423, miR-92B, miR-611, miR-2110, and miR-548H4. To our knowledge this is the first report in which placental analysis has been used for determining the pathogenesis of and predicting VSD.

Introduction: Endometrial cancer (EC) is the most common gynecologic cancer diagnosed in the United States, and high-grade cancers account for approximately 1/5 of the ECs diagnosed in non-Hispanic white (NHW) women, Hispanic women, and Asian women, but nearly 1/3 of those diagnosed in African American (AA) women. These high-grade cancers are associated with poorer outcomes, and AAs are consistently at highest risk of mortality in studies that fail to adjust adequately for potentially important treatment or comorbidity variables. Here we present survival analyses from a study of AA and NHW women with high grade EC at two academic hospitals. Methods: High-grade cancers were identified through registries at each hospital and representative slides were re-reviewed by a single gynecologic pathologist to confirm high-grade disease and subtype. The following subtypes were included: clear cell, endometrioid, mixed, and serous. We identified 258 women (n=86 NHW, n=169 AA) who were diagnosed with high-grade cancers between 1998 and 2010. Utilizing medical records and the Surveillance, Epidemiology and End Results (SEER) registry, the following data were abstracted: height, weight, comorbid conditions, type of radiation, dose and fractions, type(s) of chemotherapy, number of cycles, recurrence, and vital status. Descriptive analyses utilized chi-square and t-tests to determine differences in clinical characteristics between AA and NHW women. Kaplan Meier survival analysis was performed to test for differences by race and subtype. To compare survival while considering competing risks of death, cause-specific hazard and cumulative incidence functions were compared using Gray's test. Results: The majority of the women had ECs classified as serous carcinomas (46.1%), followed by endometrioid (39.5%), clear cell carcinomas (9.7%) and mixed cell types (4.7%). AA women with endometrial cancer had slightly higher mean body mass index (BMI) compared to NHW women (34.6 and 32.2, respectively, p-value=0.06). NHW survived significantly longer after diagnosis compared to AA women (173 months versus 87 months, respectively, log-rank p-value=0.006). This difference remained after stratification by subtype, with similar findings for endometrioid cancers (log-rank p-value=0.06) and serous cancers (log-rank p-value=0.03). When examining survival considering competing risks (death due to EC versus other causes), AA women had a greater risk of death (HR: 1.84, 95% CI: 1.10-3.03) compared to their NHW counterparts; however, no difference was seen by race for other causes of death (HR: 1.29, 95% CI: 0.71-2.32). Further analyses, showing survival differences persist despite adjustments for BMI, comorbidities, and detailed treatment, will be presented. Conclusions: AA women continue to experience greater mortality from high-grade EC despite adjustments for demographic, clinical and treatment data, warranting continued efforts to identify molecular and social factors associated with poorer survival. Citation Format: Michele L. Cote, Julie J. Ruterbusch, Tara Rangarajan, Remonda Khalil, Mohamed Elshaikh, Rouba Ali-Fehmi. High-grade endometrial cancers: Persistent racial differences in survival [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr C120.

OBJECTIVE: To assess the role of serial FLT-PET scans during early neoadjuvant treatment as a prognostic marker of response to treatment and survival. METHODS: This study is a prospective cohort study which draws from a larger original study which examined the utility of FLT-PET imaging across multiple cancers. Our cohort consisted of patients who had biopsy-confirmed breast cancer amenable to surgical resection. These patients underwent serial FLT-PET scans: the first scan prior to starting neoadjuvant chemotherapy (NAC), and a second scan shortly after starting NAC. SUV(mean) was derived using an isocontour ROI drawn approximately half way between the SUV(max) and background on three planes for each scan. The change in mean standardized uptake value (SUV(mean)) for the primary tumor between these two scans was then calculated, and patients were stratified into “responder” and “non-responder” groups based on a cut-off of 20% arithmetic decrease in SUV(mean) between the two scans. The rates of pathologic complete response (pCR) on subsequent surgical excision, overall survival (OS), and progression-free survival (PFS) were then compared between the two groups to assess for significant difference between responders and non-responders. RESULTS: 16 patients (n = 16) met criteria for inclusion and successfully underwent FLT-PET scans in the prescribed sequence of events. Seven of these patients had a decrease of 20% or larger between the two serial PET scans, making them “responders”. The remaining nine patients were “non-responders” to NAC based on PET imaging. Between responders and non-responders, there was no significant difference in median PFS (7.9 years versus 3.7 years; p = 0.425) and median OS (7.5 years versus 5.0 years; p = 0.944). In the 14 patients who underwent surgical resection (n = 14), there was no significant difference in the rate of achieving pCR (33% vs. 14%; p = 0.5846) between responders and non-responders. CONCLUSION: Further study of a larger sample size is needed to examine the potential role for FLT-PET in predicting response to neoadjuvant treatment, particularly in correlating with long-term overall and progression-free survival. Our study is limited by small sample size, but does suggest that FLT-PET has a role in the long-term prognosis of breast cancer treated with NAC and surgical resection which is worthy of further study.

Ventricular Septal Defect (VSD), the most common congenital heart defect, is characterized by a hole in the septum between the right and left ventricles. The pathogenesis of VSD is unknown in most clinical cases. There is a paucity of data relevant to epigenetic changes in VSD. The placenta is a fetal tissue and is a potentially useful surrogate for the evaluation of fetal organ development. To understand epigenetic mechanisms that may play a role in the development of VSD, a genome-wide DNA methylation assay of the placentas of 8 term subjects with isolated VSD and no known or suspected genetic syndromes and 10 normal controls was performed using the Illumina HumanMethylation450 BeadChip assay. The study identified a total of 80 highly accurate potential epigenomic markers in 80 genes for the detection of VSD; area under the receiver operating characteristic curve (AUC ROC) = 1.0 with significant 95% CI (FDR) p-values < 0.05. The biological processes and functions for these differentially methylated genes are known to be associated with heart development or heart disease, including cardiac ventricle development (HEY2, ISL1), heart looping (SRF), cardiac muscle cell differentiation (ACTC1, HEY2), cardiac septum development (ISL1), heart morphogenesis (SRF, HEY2, ISL1, HEYL), Notch signaling pathway (HEY2, HEYL), cardiac chamber development (ISL1), and cardiac muscle tissue development (ACTC1, ISL1). The study also identified eight microRNA genes that have the potential to be biomarkers for the early detection of VSD including miR-191, miR-548F1, miR-148A, miR-423, miR-92B, miR-611, miR-2110, and miR-548H4. To our knowledge this is the first report in which placental analysis has been used for determining the pathogenesis of and predicting CHD.