bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B32: Serum calcium and serum albumin can discriminate malignant from benign pelvic masses.
Authors: Schwartz Gary G. , Kelly Michael G. , Winkler Stuart S. , Lentz Samuel S. , Berliner Steve H. , Swain Melissa F. , Skinner Halcyon G. 
Published: May 2016

Abstract
Background: Biomarkers that aid in the differential diagnosis of malignant pelvic masses from benign ones prior to surgery are needed in order to triage women with malignant masses to appropriate specialist care. Because high albumin-adjusted serum calcium predicted ovarian cancer among women without evidence of disease, we hypothesized that it might predict cancer among women with pelvic masses that were evident radiographically.
Methods: We studied a cohort of 514 women with pelvic masses who underwent resection at Wake Forest University Baptist Medical Center from July 2009 through June 2013. We divided patients into a “training” set, to identify associations in the data, and a “testing” set, to confirm them. Data were obtained from medical records. A best fit model was selected using the Akaike Information Criterion.
Results: Albumin-adjusted serum calcium was significantly higher in women with malignant vs. benign masses (P= 0.0004). High normocalcemia, i.e., an albumin-adjusted serum calcium ≥ 10 mg/dL, occurred in 53% of women with malignant tumors vs. 12% of benign tumors. High normocalcemia was associated with a ~14-fold increased risk of malignancy. The best fit model (Overall) included albumin, calcium, and non-linear terms. Overall achieved an AUC of 0.83 with a sensitivity of 72% and specificity of 83%, a PPV of 71% and a NPV of 85%.
Conclusions: A model using serum calcium and serum albumin to predict malignancy in women with pelvic masses has high sensitivity and is economical.
Impact: Our model can help triage women with ovarian cancer to appropriate surgical care.
Citation Format: Gary G. Schwartz, Michael G. Kelly, Stuart S. Winkler, Samuel S. Lentz, Steve H. Berliner, Melissa F. Swain, Halcyon G. Skinner. Serum calcium and serum albumin can discriminate malignant from benign pelvic masses. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr B32.
Abstract B36: In vivo laser-based imaging of the human fallopian tube for future cancer detection.
Authors: Swisher Elizabeth M. , Melville C. David , Johnston Richard S. , Agnew Kathy , Chiang Seine , Seibel Eric J. 
Published: May 2016

Abstract
Inherited mutations in BRCA1 and BRCA2 cause a 20-50% lifetime risk of ovarian, fallopian tubel, or peritoneal carcinoma. Clinical recommendations for these high-risk women include the prophylactic removal of the ovaries and fallopian tubes by age 40 after child-bearing. Recent findings suggest that many presumed ovarian or peritoneal carcinomas arise in fallopian tube epithelium. Although survival rate is &gt;90% when ovarian cancer is detected early (Stage_I), 70% of women have advanced disease (Stage_III/IV) at presentation when survival is less than 30%. Over the years, effective early detection of ovarian cancer has remained elusive, possibly because screening techniques have mistakenly focused on the ovary as the origin of ovarian carcinoma. Unlike ovaries, the fallopian tubes are amenable to direct visual imaging without invasive surgery, using access through the uterine cervix. To develop future screening protocols, we investigated using our 1.2-mm diameter, forward-viewing, scanning fiber endoscope (SFE) to image luminal surfaces of the fallopian tube before laparoscopic surgical removal. Three anesthetized human subjects participated in our protocol development which eventually led to 70-80% of the length of fallopian tubes being imaged in scanning reflectance, using red (632nm), green (532nm), and blue (442nm) laser light. A hysteroscope with saline uterine distention was used to locate the tubal ostia. To facilitate passage of the SFE through the interstitial portion of the fallopian tube, an introducer catheter was inserted 1-cm through each ostia. During insertion, saline was flushed to reduce friction and provide clearer viewing. This is likely the first high-resolution intraluminal visualization of fallopian tubes
Citation Format: Elizabeth M. Swisher, C. David Melville, Richard S. Johnston, Kathy Agnew, Seine Chiang, Eric J. Seibel. In vivo laser-based imaging of the human fallopian tube for future cancer detection. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr B36.
Abstract B40: Prediagnosis leukocyte telomere length and risk of ovarian cancer.
Authors: Yang Meng , Prescott Jennifer , Poole Elizabeth M. , Rice Megan S. , Idahl Annika , Lundin Eva , Vivo Immaculata De , Tworoger Shelley S. 
Published: May 2016

Abstract
Introduction: Ovarian cancer is characterized by substantial genomic instability. Telomeres, which protect the physical integrity of chromosomes, are shortened by each cell division, and evidence supports that longer telomeres may reduce genomic instability. While retrospective studies generally support an inverse association of telomere length and ovarian cancer risk, the measures of telomere length after diagnosis may be influenced by treatment. Therefore, we examined the relationship between leukocyte telomere length (LTL) assessed prior to diagnosis and risk of ovarian cancer in three prospective studies.
Methods: We used buffy coat samples collected from healthy participants in the Nurses' Health Study (NHS), NHSII, and the Northern Sweden Health and Disease Study (NSHDS). Women who later developed ovarian cancer were matched to one or two controls on age, menopausal status, and date of blood collection. LTL was assessed using quantitative PCR-based assays in 5 batches with coefficients of variation of 10-15%. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression, based on study-specific quartiles in controls, for each study separately. We used fixed-effects models for meta-analysis. Multivariate models adjusted for oral contraceptive use, tubal ligation, family history of ovarian cancer, parity, smoking status, and body mass index.
Results: In total, there were 487 cases and 810 controls across the three studies. The mean age at blood collection ranged from 45 (NHSII) to 57 (NHS) years. In unadjusted and multivariate models, we observed a suggestion of an inverse association between LTL and ovarian cancer risk in each study, although none of the trend tests were statistically significant. In a meta-analysis of the multivariate adjusted models, women in the longest versus shortest quartile of LTL had a non-significant 26% lower risk of ovarian cancer (OR=0.74; 95%CI=0.49-1.12; p-trend=0.33).
Conclusion: In this first prospective study of telomere length and ovarian cancer risk, we observed that longer leukocyte telomere length was suggestively associated with lower ovarian cancer risk. Given that serous tumors are more likely to exhibit genomic instability, we are currently evaluating the association for this subtype as well as conducting pooled analyses with common quartile cut points across studies.
Citation Format: Meng Yang, Jennifer Prescott, Elizabeth M. Poole, Megan S. Rice, Annika Idahl, Eva Lundin, Immaculata De Vivo, Shelley S. Tworoger. Prediagnosis leukocyte telomere length and risk of ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr B40.
Abstract B58: Functional analysis of the cell adhesion molecule Nectin-4 in the unique tumor microenvironment of ovarian cancer.
Authors: Boylan Kristin L.M. , Buchanan Petra C. , Shukla Dip , DeRycke Melissa , Walcheck Bruce , Skubitz. Amy P.N. 
Published: May 2016

Abstract
A unique aspect of ovarian cancer progression is the collection of ascites fluid in the abdominal cavity, which contains free-floating tumor cells in the form of single cells and multicellular aggregates (spheroids). In previous studies, we showed that the cell adhesion molecule Nectin-4 is overexpressed in ovarian cancer tumors and that the soluble fragment of Nectin-4 (sN4) is detected in the ascites fluid and sera of ovarian cancer patients. The objectives of this study were to determine how Nectin-4 is cleaved from the surface of ovarian cancer cells and the functional role that Nectin-4 plays in the aggregation, invasion, and proliferation of ovarian cancer cells. Functional assays were conducted using human ovarian cancer cell lines that differed in their levels of expression of Nectin-4. First, NIH:OVCAR5 cells, which express moderate levels of Nectin-4, were either: (a) transfected with shRNA targeting Nectin-4 (resulting in almost complete knockdown of Nectin-4 expression) or (b) transfected with full length Nectin-4 to overexpress Nectin-4. Second, MA148 cells, which do not endogenously express Nectin-4 were transfected with a full length Nectin-4 cDNA. Cells that expressed high levels of Nectin-4 formed multicellular aggregates and proliferated more rapidly than cells in which Nectin-4 levels had been knocked down by shRNA. Nectin-4 knock down cells also migrated more slowly in a wound healing assay than cells transfected with a control shRNA. Cells that overexpressed Nectin-4 took a longer time to disaggregate and invade monolayers of mesothelial cells. In addition, cells that overexpressed Nectin-4 shed sN4 following 3 hours of stimulation with phorbol myristate acetate. A broad spectrum inhibitor of matrix metalloproteases and A Disintegrin And Metalloproteases (ADAMs) completely inhibited Nectin-4 shedding. Our results suggest that Nectin-4 promotes cell-cell adhesion (important in the formation of multicellular aggregates), yet it can be cleaved from the surface of cells to allow cells to disaggregate (important in invasion). Understanding the role of Nectin-4 in the multifaceted ovarian cancer tumor microenvironment is critical in order to facilitate its development as a novel therapeutic target for ovarian cancer.
Citation Format: Kristin L.M. Boylan, Petra C. Buchanan, Dip Shukla, Melissa DeRycke, Bruce Walcheck, Amy P.N. Skubitz. Functional analysis of the cell adhesion molecule Nectin-4 in the unique tumor microenvironment of ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr B58.
Abstract IA13: Myc, metabolism, and cancer.
Authors: Dang. Chi Van 
Published: May 2016

Abstract
The MYC oncogene is highly amplified in many human cancers, and importantly is frequently amplified in ovarian cancer. It encodes a helix-loop-helix transcription factor, Myc, that dimerizes with a partner, Max, to bind the DNA consensus E-box sequence and broadly affects transcription by alleviating RNA polymerase pausing. Myc activates hundreds to thousands of genes that involve ribosome biogenesis, metabolism, and cell cycle control. Its deregulated expression in cancer cells causes a constitutive drive for cell growth, thereby rendering MYC-overexpressing cells addicted to specific metabolic pathways that may be dependent on the mutational spectrum of the cancer cell. For example, loss of p53 in combination with deregulated MYC, relieve cells from apoptotic pressure and unleash MYC's full potential as an oncogenic transcription factor. The dependence of MYC-overexpressing cells on nutrients provide a synthetic lethal approach to target metabolism for therapy. Further, deregulated MYC disrupt the circadian clock and metabolism in favor of cell growth-related metabolism. Hence, timing of metabolic therapies for MYC-induced cancers such as ovarian cancer may provide a new therapeutic window for emerging metabolic therapies.
Note: This abstract was not presented at the conference.
Citation Format: Chi Van Dang. Myc, metabolism, and cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr IA13.
Abstract IA17: Molecular characterization of mucinous ovarian carcinoma.
Authors: Levine Douglas A. , Schlappe Brooke 
Published: May 2016

Abstract
Mucinous ovarian carcinoma (MOC) is a rare, chemoresistant tumor that shares pathologic features with tumors of the gastrointestinal and pancreaticobiliary tracts and remains clinically, morphologically, and epidemiologically distinct from other more common ovarian cancer histologic subtypes. MOC accounts for 1-8% of all ovarian, typically affecting younger women and has a poor prognosis when disease has spread beyond the ovary. Unlike other epithelial ovarian cancers, increased risk of MOC is associated with cigarette smoking in a dose-dependent fashion. Oral contraceptive use that has been shown to be protective in serous ovarian cancer does not extend to MOCs. Despite clinical, pathologic, and epidemiologic differences from other epithelial ovarian cancers, MOC treatment continues to use standards defined for high grade serous ovarian cancer including comprehensive surgical staging followed by platinum and taxane combination chemotherapy for disease spread beyond the ovary. Most mucinous adenocarcinomas that involve the ovary are now recognized to be metastatic disease from an extraovarian site, most commonly gastrointestinal and pancreatic. In advanced stage cases, defining clear diagnostic criteria that reliably differentiates primary versus malignant tumors remains a challenge. Despite a similar site of origin, the molecular profile of MOC has few similarities to high-grade serous ovarian carcinoma, which is characterized by ubiquitous TP53 mutations, frequent BRCA1/2 mutations, and few KRAS mutations. The mutational landscape of MOC is characterized by frequent KRAS, TP53, ARID1A, and PIK3CA mutations as well as frequent CDKN2A homozygous deletions. Co-mutations of KRAS and TP53 are common. New data describe the molecular features of MOC using an integrative and comprehensive approach including next-generation sequencing, copy number analysis and immunohistochemistry that may lead to expanded treatment options for women with this rare disease. Data suggest a shared molecular pattern with pancreatic adenocarcinoma that may guide future therapeutics.
Citation Format: Douglas A. Levine, Brooke Schlappe. Molecular characterization of mucinous ovarian carcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr IA17.
Abstract PR03: Combinatorial blockade of PD-1, CTLA-4, and LAG-3 pathways inhibits murine ovarian tumor growth.
Authors: Huang Ruea-Yea , McGray AJ , Odunsi Kunle 
Published: May 2016

Abstract
We have previously shown that tumor-associated or infiltrating T cells (TALs or TILs) often co-express immune inhibitory receptors lymphocyte activation gene-3 (LAG-3) and programmed cell death 1 (PD-1) in human and murine ovarian tumor microenvironment (TME). Dual antibody blockade or genetic knockout of LAG3 and PD1 significantly enhanced T effector function and delayed ovarian tumor growth. The relative contribution of other immune inhibitory receptors to immune suppression in the ovarian TME, and whether they co-regulate each other are currently unknown. To address this, we analyzed the expression of multiple immune checkpoint proteins and their cognate ligands in ovarian tumor-bearing wild-type (WT), LAG3KO and PD1KO mice. We found that PD-1, cytotoxic T lymphocyte antigen 4 (CTLA-4), LAG-3, T-cell immunoglobulin domain and mucin domain 3 (TIM-3) and CD160 were elevated in TILs from the WT mice. Interestingly, compared with TILs of WT mice, the levels of LAG-3, TIM-3, and CTLA-4 were further significantly elevated in TILs from the tumor-bearing PD1KO mice; while the levels of PD-1, CTLA-4, and CD160 were further increased in the tumor-bearing LAG3KO mice. These results suggest that PD-1 and LAG-3 regulate the expression of multiple inhibitory receptors in the ovarian TME. Furthermore, combinatorial blockade with anti-LAG3 and anti-CTLA4 antibodies in the tumor-bearing PD1KO mice resulted in 30% tumor-rejection as compared to 10% by anti-CTLA4 alone or only delayed tumor growth by anti-LAG3. These data provide a strong basis for rational clinical testing of combinatorial blockade of the PD-1, LAG-3 and CTLA-4 immune inhibitory pathways for ovarian cancer immunotherapy.
This abstract is also presented as Poster A51.
Citation Format: Ruea-Yea Huang, AJ McGray, Kunle Odunsi. Combinatorial blockade of PD-1, CTLA-4, and LAG-3 pathways inhibits murine ovarian tumor growth. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr PR03.
Abstract 01: Development of a targeted panel for acute myeloid leukemia (AML) by using next-generation sequencing (NGS)
Authors: Tilak Anup , Sompallae Ramakrishna , Stence Aaron , Guseva Natalya , Bossler Aaron 
Published: May 2016

Abstract
Background: AML is a clinically and genetically heterogeneous clonal disorder. Approximately 50% are characterized by recurrent clonal chromosome aberrations which have contributed to the classification of disease and are recognized as important prognostic factors. AML patients who lack these recurrent structural abnormalities have been grouped as “intermediate cytogenetic risk” and are being further subcategorized by the sequence alterations that are being identified. A more complete understanding of the genetic changes that are relevant to the pathogenesis of AML will improve the classification of risk and ultimately better selection of therapy. Our hypothesis is that mutational profiling and analysis of patient outcomes will help better define the risk subgroups of patients and predict prognosis in patients with AML.
Methods: Archived DNA from 37 patients with various AML diagnoses were obtained with IRB approval (IRB#201502763). A panel of 30 commonly mutated genes in AML were designed using the Ion Ampliseq Designer (Ion Torrent) and targeted for “hotspot” or complete coding sequence (CDS). Genomic libraries were prepared using Ion AmpliSeq™2.0 (ThermoFisher) technology. Library clonal amplification was performed by emulsion PCR using Ion PGM™ Template OT2 Reagents Kit200. Simultaneous sequencing of clonally amplified DNA targets was performed by Ion-Torrent Personalized Genome Machine (IT-PGM) using 318v2 chip. Genomic variants were identified by variant caller3.4 and further filtered and analysed through a custom-made clinically validated pipeline. Novel mutations were confirmed by either single nucleotide primer extension or Sanger sequencing.
Results: The assay successfully identified previously identified point mutations in FLT-3 and CEBPA genes. Additional variants were identified in 81% (30/37) of specimens; no mutations were found in 19% (7/37) specimens. The genes most frequently mutated were DNMT3A (23%), TET2 (17%), IDH2 (14%) and TP53 (14%). U2AF1 (11%) and RUNX1 (8%) were exclusively mutated in specimens with non-recurrent cytogenetic abnormalities. The identified variants will be used to risk stratify patients based on clinical outcome.
Conclusion: This targeted multi-gene panel successfully identified several variants along with previously known mutations in archived specimens.
Citation Format: Anup Tilak, Ramakrishna Sompallae, Aaron Stence, Natalya Guseva, Aaron Bossler. Development of a targeted panel for acute myeloid leukemia (AML) by using next-generation sequencing (NGS). [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr 01.
Abstract 09: Laminin binding integrin copy number variations in distinct types of epithelial cancers
Authors: Pond Erika , Harryman William L. , Cress Anne E. 
Published: May 2016

Abstract
Background: The laminin binding integrin (LBI) family are adhesion molecules that are essential for invasion and metastasis of human epithelial cancers and cell adhesion mediated drug resistance. Our objective was to investigate whether copy number variation (CNV) of a five gene signature (ITGB4, ITGA3, LAMB3, PLEC and SYNE3) comprised of essential genes for laminin adhesion would correlate with the reported clinical outcome in human epithelial tumors.
Methods: We investigated the relative alteration frequency of the CNV of integrin B4 (ITGB4), integrin A3 (ITGA3), laminin beta 3 chain (LAMB3), plectin (PLEC) and nesprin 3 (SYNE3) as a five gene signature independent of the epithelial cancer type using the publically available and published data. Provisional data was excluded from the analysis. We rank ordered the results using a 20% alteration frequency cut off and limited the analysis to studies containing at least 100 samples. The Kaplan Meier survival curves were analyzed to determine any alterations in patient survival in terms of months.
Results: Eight different cancer types representing 1,985 samples, contained at least a 20% alteration frequency of the five gene signature. The frequency of alteration ranged from 32.2% to 22.9% with the rank order (highest to lowest) as skin cutaneous melanoma, ovarian serous adenocarcinoma, stomach adenocarcinoma, lung adenocarcinoma, bladder urothelial carcinoma, breast invasive carcinoma and uterine corpus endometrial carcinoma. Within the gene signature, PLEC was the most commonly altered followed by LAMB3, ITGB4, ITGA3 and SYNE3 across all eight cancer types. Although specific mutations occurred in PLEC, amplification was the most common feature. Within a cancer type, there was little overlap of the individual amplified genes with the specific case, suggesting different specific amplicons may alter the LBI adhesion structures. Of the eight cancer types, a significant alteration in survival was indicated in bladder urothelial carcinoma (p=0.052714) with a median survival change of 19.02 to 24.28 months.
Conclusions: A five gene signature was created representing the essential and genetically verified functional components of laminin binding integrins and their adhesion structures. The CNV signature of the laminin binding integrins may have prognostic and predictive significance depending on the type of epithelial cancer. These may be promising biomarkers but also rational targets for personalized therapy in selected epithelial tumors for preventing metastatic spread. (Supported in part by NIH grants CA 23074 and CA 159406)
Citation Format: Erika Pond, William L. Harryman, Anne E. Cress. Laminin binding integrin copy number variations in distinct types of epithelial cancers. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr 09.