bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4917: The Fallopian tube epithelium as the field of origin for ovarian serous carcinoma
Authors: Levanon Keren , Ng Vivian , Vermeer Paola D , Drapkin Ronny I 
Published: May 2019

Abstract
Ovarian cancer is the most lethal gynecological malignancy in Western countries. Serous carcinoma is the most aggressive sub-type, yet a clear understanding of its pathogenesis, including identification of precursor lesions, is lacking. Research on ovarian carcinogenesis has traditionally focused on the ovarian surface epithelium (OSE), or surface-derived intracortical Mullerian inclusions as the fields of origin. Our recent studies suggest that the Fallopian tube (FT) fimbria, rather than the OSE, may be the site of origin for over 50% of sporadic and hereditary serous carcinomas. The earliest precursor lesion identified, the ‘p53 signature’, is characterized by DNA damage, p53 gene mutations and p53 protein accumulation in normal-appearing secretory epithelial cells. Thus the FT secretory epithelial cell (FTSEC) emerges as a candidate cell-of-origin for most serous carcinomas. We hypothesize that the FTSEC is susceptible to DNA damaging effects associated with ovulation and that repeated and prolonged genotoxic stress leads to the development of precursor lesions, and, eventually, carcinoma. To address this possibility we have taken two approaches. First, using genome-scale approaches, we are defining the unique genetic ‘fingerprint’ of each morphologic step along the continuum from benign FT epithelium to p53 signatures, to intraepithelial carcinoma, and to invasive serous carcinoma. This investigation has identified key elements of signaling pathways that participate in the neoplastic process of serous cells. In addition, we have identified candidate biomarkers that may serve as sentinels of early stage disease. To experimentally address the biology and susceptibility of the serous cell to transformation, we have established an ex vivo co-culture system of FTSECs and ciliated cells that enables us to experimentally manipulate and characterize this epithelium. Specifically, we found that the serous cell has a unique DNA damage response compared to the neighboring ciliated cells. This altered response may contribute to its susceptibility to genotoxic stressors and neoplastic transformation. We have also identified markers that uniquely mark serous versus ciliated cells in this culture system. These markers enabled us to isolate pure FTSECs and immortalize them in culture. We are now able to study the effects of define genetic alterations (for instance, p53, BRCA mutations, c-myc, Akt activation) both in vitro and in vivo with the goal of understanding the underlying mechanism of transformation in this cell type. We hope that this novel approach will provide new insights into the nature of the ‘p53 signature’ and the molecular events that drive tumorigenesis. A firm understanding of these processes is essential for the development of new prevention strategies and therapeutic modalities.
Abstract LB-200: Evidence of efficacy of antibody directed enzyme prodrug therapy (ADEPT) in a Phase I trial in patients with advanced carcinoma.
Authors: Wilkins Duncan K , Mayer Astrid , Sharma Surinder K , Tolner Berend , Francis Roslyn J , Springer Caroline J , Hartley Janet A , Boxer Geoff M , Bell James , Green Alan J , Parker Sweta , Griffin Natalie , Shahbakhti Hassan , Grudus Edward , Chester Kerry A , Begent Richard H 
Published: May 2019

Abstract
Background: Antibody Directed Enzyme Prodrug Therapy (ADEPT) uses an antibody linked to an enzyme to deliver enzyme selectively to tumor deposits. When enzyme has localized to the tumor and cleared from the circulation, a low-toxicity prodrug is given. The prodrug is converted into an active cytotoxic drug by the enzyme in tumor deposits. Each targeted enzyme can convert many molecules of the prodrug and a bystander effect is generated. We have previously reported on dose-finding, immunogenicity, and toxicity in a Phase I clinical trial and that the components of ADEPT function as designed in patients (Mayer A, et al. Clin Cancer Res 2006;12:6509-16). Evidence of efficacy is now reported in relation to total prodrug dose (TPD), toxicity, and repeated treatment.
Methods: A fixed dose of recombinant fusion protein (MFECP1) was administered intravenously (iv). It consisted of single chain Fv targeting carcinoembryonic antigen (CEA) and carboxypeptidase G2 (Tolner B, et al. Nature Protocols 2006;1:1006-21; Tolner B, et al. Nature Protocols 2006;1:1213-22). Bis-iodo phenol mustard prodrug was given iv when carboxypeptidase activity had cleared from the blood. Patients had measurable, previously treated, advanced malignancy. Either 1, 2, or 3 ADEPT treatments were given over 2 to 10 days.
Results: 43 patients with CEA expressing tumors were treated (colorectal, gastro-esophageal, breast, unknown primary, gallbladder, peritoneal, appendix, pancreas). TPD per patient was escalated from 37 mg/m2 to 3226 mg/m2. Thrombocytopenia and neutropenia were the principal side effects, resulting in a maximum tolerated TPD dose of 1200 mg/m2 divided into 2 complete ADEPT treatments. Human anti-enzyme antibody developed in 40% of patients having a single treatment, in 75% of patients after 2 treatments, and in 100% of patients after 3 treatments; it is not yet known whether this will compromise repeated therapy. Efficacy was assessed by 18F FDG-PET using the criteria for partial response defined by Green et al. and shown to predict significant survival prolongation (Eur J Nucl Med Mol Imaging 2008;35:393-406). Four of 9 patients had partial response at TPD ≥ 900 mg/m2. There was a significant correlation between TPD and reduction of tumor FDG uptake (P=0.031). Response was corroborated by falls in serum CA19-9 ≥ 25% in the 3 patients with partial response who had raised levels before treatment. Stable disease by RECIST criteria was seen in 69% of patients having TPD ≥ 900 mg/m2.
Conclusions: Evidence of efficacy was shown at a TPD ≥ 900 mg/m2 with clinically significant responses in 44% of patients. These results support the case for conducting a randomized Phase II clinical trial.
Abstract LB-246: A Phase I and first time in human study of the centromere associated protein E (CENP-E) inhibitor GSK923295A in patients with advanced solid tumors
Authors: Chung Vincent , Fleming Ronald A , Johnson Brendan M. , Gauvin Jennifer L.s. , Lu Emily , Lager Joanne J. , Alberti Dona B. , Williams Brenda , Weber Barbara L. , Holen Kyle D. 
Published: May 2019

Abstract
Background: CENP-E plays a critical role in maintaining and silencing mitotic checkpoint signaling. CENP-E mRNA is overexpressed in a variety of human tumors relative to adjacent normal tissue, suggesting that it may have an important role in tumor cell proliferation. GSK923295A is a potent and selective small molecule inhibitor of CENP-E with broad preclinical activity against solid and hematologic cancer cells in vitro and in murine tumor xenograft models. The purpose of this Phase I study is to determine the maximally tolerated dose, dose-limiting toxicities (DLTs), pharmacokinetics (PK), and pharmacodynamics of GSK923295A in patients with advanced solid tumors.
Methods: Adult patients with refractory advanced solid tumors are administered GSK923295A by a 1-hour intravenous infusion on days 1, 8, and 15 of 28-day treatment cycles. Doses are escalated in cohorts of 2 patients using an accelerated titration scheme. Transition to a standard (40% or 33%) dose escalation scheme is planned if 2 grade 2 toxicities or 1 DLT are observed in the first treatment cycle. Blood samples are collected on days 1 and 15 over 48 hours to determine the plasma PK of GSK923295A. Pre- and post-treatment FDG-PET and tumor biopsies are performed in selected patients.
Results: Eight patients [4 males, 4 females; median age 54.5 years; cancers of pancreas (2), lung (2), stomach (1), colon (1), parotid gland (1), and liver (1)] have been treated at 10, 20, 40, and 80 mg/m2 (median of 1.5 and total of 15 cycles completed). One DLT (AST elevation) has been reported at 80 mg/m2. We have expanded this dose level to 3 patients. At the 4 dose levels studied thus far, PK appears dose proportional with low intrapatient variability, modest interpatient variability, and no apparent accumulation or time-dependent PK.
Conclusions: One DLT has been observed at the 80 mg/m2 dose level. Evaluation of GSK923295A continues at a dose level of 80 mg/m2.
Dose Level (mg/m2)NDayCmax* (ng/mL)AUC(0-¥)* (ng.h/mL)Clearance* (L/h/m2)Half-life* (h)1021279-377413-61516.3-24.22.72-3.7610215228-409377-76613.1-26.55.22-6.772021546-767992-156012.8-20.19.02-9.7020215499-889927-189010.6-21.68.11-8.9640211300-25302130-71305.61-18.84.50-13.6402151690-24202290-72705.50-17.55.64-20.580212090-25005210-655012.2-15.412.4-13.0*Denotes range from 2 patients.
Abstract LB-331: Bidirectional crosstalk between leptin and IGF-1 signaling transactivates epidermal growth factor receptor and promotes invasion and migration of triple-negative breast cancer cells
Authors: Saxena Neeraj K , Taliaferro Smith LaTonia , Brandon Brandi , Anania Frank A , Sharma Dipali 
Published: May 2019

Abstract
Introduction: Obesity is an independent risk factor for breast cancer and obese breast cancer patients exhibit a higher risk for larger tumor burden, increased metastasis, and poor response to endocrine therapy. Obesity affects breast carcinogenesis by autocrine and paracrine effects of adipocytokine leptin and IGF-1. We have previously shown that leptin induces growth stimulation of breast cancer cells by recruiting histone acetyltransferases and mediator complex to cyclin D1 promoter via activation of Stat3. In the present study, we found a novel bidirectional crosstalk between IGF-1 and leptin signaling that promotes invasion and migration of triple-negative (ER, PR, HER2 negative) breast cancer cells MDA-MB-231, MDA-MB-468, MDA-MB-435, and HCC-1806.
Methods and Results: IGF-1 induced significant tyrosine phosphorylation of leptin receptor (Ob-Rb) and leptin induced tyrosine phosphorylation of IGF-1 receptor (IGF-1R). Combined treatment of leptin and IGF-1 induced synergistic activation of both Ob-Rb and IGF-1R along with activation of Akt and ERK. Furthermore, IGF-1 and leptin synergistically transactivated epidermal growth factor receptor (EGFR) and induced proliferation of triple negative breast cancer cells. We also found that tyrosine phosphorylation of EGFR induced by combined treatment of leptin and IGF-1 was significantly inhibited not only by EGFR tyrosine kinase inhibitor AG1478 but also with a broad-spectrum matrix metalloproteinase inhibitor, GM6001, indicating that leptin and IGF-1 induced EGFR transactivation is dependent on proteolytic release of EGFR ligands. Intriguingly, we also found that combined treatment of leptin and IGF-1 potently induced invasion of triple negative breast cancer cells in Matrigel invasion and quantitative Electric Cell-Substrate Impedance Sensing invasion assays. Inhibition of leptin and IGF-1 mediated EGFR activation using a highly potent, reversible inhibitor of HER1/EGFR tyrosine kinase (erlotinib) or dual EGFR/HER2 kinase inhibitor (lapatinib) effectively inhibited leptin and IGF-1 induced invasion. Also, inhibition of EGFR activation using erlotinib and lapatinib reduced leptin- and IGF-1 induced migration of triple negative breast cancer cells. Conclusions: Taken together, these data indicate a novel bidirectional crosstalk between leptin and IGF-1 signaling that transactivates EGFR and promotes metastatic properties, invasion, and migration of triple negative breast carcinoma cells. Our novel findings indicate the possibility of using EGFR inhibitors erlotinib and lapatinib to counter the pro-cancerous effects of leptin and IGF-1 signaling in triple negative breast cancers.
Abstract P2-01-01: Prospective study of the need for axillary dissection and outcomes in Z11 eligible patients accounting for the use of nodal RT
Authors: Morrow M , Mamtani A , Patil S , Barrio A , Pilewskie ML , Cody HS , Gemignani M , Sclafani LM , Ho AY , Van Zee KJ 
Published: May 2019

Abstract
This abstract was withdrawn by the authors.
Abstract P2-01-30: Limited effectiveness of patent blue dye in addition to isotope scanning for identification of sentinel lymph nodes: Cross-sectional real-life study in 1024 breast cancer patients
Authors: Merlin J-L , Rauch P , Leufflen L , Salleron J , Harlé A , Olivier P , Marchal F 
Published: May 2019

Abstract
This abstract was withdrawn by the authors.
Abstract P3-11-06: Development and application of whole processing management for patients with breast carcinoma: A novel management strategy for breast health
Authors: Chen J , Yu K , Liu G , Shao Z , Wu J 
Published: May 2019

Abstract
The reformation on the management strategy of patients led by medical institutions could show the real value of medical services and match the needs of both patients and physicians. A novel patient management strategy, the whole processing management mode, was developed in Department of Breast Surgery, Fudan University Shanghai Cancer Center. Based on the online tools, the e follow-up Wechat public platform, the department provides several humanistic medical services in every aspects of breast health management, such as education, screening and diagnosis, multi-disciplinary comprehensive treatment and follow-up, including the remote medical reports reading. After the application of the novel patient management mode, regular appointments before seeing doctors, triage on-demand are realized. Between Jun-2015 and March-2016, a total of 7,668 person-time patients made the reservation for chemotherapy and over two thousand patients made the reservation for endocrine therapy prescription through the online approach. The total volume of out-patient clinic was 169,246 person-time in 2015, gained a 26.8% increase compared with in 2014. However, the queuing time for consultation was deceased by 28.8% in 2015. The doctor-patient relationship is extended online and the follow-up rate is improved. Between Jun-2015 and December-2015, a total of 823 patients online submitted the medical reports during follow-up period, among those, four patients were found disease relapse or metastasis and were call back to the hospital for further treatment. The novel mode may promote the cooperation among the multi-disciplinary comprehensive treatment teams, realize the hierarchical medical system among the department, and provide guarantee for the clinical and basic research based on the principle of precision medicine.
Citation Format: Chen J, Yu K, Liu G, Shao Z, Wu J. Development and application of whole processing management for patients with breast carcinoma: A novel management strategy for breast health [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-11-06.
Abstract P3-13-18: Technical skill of surgical residents may affect margin status of breast conserving operations
Authors: Komenaka IK , Djenic B , Hsu C-H , Nodora J , Winton L , Bouton M , Martinez ME 
Published: May 2019

Abstract
Background: Quality of patient care and surgical outcomes have come under increased scrutiny. Numerous other studies have examined outcomes at teaching hospitals compared to non-teaching hospitals. The most important factor to determine early success of breast conservation is the attainment of pathologically negative margins. Few studies, however, have examined the effect of teaching residents on margin status. The current study was performed to evaluate the effect teaching residents on margin status after lumpectomy.
Methods: Retrospective review of all patients from July 2006-June 2015 was evaluated. A resident was usually considered the primary surgeon. If the resident was unavailable or unprepared to operate, the attending surgeon was the primary surgeon. As part of the routine evaluation of surgical residents, technical ability was classified as satisfactory or unsatisfactory for level of training. All evaluations of the technical ability of the residents were completed prior to the collection of the current data. The effect of surgical residents' participation and their technical ability to perform lumpectomy was evaluated to determine if there was an effect on margin status. Logistic regression analysis was performed to adjust for clinical variables known to affect margin status.
Results: Of 292 patients, 15% of patients had positive margins. The attending surgeon has positive margin rate of 10.7% vs 16% for Residents (p = 0.32).When technical skill evaluation was included, Residents with unsatisfactory technical skills had positive margin rate of 27% compared to 10.2% for residents with satisfactory skills (p = 0.002). In multivariate logistic regression analysis, operating surgeon remained significantly associated with positive margins. Operations done by residents with satisfactory technical skills or attending surgeon were less likely to have positive margins than those done by residents with unsatisfactory technical skills (OR 0.39, 95% CI 0.22-0.86; p = 0.03). Patients who underwent preoperative chemotherapy were also less like to have positive margins (OR 0.40, 95% CI 0.18-0.91); p = 0.04). In patients with at least 2 years of followup (mean follow up of 48 months) breast cancer specific survival was 94% and 2% had local recurrences as a first event.
Conclusions: Technically ability of residents may affect margin status after lumpectomy. With the increased use of surgical outcomes to measure quality of care in medicine, the importance of teaching surgical residents needs to be considered in future quality of care evaluation.
Citation Format: Komenaka IK, Djenic B, Hsu C-H, Nodora J, Winton L, Bouton M, Martinez ME. Technical skill of surgical residents may affect margin status of breast conserving operations [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-13-18.
Abstract P5-16-18: The effect of participation in neoadjuvant clinical trials on outcomes in patients with early breast cancer
Authors: Brennan MB , Wang D , Gass P , Hein A , Beckmann MW , Fasching PA 
Published: May 2019

Abstract
Pathological complete response (pCR) has been shown to demonstrate improved outcomes in breast cancer. Often novel treatments, such as taxanes or HER2 based therapies, trastuzumab or pertuzumab, have shown an increase of pCR with possible impact on the prognosis of breast cancer patients. These therapies are usually introduced into the patient population through clinical trials. Therefore, it can be hypothesized participation in neoadjuvant clinical trials might improve the pCR rate in early breast cancer patients. The aim of this study was to explore this association.
Methods: This is a retrospective study of consecutive breast cancer patients who were treated with a neoadjuvant chemotherapy at a single institution. Trial participation status was known for all patients. From 1995 to 2012 the institution participated in 10 different neoadjuvant chemotherapy trials. Outside those clinical trials, patients were treated according to national neoadjuvant therapy guidelines. Patients who took part in clinical trials were compared with patients who did not take part in clinical trials with appropriate univariate tests. Additionally, logistic regression was performed with pCR as the dependent variable and commonly known predictors of pCR (tumor size and molecular subtype) as independent variables. The model was adjusted for age at diagnosis, year of treatment and trial participation status. Furthermore, exploratory survival analyses were performed.
Results: A total of 281 patients were treated within a neoadjuvant clinical trial and 822 patients outside a clinical trial. There are significant differences in the patient populations with regards to age (p=0.0009) and tumor size (&lt;0.0001). pCR rate in patients with trial participation was 21.4% and 19.0% in patients who did not take part in clinical trials. Multivariate logistic regression showed an OR of 1.393 (95%CI 0.937-2.071, p=0.1012). Exploratory survival analyses showed a better prognosis in patients taking part in clinical trials.
Conclusions: This study shows an increased chance of pCR in patients taking part in clinical trials; however the statistical test could not show statistical significance. Most likely the effect can be explained by trial participants having access to drugs which improved pCR rates, such as HER2 based therapies or taxanes.
Citation Format: Brennan MB, Wang D, Gass P, Hein A, Beckmann MW, Fasching PA. The effect of participation in neoadjuvant clinical trials on outcomes in patients with early breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-16-18.
Abstract P6-07-34: The prognostic impact of inositol polyphosphate 5-phosphatase PIPP (INPP5J) expression in breast cancer tissue
Authors: Kondo N , Kim T-S , Wanifuchi Y , Hato Y , Hisada T , Nishimoto M , Nishikawa S , Toyama T 
Published: May 2019

Abstract
Background : Inositol polyphosphate 5-phosphatase PIPP (INPP5J) has been identified as a suppressor of oncogenic PI3K/Akt signaling in breast cancer.INPP5J depletion increases transformation and accelerates oncogene-driven tumor growth in vivo, while paradoxically reducing cell migration, invasion, and metastasis. Therefore, we hypothesized that INPP5J gene expression in human breast cancer tissues would be prognostic in early breast cancer patients over long-term follow-up.
Methods: A total of 478 breast cancer tissue samples collected between 2003 and 2008 was available for analysis. We measured INNPP5J mRNA using a TaqMan gene expression assay. PIK3CA mutation status was evaluated using a TaqMan mutation detection assay. We then investigated the correlations of clinicopathological factors and prognosis with levels of INPP5J mRNA and the PIK3CA mutation status.
Results: INPP5J mRNA was expressed at a low level in 30.1% (144/478) and at a medium to high level in the remaining breast cancer samples. Low INPP5J mRNA correlated with larger tumor (p=0.015), high grade (p&lt;0.0001) and, ER-negativity (p&lt;0.0001). PIK3CA mutations were detected in 46% (63/138) of patients analyzed. We found that disease-free survival (DFS) was significantly worse in patients with low levels of INPP5J (p=0.008). Although DFS and INPP5J levels tended to be associated in estrogen receptor (ER)-positive patients (p=0.052), DFS was significantly worse in patients with wild-type PIK3CA and low INPP5J mRNA expression (p=0.008).
Conclusion: We shows that the level of INPP5J mRNA expression is prognostics in breast cancer patients and that its prognostic impact is affected by PIK3CA mutation status.
Citation Format: Kondo N, Kim T-S, Wanifuchi Y, Hato Y, Hisada T, Nishimoto M, Nishikawa S, Toyama T. The prognostic impact of inositol polyphosphate 5-phosphatase PIPP (INPP5J) expression in breast cancer tissue [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-07-34.