bluuebunny/crossref_metadata_2025_split huggingface dataset:
γ-synuclein expression in ovarian cancer.
Authors: Mori Kristina , Akers Stacey , Bshara Wiam , Buttin Barbara , Frederick Peter J. , Helenowski Irene B. , Morrison Carl D , Odunsi Kunle , Schink Julian C. , Scholtens Denise M. , Wei Jian-Jun , Kim J. Julie 
Published: March 2020

5574 Background: γ-synuclein (SNCG) expression is associated with advanced disease and chemo-resistance in multiple solid tumors. Our goal was to determine if SNCG expression in ovarian cancer was correlated with clinicopathologic variables and patient outcomes. Methods: Tissue microarrays from primary tumors of 358 ovarian, fallopian tube, and primary peritoneal cancer patients, who underwent primary surgery at Roswell Park Cancer Institute between 1995 and 2007 were constructed and stained for SNCG. A blinded pathologist scored tumors as positive if ≥10% of the sample stained. Medical records were reviewed for clinicopathologic and demographic variables. Between the positive and negative groups, Wilcoxon rank-sum test was used to compare the median ages and Fisher’s exact test was used to compare groups in categorical variables. Cox proportional hazard models were used to determine associations between SNCG and overall (OS) and progression-free survival (PFS). Results: The median follow-up was 36 months, median OS was 39 months, and median PFS was 18 months. SNCG presence was significant in patients with serous histology, grade 3 disease, suboptimal debulking, ascites at surgery, FIGO stage III-IV cancer, or initial CA-125 level >485. There was no significant difference in OS (HR 1.06 95% CI 0.81-1.39 P 0.69) or PFS (HR 1.16 95% CI 0.89-1.50 P 0.28) for patients with SNCG expression. Conclusions: SNCG expression in ovarian cancer is more frequent in patients with high-risk features, but it does not correlate with chemotherapy response, OS, or PFS. [Table: see text]
Inhibition of gamma-secretase activity in combination with paclitaxel to reduce platinum-resistant ovarian tumor growth.
Authors: Groeneweg Jolijn W , DiGloria Celeste M , Growdon Whitfield Board , Sathyanarayanan Sriram , Foster Rosemary , Rueda Bo R 
Published: March 2020

5578 Background: Ovarian cancer (OvCa) is the most lethal gynecologic malignancy in the United States. Chemotherapy is effective but seldom curative, mainly due to the development of chemoresistant recurrent disease. Our current research investigates the efficacy of inhibiting the Notch pathway with a gamma-secretase inhibitor (GSI), MRK-003, in an OvCa xenograft model as a single agent therapy and in combination with standard chemotherapy. Methods: Mice bearing xenografts derived from clinically platinum sensitive human ovarian serous carcinomas were treated with GSI or vehicle, or with either vehicle, GSI alone, paclitaxel and carboplatinum (T/C) alone, or the combination of GSI and T/C. In addition, mice bearing xenografts derived from patients with clinically platinum resistant disease were given GSI with or without paclitaxel. Gene transcript levels of several factors in the Notch pathway were analyzed using RT-PCR. Notch1 and Notch3 protein levels were evaluated by western blotting. The Wilcoxon rank-sum test was used to assess significance between the different treatment groups. Results: Expression of Notch1 and Notch3 was highly variable across all analyzed OvCa samples. Treatment with GSI alone significantly decreased tumor growth in 3 of 4 platinum sensitive ovarian tumors (all p < 0.05), as well as in 1 of 3 platinum resistant tumors (p = 0.04). Furthermore, the combination of GSI and paclitaxel was significantly more effective than GSI alone and paclitaxel alone in all platinum resistant ovarian tumors (all p < 0.05). The addition of GSI did not alter the effect of T/C in platinum sensitive tumors. Although the response of each tumor to GSI did not correlate with its endogenous level of Notch expression, 2 of the 3 tumors resistant to paclitaxel but sensitive to the combination of GSI and paclitaxel showed elevated Notch activity by RT-PCR. Conclusions: Inhibition of the Notch signaling cascade with a gamma-secretase inhibitor reduces tumor growth in vivo, most notably in combination with paclitaxel in a platinum resistant setting. These promising findings underscore the need for further investigation of the preclinical and clinical effectiveness of Notch inhibitors in OvCa.
Multimodal therapy in patients with node-positive (stage IIIC) uterine papillary serous carcinoma: A National Cancer Database study.
Authors: Lin Jeff Feng-Hsu , Sukumvanich Paniti , Parada Keila , Krivak Thomas C. , Beriwal Sushil , Kelley Joseph L. , Olawaiye Alexander 
Published: March 2020

5585 Background: Uterine papillary serous carcinoma (UPSC) is an aggressive endometrial cancer that carries a 30-40% risk of nodal metastasis. Adjuvant systemic chemotherapy has become standard of care in advanced UPSC, but the role of additional adjuvant radiotherapy is unclear. This study aims to evaluate survival outcomes of multimodal therapy through the use of the National Cancer Data Base (NCDB). Methods: All patients diagnosed with surgically-staged FIGO stage IIIC uterine papillary serous carcinoma were identified in the NCDB from 1/1998 through 12/2010. Patients were divided into those who received chemotherapy only (CT) and both chemotherapy and radiation therapy (CT+RT). Overall survival was estimated using the Kaplan-Meier method. Univariate comparison by log rank test and multivariable analysis by Cox regression modeling were performed to identify and control for prognostic factors. Results: A total of 13,356 cases of uterine cancer were identified, of which 794 were UPSC. Of these patients, 387 underwent lymphadenectomy (median 14 nodes removed) with 75 patients (median age 65) found to have stage IIIC disease. Median follow up is 20.4 (range: 0-114) months. There were no significant differences were found between the RT and CT+RT group with regards to patient demographic, medical comorbidity, treatment facility or disease characteristics. The median overall survival was 23.2 (95% CI 14.5-31.9) and 40.3 (95% CI 31.5-49.1) months, (p<0.05) for the CT and CT+RT groups, respectively. Multivariate analysis controlling for age, race, income, Charlson-Deyo comorbidity index, treatment facility type, year of diagnosis, number of lymph nodes removed, number of positive lymph nodes and tumor size found radiotherapy independently predicted improved survival [HRdeath0.024 (95% CI 0.001-0.668)]. Conclusions: Patients with stage IIIC UPSC benefit from adjuvant radiotherapy in addition to adjuvant chemotherapy.
Long-term survival in advanced-stage uterine papillary serous carcinoma.
Authors: Holman Laura L. , Iglesias David A. , Soliman Pamela T. , Pal Navdeep , Klopp Ann , Broaddus Russell , Ayeni Tina , Fleming Nicole Dierschke , Munsell Mark F. , Lu Karen H. , Westin Shannon Neville 
Published: March 2020

5596 Background: Advanced-stage (III/IV) uterine papillary serous carcinoma (UPSC) has a median overall survival (OS) of ~ 3 yrs. The study objective was to determine factors associated with long-term survival in advanced stage UPSC. Methods: We performed a retrospective review of pts diagnosed with stage III or IV UPSC between 1993 and 2012. Summary statistics were used to describe demographic and clinical characteristics. OS was estimated with the Kaplan-Meier estimator. Fisher’s exact test and the Wilcoxon rank sum test were used to compare pts surviving >3 yrs with those surviving <1 yr. Results: With a median follow-up of 2.2 years (range 0.06-13.2), 262 pts with advanced stage UPSC were identified. The probability of surviving >3 yrs was 0.462, >4 yrs was 0.310, and >5 yrs was 0.228. Thirty-six (14%) pts survived >3 yrs and 37 (14%) survived <1 yr. There was no difference in median age of pts surviving >3 yrs compared to pts surviving <1 yr (60 vs 66, p=0.21). There was also no difference between groups in demographics or medical history. There were several significant differences in pathologic and treatment variables between groups (Table). Conclusions: Though rare, long-term survival in advanced stage UPSC is associated with mixed histology, combination treatment including chemotherapy, and complete response to primary therapy. Further study of the molecular basis for these differences has the potential to improve survival for all pts with this disease. [Table: see text]
Adjuvant radiation therapy in node-positive vulvar cancer.
Authors: Xanthopoulos Eric , Grover Surbhi , Corradetti Michael Nino , Mangaali Margaret , Heskel Marina , Lin Lilie 
Published: March 2020

5609 Background: Adjuvant radiation (RT) has been demonstrated to improve overall survival (OS) in vulvar cancer patients with 2+ positive lymph nodes, but its role in patients with one positive lymph node is uncertain. We report on the largest and longest study of survival in patients with and without radiation following surgery in patients with vulvar cancer. Methods: Using the Surveillance, Epidemiology, and End Results (SEER) database, we identified node-positive women with squamous cell carcinoma of the vulva treated with and without external beam radiation following surgery. The Kaplan-Meier approach, log-rank tests and Cox modeling assessed OS. Results: All results are listed as women without vs with adjuvant radiation. From 1988 – 2008, 420 patients received surgery alone vs 753 women who received adjuvant radiation. Patient characteristics were well balanced across cohorts, including tumors ≤ or > than 2 cm (p = 0.31), grade (p = 0.41), marital status (p = 0.20), provider type (p = 0.49), and AJCC stage (p = 0.35). Both groups also had similar incidence of biopsy of any kind (p = 0.40), lymph node dissection (p = 0.77), median number of nodes excised (p = 0.12), and type of surgery (p = 0.49). Median age (75 vs 70 y, p <0.01) and race (94% vs 89% white, p = 0.01) were adjusted using Cox regression. Median survivor follow-up was 45 m (range 0 - 236 m). Adjuvant radiation was associated with survival across all node-positive patients (22 vs 29 m, p <0.01), as well as in the subset of women with just one positive lymph node (37 vs 70 m, p <0.01) or 2+ positive lymph nodes (14 vs 18 m, p <0.01). On multivariable Cox regression, adjuvant radiation (95% CI 0.85 - 0.96), diameter (CI 1.28 - 2.01), marital status (CI 0.65 - 0.93), the number of positive nodes (CI 1.06 - 1.11), and the ratio of positive-to-excised nodes (CI 1.61 - 2.98) were all associated with survival (p <0.01 for each). Conclusions: The largest cohort study of node-positive squamous cell carcinoma of the vulva suggests adjuvant radiation is associated with OS.Studies have reported that adjuvant radiation may provide a survival benefit in women with 2+ positive lymph nodes. Our findings suggest patients with one positive lymph node also may benefit from adjuvant radiation.
Phase II trial evaluating the use of 21-gene recurrence score (RS) to select preoperative therapy in hormone receptor (HR)-positive breast cancer.
Authors: Zelnak Amelia Bruce , Murali Sujatha , Styblo Toncred Marya , Carlson Grant Walter , Gabram Sheryl G. A. , Rizzo Monica , Torres Mylin Ann , Newell Mary , Liu Yuan , O'Regan Ruth 
Published: March 2020

562 Background: Hormone receptor (HR)- positive breast cancer patients (pts) typically have lower pathological responses to pre-operative chemotherapy than HR-negative breast cancers. Objective: We evaluated the pathologic and radiologic response rates to pre-operative endocrine therapy or chemotherapy, as directed by RS, in pts with HR-positive resectable breast cancers. Methods: Pts with HR-positive breast cancers had RS performed on the initial diagnostic biopsy. Pts were treated pre-operatively as follows based on RS: ≤10, exemestane +/- goserelin for 6 to 12 months (ET); 11 to 25 randomized to ET or docetaxel-cyclophosphamide (TC) for 6 cycles (CT); ≥ 26, CT. Results: From 4/2009 to 12/2012, 66 pts signed consent for RS testing and 46 are evaluable for efficacy analysis. Median age is 57 (40 to 78); one-third of pts are African-American; 41% have clinically node positive disease. RS ranged from 2 to 57. 28 pts received CT: Pathologic complete response (PCR) rate was 10% and 60% of cancers were down-staged based on initial T-stage. Radiologic response is available for 20 pts: complete radiologic response (CRR) 15%, partial RR (PRR) 40%, progressive disease (PD) 5%. In 11 pts with RS 11 to 25: PCR 0%, down-staged 45%, up-staged 18%, radiologic responses: CRR 17%, PRR 50%, PD 17%. In 17 pts with RS ≥ 26: PCR 18%, down-staged 71%, up-staged 0%, radiologic responses: CRR 14%, PRR 36%, PD 0%. 18 pts received ET for between 6 to 22 months, 5 remain on study and have not had surgery: PCR 0%; down-staged 38%; up-staged 15%; radiologic responses: CRR 13%, PRR 40%, PD 0%. There was no correlation between RS and efficacy of ET. To date, 3 pts have relapsed, all of whom received CT. Conclusions: This is the first prospective use of the 21-gene RS to select pre-operative therapy for pts with HR-positive breast cancer. Pre-operative CT results in tumor down-staging in the majority of cancers with RS ≥ 11, though it appears to be more effective with RS ≥ 26. ET was moderately effective in down-staging cancers with RS ≤ 25. Updated results will be presented. Clinical trial information: NCT00941330, NCT00832338.
Effect of nanosomal docetaxel lipid suspension (NDLS) on response rate compared to docetaxel: A randomized phase II study in patients with locally advanced or metastatic breast cancer.
Authors: Ahmad Ateeq , Sheikh Saifuddin , Taran Rakesh , Srivastav Shanti P , Prasad Krishna , Rajappa Senthill J , Kumar Vijay , M Gopichand , Paithankar Mahesh , Sharma Manish , Rane R. C. , Ahmad Imran 
Published: March 2020

577 Background: Docetaxel formulated inpolysorbate 80 and ethanol (Docetaxel) is among the most active agents in the treatment of breast cancer. The primary rationale for developing nanosomal docetaxel lipid suspension (NDLS) is to improve the drug’s safety profile by eliminating polysorbate 80 and ethanol from docetaxel formulation. Previously, we conducted a clinical study comparing pharmacokinetic parameters of NDLS and docetaxel at 75 mg/m2. The log transformed NDLS/docetaxel ratio for Cmax and AUC0-t was 149.3% and 119.3% respectively. The higher systemic availability of NDLS prompted us to conduct current efficacy study. Methods: 72 locally advanced or metastatic breast cancer patients were enrolled into the study after failure of prior chemotherapy. The mean age for the enrolled patients was 47 years and the racial make-up of the study was 100% Asian. Patients were administered NDLS or docetaxel at 75 mg/m2 as per randomization schedule, by IV infusion for one hour in each cycle of 21 days. Each patient received maximum of 6 cycles of NDLS or docetaxel. No premedication was given to the patients in NDLS treatment group. Results: Safety - The total number of post-dose AEs observed in the study was 510. The breakdown by treatment groups is as follows: AEs were reported in 91.30% and 93.88% patients who received the docetaxel and NDLS respectively. There were 34 SAEs in the study, out of which 04 SAEs resulted in death of the patients (3 in docetaxel and 1 in NDLS). Efficacy - The results showed that 4.2% patients had complete response (CR) in NDLS treatment group while there was no CR in docetaxel treatment group. Further, 31.3% partial response rate (PR) was observed in NDLS treatment group and 26.3% in docetaxel treatment group. Overall response (CR+PR) rate was 35.4% in NDLS treatment group and 26.3% in docetaxel treatment group. Stable disease (SD) was observed in 45.8% patients in NDLS group and 63.2% patients in docetaxel group. Conclusions: Overall, the NDLS was well tolerated in the multiple doses of 75 mg/m2 and found to increase response rate compared to docetaxel in breast cancer patients. Clinical trial information: CTRI/2010/091/000610.
Collaboration of AR and ERα in conferring resistance to an aromatase inhibitor.
Authors: Rechoum Yassine , Iacopetta Domenico , Barone Ines , Rovito Daniela , Ando' Sebastiano , Weigel Nancy , Fuqua Suzanne A. W. 
Published: March 2020

579 Background: We have previously shown a role for AR overexpression in tamoxifen resistance in ERα-positive MCF-7 breast cancer cells; here we hypothesized that AR overexpression might similarly be involved in resistance to the aromatase inhibitor anastrazole (Anas). Methods: MCF-7 cells were transfected to express the aromatase gene (MCF-7 Arom), or the aromatase and AR (MCF-7 AR Arom cells). Western blot analysis was used to evaluate protein levels, MTT and soft agar assays to evaluate proliferation, luciferase reporter assays to evaluate transcriptional activities and confocal microscopy was used for localization. Results: Anas inhibited androstendione (AD)-stimulated growth in MCF-7 Arom cells but not in MCF-7 AR Arom cells. Similarly, Anas did not inhibit ERα transcriptional activity in MCF-7 AR Arom cells. Enhanced activation of pIGF-1R, pIRS-1, pAKT, and pMAPK were also observed in AR Arom cells, suggesting constitutive activation of nongenomic signaling in these cells. Consistent with activation of these potential treatment “escape” mechanisms, inhibitors of AKT and IGF-1R restored sensitivity to Anas. Sensitivity to Anas was also restored using the AR antagonist MDV3100, however use of Abiraterone acetate as a single agent most effectively blocked proliferation of AR-overexpressing cells. These results suggest that both AR and ERα must be blocked to restore sensitivity to hormonal therapies in AR overexpressing ERα-positive breast cancers. Unexpectedly, AR contributed to ERα transcriptional activity in MCF-7 AR Arom cells, as shown by inhibition with the AR antagonist bicalutamide. AR and ERα co-localized both in the cytoplasm and in the nucleus of AD+Anas-treated cells, suggesting potential activation of both non-genomic and nuclear-mediated effects when AR is overexpressed in ERα-positive cells. We confirmed these findings in breast cancer cells with acquired resistance to tamoxifen. Conclusions: These results show the necessity to block both AR and ER in patients whose tumors express elevated levels of AR. In addition, inhibitors to the AKT/IGF-1R signaling pathways or direct inhibition of androgen/estrogen synthesis provide alternative approaches to restore hormone sensitivity in resistant breast tumors.
Association of the canonical NF-κB pathway with clinical outcome measures in ER-negative breast cancer.
Authors: Doughty Julie C , Bennett Lindsay , Mallon Elizabeth A , Horgan Paul G. , Edwards Joanne 
Published: March 2020

588 Background: Although breast cancer morality rates have fallen, resistance to treatment remains a major problem. The NF-κB pathway regulates transcription of a wide range of genes involved in inflammation, proliferation and apoptosis and are hypothesized to play a role in tumor progression. Methods: Immunohistochemistry was employed to assess expression of members of the NF-κB pathway in a cohort of 544 breast cancer specimens with full clinical follow-up. Antibodies for the p65 subunit, phosphorylated p65 at the serine 536 residue (p-p65 S536), nuclear localization signal of p65 (p65 NLS), IKKα and IKKb had specificity confirmed by both a single band of appropriate size on a western blot and appropriate expression patterns in cell pellets treated with TNFα. Results: When the full cohort was considered patients with tumors that expressed high levels of cytoplasmic IKKα had significantly shorter disease free survival compared to those with low expression (P=0.015). Increased expression of nuclear p-p65 S536 was also associated with shorter disease free survival (P=0.005). By western blot analysis we observed that expression levels of p-p65 S536 were higher in MD-MBA-231 cells which are ER negative compared to MCF-7 cells that are ER positive, suggesting that NF-κB may have a prominent role in ER negative disease. However when the cohort was subdivided, by ER status the association observed for IKKα expression and shorter disease free survival was attenuated in ER positive tumors (p=0.008). In addition this attenuation with the ER positive cohort was also observed for nuclear p-p65 S536 (P=0.002). Other members of the pathway investigated (p65, p65 NLS and IKKb) were not associated with disease free survival. Conclusions: These results suggest that in the clinical setting the NF-kB canonical pathway is associated with poor prognosis in ER positive tumors and not with ER negative tumors as the cell line work would suggest. These results require validation in an independent cohort, but highlight the need to consider subtypes of breast cancer as individual diseases with increasingly different therapeutic targets.
Differential impacts of Oncotype DX and Mammostrat prognostic indices upon the management of ER+ N0 breast cancer.
Authors: Schneider Jeffrey Gary , Ogden Lorna , Farhadfar Nosha , Turi George , Khalil Danny 
Published: March 2020

599 Background: Oncotype DX (Genomic Health, Redwood City CA) and Mammostrat (Clarient, Aliso Viejo CA) are two distinct prognostic measures currently marketed to facilitate adjuvant chemotherapy decision making for ER+ breast cancer patients and their physicians. Both assays define three prognostic strata—favorable, intermediate, and unfavorable. Both assays were also validated in the same retrospective cohorts, but there is significant discordance between these assays, suggesting that assay selection may affect clinical decisions. Methods: We have previously reported that Oncotype DX significantly reduces adjuvant chemotherapy use in 89 consecutive ER+, N0 patients for whom this assay was ordered at our institution. Mammostrat assays were performed on 46 of these cases for which tumor blocks were available. Decision analysis was applied to determine changes in management that would have been most likely if Mammostrat had been substituted for Oncotype DX. Results: Oncotype DX and Mammostrat were concordant for prognostic strata in just 11 (24%) cases. Oncotype DX predicted a more favorable prognosis than Mammostrat in 27 (59%) cases, while Mammostrat predicted a more favorable prognosis in the remaining 8 (17%) cases. As shown in the Table, Oncotype DX reduced chemotherapy utilization whereas Mammostrat would have increased it. Conclusions: Despite being validated in identical patient cohorts, Oncotype DX and Mammostrat are frequently discordant and may often affect adjuvant treatment decisions in opposite directions. [Table: see text]