bluuebunny/crossref_metadata_2025_split huggingface dataset:
The role of the glucocorticoid receptor (GR) in inhibiting chemotherapy-induced apoptosis in high-grade serous ovarian carcinoma (HGS-OvCa).
Authors: Stringer Erica Michelle , Skor Maxwell N. , Fleming Gini F. , Conzen Suzanne D. 
Published: March 2020

11101 Background: Ovarian cancer is the leading cause of death from gynecologic malignancies. High-grade serous ovarian cancer (HGS-OvCa) is often initially sensitive to platinum-based therapy, but relapse rates remain high. The TCGA recently found that HGS-OvCas have a gene expression and mutational profile similar to that of triple negative breast cancer (TNBC). Previously, our group demonstrated that dexamethasone treatment decreased chemotherapy-induced tumor cell apoptosis in TNBC and HGS-OvCa cell lines. We have also shown that glucocorticoid receptor (GR) activation induces expression of anti-apoptotic genes SGK1 and MKP1/DUSP1 in both HGS-OvCa and TNBC cell lines and in primary human ovarian and TNBC tumors. Methods: We examined glucocorticoid receptor (GR), estrogen receptor (ER), and progesterone receptor (PR) expression in a panel of HGS-OvCa cell lines by Western analysis and qRT-PCR. We also performed apoptosis assays with and without mifepristone, glucocorticoid and/or chemotherapy treatment using IncuCyte live-cell imaging technology in order to measure the effect of GR modulation of chemotherapy sensitivity. Results: HGS-OvCa cell lines (including CAOV3, HeyA8, SKOV3, Monty-1) all had detectable GR expression; HeyA8, SKOV3, and Monty-1 cell lines expressed very low levels of ER-alpha while all other HGS-OvCa cell lines did not express any detectable ER-alpha. Furthermore, none of the HGS-OvCa cell lines tested expressed PR.Apoptosis assays revealed that GR activation significantly inhibited gemcitabine/carboplatin-induced apoptosis in HGS-OvCa cell lines and that mifepristone could reverse this cell survival effect, presumably through GR antagonism. Conclusions: These results suggest that treatment with mifepristone, a GR antagonist, reverses GR-mediated cell survival signaling in HGS-OvCa and increases chemotherapy-induced tumor cell death. To further investigate the role of GR activity in HGS-OvCa, we are currently performing xenograft experiments with chemotherapy +/- mifepristone treatment.
Characterization of a lung cancer growth factor, LASEP1, as a serologic and prognostic biomarker and a therapeutic target.
Authors: Takano Atsushi , Nakamura Yusuke , Daigo Yataro 
Published: March 2020

11104 Background: Identification and evaluation of oncoproteins are an effective approaches to develop novel diagnostic/prognostic biomarkers or therapeutic targets. Methods: We established a strategy as follows. i)To identify up-regulated genes in non-small cell lung cancers (NSCLCs) using the cDNA microarray, ii) To verify the candidate genes for their no or low expression in 23 normal tissues by northern-blot, iii)To validate clinicopathological significance of their protein expression by tissue microarray, iv)To verify whether they are essential for the growth of cancer cells by siRNA, and v)To measure their serum protein levels by ELISA. Results: We identified LASEP1 (Lung cancer Associated Serum Protein 1) as a candidate target molecule. Immunohistochemical staining using tumor tissue microarrays consisting of 374 NSCLC confirmed positive staining of LASEP1 was observed in 210 (56.1%) of 374 NSCLC. In addition, a high level of LASEP1 expression was associated with poor prognosis of NSCLC patients. Serum LASEP1 levels were higher in NSCLC than in healthy volunteers. The proportion of serum LASEP1-positive cases was 127 (38.6%) of 329 lung cancers, while 4 (3.9%) of 102 healthy volunteers were falsely diagnosed. Furthermore, treatment of lung cancer cells with siRNAs against LASEP1 suppressed its expression and resulted in growth suppression of the lung cancer cells; on the other hand, induction of exogenous expression of LASEP1 conferred growth-promoting activity in vitro. We found its 50-kDa receptor (LASEPR) which interacts with LASEP1 on lung cancer cell surface. Suppression of LASEPR expression by siRNAs inhibited the growth of cancer cells. The LASEP1-LASEPR interaction promoted the cell growth in an autocrine manner. In addition, the growth activity of the LASEP1-positive cells was neutralized by the addition of originally developed anti-LASEP1 monoclonal antibodies into their culture media. The systemic administration of the anti-LASEP1 antibody to tumor-implanted mice significantly suppressed tumor growth without any adverse events. Conclusions: We have identified LASEP1 as potential targets for development of biomarkers and therapeutic target for lung cancer.
Can BCL2L12 be a promising favorable prognostic biomarker in breast cancer?
Authors: Tzovaras Alexandros , Kladi Athina , Michaelidou Kleita , Tsoukalas Nikolaos , Tsoukalas Grecory , Kountourakis Pantelis , Stamatopoulou Sofia , Oikonomopoulos Georgios , Misitzis Ioannis , Ardavanis Alexandros , Scorilas Andreas 
Published: March 2020

11117 Background: Many genes of the BCL2 family were found to be implicated in breast carcinogenesis and to serve as possible prognostic markers. BCL2-like 12 (BCL2L12) is a new member of BCL2 gene family which was discovered and cloned by members of our group and found to be expressed in the mammary gland. The aim of the study was the quantification and the evaluation of the prognostic value of BCL2L12 in breast cancer. Methods: BCL2L12 mRNA levels were determined in 140 samples (81 cancerous and 59 adjacent non-cancerous) of breast tissue using a highly sensitive quantitative real-time polymerase chain reaction (qRT-PCR) method. Relative quantification analysis was conducted using the comparative CT (2-ddCT) method, whereas the association between BCL2L12expression and clinopathological data, disease free survival (DFS) and overall survival (OS) were defined by statistical analysis. Results: Significant relationships between BCL2L12 expression and early TNM stages (P=0.021), absence of metastasis (P<0.001), Estrogen Receptor (ER) positivity (P=0.031) and breast tumors of 2-5cm diameter (P=0.032) were observed. Moreover univariate analysis indicated that BCL2L12 expression is a significant prognostic factor of disease-free survival (DFS) and overall survival (OS), whereas multivariate analysis revealed strong association between BCL2L12 expression and DFS. Conclusions: With regard to breast cancer, patients bearing BCL2L12-positive tumors have significantly longer DFS and OS. These results denote a promising, independent favorable prognostic marker and a significant association of BCL2L12 expression with good outcome.
Prognostic significance of reduction rate of Ki-67 after neoadjuvant chemotherapy in breast cancer patients with non-pCR.
Authors: Matsubara Nobuaki , Mukai Hirofumi , Naito Yoichi , Hosono Ako , Itoh Kuniaki , Fujii Satoshi , Yoneyama Kimiyasu , Wada Noriaki 
Published: March 2020

1113 Background: A pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) is well established predictive marker for long-term prognosis in patients (pts) with HER2 or triple negative (TN) breast cancer. However, predictive marker has not been established in pts with non-pCR after NAC yet. Reduction of Ki-67 value after NAC has been reported to be associated with a favorable prognosis. However, the association between the reduction rate of Ki-67 and prognosis has not been investigated in detail. This study investigates whether reduction rate of the Ki-67 could indicate a survival advantage in pts with non-pCR. Methods: A total of 450 pts who had received neoadjuvant anthracycline with or without taxane chemotherapy and surgery were analyzed retrospectively. Ki-67, hormone receptor and HER2 status were examined by immunohistochemistry (IHC) in pre-NAC biopsy samples and post-NAC surgical specimens. Pts with non-pCR were subdivided into threesubgroups according to Ki-67 change after NAC: High-reduction (absolute value of Ki-67 was reduced by > 80% compared with that prior to NAC), low-reduction (absolute value of Ki-67 was reduced by from 0% to 80% compared with that prior to NAC), and increase groups (absolute value of Ki-67 was increased compared with that prior to NAC). The relapse-free survival (RFS) rates were compared among subgroups. Results: pCR was observed in 19.5% of pts. In pts with non-pCR, a reduction in Ki-67 was observed in 64% (232/362 pts) and the median reduction rate was 60%. A total of 15% of pts were in the high-reduction, 63% in the low-reduction and 22% in theincrease group. The median follow-up was 64.5 months. The 5-year RFS rates among three groups were significantly different (p<0.0001). Similar positive results were observed in the HER2(p=0.033), TN (p=0.034) and luminal subtype (p=0.001). Pts in the high-reduction group showed comparable RFS to pts with pCR (hazard ratio 1.12 p=0.792). Conclusions: In pts with non-pCR, the reduction rate of Ki-67 after NAC significantly predicted RFS regardless of their tumor subtypes. Pts who are non-pCR but achieve a high reduction of the Ki-67 can be expected to have a favorable prognosis similar to that of pts with pCR.
A phase I-II study of tipifarnib plus weekly paclitaxel (P) followed by dose-dense doxorubicin/cyclophosphamide (AC) in stage IIb-IIIc breast cancer (BC).
Authors: Andreopoulou Eleni , Vigoda Ivette Sara , Valero Vicente , Hershman Dawn L. , Raptis George , Vahdat Linda T. , Han Hyo S. , Wright John Joseph , Pellegrino Christine M. , Alvarez Ricardo H. , Fehn Karen , Fineberg Susan , Sparano Joseph A. 
Published: March 2020

1118 Background: Tipifarnib (T) is an orally bioavailable farnesyl transferase inhibitor (FTI) that has activity in metastatic BC (J Clin Oncol 2003; 21:2492-9). We previously showed that adding T (200 mg PO BID days 2-7) to preoperative AC was associated with a higher pathologic complete response (pCR) than expected compared with historical data (Clin Cancer Res. 2009;15;2942-8), and preclinical data suggest that FTIs enhance the antineoplastic effects of P (Cancer Res 2005; 65:3883-93). Methods: Eligible pts with HER2-negative clinical stage IIB-IIIC BC received 12 weekly doses of P (80 mg/m2) followed by AC (60/600 mg/m2 every 2 weeks and pegfilgrastim), plus T 100 mg or 200 mg on days 1-3 of each P dose in cohorts of 3-6 pts in the phase I (and T 200 mg PO BID on days 2-7 each AC cycle in both the phase I and II). Simon two-stage design used for the phase II in two strata generally resistant to neoadjuvant chemotherapy. The trial was powered to detect an improvement in breast pathologic complete response (pCR) from 15% to 35% in each stratum (alpha 0.10, beta 0.10), which required breast pCR in at least 4/19 eligible pts in stage I to proceed to stage II, and at least 8/33 pts in stage I and II to be considered promising. Results: Sixty patients accrued in both the phase I and II. Two patients were non evaluable. There were no DLTs in the first 6 evaluable patients treated at dose level 1 and 2.The recommended phase II dose of T identified in the phase I trial was 200 mg BID.All protocol therapy was completed in 43/55 pts (78%) in the phase II, and one pt died of pneumonitis during therapy of uncertain cause. The prespecified efficacy endpoint was not met for either stratum. Conclusions: The addition of the FTI tipifarnib to neoadjuvant sequential weekly paclitaxel followed by dose-dense AC did not result in a higher breast pCR rate compared with historical data. Clinical trial information: NCT00049114. [Table: see text]
Sentinel lymph nodes before chemotherapy: The Besançon experience.
Authors: Chaigneau Loic , gannard Pechin Elsa , Almotlac Hamidi , Mouillet Guillaume , Bazan Fernando , Villanueva Cristian , Cals Laurent , Montcuquet Philippe , Meneveau Nathalie , Nguyen Thierry , Curtit Elsa , Sautiere Jean-Loup , Maisonnette Yolande , Algros Marie-Paule , Pivot Xavier B. 
Published: March 2020

1122 Background: It is debatable whether sentinal lymph node (SLN), before chemotherapy in locally breast cancer (LBC) is feasible. Impact on survival and locoregionally recurrence are unknown. Methods: 256 consecutive patients with LBC treated in Franche Comté (France) between 2004 and 2010 by standard neoadjuvant chemotherapy were retrospectively studied. 177 patients underwent axillary lymph node (ALN) dissection after chemotherapy (cohort A) and 79 patients underwent SLN before chemotherapy (cohort B). The aim of this study was designed to confirm the feasible of SLN before neoadjuvant chemotherapy without negative impact of recurrence and survival. Disease-free survival (DFS) and overall survival (OS) were calculated using Kaplan-Meier method. Differences in OS and DFS according ALN exploration were tested for significance using the Log-Rank test. Results: No statistically significant differences were observed in terms of median age (respectively 59 and 48 years in cohort A and B), tumor size, histological type, grading score, estrogen receptor, progesteron receptor and human epidermal receptor-2 status. No difference of breast conserving surgery was observed between cohort A and B (56.25 vs. 64.56%, p = 0.21). In cohort B, 38 patients (48.10%) of patients underwent SLN alone. For others patients (n = 41, 51.90%), secondary complete axillary lymphadenectomy was performed in the same time of breast surgery. After a median follow up of 57 months (range: 38-105), there was no significant difference in termsof local and axillary recurrences (1.13 vs. 1.27%), metastatic recurrence (11.30 vs. 11.40%). Five-year DFS (76 vs 81%, p = 0.55) and 5-year OS (91 vs. 97%, p = 0.76) did not differ between patients in cohort A and B. Conclusions: SLN before neoadjuvant chemotherapy is feasible and allows to avoid ALN dissection in nearly 50% of patients without impact on recurrence and survival.
Volume-based parameters on FDG-PET/CT as early predictors of disease recurrence in postmastectomy breast cancer patients with one to three positive axillary lymph nodes without adjuvant radiotherapy.
Authors: Nakajima Naomi , Kataoka Masaaki , Nishikawa Atsushi , Sugawara Yoshifumi , Sakai Shinya , Ohsumi Shozo , Kiyoto Sachiko , Mochizuki Teruhito 
Published: March 2020

1124 Background: The indication for postmastectomy radiotherapy (PMRT) in patients with 1-3 lymph node metastases in the axilla have been controversial, despite the recommendation that PMRT should be applied. In the current study, we focused our study on volume-based parameters of pretreatment FDG-PET/CT, with the aim of investigating a measurement that could help identify high-risk populations for recurrence. Methods: We retrospectively analyzed 88 patients of breast cancer treated with modified radical mastectomy and were found to have 1-3 metastatic axillary lymph nodes between 2006 and 2010. All of them were studied with FDG-PET/CT for initial staging. We evaluated the relationship between clinicopathologic factors or PET parameters including the maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) and recurrence. MTV and TLG of the primary tumor and metastatic lymph node were measured by using semi-automatically delineated volume of interest (VOI) with an isocontour threshold of 40 % of the SUVmax. The optimal cutoffs of PET parameters were determined by ROC curve analysis. Results: The median follow up duration was 39 months. Median MTV was 21.1and median TLG was 42.7. Recurrence was observed in 10 patients. The area under the ROC curve of MTV and TLG for DFS was 0.82 and 0.85, respectively. In Cox univariate analysis, estrogen receptor status (HR = 6.8, p = 0.003), triple negativity (HR = 10.4, p = 0.0008), SUVmax (HR = 71.1, p = 0.001), MTV (HR = 130.3, p < 0.0001), and TLG (HR = 234.1, p = 0.0001) were significantly related to disease free survival (DFS). The estimated 3-year DFS rates were 96.4 % for the lower MTV group (< 31.8) and 71.4% for the higher MTV group (≥ 31.8, p = 0.0005). The estimated 3-year DFS rates were 95.8 % for the lower TLG group (< 109.6) and 50.0 % for the higher TLG group (≥ 109.6, p < 0.0001). On multivariate analysis, TLG was an independent prognostic factor of DFS (HR = 8.5, p = 0.005). Conclusions: Volume-based parameters on FDG-PET/CT were significant predictors of DFS in postmastectomy breast cancer patients with 1-3 metastatic axillary lymph nodes.
Distinctive lipid profiles of human breast cancer and adjacent normal tissues by desorption electrospray ionization mass spectrometry imaging.
Authors: Caragacianu Diana L. , Liu Xiaohui , Norton Isaiah , Ide Jennifer , Richardson Andrea , Dillon Deborah , Jolesz Ferenc A. , Golshan Mehra , Agar Nathalie Y.R. 
Published: March 2020

1132 Background: Routine intra-operative distinction between normal breast tissue and tumor is currently not possible in breast conserving surgery (BCS). This limitation affects the success of surgery, resulting in up to 40% requiring more than one operative procedure. Desorption electrospray ionization mass spectrometry (DESI MS) has been successfully used to discriminate between normal and cancerous human tissues from anatomical sites such as the liver and brain. The aim of this proof of concept study was to determine the feasibility of using DESI MS imaging for tissue identification and differentiation of breast cancer versus normal tissue. Methods: DESI MS imaging was carried out on 14 human invasive breast cancer samples. Breast cancer and adjacent normal paired human tissue sections (margin of tumor, 2cm and 5 cm from tumor) from 14 patients undergoing mastectomy were flash frozen in liquid nitrogen, sectioned, and thaw mounted to glass slides. All samples were imaged using DESI MS at 200 μm imaging resolution. DESI MS images were overlaid and compared with hematoxylin and eosin (H&E) images of the same sections. Results: Discrimination between cancer and adjacent normal tissue was achieved on the basis of the spatial distribution and varying intensities of particular fatty acids and lipid species. Several fatty acids such as oleic acid (m/z 281) and arachidonic acid (m/z 303) displayed much greater signal intensities in the cancer specimen compared to low or undetectable intensities in normal tissue. The cancer margins delineated by the DESI MS images of these molecules were consistent with H and E images of the tumor edge. Cancerous tissue was distinguished from normal tissue based on the qualitative assessment of molecular signatures and the distinction was in agreement with expert histopathology evaluation in 85% of samples. Conclusions: Our findings offer proof of concept that examination and classification of breast normal and cancer tissue by mass spectrometry imaging is highly accurate. The results are encouraging for development of a MS-based method that could be utilized intra-operatively for rapid detection of residual cancer tissue in the lumpectomy bed in BCS.
Breast cancer surveillance in high-risk women with magnetic resonance imaging every 6 months.
Authors: Guindalini Rodrigo Santa Cruz , Huang Yi-Ching , Obeid Elias , Patrick-Miller Linda , Bradbury Angela R. , Verp Marion S. , Hong Susan , Wroblewski Kristen , Abe Hiroyuki , Karczmar Greg S. , Newstead Gillian , Olopade Olufunmilayo I. 
Published: March 2020

1506 Background: Surveillance with mammography (MMG) and magnetic resonance imaging (MRI) is recommended for women at high-risk for breast cancer, but there is no consensus on screening strategy. Aim of this study was to evaluate the efficacy of semi-annual MRI in high-risk women. Methods: A multi-modality surveillance program was initiated in 2004. Yearly MMG was supplemented with semi-annual MRI. After 5 years, an additional 5 years of follow-up with yearly MMG and MRI was offered to mutation carriers. Defining positive screening as BIRADS 0, 4 and 5, sensitivity, specificity, NPV, and PPV of semi-annual MRI were analyzed. Results: From 2004 to 2012, 226 patients underwent 1467 MRI and 851 MMG with a mean follow-up of 3.6 yrs. Median age at entry was 43 yrs (range 21-73), 48% were mutation carriers (105 BRCA1/2, 2 CDH1, 1 P53) and 19% had personal history of breast cancer. Eleven cancers were screen-detected, of which 6 (55%) were detected only by MRI, 1 (9%) only by MMG, and 4 (36%) by both. Of these tumors, 4 were detected in the first round of MMG/MRI screening and 7 (64%) in mutation carriers (5 BRCA1, 1 BRCA2, 1 CDH1), and 3 tumors (27%) were detected due to the additional MRI during semi-annual screening. No interval cancers occurred. Sensitivity, specificity, PPV and NPV of MRI were 91%, 97%, 18%, 99%, respectively. Of the incident cancers, 3 (27%) were stage 0 (ductal) and 8 (73%) were stage 1 (7 ductal and 1 lobular). Mean size of the invasive cancers was 0.78 cm (range 0.1-1.6; only 2 tumors > 1.0 cm), none had lymph node metastasis, and 75% were high grade and hormone receptor positive. The largest tumor detected was invasive lobular in a 73 year old CDH1mutation carrier. Conclusions: To our knowledge, this is the first surveillance protocol with repeated screening rounds that detected mean size of invasive tumors less than 1 cm. Absence of interval cancers, high sensitivity/specificity, and detection of all tumors in early stages (stages 0 or 1) support this screening strategy as a viable alternative to prophylactic mastectomy. Ongoing work will examine quality of life, cost effectiveness and impact on overall survival of this screening approach. Clinical trial information: NCT00989638.
Comparison of false positive rates for screening breast MRI in high risk women when studies are done stacked versus alternating.
Authors: Othman Edress , Wang Jue , Sprague Brian , Ji Yongli , Herschorn Sally D. , Wood Marie 
Published: March 2020

1512 Background: Screening breast MRI added to mammography increases screening sensitivity for high risk women. However, false positive rates are high for MRI and the optimal screening schedule is unclear. In this study we compare rates of false positive MRI when studies were performed on a stacked or alternating schedule. Methods: We reviewed charts for women at increased risk for breast cancer who had screening breast MRI between 2004 - 2012 at the University of Vermont. Eligible women had at least 1 MRI and 1 mammogram performed within one year. Charts were abstracted for clinical, radiological, and biopsy data. Screening was considered stacked if both studies were performed within 90 days and alternating if studies were 4-8 months apart. False positive was defined as MRI result of BI-RADS 3-4-5-0 with additional negative imaging within 12 months or benign biopsy. Results: 143 women had screening which met inclusion criteria; 45 per stacked schedule, 52 alternating, 40 mixed and 6 neither. Women in this study had similar characteristics with respect to age, ethnicity, menopausal status and indications for MRI (i.e. family history, BRCA mutation, biopsy history and prior chest irradiation). 371 MRIs were reviewed (165 stacked and 206 alternating). The overall false positive rate was higher in the stacked group vs. alternating [30(18.2%) vs. 21(10.2%), p=0.0264]. Using only BI-RADS 4-5-0 as a positive result that difference was lost. There were significantly more BI-RADS category 3 interpretations in the stacked vs. alternating MRIs [16(9.7%) vs. 6(2.9%), p=0.006]. The rate of BI-RADS category 4-5-0 was not different between the two groups [16(9.7%) vs. 17(8.3%), p= 0.6272]. A similar number of biopsies were performed in both groups Conclusions: MRI added to mammography for women at increased risk for breast cancer was associated with higher rates of false positive interpretations when studies were done on a stacked compared to alternating schedule. In this study the greater number of BI-RADS 3 interpretations with a stacked schedule accounted for this difference. Further studies are needed to identify the optimal screening schedule when adding MRI to mammography.