bluuebunny/crossref_metadata_2025_split huggingface dataset:
Diffuse large B-cell lymphoma (DLBCL) in African American patients: A retrospective study of clinical, molecular, and therapeutic differences in a sample population treated at UAB Comprehensive Cancer Center (UAB CCC)
Authors: The A. S. , Reddy V. , Li Y. , Davis R. , Baird M. , Foran J. M. 
Published: March 2020

21035 Background: SEER registry data indicate African Americans (AA) have a lower incidence of non-Hodgkin's lymphoma (NHL) but face higher lymphoma-specific mortality rates than Caucasians (C). To investigate this we compared outcomes between AA & C patients (pts) with DLBCL treated at UAB CCC. Correlative histologic & molecular studies of established prognostic features were performed to investigate differences. Methods: After IRB approval, DLBCL pts diagnosed '95-'06 were identified from pathology & referral databases. Baseline demographic & clinical data were extracted, including treatment (Rx), response & survival. Expression patterns of CD10, bcl-6, & MUM-1 were used to identify germinal center B-cell-like (GCB) vs non-GCB molecular subtype of DLBCL based on algorithm of Hans et al (2004). HLA-DR, bcl-2, & CD138 expression was determined. A 2:1 age- & gender-matched comparison of C to A pts was performed to evaluate differences. Descriptive analysis with X2 & Wilcoxon nonparametric tests & Kaplan Meier survival analysis were performed to determine differences. Results: 188 DLBCL patients were identified. Race was noted in 129, including 18 AA pts (14%). In comparison to 36 C pts (2:1 match), no differences were seen in LDH or stage at presentation. AA pts achieved better response to 1st-line Rx (p=0.01) & received fewer regimens (1 vs >1, p=0.05), however they were more likely to receive rituximab with 1st-line Rx (p=0.02), likely reflecting presentation in the post-rituximab era. Median survival, not yet reached for AA's, was 23 months for C pts (p=0.0509). Univariate & parametric survival analyses demonstrated LDH (p=0.0217) & 1st-line rituximab (p=0.0048) independently affected survival. In a separate cohort, no significant difference between races was seen in frequency of GCB vs non-GCB subtype or in expression of bcl-2, CD-138, or HLA-DR. Conclusions: Contrary to SEER observations, the outcome of AA DLBCL pts was superior to C pts in this single center study. No molecular or clinical prognostic feature dominated in either race. The fact that more AA than C patients received rituximab upfront confirms the benefit of adding this agent to 1st-line Rx. No significant financial relationships to disclose.
Sarcomas predominate in mice deficient for PrPc and p53
Authors: Michael D. , Okuducu A. F. , Holtkamp N. , Bamme T. , Jehn C. F. , Riemer C. , Baier M. 
Published: March 2020

21039 Background: For cellular prion protein (PrPc) putative roles in many cellular processes including signalling, survival, adhesion, proliferation and differentation have been proposed. The hallmarks of cancer include some of these traits and in human tumors both increased and decreased levels of PrPc have been observed. However PrPc deficient mice show no increased rate of tumor formation. To characterize the possible role of PrPc in tumorigenesis we generated PrPc-/-/p53-/- mice. Methods: Organ and tumor samples were surgically removed post mortem and processed for histological analysis. Time to death was defined as the latency between birth and spontaneous death or a terminal disease state as indicated by tumor burden and other symptoms of severe disease. Results: As reported previously lymphomas are the most frequent tumors in p53-/- mice [5 out of 7 (71 %)]. In contrast, sarcomas predominate in PrPc-/-/p53-/- mice [9 out of 21 (43 %)]. This was accompanied by a decrease in the incidence of lymphomas in PrPc-/-/p53-/- mice [7 out of 21 (33 %)]. Conclusions: These results indicate for PrPc, in the context of p53 deficiency, a role in sarcoma tumorigenesis and the PrPc-/-/p53-/- mice might provide a clinical relevant model for the study of sarcomas. No significant financial relationships to disclose.
Prognostic value of immunohistochemical phenotypes (IP) of 141 operable breast cancer patients (pts) included in phase III trials of adjuvant therapy
Authors: Trujillo R. , Gallego E. , Márquez A. , Ribelles N. , Trigo J. , Perez D. , Quero C. , Medina A. , Vicioso L. , Alba E. 
Published: March 2020

21040 Background: Gene expression arrays and IP studies classified breast cancer in three distinct subtypes: basal, HER2/neu and luminal that are associated with different clinical outcomes. Methods: In 141 pts with operable breast cancer, included in phase III trials of adjuvant therapy in our center, immunohistochemical staining was performed on 3μm sections of paraffin blocks, containing tissue-arrays of tumour tissue.A basal phenotype (BP) was defined by negative estrogen receptor (ER) and progesterone receptor (PR) and positive cytokeratin (CK) 5/6 or EGFR immunoreactivity. HER2/neu phenotype as positive c-erb B2 by HercepTest™ and luminal phenotype (LP) by positive ER, PR and CK 7/8 and negative HER-2. Survival curves were calculated by the Kaplan-Meier method. The differences between survivals were estimated using the log rank test. Multivariate Cox regression analysis was used to evaluate any independent prognostic effect of the variables on disease-free survival (DFS). Results: Complete clinical follow-up information was available for 141 pts. The median follow-up period was 52 months (range 1–103 months). During this period, 13.8% pts died from breast cancer and 27.7% pts relapsed. At the time of the primary diagnosis 10.4% of the pts had lymph node negative disease and 89.6% had positive lymph nodes. 50.8% pts received taxane chemotherapy, 7.7% Trastuzumab, 62.3% radiotherapy and 61% pts received hormonotherapy. Positivity for LP was 65.2%, BP 9.9% and Her-2 phenotype 8.5%. 16.3% didn't fit for any of the three subtypes. Median DFS for BP: 24 moths, for LP and Her-2 phenotypes median DFS was not reached. 5 years DFS were; BP: 19%, LP: 63% and Her-2: 56%. Kaplan-Meier survival analyses demonstrated that the presence of a detectable BP was highly significantly associated with a worse DFS compared with the presence of a LP, log rank test (p= 0.0001). Multivariate Cox regression analyses estimated that the prognostic effect of BP in relation to DFS was independent of lymph node, stage and tumor size, HR: 0.12 95% CI (0.05–0.2). Conclusions: We found that expression of BP was associated with poor prognostic in the context of randomized phase III trials. No significant financial relationships to disclose.
Translation of gene expression profiles into a nine antibody IHC multivariate index assay for colorectal carcinoma
Authors: Schreeder M. T. , Seitz R. S. , Beck R. , Ring B. Z. , Ross D. T. 
Published: March 2020

21042 Introduction: Pathologic stage is the most powerful predictor of outcome in colorectal cancer. However, in early stage disease there continues to be a need for better identification of patients at high risk of disease progression after surgical resection. We have undertaken a large scale effort translating gene expression profiles into immunohistochemical biomarkers that classify carcinoma in novel ways. Herein we report the identification of a colorectal tailored antibody “panel of diversity” that distinguishes tumor heterogeneity and propose a multivariate index assay (MIA) for predicting outcome. Methods: 744 stage I-III consecutive colon cancer patients treated by the CCIH between 1992 and 2000 were identified. Clinical followup through 2005 was obtained from the tumor registry and verified by chart review . Tissue micorarrays (TMA) were constructed from these patients resected primary tumors. Over 700 antibodies targeted by carcinoma gene expression experiments or literature review were first screened on a 30 case TMA. Of these, 34 were selected as showing subjectively high quality stains and the ability to classify patient populations. These antibodies were used to stain the clinical TMA and scored using a semi-quantitative scale. We used a number of approaches including Cox, RPART, and Bayesian to derive candidate MIA's to predict recurrence. Results: 13 antibodies showed a significant or near significant association with either overall recurrence or recurrence at 5 years. We have previously shown these antibodies to have similar prognostic abilities in other solid tumor carcinomas. We propose a model combining nine markers (p53, CCNA2, TFF3, RERG, AKR1C1, TLE3, IRX3, SYP, TTC7) as an MIA for predicting outcome in Stage II patients. The model is independent of pathologic stage. Conclusions: This colon tailored antibody ‘panel of diversity’ is a tool for characterizing the biologic diversity in colon cancer cohorts. The identification of nine prognostic markers that can be effectively combined using an MIA suggests that combination of multiple markers will be useful for developing sensitive and specific prognostic assays. The model proposed herein should be validated using additional cohorts to evaluate its overall clinical utility. No significant financial relationships to disclose.
Prognostic value of HER-2/neu overexpression for the development of brain metastasis after treatment of early breast cancer
Authors: Ahn J. , Kim S. , Kim W. , Gong G. , Kim M. , Son B. , Ahn S. , Lee S. , Kim H. 
Published: March 2020

21044 Background: Several studies have addressed the incidence of brain metastasis in HER-2/neu-overexpressing metastatic breast cancer. However, the relevance of HER-2/neu overexpression as a risk factor for brain metastases in breast cancer has not yet been clearly defined. The aim of this study is to analyze the risk of brain metastasis in HER-2/neu-positive early breast cancer patients in comparison with HER-2/neu-negative patients. Methods: We used tissue microarray to examine HER- 2/neu overexpression by immunohistochemistry (IHC) in 773 consecutive patients diagnosed with breast carcinoma who underwent surgery between January 1993 and December 1998. Patients were considered HER-2/neu-positive if they were 3+ on IHC testing. A total of 194 (25.1%) patients with HER-2/neu-overexpressing newly diagnosed breast cancer were identified in our study. The medical records and pathologic data of all 773 patients were reviewed retrospectively. Results: During a median follow-up period of 8.1 years, brain metastasis were identified in 7.2% (14 patients) with 194 HER-2/neu-overexpressing breast cancer compared with 2.6% (15 patients) in 597 HER-2/neu-negative patients (hazard ratio 2.924 [1.385–6.175], P=0.005). More HER-2/neu-overexpressing patients developed distant metastasis (33.5% vs. 18.8%, P=0.0001). The 8-year overall survival was 76.1% for HER-2/neu-negative patients versus 56.4% for HER-2/neu-positive patients (P<0.00001). By multivariate analysis, HER-2/neu overexpression, tumor size larger than 2 cm, at least one positive node, and progesterone receptor (PR)-negativity were independent risk factors for the development of brain metastases. Conclusions: Our data show that HER-2/neu overexpressing early breast cancer patients are at significantly increased risk for brain metastases. Also, our results demonstrate that HER-2/neu overexpression is an important independent prognostic factor of early breast cancer, and suggest that more aggressive adjuvant chemotherapy and radiologic screening to detect brain metastases should be considered in this population. No significant financial relationships to disclose.
Stage and histology influence the relationship between MDM2 promoter polymorphism and esophageal cancer and overall survival (OS)
Authors: Mackay H. J. , Bradbury P. , Asomaning K. , Zhou W. , Kulke M. , Su L. , Suk Heist R. , Lynch T. J. , Christiani D. C. , Liu G. 
Published: March 2020

21047 Background: A single nucleotide polymorphism in the MDM2 promoter (SNP309) has been found to affect OS of advanced stage gastric adenocarcinoma (AD) and early stage squamous (SQ) cell carcinoma of the lung. The aim of this study was to evaluate the role of this polymorphism in the prognosis of esophageal cancer, another aerodigestive cancer. Methods: 150 early stage (E) and 118 locally advanced stage (LA) esophageal cancers were genotyped for MDM2 SNP309 using Taqman. The primary endpoint was overall survival (OS). Results: E disease: n=23 stage I; n=127 stage II. LA disease: n=93, Stage III; n=25, Stage IVA. AD comprised 215 (81%), while SQ comprised 45 (17%) of cases; 8 (3%) had poorly differentiated tumors. Median follow-up = 32 months. Median OS were 36 and 21 months for E and LA disease, respectively. Both histology and disease stage affected the relationship between SNP309 and esophageal cancer OS (see Table ). The wildtype T/T genotype conferred a worse OS in E patients (log-rank, p=0.03), especially those with AD (log-rank, p=0.003). In Cox proportional hazards interaction analyses, after adjusting for age, gender, stage and PS, there were statistically significant interactions between MDM2 SNP309 and disease stage (interaction p=0.004) and between MDM2 SNP309 and histologic subtype (AD vs. SQ)(interaction p=0.02). Thus, the direction of SNP309 association from our AD and E esophageal cancer patients are opposite to those of our SQ and LA esophageal cancer patients. However, our SQ and LA results are similar to the SQ lung cancer and advanced stage gastric cancers previously reported. This suggests that biologic mechanisms underpinning the prognostic role of SNP309 are dependent on extent of disease and histologic subtype. Conclusion: Histology and disease stage interact with the prognostic role of MDM2 SNP309 polymorphism in esophageal cancer OS. [Table: see text] No significant financial relationships to disclose.
One Step Nucleic Acid Amplification (OSNA) for intra-operative detection of lymph node metastases in breast cancer patients
Authors: Schem C. , Maass N. , Bauerschlag D. O. , Hilpert F. , Roder C. , Löning T. , Carstensen M. , Jonat W. , Tiemann K. 
Published: March 2020

21053 Background: Sentinel lymph node metastasis in breast cancer patients has conventionally been determined by intra- operative histopathological examination of frozen sections followed by definitive post-operative examination of permanent sections. The purpose of this study is to evaluate a more efficient method for intra-operative detection of lymph node metastasis in a clinical setting. Therefore, a new rapid method of detection of CK19 mRNA by One Step Nucleic Acid Amplification (OSNA) and Reverse Transcription Loop Mediated Isothermal Amplification (RT-LAMP) was tested against standard histological techniques. Methods: The clinical study was conducted at two facilities using 188 lymph nodes (46 patients). Lymph nodes from axillary dissected patients with breast cancer were divided into four slices. Alternate slices were used for the new method of CK19 mRNA detection (OSNA) and histopathological examination by hematoxylin & eosin and cytokeratin staining. For the analysis of concordance between both methods, the slices for histopathology were cut in 4 μm sections. For the OSNA method the other 2 slices were homogenised in a short sample preparation step. Afterwards CK19 mRNA was directly amplified from the tissue lysate within 16 minutes. Results: In the clinical study, an overall concordance rate between the OSNA assay and histopathology was 92%. Several discordant results are explainable with the expected uneven distribution of metastases within the lymph nodes. Conclusions: The study indicates that OSNA is a reliable and fast diagnostic tool for the detection of lymph node metastases in breast cancer patients. This method could be beneficial to avoid diagnostic delay for the patient or second surgery based on a post-operatively diagnosed positive lymph node. No significant financial relationships to disclose.
The MUC16 mucin gene upregulates gene transcripts associated with invasion
Authors: Diaz J. P. , Kehoe S. , Thapi D. , Rosales N. , Ma X. , Yan X. J. , Spriggs D. R. 
Published: March 2020

21057 Background: The MUC16 gene encodes the CA125 ovarian cancer antigen and may play a role in invasion. The aim of this study is to investigate the properties of MUC16 in vitro. Methods: PCR was used to create a DNA construct, MUC16–1R-GFP, containing all of the MUC 16 sequence proximal to the second cysteine loop repeat and a GFP-vector construct. SKOv-3 and T-80 cell lines were selected because they are negative for immunologically active CA125. Transfections were performed utilizing the phrGFP II C vector system. Stable transfectants were sorted for GFP by FACS and were grown as populations. The growth rate of the transfected populations were compared to vector only. Periodically the stable transfectants were analyzed by FACS for GFP and OC125 mAb. The in vitro invasive potential was examined, using a Matrigel® invasion assay. RT PCR was used to examine the effect of MUC16 constructs for a panel of invasion focused genes. Immunoblotting was performed on the 1R protein and probed for all genes that were significantly changed on RT PCR. Results: The SKOv-3 1R transfected cell lines produce measurable CA125 into the cell culture medium (4–10 U/mL) while T-80 1R cell lines did not. Analysis of the in vitro growth rate did not demonstrate any difference between the transfectant and vector only cell lines. The 1R-GFP transfected lines showed MUC16 cell surface expression by FACS analysis. Invasion assay of the MUC16 transfectants demonstrated substantially more invasive potential than vector only (SKOV-3: 36% vs. 15% invasion; T-80: 35% vs. 23% invasion). Several transcripts associated with invasion and metastasis were up-regulated 3–9 fold including CDH1, FN1, IL1B, MMP7 and MMP9. Transcripts for the tyrosine kinases SYK and HTATIP2 were down-regulated 16–20 fold respectively. Western immunoblotting confirmed the RT PCR findings. Conclusions: The1R-GFP construct did not alter the growth rate of transfectants in vitro; however; the SKOV-3 1R and T-80 1R cell line did have substantially more invasive potential than vector only. Five transcripts associated with invasion were up-regulated, and 2 transcripts for kinases were down-regulated in the transfected cell lines. These data supports an association between MUC 16 and invasive potential. No significant financial relationships to disclose.
Transforming genomic grade index (GGI) into a user-friendly qRT-PCR tool which will assist clinicians and patients in optimizing treatment of early breast cancer (BC)
Authors: Durbecq V. , Toussaint J. , Haibe-Kains B. , Desmedt C. , Rouas G. , Larsimont D. , Bontempi G. , Buyse M. , Piccart M. , Sotiriou C. 
Published: March 2020

21058 Background: We have recently shown that proliferation captured by the genomic grade index (GGI) is the most important prognostic factor in BC, far beyond estrogen receptor (ER) status and may encompass a significant portion of the predictive power of many previously published prognostic signatures. Furthermore, we have demonstrated that GGI can identify two clinically distinct ER-positive molecular subtypes in a simple and highly reproducible manner across multiple datasets. The aims of this study were to convert and validate by qRT-PCR assay the prognostic value of the GGI using frozen (FS) and paraffin-embedded tumor samples (FFPE) from early BC patients. Methods: We first developed a qRT-PCR assay based on 8 selected GGI genes involved in different phases of the cell cycle and 4 reference genes. We then tested its accuracy and concordance with the original microarray derived GGI using a BC population from which FS, FFPE tissues and microarray data were available (N=30). Finally, we assessed its prognostic value on an independent ER-positive tamoxifen only treated BC population (N=82). Results: A statistically significant correlation was observed between GGI generated by microarray and qRT-PCR assay using FS material (r=0.91; p<0.0001) as well as between GGI using qRT-PCR derived from FS and FFPE tumor samples (r=0.86; p<0.0001). A high GGI levels assessed by qRT-PCR (GGRI) was associated with a higher risk of recurrence in the ER-positive tamoxifen only treated patients [HR= 2.319 (95% CI: 1.245–4.321), p=0.008] in accordance with our previous microarray results. Interestingly, in a multivariate analysis, GGRI remained significant [HR=1.956 (95% CI: 1.031–3.710), p=0.04] together with age (<50y) and tumor size (>2cm). Conclusions: In this study, we report a qRT-PCR assay based on a limited number of genes, which recapitulates in an accurate and reproducible manner the prognostic power of the microarray derived GGI using both FS and FFPE tumor samples. Further validation of its prognostic value is currently ongoing on two independent populations totaling over 500 BC patients. No significant financial relationships to disclose.
Lack of p21/Waf-1 expression and lymphocyte infiltration in primary ovarian cancer correlate with the somatic HLA-A2 expression
Authors: Andersson E. , Villabona L. , Kanter L. , Gamzatova Z. , Kiessling R. , Dalianis T. , Bergfeldt K. , Masucci G. V. 
Published: March 2020

21059 Background: HLA-A2 allele is highly prevalent in Scandinavia and decreases with latitude in Europe. Similarly, ovarian cancer mortality decreases with latitude in European countries. We have previously shown that HLA-A2 is associated to a severe prognosis in serous adenocarcinoma of the ovary in stage III-IV. Others have shown that lack of p21/Waf-1 and lymphocyte infiltration in this tumour is correlated to poorer prognosis as well. Here we analyse a possible linkage between these variables. Methods: Thirty eight Swedish women with epithelial ovarian cancer were analyzed for the HLA-A genotype locus by PCR/sequence-specific oligonucleotide hybridization procedure (PCR/SSOP). Tissue slides from paraffin embedded tumour material were stained with haematoxylin and antibodies anti-p21 and -p53. Results: Twenty two patients were HLA-A2 positive. Fourteen of them (37%) lacked lymphocyte infiltration wich differed significantly from HLA-A2 negative patients (n=4, 11 %) (p=0.002). All of the HLA-A2 positive patients, with serous adenocarcinoma that showed absence of tumour lymphocyte infiltration, did not express p21/waf-1 (n=7 18 %). No cases in the HLA-A2 negative group with the same parameters were identified (p=0.009). Conclusions: These observations identify a high risk group of patients by linking together the somatic expression of HLA-A2 to the lack of lymphocyte infiltration and absence of p21/Waf-1 expression at the tumour level as prognostic negative factors. The information might have a relevant impact on the patient management.. In order to obtain a stronger power the analysis will be extended to a larger group of patients. No significant financial relationships to disclose.