bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of slug in TGF-β1 mediated MMP-9 expression in human oral squamous cell cancer
Authors: Joseph M. J. , Ananthanarayanan V. , Diamond M. E. , Sun L. , Munshi H. G. 
Published: March 2020

21000 Background: Oral squamous cell cancer (OSCC) causes significant morbidity and mortality as a result of loco-regional invasion and distant metastasis. Invasive OSCC tumors demonstrate increased expression of matrix metalloproteinases (MMPs), including MMP-9. TGF-β1, which promotes MMP-dependent invasion, is also frequently overexpressed in OSCC. Recent reports indicate that TGF-β1 can signal through Snail family of transcription factors, including Slug, which are key regulators of epithelial to mesenchymal transition. Methods: To examine the relationship between TGF-β1 and MMP-9 in human OSCC tumors, phospho-Smad2 and MMP-9 expression was quantified in an oral cancer tissue microarray, and then the relationship determined using Pearson correlation coefficient. To understand the role of Slug in TGF-β1-mediated MMP-9 expression, premalignant oral keratinocyte cell lines (OKF4 and OKF6) and malignant OSCC lines (SCC25 and UMSCC1) were treated with TGF-β1 (10 ng/ml) and analyzed for Slug and MMP-9 expression at the message and protein levels. The specific role of Slug was determined by transfecting OSCC cells with Slug specific siRNA or control siRNA, treating with TGF-β1 for 24h, and determining the effect on MMP-9 expression. Results: There was a statistically significant correlation between phospho-Smad2 and MMP- 9 expression in human OSCC samples, with a Pearson correlation coefficient of 0.4392 (p=0.0007). In vitro, treatment of premalignant and OSCC cells with TGF-β1 induced both Slug and MMP-9 expression at the message and protein level. Interestingly, transfection of Slug siRNA in OKF4 and OKF6 cells increased both basal and TGF-β1-mediated MMP-9 expression, while transfection of Slug siRNA in SCC25 and UMSCC1 cells decreased basal and TGF-β1-mediated MMP-9 expression. Conclusions: Overall, our data indicate that TGF-β1 may regulate MMP-9 expression in human oral squamous cell cancer. Additionally, our data indicate a role for Slug in TGF-β1-mediated MMP-9 expression in oral cancer cells. Future experiments will examine the mechanism by which Slug differentially regulates MMP-9 expression in premalignant and malignant OSCC cells. No significant financial relationships to disclose.
A high serum level of YKL-40 in patients with cervical cancer is associated with short survival
Authors: Roslind A. , Palle C. , Johansen J. S. , Christensen I. J. , Nielsen H. J. , Price P. A. , Nielsen D. L. , Mosgaard B. J. 
Published: March 2020

21004 Background: YKL-40 is secreted by tumor cells, macrophages and neutrophils. The exact function of YKL-40 in cancer is unknown. It may be a growth, differentiation or survival factor and play a role in angiogenesis. High serum levels of YKL-40 are associated with a poor prognosis in a variety of solid and hematological malignancies. The aim of this study was to examine if serum YKL-40 is a prognostic biomarker in patients with cervical cancer. Methods: YKL-40 was determined by ELISA (Quidel, Santa Clara, CA) in pretreatment serum samples from 116 patients with cervical cancer (FIGO stage Ia (N=5), Ib (N=55), II (N=27), III (N=25) and IV (N=4); median age 50, range 27–87 years). The median follow-up time was 3.2 years (range 2.1–4.4 years). 18 patients had a recurrence and 28 patients died. Results: Serum YKL-40 was increased (p<0.001) in the patients with cervical cancer (median 76 μg/l, range 20–2310) compared to healthy women (43 μg/l, range 20–172). Serum YKL-40 was higher than the age-corrected 95th percentile of serum YKL-40 in healthy women in 35% of the patients. Patients with high serum YKL-40 had significantly shorter survival than patients with normal serum YKL- 40 (HR=3.1, 95% CI: 1.5–6.5, p=0.002, logrank test). Univariate Cox analysis of serum YKL-40 (log transformed and treated as a continuous covariate) showed significant association with overall survival (HR=2.3, 95% CI: 1.7–3.2, p<0.0001). Multivariate Cox analysis including stage, menopausal status and serum YKL-40 (log transformed and treated as a continuous covariate) showed that stage (stage II+III vs. I: HR=6.4, 95% CI: 1.8–22.5, p=0.004) and serum YKL-40 (HR=1.6, 95% CI: 1.1–2.4, p=0.02) were independent prognostic variables of overall survival. Univariate Cox analysis of serum YKL-40 (log transformed and treated as a continuous covariate) demonstrated a significant association with risk of recurrence (HR=1.7, 95% CI: 1.1–2.7, p=0.02). Conclusion: Serum YKL-40 is a prognostic biomarker of recurrence-free and overall survival in patients with cervical cancer. No significant financial relationships to disclose.
BRCA1 and BRCA2 mutation carrier predictions using the BRCAPRO model in clinic-based minority families enrolled in the Breast Cancer Family Registry (B-CFR)
Authors: Huo D. , Senie R. T. , Terry M. B. , Daly M. B. , Buys S. S. , Olopade O. I. 
Published: March 2020

21037 Background: BRCA mutation prediction models, such as BRCAPRO, are used in cancer risk clinics, but they were developed based on mutation rates and penetrance observed in individuals of Ashkenazi Jewish and European ancestry. Furthermore, in clinical counseling it is not always clear whether to test additional family members for BRCA mutations after the proband tests negative. The aim of this study is to evaluate the performance of the BRCAPRO model among clinic-based minority families and to evaluate the clinical utility of testing additional family members in high risk families. Methods: A total of 314 families with at least one member having been tested for BRCA mutations were enrolled through the B-CFR. Families of Ashkenazi Jewish ancestry were excluded. Using the BRCAPRO model with default penetrance and allele frequency for non-Ashkenazi Jewish populations, the predicted likelihood of carrying either a BRCA1 or BRCA2 mutations was generated. Sensitivity, specificity, and area under the receiver operating characteristic curves (AUC) were calculated. Results: There were 55 African American, 181 Hispanic, 42 Asian American and 36 other minority families. The AUC was 0.771 (95% confidence interval, CI: 0.720–0.816) for all minorities combined. At a predicted probability of 10%, the sensitivity for identifying mutation carriers was 65% and the specificity was 76%. The performance was marginally significantly better for Hispanic families than the other minority groups (p=0.07). In 228 families (73%), multiple individuals were tested for BRCA mutations. After taking into account the mutation status of family members, the performance of the BRCAPRO model was improved: the AUC increased to 0.862 (95% CI: 0.820–0.899) and the specificity at the 10% threshold increased to 83%, while the sensitivity remained the same. Conclusions: The data support the use of BRCAPRO in pretest prediction of BRCA1/2 mutations for minority families in high risk clinic settings. Mutation status of family members provides additional predictive value, which may help counselors decide whether to offer other family members the test when one member has already tested negative, given a positive family history of breast and ovarian cancer. No significant financial relationships to disclose.
Progesterone receptor gene polymorphism (PROGINS) in 701 women from a mammographic breast cancer screening program (NMPOA) in Southern Brazil
Authors: Giacomazzi J. , Aguiar E. , Palmero E. I. , Kalakun L. , Schuler-Faccini L. , Duarte Filho D. , Bedin A. , Caleffi M. , Giugliani R. , Ashton-Prolla P. 
Published: March 2020

21048 Background: Several genetic polymorphisms in hormone receptor genes have been associated with breast cancer (BC) risk. Among these, a 306 base-pair insertion of the Alu subfamily in intron 7 of the progesterone receptor (PR) gene, (PROGINS), has been associated with decreased BC risk in several populations. In Brazil, BC is a significant public health problem, due to its high incidence and mortality rates. In Porto Alegre, Brazil`s southernmost capital, a multidisciplinary Breast Cancer Prevention Project - the Nucleo Mama Porto Alegre Cohort (NMPOA) was started in 2004 and includes a mammographic screening program for women ages 40–69 years. Goal: Determine the allelic and genotypic frequencies of PROGINS in women undergoing annual BC screening and correlate its presence with mammography results and presence of additional BC risk factors (family history of BC, body mass index, estimated BC risk by the Gail model and age) at baseline and after 10 years. Methods: A sample of 701 women from the NMPOA BC screening program was consecutively enrolled in the study from November/2005 until March/2006. Clinical data, mammography results (as BIRADS categories) and BC risk information was obtained by chart review. PROGINS genotyping was performed by polymerase chain reaction (PCR). Results: Of the 701 patients studied, 504 (71,0%) were wild-type homozygous, 184 (26,2%) heterozygous and 13 (1,8%) homozygous for the PROGINS polymorphism. These genotypic frequencies are similar to those of other reports in different populations. Genotype was correlated with 5-year and vital BC risk estimates (Gail model), body mass index, family history of BC and mammography findings. A statistically significant association was found between the presence of PROGINS and a positive family history of BC (p< 0,05). Conclusions: The genotypic and allelic frequencies of the PROGINS polymorphism were not significantly different from those reported previously for other populations. Prospective clinical evaluation of the women followed in this program and correlation of genotype with clinical findings may be important to elucidate additional risks associated with the PROGINS polymorphism. No significant financial relationships to disclose.
Epidermal growth factor receptor (EGFR) as a prognostic factor over 10 years in non-metastasic colon carcinoma (NMCC)
Authors: Pericay C. , Santos-Vivas C. , Pous-Saltor E. , Bonfill-Abella T. , Dotor-Navarro E. , Fernández-Morales L. , Dalmau- Pórtulas E. , Casalots-Casado A. , Rey-Ruhí M. , Saigí-Grau E. 
Published: March 2020

21062 Background: EGFR is a protooncogen that facilitates metastasis in cancer. It is overexpressed in colorectal carcinoma in 40% to 80%, and correlates a worse prognosis. Aim: To find patterns of EGFR overexpression in NMCC and to correlate these patterns with the follow-up. Methods: We analized NMCC with a selection criteria: 1. primary adenocarcinoma of the colon, without metastasis and with curative surgery, 2. pT3 pN0–2 pM0, progression-free in the first 6 months postsurgery, 3. initial follow-up began 6 months postsurgery, 4. minimum follow-up over 5 years. Dako PharmaDx kit (Glostrup, Denmark) was used for immunohistochemical study for EGFR. Dako staining and A431-AAM cells were used as positive control. Immunoreactivity for membrane (1(+), 2(+) and 3(+) intensity) and for cytoplasma was evaluated. Proportions of immunostained cells were also assessed. Results: 195 patients (p) were eligible. Year of diagnosis: 1994: 1p; 1995: 4p; 1996: 20p; 1997: 29p; 1998: 33p; 1999: 36p; 2000: 34p; 2001: 38p. Male/female: 93/102; Mean age: 71 years (28- 94). Location: 116/79 left/right. Stage II/III: 125/70. EGFR membrane positivity: 84/195 cases (43%), 49/125 (39%) in Stage II and 35/70 (50%) in Stage III. With a median follow-up of 7 years: Stage II: 29/125 relapsed (EGFR±: 12(24%)/17(22%)). Stage III: 33/70 relapsed (EGFR± : 21(60%)/12(34%)). EGFR membrane positivity was a poor prognostic factor with a significant progression-free survival (PFS) (p=0.042) and a non-significant overall survival (OS) (p=0.066). When follow-up period was increased over 10 years (patients from 1994 to 1998), EGFR membrane positivity maintained its poor prognostic factor in PFS (p=0.009) and presented a significant OS (p=0.02). Non-significant differences were found in immunostaining ratios. Conclusions: In patients with non-metastatic colon cancer, EGFR membrane positivity was a tumor progression prognostic factor, and this poor prognosis was maintained over time. Study supported by a grant from C.I.R. Hospital de Sabadell. Consorci Sanitari Parc Taulí. Sabadell and a grant from Merck Laboratory. No significant financial relationships to disclose.
Clinical validation of a self-organizing map (SOM)-based quantitative prediction algorithm to determine the site of origin of cancers of unknown primary (CUP)
Authors: Potts S. J. , Chen R. , Qu K. Z. , Crossley B. , Bender R. A. 
Published: March 2020

21064 Background: As many as 100,000 new cases of CUP are diagnosed each year in the United States. Identifying the site of origin of the CUP is critical for effective cancer management, and several genomic assays have been developed to facilitate this process. The genomic profile generated does not always fit into a discrete classification, however, and communicating results in a simple, easily understood format is important to clinical practice. Methods: We created a novel algorithm that combines SOMs for qualitative visualization with a quantitative clustering algorithm to predict the site of origin of metastatic cancers. We trained the algorithm on a dataset of 231 tumor-bank samples from 9 primary sites. After fixing all thresholds and algorithm settings, we evaluated the algorithm's performance in making a correct first or second prediction on a second blinded and independent dataset of 63 samples. Results: The algorithm correctly predicted the primary site in 82% of cases with the first prediction, and 89% with either the first or second prediction. The map visualization component helped to reduce the biological and mathematical complexity of the test into an easy to understand format for practicing physicians. The map- based approach allowed a fuzzy prediction that complements a class-based prediction and provides substantial additional information on the relationship between an unknown specimen and other related specimens of known provenance. Conclusion: CUP is a formidable clinical problem; correctly identifying the primary site and rendering specific treatment translates into improved patient outcomes. The use of an SOM to depict the genomic profile of the tumor specimen makes it easier for the clinician or pathologist to understand what tumor type the CUP most closely resembles and facilitates further diagnostic or therapeutic decisions. No significant financial relationships to disclose.
Expression of the glutathione-S-transferase π (GST-π) protein correlates with survival in patients with stage I non-small cell lung cancer (NSCLC)
Authors: Gajra A. , Vajpayee N. , Wade M. , Gamble G. P. , Rajan A. , Graziano S. L. 
Published: March 2020

21065 Background: It is important to identify prognostic markers in stage I NSCLC given the 30%-40% risk of recurrence and death despite resection. The role of platinum-based adjuvant chemotherapy remains unclear in stage I NSCLC. The glutathione pathway prevents cellular DNA damage by oxygen free radicals and cytotoxic compounds. GST-p catalyzes conjugation of glutathione to cytotoxic agents and high expression may predict for platinum resistance. The role of GST-p as a prognostic factor in early stage lung cancer is not well evaluated. Methods: In a retrospective cohort of 93 patients with resected stage I NSCLC we used immunohistochemistry (IHC) to study the association of GST-p expression with risk of tumor recurrence and death. None of the patients received adjuvant therapy. IHC was quantified by a visual grading intensity of cytoplasm staining (0= no immunoreactivity; 1=weak; 2= clear reactivity in >50% cancer cells and 3= strong immunoreactivity). Grades 2 and 3 were classified as high and grades 0 and 1 as low GST-p respectively. Results: The mean age of the patients was 67 years. Of the 93 patients, there were 45 (48%) men, 71 (76%) had adenocarcinoma and 66 (71%) had stage IA disease. The median follow-up time was 5.4 years. High GST-p expression was noted in 40 (43%) and 53 had low GST expression. The overall survival at 5 years was 67% with 31 deaths. Patients with high GST expression had a higher overall survival at 5 years- 32/40 (75%) vs. 30/53 (57%) in the low GST group (p=0.018). There was no significant difference in terms of tumor recurrence or recurrence free survival. After adjusting for age, gender, histology, and T stage, patients with low GST-p expression remained at an increased risk of death with a hazard ratio of 2.86 (1.16–7.61, p= 0.015). Conclusions: In this cohort, high expression of GST-p served as an independent prognostic factor in resected stage I NSCLC. These early findings with GST-p are similar to those from the IALT trial wherein the high expression of ERCC1 was associated with chemoresistance but conferred a survival advantage in the absence of chemotherapy (Olaussen, NEJM 2006). These findings merit evaluation in larger prospective series given the small, exploratory and retrospective design of the present study. No significant financial relationships to disclose.
A de novo deletional germline mutation in the MLH1 gene resulting in early onset colorectal cancer in a woman with a negative family history: A case report
Authors: Zakalik D. , Goldstein N. S. , Ducaine W. L. 
Published: March 2020

21067 Background: Hereditary non-polyposis colorectal cancer (HNPCC) is a genetic disorder that results in an increased risk of early onset colorectal cancer (CRC). HNPCC is caused by germline mutations in DNA mismatch repair (MMR) genes, including MLH1 and MSH2, and is transmitted in an autosomal dominant manner. De novo germline mutations in MMR genes are exceedingly rare. We now describe a case of a de novo germline mutation in MLH1 associated with early onset CRC in a young woman with a negative family history. Methods: We present a case of a 31-year-old Caucasian female who presented with abdominal pain. Colonoscopy revealed a moderately differentiated adenocarcinoma with focal mucin production involving the sigmoid colon, with a final staging of T4N0M0. Genetic testing was offered because of her young age at diagnosis, having fulfilled the Bethesda guidelines. Microsatellite instability (MSI) testing using a panel of six microsatellite loci was performed on the tumor sample from the affected patient. Immunohistochemistry (IHC) testing for MLH1 and MSH2 was performed. Following counseling and with informed consent, DNA was isolated and sequenced using bi-directional PCR of the MLH1 gene. All exons of MLH1 and MSH2 were analyzed by standard Southern blot methods. Paternity was established using eight genetic loci. Results: The patient's tumor revealed high MSI and complete absence of MLH1 immunoreactivity. MSH2 IHC staining was normal. A large deletional mutation involving exons 5–12 of MLH1 was identified by Southern blot analysis. The patient's parents and siblings were tested and found to have wild type MLH1. Paternity was confirmed with greater than 99.9% certainty. Conclusions: De novo mutations in MMR genes are a rare cause of HNPCC. We report the first case of a large de novo deletion in the MLH1 gene accounting for early onset CRC. Such de novo mutations, albeit rare, must be considered in patients who present with early onset CRC and a negative family history. These results support the use of the Bethesda guidelines to identify individuals who may carry mutations in the MMR genes. No significant financial relationships to disclose.
Predicting nonsentinel node status in breast cancer preoperatively by molecular characterization of core needle biopsies with multiparametric protein analyses
Authors: Sauer G. W. , Schneiderhahn-Marra N. , Kurzeder C. , Koretz K. , Kreienberg R. , Joos T. , Deissler H. 
Published: March 2020

21068 Background: Axillary lymph node dissection (ALND) still remains the standard treatment for breast cancer patients with sentinel lymph node (SLN) metastases. However, since only 40% to 60% of patients show additional lymph involvement, complete ALND offers no additional benefit for almost 50% of patients but carries a significant risk of axillary morbidity. In an attempt to achieve a more precise prediction for the individual patient a multivariable logistic-regression analysis of a large data set of eight histopathological variables has been published by the Memorial Sloan-Kettering Cancer Center (MSKCC) that predicts the likelihood of metastases in Non-SLNs with a ROC of 0,71. To achieve a more precise estimation of additional lymph node involvement preoperatively we analysed molecular markers of potential predictive value. Methods: Beside histopathological variables, fifty proteins of potential prognostic and predictive value were preoperatively quantified in lysates from 120 core needle biopsies with multiplex sandwich immunoassays. Biopsies, taken at the Breast Cancer Center of the University of Ulm Medical School, were classified as invasive mammary carcinomas. Variables which could be used to improve the accuracy of prediction of non-sentinel lymph node (NSLN) involvement were defined. Results: We demonstrated appropriate sensitivity, reproducibility, and robustness for this protein microarray technology to characterize proteins in core needle biopsies and generate reliable data sets. In an initial univariate data analysis (Mann Whitney test) six of the analysed parameters (TIMP2, p= 0,027; FasR, p = 0,0025; MIF, p= 0,030; FGF-2, p= 0,0020, PDGF AA/BB p= 0,027; RANTES p= 0,024) correlated with NSLN involvement beside known histopathological variables (i.e. tumor size, p= 0,006; grading, p = 0,0009). Conclusions: We defined molecular markers of diagnostic value to predict NSLN involvement. This might be an acceptable substitute to the known histopathological variables by the MSKCC nomogram to predict potential NSLN involvement preoperatively. No significant financial relationships to disclose.
The prognostic value of nodal ratios in node-positive breast cancer: AUBMC experience
Authors: Shamseddine A. , Hatoum H. , Salem Z. , Abdel Khalek Z. , El Saghir N. , Taher A. 
Published: March 2020

21072 Background: Axillary lymph node metastasis has proven to be the most important factor affecting overall survival (OS) and disease free survival (DFS) in patients with breast cancer. Recent evidence suggests that axillary lymph node ratio (LNR) may be at least as important as absolute number of involved lymph nodes in predicting OS and DFS. The aim of this retrospective study is to evaluate the impact of axillary nodal ratios in node-positive breast cancer as a prognostic factor for survival. Methods: Data from 1181 patients with stage I, II and III breast cancer diagnosed at AUBMC between 1990 and 2001 were studied. The median age at diagnosis was 50 years (23 - 88); the median number of lymph nodes dissected was 17 (0 - 49). Survival was compared in 737 patients with node-positive disease according to a LNR below or more than 0.25 (defined as number of involved lymph nodes divided by total dissected axillary lymph nodes). Results: Patients with LNR = 0.25 had a median follow-up of 30 months (1.2–156) and a median DFS of 26 months (1–156). The 5-year survival was 26.2% (94/358) and the 5-year DFS was 22.9% (82/358). Patients with LNR <0.25 had a median follow-up of 36 months (1.2–157) and a median DFS of 36 months (1–157). The 5-year survival of 33.2% (245/737) and the 5-year DFS was 29.8 % (220/737). LNR showed significance as a continuous variable and a categorical variable (0, < 0.25, and = 0.25) with a p < 0.001 Conclusions: LNR significantly predicts OS and DFS in node-positive primary breast cancer. No significant financial relationships to disclose.