bluuebunny/crossref_metadata_2025_split huggingface dataset:
Late relapse associated with CEP 17 polysomic breast cancer
Authors: Theobald L. J. , Dobin S. , Beeran S. , Miltenburg D. , Rajab H. , Song J. , Boyle T. 
Published: March 2020

20011 Background: The clinicopathologic features associated with chromosome enumeration probe 17 (CEP 17) polysomy by fluorescence in situ hybridization (FISH) are not well defined. CEP 17 polysomy is frequently encountered in assessing Her-2neu amplification, which has become an important adjuvant therapeutic target. One mechanism to increase Her-2neu gene copy is polysomy. In this analysis the prognostic and predictive factors associated with CEP 17 polysomy are compared to similar factors in Her-2neu gene amplification. Methods: All cases of Her-2neu gene amplification and CEP 17 polysomic breast cancers from 2000 to present were abstracted. The polysomy group was defined as at least 3 gene copies and was further subdivided into two groups; 3–4 copies and ≥ 5 copies. This resulted in 193 cases of invasive breast cancer, which became the study cohort. Polysomic status and her-2neu gene amplification was compared to age, estrogen receptor (ER), progesterone receptor (PR), grade, tumor size, cell type, mitotic rate, nodal status, number of positive nodes and relapse. Descriptive statistics were used for categorical variables. The χ2 test was used to compare each clinicopathologic factor. Results: Both the ER and PR status was significantly different in the 3 groups. For the Her-2neu amplified, the polysomic 3–4, and the polysomic ≥ 5, the ER positive status was 53%, 67% and 81%, respectively (p = .012). Histologic grade, tumor size and nodal status were not significantly different between groups. Lobular pathology was present in 15% of the polysomy ≥ 5 group, 8% of the polysomy 3–4 group and 1.7% of the amplified group and this difference was significant (p = .03). Relapse disease status was significantly more frequent in the polysomy ≥ 5 group (18.5%) compared to the amplified group (2.6%) (p = .007). Within the relapsed group the median time to relapse was 4 years for the amplified patients versus 12 years and 10 years for the polysomic patients. Conclusion: The incidence of CEP 17 polysomy varies in the literature from 10–50% depending on definitions. Our study is unique in that we divided the polysomic group into 3–4 copies which can be complicated by proliferative activity versus ≥ 5 copies. A significant association between relapse and polysomic breast cancer is described in our dataset. No significant financial relationships to disclose.
Transient transcriptional response to low-dose ionizing radiation in humans undergoing IMRT
Authors: Goldberg Z. , Berglund S. R. , Dai J. , Santana A. , Rocke D. M. 
Published: March 2020

20018 Background: As intensity modulated radiation therapy techniques are increasingly utilized to treat cancer, the area of normal tissue exposed to ionizing radiation is increasing. The biologic risks associated with this normal tissue low dose exposure (LDIR) are fundamentally unknown and of concern to cancer survivors following therapy. Current modeling for health regulations presupposes a linear, no-threshold model of radiation effects, which estimates the effect and risk at low dose by extrapolation from measured effects at high doses. Cell culture models of ionizing radiation (RT) exposure show variable effects, not consistent with a linear dose-response relationship. We therefore undertook the first study to our knowledge of transcriptional effects of LDIR over time in vivo in solid tissue in humans. Methods: Tissue was collected at pre-RT, 3, 8, and 24 hours post-IR at sites receiving 10cGy. Transcriptional response at 3 and 8 hours were compared to the 0 and 24 hour time points. If transcripts are up regulated or down regulated at 3 and 8 hours compared with 0 and 24 hours, we have detected a transient response. The method of Rocke (2005), which was designed to detect differentially expressed gene groups using the responses of multiple probe sets corresponding to gene groups, was used to allow us to test whether there is differential expression for each patient separately, as well as for all the patients together. Results: Significant (p < 0.05) transient up regulation was shown in zinc finger proteins, keratins, BMP receptors, BAG, cyclins and BCL 6. Down regulation was detected in TNF, protein disulfide isomerase, interleukins, heat shock proteins, and S100. Nine gene groups did not show significant change; however, the number of significant gene groups (11) far exceeds the number expected by chance (2). In most cases in which a gene group was shown to be transiently altered, the tests of individual patients showed that most or all of the individuals also had differential expression of the same type. Conclusions: We have shown that it is possible to detect transient responses to LDIR in vivo in humans, and have identified eleven gene groups that demonstrate transient changes, as measured by a statistically principled analysis method. No significant financial relationships to disclose.
Relationship between survival and PET measurements of tumour blood flow, in patients with metastatic colorectal cancer
Authors: Charnley N. G. , Azeem S. , Gupta N. , West C. , Swindell R. , Bruce J. , Price P. 
Published: March 2020

20021 Background: There are conflicting reports on the relationship between tumour blood flow and patient survival. Poor flow is associated with tumour hypoxia and has been associated with a poor outcome (Lehtio et al 2004;Int J Radiat Oncol Biol Phys:59, 971–982). However, good flow is associated with angiogenesis which drives tumorigenesis, and has also been linked with a poor prognosis (Hermans 200 Int J Radiat Oncol Biol Phys:57, 1351–6). In this study, we examined the relationship between PET measurements of blood flow in liver metastases, and survival, in patients with colorectal cancer. Methods: Thirty seven patients with metastatic colorectal cancer, with a range of previous treatments, were studied. Regional perfusion was measured in liver metastases using H2[15O] or C[15O]2 PET. Blood flow was correlated with overall survival from the time of PET scan. Relationship between outcome and flow was analysed separately for patients with 1 or >1 metastatic sites; a recent meta-analysis of patient with metastatic colorectal cancer showed number of metastatic sites to be an independent prognostic factor (Kohne et al 2002; Ann Oncol. 13, 308–317). Results: There was no significant relationship between survival and metastasis blood flow when the data were taken as a whole. However, when the data were corrected for number of metastatic sites, there was a trend for high flow to be associated with shorter survival (p = 0.063). Specifically, for patients with multiple metastatic sites, median survival times for patients with high flow (n = 9) was 171 days [95% CI 25–317] compared with 441 days [95% CI 12–870] for patients with low flow (n = 7) (p = 0.026). Conclusions: In patients with multiple sites of metastasis, high tumour blood flow is a poor prognostic factor. This may be due to angiogenesis, which promotes tumorigenesis. No significant financial relationships to disclose.
Hereditary breast/ovarian cancer families: The impact of mutation prediction models on BRCA1/2 mutation screening costs
Authors: Capalbo C. , Ricevuto E. , Marchetti P. , Adamo B. , Adamo V. , Vestri A. , Frati L. , Screpanti I. , Gulino A. , Giannini G. 
Published: March 2020

20027 Background: The considerably high costs of BRCA1/2 mutation screening together with the expanding request for inherited breast/ovarian cancer genetic counselling and testing, dictates the need for more accurate selection of the appropriate candidates for analysis. The aim of the present study was to evaluate, the impact that careful selection of appropriate candidates by means of BRCAPRO, Myriad tables and IC software prediction models might exert on reduction of societal costs. Methods: 86 unrelated high risk breast/ovarian cancer families were selected for mutation screening; BRCA1/2 entire coding sequences and each intron/exon boundary were screened by direct sequencing (PTT limited to BRCA1 exon 11). The a priori probability of carrying a pathologic BRCA1/2 germline mutation was calculated by either BRCAPRO or IC software (country-customized versions of BRCAPRO), or by the Myriad prevalence mutation tables (2004). We classified our index cases as “carrier-positive” when their carrier probability exceeds 10%. According to recent literature, our analysis assumed a cost of $1,713 for genes sequencing of each proband. Results: We observed 19 pathogenic germline mutations with an overall detection rate of 22.1%. IC software and Myriad tables were more efficient in predicting mutated cases, showing higher sensitivity (95% and 84%, respectively) and a better negative predictive value (NPV, 96% and 91%, respectively) compared to BRCAPRO (sensitivity 74% and NPV 87%). Particularly, the IC software misclassified a pathogenic mutation carrier in only one case. The costs afforded for genetic testing on the whole sample was $147,318. The family selection assisted by the IC software, BRCAPRO, Myriad tables could result in a total cost of $104,493, $78,798 and $90,789, respectively. Even maintaining high accuracy in carrier status prediction, the country-customized version of BRCAPRO imparted more than 30% cost reduction. Conclusions: Considering a balance between economical advantages and the different performances in mutated status prediction, our analysis suggest that the country-customized versions of BRCAPRO and Myriad Tables allow efficient selection of candidates for BRCA1/2 mutation analysis and a significant impact on societal costs. No significant financial relationships to disclose.
Quantitative real time-PCR of CD133 mRNA: A potential surrogate angiogenic marker of response for patients with metastatic sarcoma
Authors: Lin E. H. , Li Y. , Trent J. , Patel S. M. , Burgess M. A. , Steinert D. M. , Benjamin R. S. , Li D. , Chen L. L. 
Published: March 2020

20034 Background: CD133 antigen is a specific surface marker for circulating endothelial progenitor cells (CEPs), pivotal in post-natal angiogenesis. We hypothesize that changes in levels of the CD133 mRNA expression and vascular endothelial growth factor (VEGF) may correlate with tumor response. Methods: After informed consent, we obtained 48 peripheral blood samples from patients with metastatic sarcoma including gastrointestinal stroma tumors (GIST). There were 16-paired samples before and after treatment including chemotherapy, or surgery, or imatinib. Of 24 patients with metastatic GIST enrolled, seven were paired samples. We measured CD133 mRNA levels by method (Lin E et al AACR 2003# 5392) and VEGF levels by ELISA (Genzyme, MA). The measurements were done in duplicates in two experiments. Results: The mean CD133 levels and VEGF levels before and after treatment was in Table 1 . The treatment resulted in significant reduction of CD133 mRNA expression (p = 0.035) as well as the level of VEGF (p = 0.014). Three patients experienced increase in CD133 expression had progressive disease. Among the paired GIST patients, there was a trend of increased CD133 mRNA expression levels in patients with progressive disease, death, or tumor recurrence. CD133 mRNA levels appeared elevated among the imatinib naïve patients and imatinib appeared to reset CD133 mRNA levels among the responding GIST patients to that of healthy volunteers. Conclusion: CD133 mRNA expression levels in sarcoma patients measured by real time-PCR assay appeared to correlate with tumor response. Unpublished independent work with NASBA assay platform in other solid tumors supported our findings ( www.primagen.com ). Further work is needed to reduce assay variability, and to determine the sensitivity and specificity of assay comparing to flow cytometry and to test assay’s applicability in the antiangiogenic therapy of cancer and the angiogenic therapy of cardiovascular diseases. [Table: see text] No significant financial relationships to disclose.
Spectrum of EGFR mutations associated with non-small cell lung cancer in an Asian Chinese population
Authors: Wong C. , Chan W. , Lam H. , Chan W. , Wang L. , Ma E. 
Published: March 2020

20055 Background: Somatic mutations in tyrosine kinase (TK) domain of the EGFR gene, predicting for sensitivity to TK inhibition therapy, are over-represented in lung cancer with adenocarcinoma or bronchioloalveolar histology, non-smokers, female gender and East Asian ethnicity. Methods: We prospectively screened for EGFR mutations at exons 19–21 on micro-dissected specimen enriched for tumor cells by direct nucleotide sequencing in Hong Kong Chinese patients. Results: From May 2005 onwards, a total of 27 patients were analyzed. They comprised 11 males and 16 females with a median age of 67 years. Histological diagnoses were adenocarcinoma (n = 22), bronchioloalveolar carcinoma (n = 4) and squamous cell carcinoma (n = 1). Samples included primary tumor (n = 20) as well as metastatic lesions (n = 7). EGFR mutations were detected in 17 patients (63%), the most common being L858R at exon 21 (n = 7) followed by exon 19 deletions (del(746–750) = 3, del(747–751) = 1, del(747–753) = 3) and G719C at exon 18 (n = 1). Two patients showed novel EGFR mutations, namely 4-base pair insertion deletion at exon 19 leading to substitution of Glu746-Leu747 by Val746-Pro747 and three base pair deletion at exon 18 leading to replacement of Glu709-Thr710 by Asp. Furthermore, two patients showed double mutations, including novel S768I at exon 20 in combination with G719C, and novel K860I at exon 21 in combination with L858R. Finally, one patient showed homozygous del(747–753) as detected by sequencing in both primary lung tumor and brain secondary, which might represent loss of heterozygosity. Conclusions: Similar to other series, two hotspots i.e. exon 19 deletion and L858 account for the majority (82%) of detectable EGFR mutations in our patient population. For the rare and novel variants, it would be of interest to document the clinical responsiveness to TK inhibitors gefitinib and erlotinib, so that a more complete picture of cancer genotype phenotype correlation can be achieved. No significant financial relationships to disclose.
Use of epigenetic aberrant promoter methylation in serum DNA for detection of pneumoconiosis-associated lung cancer
Authors: Umemura S. , Fujiwara K. , Tabata M. , Kishimoto T. , Gemba K. , Kodani T. , Takigawa N. , Kiura K. , Ueoka H. , Tanimoto M. 
Published: March 2020

20059 Background: Pneumoconiosis is known to be associated with an independent increased risk of lung cancer. However, it is difficult to detect lung cancer radiographically in patient with pneumoconiosis because of pre-existing diffuse pulmonary shadows. The purpose of this study is to evaluate the usefulness of serum DNA methylation for detection of pneumoconiosis-associated lung cancer. Methods: We investigated to identify promoter methylation status of RAR-beta, p16INK4a, MGMT, DAPK, and RASSFIA gene in serum DNA using methylation-specific PCR. Sera were obtained from 31 control patients with non-malignant-non-pneumoconiotic pulmonary disease (Group I), 36 with pneumoconiosis (Group II), and 5 with pneumoconiosis-associated lung cancer (Group III). DNA was extracted using QIAamp DNA Blood Midi Kit (Qiagen, CA). Following DNA bisulfite modification using CpGenome DNA Modification Kit (Intergen, NY), PCR was performed with primers for methylated or unmethylated promoter sequences. Results: Median (range) age of patients were 61 (26–78), 71 (49–86), and 69 (56–78) for Group I, II, and III respectively. Median (range) duration of silica and asbestos exposure were 33 (3–47) years and 33(32–40) years for Group II and III respectively. All of 5 pneumoconiosis-associated lung cancer were adenocarcinoma. Eleven patients (35.5%) in Group I, 19 patients (52.8%) in Group II, and 5 patients (100%) in Group III were shown to have methylation of at least one gene. The total number of methylated genes per patient were, 0.35, 0.69, and 1.20 for groups I, II, and III respectively (p = 0.013, Kruskal-Wallis analysis). In Group II, methylation status did not correlate with duration of occupational exposure, smoking history, radiographic findings, and age. Conclusions: In patients with pneumoconiosis, monitoring of aberrant promoter methylation of serum DNA might be useful for assessing the risk of lung cancer and early detection of lung cancer. No significant financial relationships to disclose.
Low-level amplifications of the human telomerase gene (TERC) regularly is associated with vulvar intraepithelial neoplasia
Authors: Gebauer G. , Schleibaum J. , Aulmann S. , Schirmacher P. , Sohn C. , Sinn P. 
Published: March 2020

20060 Background: Invasive squamous carcinomas of the vulva frequently harbor gains on the long arm of chromosome 3, including the human telomerase gene locus (TERC). Vulvar cancer develops from precursor lesions known as vulvar intraepithelial neoplasia (VIN) which frequently occur simultaneously in multiple locations and have a considerable risk or recurrence during follow-up. We investigated TERC gene copy number in a series of vulvar intraepithelial neoplasias to determine the risk of progression in these lesions. Methods: A total of 20 cases of high grade vulvar intraepithelial neoplasias (VIN 3) were analyzed using a two-color fluorescence in situ hybridization (FISH) assay detecting the human telomerase gene locus (3q26) on paraffin embedded tissue sections. Two samples were excluded for technical reasons. Results: In 11 cases, gains of chromosomal material at 3q26 were detected with an average of 1.48 copies per chromosome. In another patient a high level amplification was found. The remaining two cases, four centromere and 3q26 hybridization signals were observed, consistent with a tetraploidy of chromosome 3. No changes in DNA copy number on chromosome 3q were detected only in four lesions. Conclusions: Our findings demonstrate high frequency of gains on chromosome 3q in the majority of high grade vulvar lesions. This suggests an involvement of the human telomerase gene locus in the pathogenesis of vulvar cancer. No significant financial relationships to disclose.
Effect of antioxidants on STAT3, cell survival gene products, apoptosis and chemoresistance in lung cancer cells
Authors: Pathak A. K. , Bhutani M. , Pathak R. , Mohan A. 
Published: March 2020

20067 Background: We had earlier demonstrated that antioxidants (beta carotene, vitamins C and E) enhance the apoptotic effect of paclitaxel and carboplatin in vitro and there was a suggestion that when used as an adjunct to the above chemotherapeutic agents in patients with NSCLC, they might enhance the efficacy of the latter. To elucidate the mechanism underlying the synergistic effect between antioxidants and chemotherapy, in the present study we evaluated the effect of antioxidants on STAT3 activation in NSCLC cells. Since this transcription factor has been shown to regulate multiple oncogenic pathways, including pathways regulating tumor cell survival, we further studied how STAT3 modulation relates to apoptosis and downstream apoptosis regulatory proteins. Methods: H520 cells were treated with antioxidants. STAT3 proteins were assessed by western blotting and their nuclear localization was evaluated by immunocytochemistry. Antiapoptotic proteins (survivin, Bcl-2, Bcl-xl and cyclin D1) were evaluated by Western blotting. To assess the interaction, cells were treated with chemotherapy (Paclitaxel and Carboplatin) with or without antioxidants and the effect was assessed by Live & Dead assay, MTT assay and flowcytometry. Results: Antioxidants inhibited STAT3 phosphorylation in a dose and time dependent manner before the initiation of cell death and depleted the nuclear pool of STAT3. This effect was specific since there was no effect on STAT5 phosphorylation and was reversible since STAT 3 reverted back to its constitutively activated state after the removal of antioxidants. Antioxidants suppressed the expression of antiapoptotic proteins Bcl -2, Bcl-xl, cyclin D1 and survivin. This resulted in the inhibition of proliferation of cells and induction of apoptosis as evident on caspase 3 activation and PARP cleavage. Antioxidants arrested the cells in G0/G1 phase of cell cycle making them more vulnerable to the cytotoxic effects of chemotherapy. This synergy was evident on live and dead assay. Conclusions: Our results demonstrate that antioxidants are potent inhibitors of STAT3 phosphorylation and can have a potential role as an adjunct to chemotherapy in lung cancer. No significant financial relationships to disclose.
Combined expression of bcl-2, bcl-6, HIF, HGF, c-kit, neu/cerb2 and VEGF-C and their clinical significance in laryngeal squamous cell carcinoma
Authors: Kara I. O. , Uguz A. , Sahin B. , Kilic-Bagir E. , Erkisi M. 
Published: March 2020

20079 Background: Proteins regulating the cell cycle and cell death are frequently abnormally expressed in cancer. Several of these, particularly Bcl-2, Bcl-6, neu/cerb2 have been widely suggested as possible prognostic markers in diverse human malignancies. Their role in predicting outcome in squamous cell carcinomas of the head and neck is unclear. In addition c-kit protein has been shown in tumorogenesis. Because HNSCC preferentially metastasizes to regional lymph nodes, we investigated the expression of bcl-2, bcl-6, HIF, HGF, c-kit, neu/cerb2 and VEGF-C and their clinical significance in laryngeal squamous cell carcinomas by semiquantitative immunohistochemistry. Methods: We studied 115 patients with stage I o III tumors, all were treated with surgery ± postoperative irradiation/chemotherapy by a single institute. We studied the patients retrospectively to test the association between expression of Bcl-2, bcl-6, HIF, HGF, c-kit, neu/cerb2 and VEGF-C, as assessed by immunohistochemistry in formalin-fixed paraffin-embedded tissue and evaluated by two pathologist. We scored the expression of the proteins from negativ to severe expression. In addition we evaluated the degree of tumor grade, necrosis and also inflamation, respectively. Results: Within 115 patients we found severe expression of bcl-2 in 2 (1%), bcl-6 in 16 (13%), HIF in 57 (49%), HGF in 38 (33%), c-kit in 4 (3%), neu/cerb2 in 17 (14%) and VEGF-C in 11 (9%) patients, respectively. We found significant correlation between bcl-2 and necrosis (p = 0.003), HGF and inflamation (p = 0.05), c-kit and necrosis (p = 0.04), c-kit and tumor grade (p = 0.03) respectively. We found that the significant relation between bcl-6 and HIF (p = 0.000), bcl-6 and HGF (p = 0.02), bcl-6 and c-kit (p = 0.005), bcl-6 and VEGF-C (p = 0.000), HGF and VEGF-C (p = 0.005) respectively. Also we found that the significant correlation between tumor grade and HGF (p = 0.05). Conclusion: These data indicate that assessing expression of bcl-2 or bcl-6, c-kit and HGF is unlikely to be prognostically useful for surgically treated laryngeal carcinoma. No significant financial relationships to disclose.