bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic role of microvascular density (DMV), VEGF, EGFR, and HIF-1 α expression and their relationship with epitelial mesenquimal transition (EMT) in patients with locally advanced cervical cancer (LACC) treated with chemoradiotherapy.
Authors: Rojas Puentes Luis Leonardo , Cardona Zorrilla Andres Felipe , Cetina Lucely , Otero Jorge Miguel , Carranza Hernan , Vargas-Baez Carlos A. 
Published: March 2020

e22028 Background: In low and middle income countries cervical carcinoma is the second leading cause of death among women. Methods: To describe the prognostic value of MVD and protein expression of several genes related to survival and proliferation and their relationship with EMT of LACC. Overall response rates (ORR), clinical benefit (CB), progression-free survival (PFS), and overall survival (OS) were estimated for women suffering from LACC treated with chemoradiotherapy followed by high dose rate brachytherapy (HDRB). Results: Sixty-one patients were included (mean age 52±10); all of them had LACC (2.3% 2A/47.5% 2B/4.9% 3A/37.7% 3B/3.3% 4A/3.3% not defined), a tumour mean size of 6.4cm (SD±1.8cm) and HPV infection in 46% of the cases. Fifty-eight patients (95%) had a squamous pattern, two were adenocarcinomas and >50% presented moderated or poorly differentiated neoplasms. All of them were treated with chemotherapy (transitory interruption of external radiotherapy was documented in 19% due to toxicity and in 21.4% of cases by other causes/mean cycles of platinum administered during radiotherapy 4.8 ± 1.0) and brachytherapy (77% completed all planed intracavitary treatment). The median PFS and OS was 6.6 months (4.0-9.1) and 30 months (11-48) respectively. None of the variables had effect on PFS, whilst multivariate analysis revealed that VEGF (p=0.026) and EGFR expression levels (p=0.030) and <6 cm tumour volume (p=0.02) positively influenced the OS. TWIST expression and E-cadherine lost expression (E-) also influence OS (p=0.001) and (p=0.02) respectably and are related with VEGF and EGFR expression. When EGFR or VEGF are coexpressed with TWIST or related with E- expression the patients shows the worst OS (median 14 m CI 95% 3-24 m, p=0.02 for EGFR (+) and E- ; VEGF (+) and E - median 14 m CI 95% 3-25 m p=0.0001; EGFR (+) and TWIST (+) 19 m CI 95% 15-80 m, p=0.006; VEGF (+) and TWIST (+) 18 m CI 95% 15-80 m, p=0.0001. Conclusions: Classifying LACC patients treated with cisplatin-based chemoradiotherapy by protein expression and EMT markers had a positive influence on prognosis.
In vivo isolation of circulating tumor cells in prostate cancer patients by a medical device.
Authors: Theil Gerit , Hoda M.Raschid , Fischer Kersten , Schumann Andre , Haubold Kathrin , Boehm Catrin , Krahn Thomas , Luecke Klaus , Morgenthaler Nils G. , Fornara Paolo 
Published: March 2020

e22055 Background: CTCs are discussed as a prognostic and stratification biomarker, and may help to assess the treatment efficacy. The aim was to demonstrate proof of concept of in vivo CTC isolation in Prostate cancer patients (PCa). Methods: A medical device (CellCollector) was inserted in a cubital vein for 30 minutes. The interaction of target CTCs with the CellCollector was mediated by antibodies to the epithelial cell adhesion molecule (EpCAM). To confirm binding of CTCs to the wire, immunohistochemical staining against Cytokeratin and CD45 was performed. There were 226 applications of the device in 16 metastasized PCa (PCa-m) with up to 8 wire applications per patient, 24 localized PCa (PCa-l) with up to 3 wire applications per patient as well as 19 men with benign prostate hypertrophy (BPH) and 21 women as control group with only one wire application. CTC counts from 22 PCa patients with 58 applications were directly compared to the CellSearch technology. Results: We obtained in vivo isolation of CTCs in 73 of 98 applications to PCa patients (74.5 %). The sensitivity for metastasized PCa was (86.2%) and for local PCa (57.5%), respectively. Follow up data of one patient with PCa-m: 2009 diagnosed PCa with multiple metastases. 2 years later PSA of 11.2ng/mL and 25 CTCs. After transurethral resection and removal of a brain metastasis, CTCs decreased to 20 cells with no effect on PSA levels. 4 months later we observed 187 CTCs and a PSA level of 76ng/mL, which was correlated with the patient condition. In PCa-l patients we observed prior radical prostatectomy (n=18) and 6 (n=15) and 12 (n=7) months after surgery CTC numbers on average of 18.2, 2.8 and 1.4, respectively. In the direct comparison of the CellCollector and CellSearch we showed detection rates of 65% (13/20) and 20% (4/20). Conclusions: We demonstrate the use of CTCs besides PSA during therapy adjustment in PCa patients In summary the CTC detection rate of the CellCollector in PCa-m and PCa-l in comparison to the CellSearch method increased by 26% and 45%. Further molecular genetic CTC characterization as well as multiple antibody coating at the CellCollector will assume crucial information for therapy decisions. Clinical trial information: ISRCTN10403616.
The sensitivity and specifity of DR-70 as a tumor marker for gastrointestinal cancers.
Authors: Erkol Burcak , Oven Basak Bala , Bayoglu Vedat , Paker Nurcan , Kochan Koray , Ozkara Selvinaz , Tilki Metin , Surmelioglu Ali , Yesil Atakan , Gonen Can 
Published: March 2020

e22061 Background: There is a great need to detect gastrointestinal cancers at an early stage, reduce morbidity and mortality. CEA and CA 19-9 are widely used serological markers for gastrointestinal cancers during follow-up. Their utility are limited because of their low sensitivity. In this study, a novel tumor marker DR-70 is evaluated for the sensitivity and specificity, relationship between clinical parameters and compared with CEA and CA 19-9. Methods: Blood sera of 101 histologically proven gastrointestinal cancer patients (38 female, 63 male; 42 colon, 25 rectum, 18 stomach, 9 pancreas, 4 esophagus and 3 cholangiocellular carcinomas) and 105 healthy blood donors were included. The TNM stage of the disease and histologic grade was shown. All patients and controls were also tested for CEA and CA 19-9 levels. In DR-70 immunoassay, the fibrin degradation products were quantitatively measured using ELISA DR-70 kits. Results: The median DR-70, CEA and CA19-9 levels were 1.6 µg/mL, 3.05 ng/mL and 22.2 IU/L in cancer patients, they were lower in healthy control 0.5 µg/mL, 0.9 ng/mL, 1.9 IU/L; p < 0.001. While the stage and grade increased, the levels of DR-70, CEA and CA-19-9 (p < 0.05) were increased significantly. DR-70 and CA19-9 values were highest in patients with pancreas, and lowest in rectum cancer, there was no statistically significant difference between tumor localization and CEA levels.The sensitivity, specificity and the cut-off value of DR-70, in patients with malignancy by using ROC analysis were found as 97%, 95% and < 0.75 µg/mL, respectively. The positive and negative predictive values were 95%, and 97% and the efficacy was 96%. Sensitivities of CEA (cut off value 3ng/mL) and CA 19-9 (cut off value 37 U/ml) were 52% and 39% respectively, the specificities were 94% and 99% for CEA and CA 19-9, respectively; sensitivity increased by combined use of both of them. Conclusions: Due to its high sensitivity and specificity, high positive and negative predictive values DR-70 can be used more frequently as a tumor marker for detection of gastrointestinal cancer. It can also be used in tumor progression and treatment follow-up because of positive correlation between DR-70 levels and the tumor stage.
Prediction of therapy failure after VEGF-based first-line treatment of kidney cancer patients by DNA hypermethylation biomarkers.
Authors: Peters Inga , Dubrowskaja Natalia , Abbas Mahmoud , Seidel Christoph , Kogosov Michael , Scherer Ralph , Gebauer Kai , Merseburger Axel S. , Kuczyk Markus A. , Grünwald Viktor , Serth Juergen 
Published: March 2020

e22076 Background: Kidney Cancer (RCC) is one of the top ten causes of cancer dependent death. Anti-VEGF targeted therapy has demonstrated increased progression-free (PFS) and overall survival in RCC patients, though the clinical outcome is still poor overall. Stratification of patient treatment currently depends on different clinical scoring systems such as the Memorial Sloan Kettering Cancer Center score. However, identification of molecular phenotypes of RCC patients could improve stratification of targeted therapies and prediction of clinical course. We investigated whether DNA hypermethylation-based markers can predict the PFS following first-line therapy. Methods: We examined primary tumor tissues obtained from 18 patients receiving anti-VEGF targeted therapy. Quantitative methylation-specific PCRs were carried out for CpG island (CGI) methylation analysis of 5 candidate genes CST6, GATA5, LAD1, hsa-miR124-3 and hsa-miR9.1 identified in advance as potential prognosticators for RCC. For Kaplan Meier survival analysis relative methylation values were uniformly dichotomized and logrank statistics calculated. The analyses of sensitivity and specificity were carried out using a cutoff of 6 months for PFS to categorize for therapy failure and response. Results: Hypermethylation of CST6 and LAD1 shows a highly significant association with a shortened PFS following first-line therapy (p=0.009, p=0.004, logrank test). The median survival observed for the high and low methylation group was 2.0 and 11.4 months for CST6 and LAD1. Moreover, LAD1 methylation showed a specificity of 1.0 (0.65-1.0, 95%CI) and a sensitivity of 0.73 (0.43-0.90, 95%CI) for detection of therapy failure. For CST6a specificity of 0.86 (0.49-0.97, 95%CI) and a sensitivity of 0.82 (0.52-0.95, 95%CI) was detected. Conclusions: The analysis of our discovery cohort revealed that CGI methylation of CST6 and LAD1 predicts a shortened PFS of patients after anti-VEGF therapy. Provided, these results can be confirmed in an independent larger evaluation cohort, detection of hypermethylated loci in primary RCC would allow, to our knowledge for the first time, a molecular-based clinical management of patients.
Effect of exogenous triiodothyronine [T3] on free thyroxine depletion and tumor response: A compassionate care study.
Authors: Hercbergs Aleck 
Published: March 2020

e22077 Background: A thyroid hormone receptor on plasma membrane integrin av β3 initiates the actions of the hormone thyroxine [T4] on cancer cell proliferation and angiogenesis, initiated nongenomically, independently of the classical thyroid nuclear receptor. In studies of recurrent glioma, induced hypothyroidism significantly prolonged survival but associated fatigue has restricted acceptance of this approach. Triiodothyronine[T3] is the metabolically dominant hormone but in physiological extracellular concentrations is 10-100 fold less mitogenic than T4 in solid tumor models (R Meng et al., PLoS 2011; 6[11]:e27547). Exogenous T3 also maintains eumetabolism but inhibits TSH release to induce free T4 depletion [FT4D] defined as[< 0.93 ng/dL.] Maximal therapeutic free T4 depletion [FT4D] by T3 may therefore be feasible if combined with methimasole[MET]. Aims of study: Retrospective analysis of 1.) exogenous T4 withdrawal and 2.) daily exogenous T3 [ET3] and MET on tumor response and survival Methods: 21 Patients at geographically dispersed sites with recurrent or stage IV solid tumors: GBM 8 patients, brain stem glioma 1, pancreas 1, salivary gland 2, Lacrimal duct 1, breast 1, mesothelioma 1, ovarian 4, lung 2. 1.) In 7 patients exogenous T4 was terminated and replaced by exogenous T3 [ET3] 15 to 30μg daily in three divided doses. 2.) 15 euthyroid patients received 15-30μg ET3 and 20-40 mg. methimasole [MET] daily to induce [FT4D] usually obtained within 6-10 weeks. Results: There was no treatment related toxicity. 3/7 patients had PR to withdrawal of T4 only. 20/21 patients experienced PR[16] or CR[4]. to concurrent or sequential chemo,hormonal or radiation therapy for an overall response rate of 90% CHT elicited repeated responses in some patients. The 6 month PFS for the GBM cohort [n=8] was 70%. Two survived 36 and 53 months. For other solid tumor types survival was above /in the 90th percentile of reported survival studies. Conclusions: A high response rate was observed in advanced compassionate care cancer patients undergoing exogenous T3 modulated FTD. Tumor response to exogenous T4 withdrawal is a novel observation with potentially important therapeutic implications.
Development of a high-performance, blood-based screening diagnostic to detect early-stage breast cancer.
Authors: Wagner Joseph , Chapman Karen , Prendes-Garcia Maria , Lacher Markus , Kidd Jennifer , Sheibani Nadia , Tam Orlena , West Michael 
Published: March 2020

e22083 Background: Limitations of current screening mammography, particularly in younger women, demonstrate the need for an alternative breast cancer screening strategy. A non-invasive, easily interpreted and low cost test should address this need. Methods: Gene expression microarray analysis was carried out on 128 individual tumor samples representing over 20 tumor types, 86 samples representing 31 diverse normal tissue types, 68 tumor cell lines and 97 diverse normal primary cell cultures. Genes were ranked for elevated expression in either: i) a large number and variety of tumors relative to normal tissues, or ii) in breast tumors. Elevated expression was verified for a subset of genes using qPCR in a set of independent RNA samples. Proteins coded by genes elevated in breast cancer samples were analyzed in a retrospective training set of breast cancer patient sera samples with cancer-free patient and benign pathology controls using ELISA or bead-based detection assay. Results: Based on availability of suitable reagents, 25 candidate biomarkers were assessed in patient sera samples (31-227 patient samples per biomarker) using ELISA or bead-based assays. Individually, the performance of individual markers varied (ROC AUC, 0.51 - 0.88); however, when expression levels of the best performing markers were combined, the multiplex test demonstrated high-sensitivity (>80%) and specificity (>90%) in identifying early-stage breast cancer patients. Conclusions: A multiplex, proteomic-based approach may provide for a high-performance, blood-based screening diagnostic for breast cancer.
Effect of a small-molecule MDM2/MDMX inhibitor on cell cycle arrest and apoptosis in breast cancer cells.
Authors: Geng Qian Qian , Li En Xiao , Dong Dan Feng , Wu Yin Ying , Wang Jie , Li Yi 
Published: March 2020

e22096 Background: The MDM2 inhibitor which disrupted the MDM2-p53 interaction made little effort on the activation of p53 for breast cancer treatments, due to MDMX over expression. Previously a small molecule inhibitor targeting at MDM2 and MDMX had been successfully synthesized. We tested anti-tumor activity of the small molecule MDM2/MDMX inhibitor, compared with nutlin-3α, a well characterized MDM2 inhibitor, in the wild-type (wt) and mutant (mt) p53 breast cancer cell lines. Methods: Human breast cancer cell lines MCF-7 (wt-p53), ZR-7530 (wt-p53), BT-474 (mt-p53) and MDA-MB-231 (mt-p53) were cultured and treated with the small molecule MDM2/MDMX inhibitor, nutlin-3α or phosphate buffer solution (PBS) for 48 hrs separately. MTT for cell viability, FCM for cell cycle arrest and Annexin V FITC/PI for cell apoptosis were performed. The mechanism of antitumor activity of the small molecule MDM2/MDMX inhibitor was determined by Western-Blot analysis. Results: The inhibitor of MDM2 and MDMX inhibited cell growth and induced cell cycle arrest and apoptosis in mt-p53 breast cancer cells while nutlin-3α cannot. In the breast cancer cells with wt-p53, both of them inhibited cell growth, induced cell cycle arrest and apoptosis, but MDM2/MDMX inhibitor was proven to be more effective. Western Blot revealed that there was higher level of p53 expression in breast cancer cells treated with MDM2/MDMX inhibitor than nutlin-3α. The marked increases in p21, Bax and PUMA expressions were abserved in both wt-p53 and mt-p53 breast cancer cells which indicated that the small molecule MDM2/MDMX inhibitor induced cell apoptosis through p21, Bax and PUMA over expressions. Conclusions: The small molecule MDM2/MDMX inhibitor would be able to suppress cell proliferation, induce cell cycle arrest and apoptosis, activate p53 more effective than nutlin-3α in breast cancer cells, no matter with p53 status. P21, Bax and PUMA were involved in the mechanism of apoptosis induction. The inhibitor of targeting at both MDM2 and MDMX will be a novel treatment for breast cancer p53-independent status in the future.
Using low sensitivity of direct sequencing to detect K-ras mutations? A new method for improving diagnostic accuracy.
Authors: Chen Chi-Kuan 
Published: March 2020

e22100 Background: Identifying K-ras mutation has became a standard procedure in cancer treatment. Colorectal cancer patients with K-ras mutation are likely to poorly respond to cetuximab. Therefore, detecting K-ras gene mutations should be suggested before the selection of personalized treatment in colorectal cancer. To date, general molecular biology techniques contain HRM, PCR-RFLP, TaqMan PCR and CE-IVD-validated Cobas 4800 KRAS (Roche Diagnostics) are used for K-ras mutation detection in molecular diagnosis, but the sensitivity limitation of these method is approximately 1%. Methods: Therefore, we used a new approach, a universal genetic detecting method (FemtoPath), which improves sensitivity of K-ras mutation detection and the limitation of sensitivity is closed to 0.1% of mutation type. Results: We compared the sensitivity between FemtoPath/direct sequencing test and Cobas KRAS real-time PCR. Cobas real-time PCR identifies mutations in 21 (40.38%) of the 52 tumors. Surprisingly, the FemtoPath/direct sequencing test identified mutations in 40 (76.92%) of the 52 tumors. Our data showed that the FemtoPath/direct sequencing test can identify 19 additional mutation samples. In addition, the FemtoPath/direct sequencing test can identify more unknown K-ras mutations adjacent to codon 12 and 13. Conclusions: Ensure the most timely and appropriate therapy for cancer patients is the first priority of clinical application. FemtoPath/direct sequencing test is more sensitive, accurate and inexpensive and needs fewer sample amount than Cobas real-time PCR.
Evaluation of proliferation and apoptosis markers in circulating tumor cells (CTCs) of women with early breast cancer who are candidates for tumor dormancy.
Authors: Spiliotaki Maria , Markomanolaki Haris , Kallergi Galatea , Papadaki Maria A. , Georgoulias Vassilis , Mavroudis Dimitrios , Agelaki Sofia 
Published: March 2020

e22101 Background: Clinical dormancy is frequently observed in breast cancer (BC). In the present study, we aimed to characterize CTCs in dormancy candidates (DC) with BC in terms of proliferation and apoptosis. Methods: Cytospins of peripheral blood mononuclear cells (PBMCs) were obtained from DC (n=122) disease-free for ≥5 yrs and from metastatic pts (n=37) on relapse that occurred ≥5 yrs after surgery. Sequential samples (n=27) of 8 DC with late relapse and from 8 relapse-free (n=38), were also analyzed. 106 PBMCs were stained with pancytokeratin antibody along with ki-67 and M30 as proliferation and apoptosis markers, respectively. Results: CTCs were identified in 40 (32%) of 122 DC. In 25 (61.5%), all CTCs were ki-67(-)/M30(-), 7 (17.5%) had ki-67(+), 4 (10%) M30(+) CTCs and 4 had both phenotypes. Among 243 CTCs detected, 201 (82.5%) were ki-67(-)/M30(-), 14 (5.7%) ki-67(+) and 29 (11.9%) M30(+). Of 13 (35%) CTC(+) metastatic pts, 6 (46%) had ki-67(+) CTCs (p=0.037) whereas 54 (40%) of total CTCs were ki-67(+) (p<0.001). No M30(+) CTCs were detected. When sequential samples of the 8 DC who relapsed were analyzed, 2 (25%), had only ki-67(-)/M30(-) CTCs, 6 (75%) had ki-67(+) and 4 (50%) M30(+) CTCs. The respective numbers in the non-relapsed group were 4 (50%), 3 (37.5%) and 3 (37.5%). Moreover, ki-67(+) CTCs were more frequently observed in samples of the relapsed pts (29.6% vs 13.1%). Among 382 CTCs detected in all sequential samples from the relapsed group, 337 (88.14%) were ki-67(-)/M30(-), 26 (6.7%) ki-67(+) and 20 (5.1%) M30(+), whereas the respective percentages among 78 CTCs in non-relapsed pts were 77.6%, 6.5% and 15.8% (p=0.001). Conclusions: The great majority of CTCs detected in DC with BC express neither proliferation, nor apoptosis markers. However, the apoptotic index in CTCs is increased during clinical dormancy, whereas the proliferation index is increased on relapse. In addition, apoptotic CTCs are more frequently encountered during follow-up in DC free of relapse. The above observations suggest that monitoring proliferation and apoptosis in CTCs during clinical dormancy could be used to predict subsequent late relapse.
Impact of a multigene prognostic assay on postoperative management of early-stage non-small cell lung cancer.
Authors: Dormady Shane , Jahan Thierry , Mann Michael J. , Jablons David , Broder Michael S. , DeCristofaro Alison H. , Anene Ayanna 
Published: March 2020

e22124 Background: Many stage II and most stage I non-small cell lung cancer (NSCLC) patients forgo adjuvant chemotherapy, despite the likely presence of occult metastasis in the 30-60% of these patients who die within 5 years of surgery, and despite demonstration that patients with undetected, i.e. very early, metastasis can achieve long-term survival with this intervention. A multi-gene assay using quantitative RT-PCR and run on formalin-fixed, paraffin-embedded samples (Pervenio Lung RS) has been independently validated in two large international studies to better differentiate high- and low-risk non-squamous NSCLC patients than either traditional risk assessment criteria or conventional staging. A survey of physicians who used this multi-gene assay probed whether better risk discrimination changed post-operative management. Methods: Physicians were queried via a web-based survey on practice patterns, patient characteristics and treatment recommendations. The survey was developed through cognitive interviews with oncologists and thoracic surgeons. Physicians were allowed to respond regarding up to 4 patients (stage I or II) for whom the multi-gene test was ordered. Results: Forty-one physicians (12 surgeons, 29 oncologists/internists) of 61 contacted (67%) provided responses on 77 patients. Community practices accounted for 83%, and the average years in practice was 15. Seventy-one percent provided responses on either 1 or 2 patients. Mean patient age was 66±10 years, with stage I and stage II comprising 73% and 27%, respectively. Prior to obtaining assay results, chemotherapy was recommended in 30% of patients, including 5 stage I patients. The assay characterized 5-year mortality risk as high, intermediate and low in 52%, 23% and 25% of patients, respectively. Treatment recommendations were changed post-assay in 36% of patients, including 73% of high-risk patients for whom observation was recommended initially. Change in treatment intensity correlated with the degree of assay-assessed risk. Conclusions: Refinement of risk assessment achieved via a multi-gene prognostic assay resulted in changes in treatment recommendations for a substantial number of early stage NSCLC patients.