bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transcriptome (RNA next generation sequencing) for personalizing of cancer treatment: A correlation with previous clinical resistance.
Authors: Sureda Manuel , Rebollo Joseba , González-Manzano Ramón , Martínez Elena Ma , Rostagno Roman , Mata Juan José , Monedero Elena , Ortega Jose , Brugarolas Antonio 
Published: June 2021

e15046 Background: RNA Next Generation Sequencing (transcriptome) is a potential useful tool to predict chemoresistance to available anticancer drug therapy. A correlation between previous clinical resistance and drug resistance profiling according to RNA NGS results has been studied. Methods: Since March 2018, whole transcriptome RNA NGS has been performed using Ion-Torrent GeneStudio S5 System in fresh-frozen biopsies obtained from tru-cut or surgical excision procedures from patients with resistant metastatic cancer. We have selected patients with clinically unequivocal drug resistance to previous therapies (tumor progressing to ongoing therapies or less than six months of stopped therapy). Drugs evaluated includes anthracyclines, alkylating agents (temozolomide), platinum derivatives, taxanes, TOPO 1 inhibitors (irinotecan and topotecan), antimetabolites (fluoropyrimidines, gemcitabine, methotrexate and pemetrexed), and more recently, immune checkpoint inhibitors. Results: A total of 111 procedures have been performed. In 64 patients an unequivocal clinical resistance to previous therapies could not be demonstrated, so the analyses has been performed in 47 patients with a number of different tumor histologies: colorectal cancer (13 patients), ovary/peritoneum (8), pancreas (4), NSCLC (4), breast (3), prostate (3), sarcoma (3), head and neck (2), uterus (2), kidney, bladder, cholangiocarcinoma, stomach and cervix (1 patient each). One hundred and fifty two drugs have been used in these patients (Median 3, Range 1 to 8) previous to the RNA NGS procedure. Resistance profile has been found in 120 out of 152 (78.9% of coincidence), and a favourable profile has been found in 32 (21%) previously used drugs, that could be re-used again in these patients. RNA NGS procedure gives additional information about drugs not previously used that helps in the treatment selection for the patients. Conclusions: Transcriptome provide drug resistance information that correlates in 78.9% of drugs with the previous clinical information. However, in 21% of the previously used drugs transcriptome informs as potentially active and could be tried again in subsequent therapies. Transcriptome (RNA sequencing) provides useful clinical information for treatment decision in the vast majority of pretreated cancer patients.
A phase 1 study evaluating preliminary safety, pharmacokinetic and pharmacodynamic of pemigatinib in Chinese patients with advanced malignancy.
Authors: Ba Yi , Deng Ting , Shi Yehui , Zhang Le , Bai Guiying , Pan Yueyin , Shen Aizong , Han Xinghua , Yang Zhaoyi , Cao Lian , Luo Yang , Wang Yan , Zhou Hui 
Published: June 2021

e15051 Background: Dysregulation of fibroblast growth factor receptor (FGFR) is strongly associated with establishment and progression of cancer. Pemigatinib is a selective FGFR1–3 inhibitor that are active in a targeted manner against cancers with activated FGFR pathway. The study was aimed at evaluating the tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) of pemigatinib in Chinese patients (pts) with advanced malignancy. Moreover, potential efficacy of pemigatinib was explored in a broad spectrum of FGFR alteration in variety of cancer types. Methods: In this phase 1 study, Chinese patients with advanced, recurrent or metastatic malignancy that were histologically or cytologically confirmed and harboring FGF/ FGFR 1-3 variation were enrolled. Pemigatinib was self-administered orally at 13.5 mg QD on a 3-week cycle (2-weeks-on/1-week-off schedule). Adverse events and other safety factors were monitored throughout the study. Blood samples were obtained at prespecified time points for PK and PD analysis and efficacy was assessed every 9 weeks per RECIST v1.1 guideline. Results: As of Jan 31, 2021, 12 patients with 5 different cancer types (colorectal cancer (4 pts), gastric and gastroesophageal junction carcinoma (3 pts), cholangiocarcinoma (2 pts), esophageal carcinoma (2 pts) and breast cancer (1pts)) were enrolled. Documented FGF/ FGFR1-3 alterations were FGFR amplification (6), FGFR point mutation (5), FGFR2 fusion (2) and FGF alteration (4) with 2 subjects had more than one alteration types. All the subjects were failed to at least 1 line of prior standard therapy. All patients had at least 1 treatment related adverse events (TRAE) and the most common ones were hyperphosphatemia (100%), decreased appetite (50%) and diarrhea (33.3%). Two patients (16.7%) reported ≥ grade 3 TRAEs, which were hyponatremia (8.3%) and proteinuria (8.3%). There were no TEAEs leading to death or treatment discontinuation. Among 11 efficacy evaluable patients, 2 of them had partial responses (PR) as evaluated by investigators with 1 cholagiocarcinoma harboring FGFR2 point mutation (p.F276C) and the other esophageal carcinoma carrying FGFR1 mutation (p.A354V). 3 patients had a best overall response of stable disease (SD). The objective response rate (ORR) was 16.7% (95%CI: 2–48%) and disease control rate was 41.7% (95%CI: 15–72%). Conclusions: Pemigatinib had an acceptable and manageable toxicity and demonstrated a possible anti-cancer benefit in Chinese patients with advanced malignancy that accompanied with FGF/FGFR1-3 aberrance. A significant implication of the data is that it extended the population that potentially benefit from pemigatinib other than FGFR2 fusion/rearrangement. Clinical trial information: NCT04258527.
Sequential usage of imidazole followed by tamoxifen to enhance the anticancer effect of tamoxifen in estrogen receptor-positive breast cancer cell lines.
Authors: Inci Tarik , Kahraman Erkan , Goker Erdem 
Published: June 2021

e15057 Background: In women, breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death worldwide. Tamoxifen is the most commonly used drug for the endocrine treatment of breast cancer. It reduces the risk of recurrence and death from breast cancer when given to estrogen-receptor-positive breast cancer patients. It has recently been shown that imidazoles, an antifungal drug, possess anticancer potentials, and it can be a novel therapeutic in cancer treatment. However, the effects of combined treatment with imidazole and tamoxifen are unknown in estrogen receptor-positive breast cancer cell lines. Our study aimed to investigate the effects of imidazole and tamoxifen combination in estrogen receptor-positive breast cancer cell lines. Methods: MCF7 cell line, an estrogen receptor-positive breast cancer cell line, was used in this study. Following 24 hours 50 mM imidazole (molecular grade) treatment, 15µM tamoxifen was treated to MCF-7 cells by 72 hours. As control groups, following for 24-hour imidazole alone treated, only medium treated cells for 72 hours were used. MTT assay was performed for the determination of cell viability. Apoptosis was shown using acridine orange/ethidium bromide staining. The cellular morphological alterations were observed on bright-field microscopy using Giemsa staining. Cell migration status was determined using by in vitro scratch assay. Results: MTT assay results showed that tamoxifen alone treatment for 72 hours decreased cell viability by 18 percent (p < 0.001). On the other hand, cell viability is not affected by imidazole alone treatment for 24 hours compared with the control group (p > 0.05). However, it was calculated that 24 hours of imidazole followed by tamoxifen for 72 hours decreased cell viability up to 42 percent (p < 0.001). Tamoxifen alone group, compared with combined treatment with tamoxifen and imidazole, observed an increase of apoptotic cell numbers in combined treatment with tamoxifen and imidazole group, statistically significantly (p < 0.01). It was observed that cellular morphology was affected by combined treatment with tamoxifen and imidazole. Giemsa staining results showed that MCF 7 cells changed their cellular morphology, lost cell-cell contact, differentiated from parental morphology and cellular morphology, and appeared unhealthy. Parallel to these findings, a decrease in cell migration was observed in the combined-treated group compared to the tamoxifen alone group (p < 0.01). Conclusions: Our results showed that sequential usage of imidazole followed by tamoxifen has an enhanced anticancer effect of tamoxifen in estrogen receptor-positive breast cancer cell lines. These results allow us to establish a new hormonal treatment for patients with breast cancer.
Neoadjuvant PD-1 blockade combined with chemotherapy followed by concurrent immunoradiotherapy for locally advanced anal canal squamous carcinoma patients: Antitumor efficacy, safety and biomarker.
Authors: Xiao Weiwei , Yuan Yan , Wang SuiHai , Cai Peiqiang , Chen BaoQing , Zhang Rong , Zeng ZhiFan , Gao Yuanhong 
Published: June 2021

e15500 Background: Efficacy and safety of PD-1 inhibitors have been approved for the treatment of metastatic anal squamous cancer patients, but the efficacy of neoadjuvant treatment with PD-1 in anal squamous cancer patients has not yet been defined. We report results for the cohort of patients with locally advanced anal canal squamous carcinoma treated with neoadjuvant PD-1 inhibitor toripalimab and chemotherapy followed by concurrent immunoradiotherapy. Methods: Five locally advanced anal canal squamous carcinoma patients received 4 cycles of neoadjuvant PD-1 inhibitor toripalimab and Docetaxol and Cisplatin chemotherapy followed by concurrent immunoradiotherapy. Whole exome sequencing (WES) and mIHC were performed with the pretreatment tumor tissue for biomarker analysis. Results: Complete clinical response (cCR) was achieved in 4 patients after neoadjuvant treatment before radiotherapy while the other patient achieved near cCR. cCR was achieved in all the 5 patients 3 months after definitive immunoradiotherapy. Grade 3 toxicity was noted in 1 patient. Molecular testing revealed that PD-L1 expression (≥1%) in tumor and CD4/CD163 expression in tumor and paracancerous tissue were positively correlated with tumor shrinkage in the neoadjuvant treatment phase while TMB didn’t appear to significantly impact the response. Conclusions: PD-1 inhibitor combined with chemoradiotherapy has quite promising effect in locally advanced anal canal squamous carcinoma patients, with very mild toxicity. Pretreatment PD-L1 expression is positively correlated with tumor response to PD-1 inhibitor toripalimab and chemotherapy. It is worthy of further investigation in prospective clinical trial.
LDL receptor related protein 2 to promote colorectal cancer metastasis via enhancing GSK3β/β-catenin signaling.
Authors: Zheng Xiaobin , Liu Huashan , Zhong Xiaoli , Liu Xuanhui , Cai Zerong , Chen Yufeng , He Xiaosheng , Lan Ping , Wu Xiaojian 
Published: June 2021

e15507 Background: LDL receptor related protein 2 (LRP2), a multi-ligand endocytic receptor, has been implicated in the tumourigenesis of various human cancers. However, the biological roles and underlying regulatory mechanism of LRP2 in CRC remain unclear. Methods: Real-time PCR (RT-PCR), western blot, and immunohistochemistry were used to examine LRP2 expression. Gene silencing and overexpressing efficiencies of LRP2 were confirmed by RT-PCR and western blot. Then wound-healing, migration assay and invasion assay were used to investigate the function of LRP2 in CRC cells. The protein expression and cellular localization of LRP2 and β-catenin were characterized by immunofluorescence staining. The nude mice tail vein metastasis model was established to observe the effect of LRP2 on the lung metastasis of CRC cells in vivo. In addition, gene set enrichment analysis was carried out to explore the potential mechanism of LRP2 in CRC. Results: LRP2 expression was highly upregulated in CRC compared with matched adjacent normal tissue. LRP2 overexpression was positively correlated with shorter overall survival in CRC patients. The biological function observation indicated that LRP2 promoted CRC metastasis in vitro and in vivo. Further molecular mechanism investigation demonstrated that LRP2 protein interacted with glycogen synthase kinase-3β (GSK-3β) and led to decreased expression of GSK3β at ser9, followed by enhanced β-catenin signaling pathway in CRC cells. Conclusions: Our study demonstrated that LRP2 could enhance the metastatic abilities of CRC cells in vitro and in vivo by inhibiting the expression of GSK3β and enhancing the activity of β-catenin signaling pathway, providing that LRP2 might be a novel therapeutic target for metastasis in CRC.
Correlation between driver mutation and immune microenvironment in colorectal cancer patients.
Authors: Cai Xiaochen , Bai Yuezong , Zhao Xiaochen , Cui Longgang , Chen Hui 
Published: June 2021

e15513 Background: Immune checkpoint inhibitor (ICI) therapy has made great achievements, but ICI monotherapies show less effectiveness in colorectal cancer patients. Biomarker exploration have carried out from PD-L1 expression, neo-antigen, gene mutation, etc., but no satisfactory results have been obtained. Methods: Patients, Colorectal cancer patients. Methods, Multi-color immunohistochemistry (multi-IHC) was used to evaluate CD8+ T cells, macrophages and natural killer cell (NK cell) in tumors and tumor stroma. The Shapiro-Wilk method was used to test the normality of the data, and the t-test or Mann-Whitney U test was used according to the test results. A two-sided P < 0.05 was considered a significant difference. Results: The study included 72 colorectal cancer patients, including 26 female (36.7%) and 46 male (63.8%), with a median age of 59.5 (50-67.3). There were 6 patients (8.3%) with BRAF mutation, 43 patients (59.7%) with KRAS mutation, and 56 patients (77.8%) with TP53 mutation. The results of immunohistochemistry showed that, BRAF mutation Vs BRAF wild-type or KRAS mutation Vs KRAS wild-type, the number or proportion of CD8+ T cells, macrophages or NK cells in tumor and tumor stroma were not statistically different. For TP53 mutation Vs TP53 wild-type, the number and proportion of CD8+ T cells or macrophages in tumor and tumor stroma were not statistically different. There was no statistical difference in the number and proportion of NK cells in tumor. But, the median number of NK cells in tumor stroma was 345 Vs 129, p = 0.06, and the proportion of NK cells was 5.2% Vs 1.39%, p = 0.02. Conclusions: There is no significant change in the immune microenvironment of colorectal cancer patients with BRAF mutation and KRAS mutation. There are more NK cells in tumor stroma of colorectal cancer patients with TP3 mutation.
Global BRAF testing practices in metastatic colorectal cancer (mCRC).
Authors: Desai Jayesh , Kopetz Scott , Grothey Axel , Ciardiello Fortunato , Kim Tae Won , Maughan Tim , Van Cutsem Eric , Wasan Harpreet Singh , Yaeger Rona , Yoshino Takayuki , Gollerkeri Ashwin , Edwards Michelle L. , Rodriguez Lizaso Montessa , Tabernero Josep 
Published: June 2021

e15523 Background: The BRAF V600E mutation is a marker of poor prognosis in patients with mCRC. Targeted therapy, such as encorafenib + cetuximab, is approved in the US/Europe for the treatment of BRAF V600E-mutated mCRC and demonstrated improved survival vs historical standard of care (SOC). Determining BRAF mutation status in mCRC is recommended by NCCN and ESMO guidelines; although adherence to these guidelines may not be uniform. This report’s objective is to communicate global survey results of mCRC BRAF testing practices. Identifying regions where BRAF testing is not SOC may help identify where education efforts are needed to improve effective treatment decision making. Methods: Oncology treatment centers were identified from a registry and from public information. Centers were selected for research experience, historic data quality, and estimated numbers of mCRC patients. A BRAF testing practices survey using an online platform of verified centers was conducted from March to November 2020; 425 sites in 39 countries responded. Results: BRAF testing is performed as SOC most commonly in Northern and Western Europe (97%) and East Asia (95%). Conversely, BRAF testing as SOC is least common in Eastern Europe (47%) and South America (52%). Surveyed regions generally test patients when confirming advanced disease prior to first-line (1L) treatment (35% to 78%) or at initial histological diagnosis (9% to 41%). Most regions test tumor tissue; few test both tumor tissue and blood; and none conduct blood mutation testing only. Testing practices in the US by type of site (academic vs community) will be presented. Conclusions: BRAF testing has global variability, impacting treatment decisions. Increased awareness and routine testing may lead to informed decisions regarding targeted therapies, such as encorafenib + cetuximab (where approved), in patients with BRAF V600E-mutant mCRC.[Table: see text]
ZEB1 expression in different stages of colorectal cancer.
Authors: Nepomnyashchaya Evgeniya M. , Ulianova Elena P. , Novikova Inna A. , Sagakyants Aleksandr B. , Chernyak Maksim N. , Gappoeva M. A. , Ezhova Maria O. 
Published: June 2021

e15526 Background: Colorectal cancer (CRC) is among the most common cancers. The leading cause of high mortality is tumor progression developed due to the epithelial to mesenchymal transition (EMT). The ZEB1 protein is one of the critical regulators of this process. In this regard, our study aimed to assess the ZEB1 expression in different stages of colorectal cancer. Methods: This study included samples of 206 patients with stage II-IV CRC aged 42 to 86 years (mean age 64.2±1.7). All patients were divided into three groups: group 1 - patients with T3-4 N0 M0 (stage II) with high-risk factors for recurrence, n = 6; group 2 - patients with T1-4 N1-2 M0 (stage III), n = 88; group 3 - patients with T1-4 N0-2 M1 (stage IV), n = 58. IHC study was performed using polyclonal rabbit antibodies to ZEB1 (Biorbyt Ltd.) diluted 1:200 and a Reveal Polyvalent HRP-DAB Detection System. The staining percentage and intensity were assessed: 0, 1+ weak, 2+ moderate, 3+ strong. The nuclear reaction of the ZEB1 protein was considered positive when staining was detected in more than 10% (cut-off) of tumor cells with intensities of 2+ and 3+. Statistical analysis of the results was carried out using the STATISTICA 13.0 software (StatSoft Inc., USA). Results: A positive nuclear reaction for ZEB1 was detected in 80.6% (166 of 206 patients), while negative in 19.4% (40 of 206 patients). The maximal percentage of patients with positive staining for ZEB1 was among those with stage IV (94.8%), the minimal percentage - stage II (60%). The prevalence of ZEB1+ in patients with stages III and IV significantly increased the risk of tumor progression by 3.5 (95% CI 1.8-8.4) and 12.2 (95% CI 3.4-43.6) times, respectively, compared with stage II patients. No statistical significance was observed in the comparison between patients with stages III and IV (95% CI 0.9-11.7). The percentage of ZEB1+ samples increased in more advanced tumors. The ratio of ZEB1+/ZEB1- tumors in stage II was 1.5, in stage III - 5.8, in stage IV - 18.3 (p < 0.05). Conclusions: The immunohistochemical study revealed the features of ZEB1 expression in different stages of colorectal cancer, which can serve as prognostic factors that determine the disease progression.
Proteome and phospho-proteome profiling for deeper phenotype characterization of colorectal cancer heterogeneity.
Authors: Vowinckel Jakob , Corwin Thomas , Woodsmith Jonathan , Treiber Tobias , Bruderer Roland , Reiter Lukas , von Leitner Eike-Christin , Novy Karel , Juhl Hartmut , Rinner Oliver ,   Indivumed Authors
Published: June 2021

e15536 Background: The rise of precision oncology therapeutics requires deep understanding of the molecular mechanisms implicated in cancer biology. Colorectal cancer (CRC) is one of the first solid tumors to be molecularly characterized by defined genes and pathways. Advances in tumor profiling have revealed a profound molecular heterogeneity in CRC leading to the definition of several consensus molecular subtypes (CMS). However, this molecular heterogeneity is still largely defined on the genomic and transcriptomics level. To complement the understanding of genetically defined molecular subgroups, we performed large-scale deep proteomic and phospho-proteomic profiling of CRC patient biopsies and adjacent healthy control tissue, which has enabled to explore the phenotype and obtain more functional insights in cancer biology. Methods: Sample processing from 5-10 mg of tissue per sample was performed using a liquid handling robot. Phospho-peptide enrichment was carried out with a Kingfisher Flex device and MagReSyn Ti-IMAC magnetic beads. Data-Independent Acquisition (DIA) LC-MS/MS was performed on multiple platforms consisting of a Thermo Scientific Q Exactive HF-X mass spectrometer coupled to a Waters M-Class LC. Chromatography was operating at 5 µL/min, and separation was achieved using 45 min (whole proteome) and 60 min (phospho-proteome) gradients. Results: Indivumed has built IndivuType, the world’s first multi-omics database for individualized cancer therapy, analyzing the highest quality cancer biospecimens to generate the most comprehensive dataset, including genomics, transcriptomics, proteomics, and clinical outcome information. Enabled by the DIA technology, a mass spectrometric method developed by Biognosys that obtains peptide fragmentation data in a highly parallelized way with high sensitivity, more than 7,000 proteins in the whole proteome and 20,000 phospho-peptides in the phospho-proteome workflow were profiled across more than 900 resected tissue samples of various CMS of CRC. The resulting proteome and phospho-proteome data were integrated into the IndivuType database and cross-analyzed with genomic and transcriptomic markers. Through this combined analysis, novel insights in clinically relevant signaling pathways in CRC subtypes were revealed. Conclusions: The deep phenotypic profiling of cancer samples, using next generation proteomics and phospho-proteomics, has enabled us to go beyond the genomic level in the characterization of tumor molecular heterogeneity. This multi-omics approach provides a solid foundation to advance the understanding of cancer biology, unravel key molecular events, and support the identification of novel therapeutic targets for precision medicine in CRC.