bluuebunny/crossref_metadata_2025_split huggingface dataset:
Anlotinib, a multitarget tyrosine kinase inhibitor, for advanced lung cancer patients: Efficacy in real-world study.
Authors: Feng Jifeng , Qian Lei 
Published: May 2020

e15652 Background: Anlotinib is an novel small molecule multi-target tyrosine kinase inhibitor, which has been approved as a third-line therapy for patients with advanced NSCLC by CFDA in May 2018, and also approved as third-line therapy for patients with advanced SCLC in China in 2019. The objective of this study was to assess the efficacy of Anlotinib for patients with advanced lung cancer in the real world. Methods: We reviewed the patients who were diagnosed as advanced lung cancer and had received anlotinib in Jiangsu Caner Hospital from May 2018 to Sep 2019. The primary endpoint was progression-free survival (PFS) and the secondary endpoint was objective response rate (ORR), disease control rate (DCR) and safety. Results: A total of 465 patients were included in our study, containing 384 cases of NSCLC and 81 cases of SCLC. Among patients with NSCLC, 85 cases received anlotinib alone or anlotinib based therapy as first-line and second-line treatment, whereas 299 cases received anlotinib alone or anlotinib based therapy as third-line or later treatment. There were no significant differences in PFS, ORR and DCR between cohort of 1st /2nd line treatment and those with 3rd /later treatment. However, patients received combination therapy (including anlotinib combined with PD1 inhibitors such as Nivolumab, pembrolizumab, or chemotherapy such as platinum, docetaxel, pemetrexed, paclitaxel, tegafur, etc.) showed a significant longer PFS and higher ORR and DCR (P < 0.001, table). In patients with SCLC, 44 cases received anlotinib alone or anlotinib based therapy as first-line and second-line treatment. There were no significant differences in PFS, ORR and DCR between cohort of anlotinib monotherapy and other combination therapies (P > 0.05, table). No additional safety profile was observed. Conclusions: Anlotinib shows similar effect in patients with NSCLC and SCLC in real world. Anlotinib provides more significant benefits when combining with PD1 inhibitor or chemotherapy comparing with monotherapy in patients with advanced NSCLC. [Table: see text]
Correlation of MYC gene signature variations with clinical response to fimepinostat in patients with aggressive B-cell lymphoma.
Authors: Parker Jefferson , Grayson Dena , Von Roemeling Reinhard W. 
Published: May 2020

e15654 Background: Fimepinostat (F), a small molecule dual inhibitor of PI3K α, β, and δ isoforms and Class I and II histone deacetylases (HDACs), is currently under investigation for the treatment of aggressive hematological cancers. Preclinical studies demonstrated that F both decreases transcription of myc and MYC-targeted genes (via HDAC inhibition) and increases destruction of MYC protein (via PI3K inhibition). This study sought to identify differences in transcript-level signatures of gene networks in pre-treatment tumor samples associated with future clinical response to F. Methods: Among 105 patients (pts) with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) treated in phase 1/2 clinical trials of F (± rituximab), 33 pts had pre-treatment tumor biopsy samples available for molecular testing. All pts had measurable disease at baseline and had at least 1 post-baseline tumor assessment. To be included in the analysis set, pts must have been on study for ≥42 days. RNA libraries were created and sequenced on the Illumina HiSeq platform. Gene Set Enrichment Analysis (GSEA; Subramanian et al., 2005) was used to study changes in transcript expression patterns that correlate with responder (complete/partial response) or non-responder (progressive disease) pt populations. ~20,000 genes were rank-ordered by log2-fold change and tested against the MSigDB (Liberzon et al., 2011) collection of gene expression signatures. Results: > 1500 Gene Sets with False Discovery Rate (FDR) < = 0.05 and Normalized Enrichment Score (NES) > 1.3 for genes upregulated in the F-responder population were identified. These Gene Sets represent transcriptional activity associated with well characterized biological pathways or gene expression signatures determined empirically. The top 20 signatures by NES were associated with general transcription functions (E2F, RNA polymerase), chromosomal structure (meiotic recombination, telomere maintenance) and specifically, MYC transcription targets (NES: 2.7; FDR q-val: 0). Additional signatures consistent with PI3K (GSK3b) and HDAC activity in the responder population were also identified, as would be expected for a dual inhibitor of PI3Ks and HDACs. Conclusions: GSEA analysis of genes upregulated in the F-treated responder DLBCL pts are consistent with preclinical data showing that F functions to suppress MYC in tumor cells. F is currently undergoing active clinical study in combination with venetoclax for the treatment of R/R DLBCL or high grade B-cell lymphoma (HGBL): NCT01742988.
Pan-cancer analysis to identify a novel class of glucocorticoid and androgen receptor antagonists with potent anti-tumor activity.
Authors: Tatman Philip , Fringuello Anthony , Graner Michael , Lillehei Kevin , Parasido Erika , Albanese Christopher , Tewari Ashutosh K. , Chakravarty Dimple , Nair Sujit , Theise Neil 
Published: May 2020

e15663 Background: Large public cancer databases have allowed identification of novel mechanisms of oncogenesis and development of pharmacotherapies targeting these pathways. Examples are the androgen receptor (AR) and glucocorticoid receptor (GR). The Cancer Genome Atlas (TCGA) shows these receptors to have significantly increased expression over matched, normal tissue in several cancer types including: glioblastoma (AR and GR tumor-to-tissue ratios: AR = 6.53, GR = 1.42), low-grade gliomas (AR = 5.08, GR = 1.8), kidney clear cell carcinoma (AR = 1.89, GR = 1.82), kidney papillary cell carcinoma (AR = 3.64, GR = 1.2), and pancreatic adenocarcinoma (AR = 3.77, GR = 3.31). Methods: To investigate the therapeutic potential of targeting these receptors, we produced a series of analogues from a known GR inhibitor that all have the ability to target both the GR and the AR. Of these, PT150 is a clinical stage small molecule and PT157 is a preclinical stage small molecule. We began investigating the potential of these compounds to inhibit tumor growth using the NIH 60 cell lines panel with follow up in vitro testing and validation in clinically derived samples and established cell lines, including some cancers not include in the NIH 60 cell line panel or TCGA. Results: NIH 60 panel disclosed sensitivity towards gliomas, pancreatic cancer, and prostate cancer. For brain tumors, we investigated the effects of these inhibitors on glioblastoma, meningioma, and brain metastases. One analogue in particular, PT157, was able to significantly reduce cell viability after three days in culture in a dose dependent manor for each of the three tumor types and do so at a dose that is safely achievable in humans. Dose-dependent effects of PT150 and PT157 were observed in both androgen dependent and independent prostate cell lines, reducing viability of LNCaP, 22RV1 and DU145 cells. Similar data were also achieved in an in vitro pancreatic cancer model. Using patient-derived, primary pancreatic ductal adenocarcinoma (PDAC) cells, we found that both PT150 and PT157 were effective as monotherapies, inducing cell death in a dose dependent manner. In addition, both PT150 and PT157 significantly increased nab-paclitaxel sensitivity in nab-paclitaxel-resistant isogenic PDAC cells. Based on these in vitro data, we have begun pre-clinical experiments using in vivo mouse models. Conclusions: Our work has identified previously undescribed mechanisms of oncogenesis in several cancer types, as well as an efficacious class of novel compounds with the potential to inhibit them.
Whole exome and transcriptome sequencing of colorectal and pancreatic cancer.
Authors: Basu Gargi D. , Drenner Kevin , Ozols Audrey , Bair Candyce M , White Tracey , LoBello Janine R , Royce Thomas , Sharma Sunil 
Published: May 2020

e15666 Background: Integration of Whole Exome Sequencing (WES) into clinical cancer therapeutics has revolutionized medicine in recent years. DNA sequencing alone may miss clinically actionable variants or identify aberrations that are not being transcribed. In this study we investigated the utility of integrating DNA and RNA sequencing in clinical samples. Methods: A cohort of 32 patient samples were analyzed by WES and RNA sequencing. Differential expression analysis was performed using a cohort of controls. Pathway analysis was performed using Ingenuity Pathway Analysis. WES and RNA analysis detected alterations including SNVs, indels, copy number events, fusions, alternate transcripts, TMB, MSI status and differential expression. Results: A total of 25 CRC (39-78yrs) and 7 pancreatic cancers (PCs) (51-91 yrs) were profiled by WES and RNA seq. A 66 yr old pt with neoplasm of rectosigmoid junction tumor was found to be KRAS wildtype and was treated with cetuximab plus FOLFIRI. Patient failed therapy after 2 yrs and sequencing revealed MET amplification which is a known mechanism of resistance to cetuximab treatment. Further, RNA expression analysis showed 44-fold increase in MET expression along with overexpression of AREG and EREG. Out of the 7 PCs, 3 cases that did not harbor KRAS mutation were found to harbor VTCN1/NRG1 fusion, FGFR1/G3BP2 fusion and BRAF V600E mutation respectively. A 50 year-old stage IV metastatic (met) PC pt was treated with standard of care regimens. Upon relapse the sample was found to harbor VTCN1/NRG1 fusion along with a TERT promoter mutation. RNA expression analysis revealed 54-fold increased expression of NRG1 which may lead to clinical trial enrollment. A 52 year-old male met Stage IV PC, was treated with rucaparib and irinotecan based on prior sequencing data. Upon relapse, the pt went on ATR inhibitor (BAY1895344) and progressed very quickly. Sequencing of the met lesion was found to harbor FGFR1/G3BP2 fusion which was also confirmed by RNA expression. A 55 year-old met pt with PC was treated with standard chemotherapy. Upon disease progression pt was sequenced and based on presence of BRAF V600E, pt was treated with trametinib and dabrafenib. Following disease progression on BRAF/MEKi, met sample was resequenced and RNA expression analysis found increased expression of MET, MACC1 and SMAD7 and 4-fold decrease in PTEN which could potentially cause resistance to BRAF/MEKi therapy. Conclusions: Our study highlights the utility of comprehensive testing integrating genomic and transcriptomic data, in identifying targeted therapy options for cancer patients.
Trends in primary surgical resection and chemotherapy for metastatic colorectal cancer, 2000-2016.
Authors: Sanford Nina Niu , Folkert Michael Ryan , Aguilera Todd Anthony , Beg Muhammad Shaalan , Kazmi Syed Mohammad Ali , Sanjeevaiah Aravind , Farkas Linda 
Published: May 2020

e16000 Background: When, whether and in whom resection of the primary tumor for patients with metastatic colorectal cancer (CRC) is indicated remains incompletely elucidated, although a recent randomized trial (JCOG1007, presented at GI ASCO 2020) showed no survival benefit in resection of asymptomatic primary tumors in this population. Given the emergence of multiagent chemotherapy, surgery may be used less, but patterns of care for metastatic CRC have not been reported. As such, we sought to evaluate trends in use of primary surgical resection and chemotherapy among patients with metastatic CRC. Methods: Patients diagnosed with metastatic CRC between 2000-2016 were identified from the Surveillance, Epidemiology and End Results (SEER) registry. Multivariable logistic regression defined odds of undergoing primary surgical resection, with year of diagnosis as the primary independent variable. The cohort analysis was also stratified by primary site (colon versus rectum), age ( < 50 vs. >50 years) and whether patients also underwent resection of metastatic sites (yes versus no). The secondary endpoint of interest was receipt of any chemotherapy, also assessed by multivariable logistic regression. Results: Among 99,835 patients with metastatic CRC, 55,527 (55.7%) underwent resection of their primary tumor. The odds of undergoing primary surgery decreased with later year of diagnosis, with patients diagnosed in 2016 61.1% less likely to undergo surgery than those diagnosed in 2000 (AOR 0.39, 95% CI 0.36-0.42, p < 0.0001; absolute percent 62.3% to 43.8%). Black patients and women were also less likely to have surgery (p < 0.001). Similar trends by year for primary surgery were observed among each of the subgroups, although patients with colon primary, young adults (age < 50), and patients also undergoing metastatectomy were more likely to undergo primary surgery (p < 0.001 for all). In contrast, the odds of receiving chemotherapy increased dramatically with later year of diagnosis, with patients diagnosed in 2016 221% more likely to receive chemotherapy than those diagnosed in 2000 (AOR 2.21, 95% CI 2.04 to 2.40, p < 0.0001; 45.5% to 64.0%). Conclusions: From 2000-2016, we observed a sharp decline in the rate of primary surgical resection for patients with metastatic CRC, while use of chemotherapy increased over the same period. Prospective studies are needed to define the optimal local treatment for patients with metastatic CRC, perhaps with stratification by molecular and clinical characteristics, in order to optimize both cancer-specific and symptomatic outcomes.
Real-world evidence: Adjuvant chemotherapy in colorectal cancer with liver metastases.
Authors: Kuan Feng-Che , Lin Gengping , Chin Chih-Chien , Huang Wen Shih , Fan Chung-Wei , Chiang Jy Ming , Chen Hong-Hwa , Chen Jinn-Shiun 
Published: May 2020

e16008 Background: Systematic chemotherapy with biologics improves survival in metastatic colorectal cancer (mCRC). Oxaliplatin-based adjuvant chemotherapy is suggested in stage III and high-risk stage II CRC. However, whether adjuvant oxaliplatin-based chemotherapy remains standard treatment in CRC with liver metastases after hepatectomy is not elucidated. Methods: Medical records were searched in Chang-Gung Research Database from 2004 to 2017. Patients with CRC and liver metastases who received systematic therapies and salvage hepatectomy were included. The Kaplan-Meier method was used to estimate survival, and multivariate Cox proportional hazard models were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Results: Total 454 patients received upfront hepatectomy (cohort 1) and 232 patients received neoadjuvant chemotherapy +/- biologics and salvage hepatectomy (cohort 2) were included in this study. In cohort 1 or cohort 2, the baseline characteristics of those received either postoperative oxaliplatin-containing regimen or other systematic regimens were not statistically different in gender, age, primary site, and biologic drugs. In cohort 1, overall survival (OS) in those received postoperative oxaliplatin-containing chemotherapy was significantly better than that of those received non-oxaliplatin-containing chemotherapy (median OS: 6.6 vs. 4.5 years, Log-rank p = 0.032; 5-year survival rate: 57.5 vs. 47.0%). In cohort 2, OS in those received postoperative oxaliplatin-containing chemotherapy was similar with that of those received irinotecan or biologics-containing chemotherapy (median OS: 3.1 vs. 3.5 vs. 3.8 years, Log-rank p = 0.472; 5-year survival rate: 30.9 vs. 33.3 vs. 37.0%). Conclusions: Oxaliplatin-containing chemotherapy provides better OS and remains standard adjuvant treatment in CRC with liver metastases after upfront hepatectomy. However, adjuvant chemotherapy in those received neoadjuvant chemotherapy +/- biologics and salvage hepatectomy should be individualized. Further prospective studies are warranted to validate these findings.
Prognostic significance of adipose tissue distribution and metabolic activity in PET-CT images of patients with metastatic colorectal cancer.
Authors: Karacelik Tuba , Kaya Bugra , Karaagac Mustafa , Araz Murat , Karakurt Eryılmaz Melek , Bozcuk Hakan Sat , Artac Mehmet 
Published: May 2020

e16038 Background: The metabolic activity in visceral and subcutaneous adipose tissue have different metabolic risk profiles for colorectal cancer. The aim of this study was to investigate the prognostic significance of adipose tıssue distribution and metabolic activity in PET-CT and predict the overall survival in patients with metastatic colorectal cancer (mCRC). Methods: A total of 83 patients diagnosed with mCRC between 2010-2018 were evaluated retrospectively. Pretreatment PET-CT images were reevaluated to determine adipose tissue distribution and metabolic activity. Volume and metabolic activity of subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) on FDG PET-CT images were measured. SAT volume, SAT density (HU), SAT ratio (SAT volume/ SAT density) were calculated. The maximum standardized uptake (SUV) of tumor tissue was measured. The relationship between adipose tissue and overall survival was examined. Results: 53 patients died during follow-up and the median overall survival was 33.76 months (95% CI: 28.185-39.349). According to univariate analysis results, tumor location (HR:2.5; 95% CI 1.27-4.98, p = 0.008) and SAT ratio (HR:0.5; 95% CI 0.34-1.00, p = 0.053) were the significant parameters for the OAS. VAT volume (p = 0.774), VAT density (p = 0.899), VAT suv mean (p = 0.831) and SAT volume (p = 0.423), SAT density (p = 0.353), SAT suv mean (p = 0.575), tumor suv max (p = 0.589) values were not correlated with OAS. In the multivariate analysis, SAT ratio (p = 0.011) and tumor location (p = 0.001) were correlated significantly with OAS. The median OAS for the patients with SAT ratio value < -1.1 and -1.1 were 38.5 (95% CI 31.54-45.58) and 24.5 (95% CI 14.13-34.93) months, respectively (p = 0.05). Conclusions: This study showed that SAT ratio was an independent prognostic factor for OAS in patients with mCRC. We need prospective studies for to observe the relationship between adipose tissue distribution and response to treatment in mCRC.
Postoperative XELOX therapy for patients with curatively resected high-risk stage II and stage III rectal cancer without preoperative chemoradiation: A prospective, multicenter, open-label, single arm phase II study.
Authors: Kato Takeshi , Ikeda Masataka , Ikeda Atsuyo , Hasegawa Junichi , Ota Hirofumi , Shingai Tatsushi , Yasui Masayoshi , Fujii Hitoshi , Miyake Yasuhiro , Uemura Mamoru , Matsuda Chu , Satoh Taroh , Mizushima Tsunekazu , Doki Yuichiro , Eguchi Hidetoshi 
Published: May 2020

e16039 Background: Preoperative 5-FU-based chemoradiation is currently a standard treatment for advanced rectal cancer, particularly in Western countries. Although it reduced the local recurrence, it could not necessarily improve overall survival. Furthermore, it can also produce adverse effects and long-term sphincter function deficiency. Adjuvant oxaliplatin plus capecitabine (XELOX) is a recommended regimen for patients with curatively resected colon cancer. However, the efficacy of postoperative adjuvant therapy for rectal cancer patients who have not undergone preoperative chemoradiation remains unknown. We aimed to evaluate the efficacy of surgery and postoperative XELOX without preoperative chemoradiation for treating rectal cancer. Methods: We performed a prospective, multicenter, open-label, single arm phase II study. Patients with curatively resected high-risk stages II and III rectal cancer who had not undergone preoperative therapy were treated with a 120 min intravenous infusion of oxaliplatin (130 mg/m2) on day 1 and capecitabine (2,000 mg/m2/day) in 2 divided doses for 14 days of a 3-week cycle, for a total of 8 cycles (24 weeks). The primary endpoint was 3-year disease-free survival (DFS). Results: Between August 2012 and June 2015, 60 men and 47 women with a median age was 63 years (range: 29–77 years) were enrolled. Ninety-three patients had Eastern Cooperative Oncology Group performance status scores of ‘0’ and 14 had scores of ‘1’. Tumors were located in the upper and lower rectums in 54 and 48 patients, respectively; 8 patients had stage II disease and 99 had stage III. The 3-year DFS was 70.1% (95% confidence interval, 60.8–78.0%) and 33 patients (31%) experienced recurrence, most commonly in the lung (16 patients) followed by local recurrence (9) and hepatic recurrence (7). Conclusions: Postoperative XELOX without preoperative chemoradiation is effective for rectal cancer and provides good 3-year DFS prospects.And this is probably the first and last report in the world for such cases. Trial registration: This clinical trial was registered in the University Hospital Medical Information Network registry system as UMIN000008634 at Aug 06, 2012.
Evaluation of molecular pathogenesis of colon cancer in Kerala using high-throughput expression, signaling pathways, and network analyses.
Authors: Ariyannur Prasanth , Keechilat Pavithran , Paulose Roopa , Vasudevan Damodaran M 
Published: May 2020

e16065 Background: The molecular pathogenesis of colon adenocarcinoma (COAD) is attributed to large molecular changes such as Chromosomal Instability and high somatic copy number variation or defective DNA mismatch repair and consequent microsatellite instability (MSI). The prevalence of this type of cancer is increasing in the state of Kerala, India. A detailed study of the signaling pathways could lead to a better understanding of the central molecular pathological changes and potential biomarkers particular to this population. Methods: High throughput somatic expression analysis using Nanostring PanCancer pathway panel assay was performed. Differentially expressed (DE) genes were selected and KEGG pathway enrichment analysis was performed for assessment of canonical signaling pathways. Expression profiles were compared against the public database, Colon Adenocarcinoma cohort of the Cancer Genome Atlas (TCGA-COAD), using the Genome Expression Profiling Interactive Analysis (GEPIA). Protein-protein interaction network analysis was done using Cytoscape. DE genes were compared against immune cell infiltration in the TCGA-COAD from Tumor Immune Estimation Resource (TIMER) databases. Results: Nanostring assay was performed in 10 Tumor-Normal paired FFPE samples of stage II/III colon adenocarcinoma. Out of > 700 genes, significant difference in expression was found in 83 genes (FDR adjusted p -value < 0.01) with fold-change |fc(log2)| of at least one. Fold-change |fc(log2)| ≥ 2 was found in 19/83 genes. Network analysis clustered 13 out of 17 upregulated genes. Superimposition of the current data on TCGA study showed that among the three genes, four (MET, MCM2, ETV4 and MMP7), were common. DE Genes which were not significant in TCGA COAD study such as INHBA, COL1A1, COL11A1, COMP, SFRP4, SPP1, IL11, LIF, WT1 and DDIT4, were found to be significant in the current study. A few of the unique genes identified in the current study were found to have significant correlation with antigen presenting cells infiltration in the TCGA-COAD studies. Conclusions: Many DE genes from the study population were found to be different from previous large cohort studies in other population. This may suggest a different pathogenesis of COAD in this population, warranting a detailed study on the pathogenesis.