bluuebunny/crossref_metadata_2025 huggingface dataset:
Induction of antigen specific CD8+ T cell infiltration by a novel neoadjuvant vaccine containing HSP70 and GPC3 peptides plus soluble LAG-3 and Poly-IC:LC: Interim results of a Phase I study.
Authors: Tokumitsu Yukio , Hazama Shoichi , Doi Shun , Tamada Koji , Udaka Keiko , Akinaga Shiro , Koki Yasunari , Uematsu Toshinari , Nakagami Yuki , Matsui Hiroto , Shindo Yoshitaro , Kanekiyo Shinsuke , Tomochika Shinobu , Iida Michihisa , Yoshida Shin , Suzuki Nobuaki , Takeda Shigeru , Yoshino Shigefumi , Ueno Tomio , Nagano Hiroaki
Published: May 2019

e14306

Background: Even with curative resection, the recurrence rate of HCC is still high, and no effective adjuvant therapy is currently available. Our previous Phase I study with novel therapeutic peptides and immune adjuvants demonstrated the safety, antigen specific CTL induction in PBMC and a sign of efficacy (ASCO 2017 Abstract # 3086); thus, we started Phase I study of the same therapy as a perioperative immunotherapy setting in patients with resectable HCC (UMIN000029991). Methods: Two mg each of HLA-A*24:02, 02:01, or 02:06 restricted HSP70- and GPC3-derived peptides, in combination with hLAG-3Ig (1.0 mg) + Poly-IC:LC (1.4 mg) were injected intradermally at four sites of the inguinal and axillary regions every week for 6 weeks before surgery. Patients subsequently received 10 injections of adjuvant immunotherapy over 4 months. Surgical specimens and PBMCs were analyzed by mass cytometry (CyTOF), using 66 antibodies to monitor T cell exhaustion, T cell activation, Effector Treg induction, etc. Tumor specimens were also subjected to immunohistochemical staining of CD3, CD8, PD1, HSP70, and GPC3. The reason for early reporting is the interesting findings at the foci of HCC, and the interim analyses was approved by the Data and Safety Monitoring Committee. Results: Of the 11 screened patients, 5 completed the treatments and were analyzed. We found massive CD8+ T lymphocyte infiltration in the intratumor foci of HCC, which is usually accompanied by peritumoral lymphocytic infiltration. Moreover, the density of lymphocytes was markedly higher in areas of HSP70 or GPC3 antigen expression. One case out of five recurred 5 month after surgery and it showed low CD8+ and PD1+ cell infiltration and high effector Treg (CD4+/CD25+/CD45RA-/FoxP3 +) infiltration. This trend was not observed in PBMC, suggesting the importance of TIL analysis. The high PD1 expression was accompanied by massive intratumoral infiltration of CD8+ lymphocytes. Conclusions: The novel therapeutic peptide and immune adjuvant combination induced sustained immune cell infiltration into tumor microenvironments, especially those presenting target tumor-associated antigens. Our novel immunotherapy may convert cold tumors into hot tumors containing PD1+ lymphocytes. Thus, the combination of this novel strategy with PD (L) 1 antibody is warranted. Clinical trial information: 000029991.
Genes copy number variation in tumor cells of patients with metastatic and non-metastatic lung adenocarcinoma.
Authors: Kutilin Denis S. , Leyman Igor A. , Lazutin Yuriy N. , Chubaryan Anna V. , Anistratov Pavel A. , Stateshny Oleg N. , Turkin Igor N. , Gappoeva M. A. , Kit Oleg Ivanovich
Published: May 2019

e14502

Background: Currently known markers of lung adenocarcinoma are insufficient to predict the development of this disease, which makes the search for new molecular markers a relevant problem. Our purpose was to analyze changes in genes copy number variation (CNV) in tumor and non-tumor cells of the lung in patients with (T1-3N1-2M0-1) and without (T1-3N0M0) metastasis to identify potential molecular markers for the prediction of the disease development. Methods: The study was performed on tissue sections from FFPE blocks of 90 patients diagnosed with lung adenocarcinoma. Tumor and non- tumor cells were isolated using laser microdissection (Palm MicroBeam, Carl Zeiss). Copy numbers of 32 genes (BAX, BCL2, C-FLAR, P53, MDM2, BFAR, SEMA3B, RASSF1A, CASP9, CASP3, CASP8, SOX2, OCT4, NANOG, PIK3, MKI67, HV2, HIF1A1, XRCC1, MMP1, TERT, CTNNB1, VEGFA, KRAS, EGFR, GRB2, SOS1, MAPK1, STAT1, BRAF, FTO, mir3678) were determined by Real-Time qPCR (ACTB, B2M, GAPDH - reference genes). Statistical analysis was performed using the Mann-Whitney test. Results: A pooled sample (n = 90) showed significant (p < 0.005) increase in the copy numbers of MAPK1 and SOX2 and decreased copy numbers of the mir3678, HV2, BAX and CASP3 genes in tumor cells compared to non-tumor. Patients with metastatic and non-metastatic lung adenocarcinoma had significant (p < 0.05) differences in genes copy number in tumor cells compared to non-tumor ones: patients with T1-3N1-2M0-1 (n = 50) – decreased copy numbers of the mir3678, HV2, MDM2, P53, XRCC1, CASP3 and OCT4 genes and increased SOX2 copy number; patients with T1-3N0M0 (n = 40) – increased copy numbers of the MAPK1 and mir3678 genes and decreased HV2 copy number. Conclusions: The detected changes in copy numbers of genes responsible for the regulation of apoptosis, proliferation, oxidative phosphorylation and the function of the EGFR signaling pathway in lung tumor cells revealed new molecular markers to predict the risk of metastasis ( mir3678, MDM2, Р53, SOX2, XRCC1, CASP3, OCT4, MAPK1).
A pretreatment CT model predicts survival following chemolipiodolization in patients with hepatocellular carcinoma.
Authors: Wu Dong , Fan Hengwei , Qu Shuping
Published: May 2019

e14509

Background: This study aimed to establish a computed tomography-based prognostic model for patients with hepatocellular carcinoma treated with transarterial chemoembolization. Methods: Using prospectively collected data from 195 consecutive patients with hepatocellular carcinoma who underwent chemolipiodolization at the Eastern Hepatobiliary Surgery Hospital between 2013 and 2016, we established a prognostic model based on hepatocellular carcinoma enhancement patterns on computed tomography scans to predict the outcome of transarterial chemoembolization. Furthermore, a histopathology analysis was performed on 108 different patients undergoing resection between 2014 and 2016 to identify whether there was a correlation between enhancement pattern and microvessel density. Results: The prognostic model classified hepatocellular carcinoma into 3 types: Type I, which reached peak enhancement during the arterial phase and had a high mean microvessel density (101.5 vessels/0.74 mm2); Type II, which reached peak enhancement during the portal venous or delayed phase and had an intermediate microvessel density (53.6 vessels/0.74 mm2); and Type III, in which the tumor was insignificantly enhanced and had a low microvessel density (21.1 vessels/0.74 mm2). For type I, II, and III hepatocellular carcinoma, the post-transarterial chemoembolization 1-year tumor complete necrosis rates were 13.7%, 36.5%, and 0%, respectively (p < 0.001) and the 3-year overall survival rates were 14.1%, 38.6%, and 0%, respectively (p < 0 .001). Conclusions: Our results indicate that hepatocellular carcinoma type is an independent predictor of complete necrosis and overall survival.
The influence of kinesin light chain-2 on the radiosensitivity of non-small cell lung cancer cells and the underlying mechanisms.
Authors: Li Shangbiao , Zhu Xiaoxia
Published: May 2019

e14512

Background: Our previous study found upregulated kinesin light chain-2 (KLC2) in non-small cell lung cancer (NSCLC) cell lines and tissues, which is associated with a poor prognosis. KLC2 promotes the migration ability of lung cancer cells. However, the influence of KLC2 on radiosensitivity of NSCLC has not yet been reported. Methods: Sensitivity of lung cancer cells to radiation was analyzed by colony formation, γH2AX immunofluorescent staining assay and neutral comet assay in vitro and a xenograft tumor model in vivo. Gene set enrichment analysis (GSEA), qRT-PCR and western blot assay were performed to predict and validate the potential target genes of KLC2. Results: We found that down-regulation of KLC2 could significantly improve the radio-sensitivity of lung cancer cells, while the overexpression of KLC2 had the opposite effect. GSEA identified p53 signal pathway as differentially enriched with high KLC2 expression, which was validated by western blot assay. Using data from TCGA, we found a positive correlation between the mRNA level of KLC2 and that of HuR. The expression of KLC2 mRNA and protein in lung cancer cells was significantly reduced when downregulating HuR. Interestingly, the overexpression of KLC2 could also significantly decrease the expression of HuR. Conclusions: The above results indicated that HuR could upregulate the expression of KLC2, which might decrease the phosphorylation of p53 and thereby weakened the radio-sensitivity of NSCLC cells. KLC2 could also positively regulate the expression of HuR as a positive feedback. Support: 81572279, 2016J004, LC2016PY016, 2018CR033
Cell-free DNA in uveal melanoma: Results from the first-in-human trial of mivebresib (ABBV-075).
Authors: Patel Sapna Pradyuman , Pelster Meredith , Mostorino Rosa , Wolff Johannes E. , Ramathal Cyril , Chen Xiaotian , Hu Beibei , Piha-Paul Sarina Anne
Published: May 2019

e14526

Background: Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Cell free DNA (cfDNA) is a non-invasive mechanism for monitoring malignancy in UM patients. BET proteins activate transcription of oncogenic genes, and mivebresib (ABBV-075) is a potent pan-BET inhibitor. In the first-in-human phase 1 study, safety and pharmacokinetics of mivebresib were assessed in patients with advanced cancer (NCT02391480). We compared cfDNA mutational dynamics with the survival of UM patients treated with mivebresib. Methods: Adult patients with metastatic solid tumors and ≥1 line of prior treatment were treated with mivebresib on a schedule of daily; 3 days/week; or 4 days on, 3 days off. Two mL of plasma cfDNA (≥10ng) in 5 patients (3 progressive disease [PD], 2 stable disease [SD]) were sequenced with a targeted 63-gene panel (68 Kb) to ≥800X unique depth after barcode-based error-suppression and genomic alterations discovered in all patients. Results: As of May 2018, 10 UM patients received ≥1 dose of mivebresib with median 8.1 weeks (range, 3.6–39.6) of treatment. The median age was 55 years (range, 37–73). 9 patients experienced a treatment-emergent adverse event (TEAE), most commonly (≥40% patient incidence), dysgeusia (60%), thrombocytopenia and nausea (40%, each). 9 patients were evaluable, 4 achieved a best response of SD and 5 PD (RECIST v1.1). The mean pretreatment cfDNA concentration was 21.0 ng/mL (N = 5 with plasma available). cfDNA levels increased in two patients by 0.6% (SD) and 64.4% (PD). In PD patients, elevated cfDNA concentration (32.7 ng/mL [PD] vs 3.5 ng/mL [SD]) was associated with shorter progression-free survival and overall survival. At baseline, the cfDNA mutational load (median mutant molecules/mL plasma) of pathogenic (COSMIC) mutations with AF ≥1% was highest in PD (893.9; range, 78-4951.5) vs SD patients (53.1; range, 9.3-606.2) and negatively correlated with the patient’s survival (R2= 0.531). In 1 PD patient, multiple TP53 (C23G, V203M) and CDKN2A (A148T, L63P) mutations were acquired by the time of progression. Conclusions: These data suggest cfDNA as a potential marker for survival of UM patients. Further investigation of BET inhibition in this population is warranted. Clinical trial information: NCT02391480.
Bone metastasis unique plasma exosomal microRNA signature in non-small cell lung cancer.
Authors: Pi Can , Yu Ruoying , Peng Xiaoxiao , Zhang Xuchao , Chen Zhihong , Wu Xue , Fan Xiaojun , Shao Yang , Zhou Qing
Published: May 2019

e14534

Background: 20-40% of lung cancer patients develop bone metastasis (BM) with significantly decreased overall survival. Currently, BM is mainly diagnosed by CT scan or MRI when symptom develop. Novel biomarkers with higher prediction value of BM are needed. Tumor secreted exosomes that are enriched with microRNAs have been recently implicated in site-specific tumor metastasis for establishing a distant pro-metastatic niche. Methods: Plasma exosomes from 39 stage IV non-small cell lung cancer (NSCLC) patients (n = 23 with BM; n = 16 without BM) and 16 healthy individuals were separated by ultracentrifugation. Total RNAs were extracted followed by small RNA-sequencing. miRNA identification was performed by miRDeep2. Weighted correlation network analysis (WGCNA) was used for identifying co-expression networks of highly correlated miRNA clusters. miRNA enrichment analysis and annotation (MIEAA) was applied for pathway analysis. Differential expression of individual miRNA was analyzed by edgeR. Results: Hierarchical clustering based on the total miRNA profile can clearly separate cancer patients and healthy individuals (HP), but not patients with (BM+) or without (BM-) BM. WGCNA identified three consensus clusters (A, B, C) of highly correlated miRNAs, among which cluster A (144 miRNAs) showed significantly differential expression in lung cancer patients, especially in BM+ group. Pathway analysis of cluster B miRNAs revealed enrichment in glycolysis and gluconeogenesis pathways that may involve in metabolic preconditioning of the metastatic niche. Three differentially expressed miRNAs between BM+ and BM- patients within cluster A were identified as miR-574-5p, a suppressor of Wnt/β-catenin pathway, was down-regulated, while miR-328-3p and miR-423-3p, two activators of the same pathway, were up-regulated in BM+ patients. Cluster B miRNAs (n = 49) also showed trend of upregulation in BM+ patients. Interestingly, pathway analysis indicated that 43 of them are associated with chr14, which has been suggested to promote EMT and bone metastasis. Conclusions: NSCLC patients with BM displayed unique plasma exosomal miRNA profiles, which might involve in promoting BM, and be potential biomarkers for predicting BM in NSCLC.
Circulating-free DNA analysis from long-term surviving metastatic colorectal cancer patients undergoing surgery for resectable disease.
Authors: Ghidini Michele , Hahne Jens Claus , Senti Chiara , Lampis Andrea , Ratti Margherita , Pizzo Claudio , Gobbi Angela , Tomasello Gianluca , Passalacqua Rodolfo , Valeri Nicola
Published: May 2019

e14545

Background: Liquid biopsies (LB) allow monitoring of genetically different and co-occurring cancer cell clones present in primary tumor and all metastatic sites in parallel. In metastatic colorectal cancer (mCRC), circulating-free DNA (cfDNA) can be relevant for monitoring treatment and identification of molecular alterations resulting in disease relapse often earlier than radiological examinations. Methods: Patients with mCRC at diagnosis and treated with chemotherapy (CT) in combination with antibodies (bevacizumab, cetuximab or panitumumab) before undergoing surgery for resectable disease were included in this study. LB were collected before therapy start, every four weeks during treatment, within ten days of radiological disease evaluation, at radiological relapse and until two months after relapse. Next generation sequencing based on plasma samples was performed (testing for mutations and copy number variations covering 77 genes). Results: From February 2016 to October 2018, 14 patients having surgery after first line treatment were included herein; median follow-up was 21.5 months. Five of them had RAS wild-type disease and received CT plus anti-EGFR treatment, while nine RAS mutated mCRC patients received bevacizumab. Surgery was radical in 10 cases, with no further treatment. In four cases, surgery was not radical and required further treatment. Disease relapse happened in seven cases, with subsequent death in three cases. In six out of seven cases, gene alterations were already detected in the pre-operative cfDNA. In the seven cases without disease relapse, gene variants were detected even after the surgery in two patients despite receiving radical resection. Median number of gene variants was two. Beside the well-established mutations in TP53 gene, both APC and ROS1 gene mutations were frequent, while further evaluations are required for the other variants detected. Conclusions: Evaluation of cfDNA mutations in LB from mCRC may be a useful tool for monitoring clinical response and predict treatment outcome. Moreover, this molecular analysis can help to subgroup patients with regard to risk of relapse after radical surgery. Indeed, cfDNA mutations present before surgery seem to be an indication for a higher risk of post-surgery disease relapse.
Precise prediction of the radiation pneumonitis with RPI: An explorative preliminary mathematical model using genotype information.
Authors: Du Lehui , Qu Baolin , Liu Fang , Ma Na , Xu Shouping , Yu Wei , Dai Xiangkun , Huang Xiang
Published: May 2019

e14569

Background: Radiation pneumonitis (RP) is the most significant dose-limiting toxicity and is one major obstacle for the radiotherapy of lung cancer. Reliable predictive factors or methods are strongly demanded by radiation oncologists. The purpose of this study is by determining the effectiveness of both genetic and non-genetic factors on their impact on the development of RP, to develop a clinically practicable approach for the risk assessment of RP. Methods: One hundred eighteen lung cancer patients who received radiotherapy were enrolled. RP events were prospectively scored using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (CTCAE4.0). Seven hundred thousand single-nucleotide polymorphism (SNP) sites of each patient were tested via Generalized Linear Models via Lasso and Elastic-Net Regularization (GLMNET) to determine their synergistic effects on the risk of grade≥2 RP prediction. Non-genetic factors including patient characteristics and dosimetric parameters were separately assessed by statistic test for their association with the risk of grade ≥2 RP. Based on the results of the aforementioned analysis, a multiple linear regression model named Radiation Pneumonitis Index (RPI) was built, for the assessment of grade ≥2 RP risk. Results: No statistically significant association were found between the RP risk (grade ≥2) and any of the non-genetic factors. Twenty five effective SNPs for predicting the grade≥2 RP risk were discovered and their coefficients of the synergistic effect were determined. An RPI score defined only by the information about these 25 SNPs can successfully distinguish the grade ≥2 RP population with 100% specificity and 97.8% accuracy. Conclusions: Non-genetic factors including important dosimetric parameters may not play dominant roles in the development of RP. Genotype information alone can effectively predict the risk of grade ≥2 RP. The combination of genetics and mathematical algorithms can be a new direction for radiotherapy in the field of precision medicine.
Characteristics of preceding trials associated with the outcome of subsequent phase III (P3) trials of targeted and immunological therapies in advanced cancers.
Authors: Lawrence Nicola Jane , Martin Andrew James , Roncolato Felicia , Tang Monica , Stockler Martin R.
Published: May 2019

e14576

Background: Decisions to conduct P3 trials are based on evidence of activity from preceding trials. We sought the characteristics of preceding trials that were associated with a positive outcome in subsequent P3 trials of targeted and immunological therapies in oncology. Methods: We identified P3 trials of targeted and immunological therapies in advanced, solid-organ malignancies published from 2005 to 2015, and the preceding trials that were cited as their justification. We extracted characteristics and outcomes of the preceding trials and the subsequent P3 trials. We performed univariable and multivariable analyses to identify characteristics of preceding trials that were associated with a positive outcome in P3 trials. Results: We included 205 P3 trials with 542 citations of preceding trials. The experimental agent evaluated was (P3 trial, preceding trial respectively): small molecule (47%, 39%), immunotherapy (10%, 16%), monoclonal antibody (28%, 32%), hormonal therapy (7%, 6%), and other agent (8%, 6%). The primary endpoint was positive in 40% of P3 trials. The findings of preceding trials were reported ‘positively’ by their authors in 87%, but a priori criteria for judging their findings ‘positive’ were specified in only 74%, and met in only 53%. Characteristics of preceding trials that were associated with a positive primary endpoint in the subsequent P3 trial on multivariable analysis were: conduct in the same tumour type (odds ratio 2.35, 95% CI 1.0 to 5.6, p = 0.05), and sponsored by industry (odds ratio 2.02, 95% CI 1.2 to 3.5, p = 0.01). Conclusions: Researchers designing and conducting phase 2 trials should pre-specify and report criteria for concluding that the findings are ‘positive’. Researchers designing and conducting P3 trials of targeted and immunological therapies should require evidence of activity for the specific type(s) of tumour and therapy in question. [Table: see text]
Role of radiomics to differentiate benign from malignant pheochromocytomas and paragangliomas on contrast enhanced CT scans.
Authors: Laderian Bahar , Ahmed Firas Salem , Zhao Binsheng , Wilkerson Julia , Dercle Laurent , Yang Hao , Guo Xiaotao , Pacak Karel , Lee James A. , Bates Susan Elaine , Del Rivero Jaydira , Schwartz Lawrence Howard , Fojo Antonio Tito
Published: May 2019

e14596

Background: Radiomics features, which are quantitative features generated by computational analysis of routine clinical imaging like CT scans, have been shown to be associated with clinical outcomes and tumor’s behavior in some solid tumors. We compared the radiomic features of malignant and benign pheochromocytomas/paragangliomas (P/P). Methods: Through an IRB approved study at our institution, we identified 20 consecutive patients with P/P and with available contrast-enhanced abdominopelvic CT. A radiologist with experience in oncologic imaging identified and segmented tumors on every slice using a MatLab-based imaging platform. The entire tumor image then underwent computational analysis generating 1160 radiomics features reflecting tumor size, shape, density, textural heterogeneity, and margins. These radiomics features were compared between malignant and benign P/P using Wilcoxon-Rank sum test. Results: Of the twenty patients included in this analysis, there were 6 patients with malignant P/P and 14 patients with benign tumors. Patients had been followed for at least 5 and many for at least 10 years after resection of the tumor. At diagnosis, the mean age of patients with benign and malignant tumors were 51 and 45, respectively. A 60% majority of patients with benign tumors were females while a 77% majority of patients with malignant tumors were male. Benign P/P were significantly different from malignant ones in: tumor intensity textures (spatial correlation [p-value = 0.0010], Laws [p-value = 0.0064], LoG [p-value = 0.0087], and Gabor [p-value = 0.0325]), and tumor local surface shape (Shape Index SI7 [p-value = 0.0325]). Conclusions: This initial analysis sought to discern differences in these rare tumors that might be exploited clinically. The results show that compared to benign tumors, malignant P/P tend to have more heterogenous texture, irregular edges, and less rounded shape on contrast enhanced abdominal CT scan. However, because these radiomics phenotype properties are subtle, they cannot be made reliably in an objective fashion using human visual assessment and thus these radiomics features may have a role as a quantitative imaging biomarker in P/P to predict tumor behavior. The cohort is being expanded and data will be updated at the time of the presentation. With larger numbers, the contribution to the radiomics profile of a SDHx mutation will be explored in greater depth to understand the differential impact of SDHx loss and of evolution into a cancer to the radiomics profiles.
Quantitative image profiling of the tumor microenvironment on double stained immunohistochemistry images using deep learning.
Authors: Nagy Mate Levente , Juncker-Jensen Anna , Ovadia Ben , Smale Robert , Yamamoto Karen , William Josette , Hoe Nicholas , Padmanabhan Raghav
Published: May 2019

e14619

Background: Spatial locations of immune cells in the tumor microenvironment (TME) correlate with clinical outcome in cancers. A worse patient outcome has been reported in oral squamous cancer for individuals with an increased number of regulatory T cells within 30µm of CD8+ cells [1]. The spatial relationship between CD8+ and PD-L1+ cells has become an area of interest for understanding PD-L1 inhibition. The combined assessment of CD8 and PD-L1 in NSCLC tumors was shown to outperform CD8 or PD-L1 alone as prognostic markers for predicting treatment with immune checkpoint inhibitors [2]. Methods: As reported in these cases, quantifying spatial relationships between two biomarkers is valuable in providing clinical insights. Spatial analytics of the TME requires accurate cell segmentation and classification. To that end, NeoGenomics has developed a deep learning pipeline to automatically segment and classify cells from whole slide double stained IHC images. Results: In this study, we performed IHC double staining and cell classification analysis on two sets of assays (CD8+ PD-L1+ and CD8+ FoxP3+) in NSCLC tumors by modifying our MultiOmyx analysis pipeline [3]. In addition to cell segmentation and classification image outputs, we also generate tables with cell morphological information, phenotype counts and densities, and biomarker intensities that can be used to define H-score-like measures. Advanced spatial analytics is performed to identify clustering patterns of various phenotypes. These analyses enable investigation of complex cell interactions in TMEs. Conclusions: NeoGenomics quantitative double stained IHC assay is compatible with any two biomarkers of interest even if they are expressed on the same cell as long as the sub-cellular localization of the markers is different (membrane CD8, nuclear FoxP3). The combination of double staining for CD8+ PD-L1+ or CD8+ FoxP3+ and quantifying spatial relationships between the two biomarkers is capable of providing the needed context to guide treatment decisions. References: Feng Z et al., JCI Insight. 2017 Jul 20:e93652 Steele KE et al., J Immunother Cancer 2018;6:20 Nagy ML et al., AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL
Noninvasive prediction of future macrovascular invasion occurrence in hepatocellular carcinoma based on quantitative imaging analysis: A multi-center study.
Authors: Wei JingWei , Tian Jie , Fu Sirui , Lu Ligong
Published: May 2019

e14623

Background: To investigate whether preoperative imaging-based analysis could help to predict future macrovascular invasion (MaVI) occurrence in hepatocellular carcinoma (HCC). Methods: A cohort of 224 patients with HCC was enrolled from five independent medical centers (training cohort: n = 154; independent validation cohort: n = 70). Predictive clinical factors were primarily selected by uni- and multi-variable analysis. CT-based imaging analysis was performed based on extraction of 1217 radiomic features. Recursive feature elimination and random forest (RF) were chosen as the optimal radiomics modelling algorithms. A clinical-radiomics integrated model was constructed by RF modelling. Cox-regression analyses further selected risk independent factors. Risk stratification was explored by Kaplan-Meier analysis with log-rank test, regarding to MaVI occurrence time (MOT), progression free survival (PFS) and overall survival (OS). Results: The clinical-radiomics integrated model could successfully predict MaVI occurrence with areas under curve of 0.920 (training cohort, 95% confidence index [CI]: 0.875-0.965) and 0.853 (validation cohort, 95% CI: 0.737-0.970). The radiomics signature added significant improvement to the integrated model in both training and validation cohorts with p-value of 0.009 and 0.008, respectively. Radiomic features: N25_ori_gldzm_IN (hazard ratio [HR]: 0.44; p = 0.001) and N25_Coif1_ngldm_DE (HR: 0.60; p = 0.016) were selected as independent risk factors associated with MaVI occurrence time. The cox-regression model could stratified patients into high-risk and low-risk groups in MOT (p < 0.001), PFS (p = 0.003), and OS (p = 0.007). Conclusions: The noninvasive quantitative imaging analysis could enable preoperative prediction of future MaVI occurrence in HCC with prognosis implication.
The landscape of ARID1A variants and correlation with tumor mutational burden in Chinese solid tumor patients.
Authors: Wei Jia , Zhang JieJie , Wen Qiang , Zhu Xiaoyi , Li Dapeng , Liu Baorui , Hu Jinwei , Wang Weifeng , Yao Ming , Wang Kai
Published: May 2019

e14624

Background: ARID1A (the AT-rich interaction domain 1A) is one of the most commonly mutated genes in cancer, mostly caused by frameshift variants. Here, we describe the mutational landscape of ARID1A in Chinese cancer patients and its correlation with tumor mutational burden (TMB). Methods: Formalin fixed paraffin embedded (FFPE) samples of 3,828 Chinese solid tumor patients were collected for next‐generation sequencing (NGS) based 450 genes panel assay. Genomic alterations including single base substitution, short and long insertions/deletions, copy number variations, gene fusions and rearrangement were assessed. Microsatellite stable (MSS) status and TMB were also acquired by NGS algorithms. Results: A total of 340 (8.9%) patients were found to have ARID1A variants. The frequency of ARID1A mutations was 4% in lung adenocarcinoma (N = 74/1833), 8% in squamous cell lung carcinoma (N = 23/278), 12% in colorectal adenocarcinoma (N = 61/530), 11% in hepatocellular carcinoma (N = 52/484), 14% in pancreatic adenocarcinoma (N = 25/177), 15% in gallbladder adenocarcinoma (N = 14/94), 22% in intrahepatic cholangiocarcinoma (N = 47/213), 20% in gastric adenocarcinoma (N = 39/200) and 26% in endometrial adenocarcinoma (N = 5/19). ARID1A variants included truncation (78%), missense/indel (non-frameshift substitution/indel) (16%), splicing site (4%) and rearrangement (2%). Truncation was the most common, recurring in a few hot spots (R1276*, D1850Gfs*4, A339Lfs*24, P224Rfs*8 and Q372Afs*28/Sfs*19). In general, ARID1A mutations correlated with higher TMB (median 17.6 vs 7.4 muts/Mb, P < 0.001) in MSS tumors; especially in lung adenocarcinoma (17 vs 7.5 muts/Mb, P < 0.01), squamous cell lung carcinoma (16.8 vs 11.2 muts/Mb, P < 0.01). TP53 (60%), APC (34%) and KRAS (32%) were the most common co-occurred mutated gene in ARID1A (+) tumors. In more than 20% of ARID1A mutations, PI3K/mTOR pathway genes were altered, such as PIK3CA, PTEN, RNF43 and PIK3R1 genes. Conclusions: Since ARID1A mutations correlate with higher TMB, it could be a potential predictor of response to PD-1/PD-L1 immune checkpoint pathway inhibitors. As reported, ARID1A deficiency promotes mutability and potentiates therapeutic antitumor immunity unleashed by immune checkpoint blockade. Patients harboring ARID1A and PI3K/mTOR pathway mutations may provide useful information for drug discovery and biomarker exploration.
Exceptions to the rule: Novel retrospective analysis of a single-center institution of the PSMA PET/CT modality.
Authors: Durkal Vipal P. , Rettig Matthew
Published: May 2019

e14625

Exceptions to the Rule: Using Pathology as a Gold Standard to Evaluate the Sensitivity of PSMA PET/CT Modality. Background: The experience with the novel Ga-68 PSMA PET/CT imaging and its limitations are described anecdotally in the literature. Cases of false-positive PSMA PET/CT of various benign and malignant etiologies are described in case reports. False-negative PSMA PET/CT results are significantly less well characterized. Our analysis is based on the UCLA Cancer Center experience with patients who underwent PSMA PET/CT and subsequent biopsy of target lesions. Methods: Of 44 evaluable patients, we found four patients with false negative results based on the 'Gold Standard' of pathologic biopsy. In this context, false negative is defined as PSMA PET/CT negative but proven to be PSMA-expressing adenocarcinoma of the prostate using biopsy of target lesions. Results: In our analysis, we found several stark patterns of these false-negative lesions. The vast majority were pulmonary in origin (75%). Their average size was subcentimeter (0.96 cm). The average Gleason Score at diagnosis was relatively high (8.25), while the initial PSA at diagnosis was relatively modest (4.3). A majority (75%) of these patients received radiation to the prostate. In terms of treatment: a majority were on Androgen-Deprivation Therapy (75%); Abiraterone (50%); had received prostatectomy (100%). The average age at diagnosis was 65. Conclusions: False-negative adenocarcinoma of the prostate that has been-biopsy proven to express PSMA has not been described in the literature. This is the first such instance that we can encountered. The implications of this finding are potentially far-reaching, since the lung remains the second most common site of metastasis in prostate cancer after the bone. The average sub-centimeter size of the target lesions that were biopsied suggests that the density of PSMA receptors may have a role in the detection on Ga-68 PSMA PET/CT and correlate with sensitivity.
RERG involvement in the RAS pathway and ER-dependent transcription in breast cancer.
Authors: Hsu Pei-Chen , Ho Jar-Yi , Yu Cheng-Ping
Published: May 2019

e14638

Background: Breast cancer is the highest incidence malignancies in women worldwide. Luminal breast cancers are typically estrogen receptor–positive with better prognosis. However, the rapid disease progression and the high relapse rate of this subtype of breast cancer have become a puzzle in breast cancer treatment. It gave us the motivation to figure out the anomalous molecular mechanism which devoted in. It has been well-documented that the RAS pathway is overloadly activated in more than half of human breast tumors. RAS genes encode a superfamily of small GTPases that contribute to cell growth signals. Methods: Gene expression level were measured by qPCR and Western Blot.Biological effects of each condition were evaluated in cell viability and migration. Results: In this study, we investigated one member of the RAS family, RERG, which was related to the ER pathway and contributed to inhibit Ras activated pathway. Our results showed that knockdown of RERG concomitantly promoted two major oncogenic pathways, Ras and Stat3 signaling pathways, in luminal type breast cancer cell lines. Moreover, ectopic RERG expression significantly inhibited Ras expression. It implicated that RERG mediated in RAS-driven biological effects. Our findings indicated that knockdown of RERG enhanced mobility of the breast cancer cells and made cells more intractable under SERM treatment. Conclusions: We elucidated the tumor-suppressor role of RERG in breast cancer cells though inhibition of the Ras and Stat3 signaling pathways. Therefore, this study might shed light on the important mechanistic insight into the tumorigenesis of ER-positive luminal type cancer and provided the prognostic and therapeutic improved roles of RERG.
Pooled analysis of onapristone extended release (ONA ER) in metastatic cancer patients (pts): A review of liver safety.
Authors: Cottu Paul H. , Jayaram Anuradha , Italiano Antoine , Pacey Simon , Leary Alexandra , Jones Robert J , Campone Mario , Floquet Anne , Berton Rigaud Dominique , Lhomme Catherine , Sablin Marie-Paule , Bexon Alice Susannah , Bonneterre Jacques , Attard Gerhardt , Watkins Paul B
Published: May 2019

e14647

Background: ONA, a type I progesterone receptor (PR) antagonist, prevents PR activation by disrupting PR dimerization and DNA binding, and inhibits tumor progression. ONA (immediate release) has efficacy comparable to other endocrine therapies in pts with metastatic breast cancer (BC). The only notable toxicity was transient elevation in liver chemistries in some pts. In 2 clinical trials, ONA ER was given to 88 cancer pts who underwent frequent liver chemistry monitoring. Methods: We pooled and reviewed all liver safety data from 2 trials. A hepatologist (PBW) reviewed all pts with either a hepatobiliary SOC AE or who experienced an elevation > ULN of any liver-related laboratory test. Results: Of 88 pts who received ONA ER for a median 8 weeks (3-51), 59% were female, median age 68 (36-89), 99% Caucasian, 28% had liver metastases (mets), 48% bone mets and 17% also took abiraterone (ABI), which has liver toxicity. 54 pts (61%) experienced any ONA ER-related AE. More AEs were seen in ABI pts (67%), those with liver mets (72%) and BC (76%).. In terms of liver-related TEAEs, overall 10% of pts had ALT and 13% AST elevations, while 20% pts with liver mets had raised ALT/AST and 29% of BC pts. Overall 15% pts had G3 TEAEs, compared to 28% pts with liver mets, mostly due to increased GGT (24%), which has unclear clinical impact. There were no discontinuations for LFT elevations. A relationship between the liver events and ONA ER was judged to be unlikely in each subject, except one. This event was detected at day 29 of treatment and consisted of a marked rise in serum GGT and alkaline phosphatase with only a moderate rise in serum ALT (peak – 262). These abnormalities improved quickly after stopping ONA but recurred on reintroduction: these events are not serious by international criteria and the pt was able to continue ONA at a lower dose for 40 weeks without recurrence Conclusions: The safety experience for ONA ER has been reassuring but must continue to be characterized. For new ONA ER studies, weekly liver chemistry monitoring is planned for the first 4 weeks with Q2W monitoring thereafter. The occasional G3 elevations in serum AST, ALT or bilirubin will prompt interruption, but re-starting treatment at a lower dose should be possible for most pts. Clinical trial information: NCT02052128 and NCT02049190.
Effect on tumor growth by TGF-β1/COX-2 siRNA combination product (STP705) in a human cholangiocarcinoma (HuCCT-1) xenograft tumor model in nude mice.
Authors: Molyneaux Michael , Xu John , Evans David M. , Lu Patrick
Published: May 2019

e14652

Background: Cholangiocarcinoma (CCA) is a hepatobiliary cancer and although there have been advances recently there is a need for additional treatment methods for patients. Over expressions of TGF-β1 and COX-2 have been reported to play key roles in tumorigenesis of CCA. We studied the effect of STP705 on the growth of HuCCT-1 xenograft tumors in nude mice. STP705 is a TGF-β1/COX-2 specific siRNA combination product formulated in Histidine-Lysine co-Polymer nanoparticle delivery system. Methods: HuCCT-1 xenograft tumors were implanted subcutaneously into 24 BALB/c nude female mice (n = 8/group). Group 1 received vehicle control, group 2 (low-dose) received 8µg of STP705, and group 3 (high-dose) received 16µg of STP705. Intratumoral test article administration and tumor volume measurements were conducted twice a week for 3-weeks. Qualitative analysis was performed on H&E, Picrosirius red (PSR) and immunohistochemistry (IHC) stained sections of tumor tissues. Results: High- and low- dose groups of STP705 reported significantly lower mean tumor volume at day 21 (p = 0.005 & p = 0.036, respectively) as compared to control group. High-dose group reported significantly lower tumor volume at days 11 (p = 0.042), 15 (p = 0.003), and 18 (p = 0.007) as compared to the control group. IHC assessment demonstrated that STP705-treated animals had significantly lower (H-score ± SEM) TGF-β1, COX-2, HSP70, Bcl-xL and MMP-9 staining (52±9, 39±4, 178±8, 25±7 & 7±1, respectively) as compared to control animals (94±11, 66±8, 213±7, 59±8 & 11±2, respectively – with p < 0.05). Assessment of Caspase-3 and H&E (necrosis and inflammation) slides reported higher mean score for STP705-treated animals, while PSR staining reported lower fibroplasia for STP705-treated animals as compared to the control animals. Conclusions: The data suggests that STP705-treatment suppresses TGF-β1 and COX-2 expression resulting in inhibition of (i) tumor cell survival, (ii) fibrosis, (iii) promotes apoptosis, and (iv)decreased invasiveness of tumor cells. Overall, STP705 is an innovative siRNA-based treatment that results in significant suppression of tumor growth in a HuCCT-1 xenograft mouse tumor model.
Combination mTORC1/2 and BCL- XL inhibition in endocrine and CDK4/6-resistant estrogen receptor-positive breast cancer.
Authors: Sammons Sarah , Anderson Grace , Wardell Suzanne , McDonnell Donald P. , Marcom Paul Kelly , Wood Kris
Published: May 2019

e14653

Background: Endocrine therapy plus CDK 4/6 inhibition has led to impressive improvements in progression-free survival in patients with advanced, estrogen receptor positive (ER+)/HER2-negative (HER2-) breast cancer. Resistance inevitably emerges, leaving patients with few proven therapeutic options. Our group has recently found that treatment of PIK3CA mutant ER+/HER2- breast cancer with inhibitors of mTORC1/2 and BCL-XL causes impressive synergistic growth suppression and apoptosis induction compared to either agent alone in vitro and in vivo. We sought to assess activity in clinically relevant models of PIK3CA mutant ER+ breast cancer with acquired resistance to endocrine therapy and CDK4/6 inhibition. Methods: Using orthotopic MCF-7 xenograft tumors (ER+/ PIK3CA mutant) that were evolved through serial passaging in vivo to develop tamoxifen resistance (TamR), we developed models of resistant disease. TamR xenograft- bearing mice were then treated for 4-6 weeks with palbociclib (50 mg/kg qd), fulvestrant (100mg/kg qw), or the combination. Mice in each treatment group were divided into two groups following the initial development of resistance, defined by steady growth for 1-2 weeks: one receiving vehicle and the other receiving low dose MLN0128 0.3 mg/kg qd (mTORC1/2 inhibitor) + ABT-737 25 mg/kg qd (BCL-XL /BCL-2 inhibitor). Results: Combination BCL-XL (ABT-737) + mTORC1/2 (MLN0128) inhibition significantly inhibited growth in tamoxifen (p = 0.0045), fulvestrant/tamoxifen (p = 0.0035), palbociclib/tamoxifen (p = 0.0155), and palbociclib/tamoxifen/fulvestrant (0.005) resistant tumors compared to controls. These results were observed without significant animal toxicity, dose-limiting thrombocytopenia secondary to BCL-XL inhibition, or toxicity to normal breast epithelial cells. We have observed tumor regressions in multiple models using doses five- to 12-fold lower than the equivalent doses required to cause clinically meaningful thrombocytopenia in humans and large animal models. Conclusions: Our data establish the rationale for investigating the combination of BCL-XL and mTORC1/2 inhibition in a clinical trial of advanced PIK3CA mutant, ER+/HER2- breast cancer after progression on CDK 4/6 and endocrine therapy. Preclinical work is ongoing with novel inhibitors of BCL-XL.
Prognostic significance of amplifications of stemness genes in primary luminal breast cancer depending on the response to neoadjuvant chemotherapy.
Authors: Kazantseva Polina , Slonimskaya Elena , Litviakov Nicolay , Tsyganov Matvey , Ibragimova Marina
Published: May 2019

e14655

Background: Neoadjuvant chemotherapy (NAС) is one of the treatment options for breast cancer (BC). However, chemotherapy is known can cause intratumoral changes that increase the risk of metastasis. We have previously found that the appearance of new amplifications in the chromosomal regions harboring stemness genes (3q, 5p, 6p, 7q, 8q, 9p, 9q, 10p, 10q21.1, 13q, 16p, 18Chr, 19p) is associated with the development of hematogenous metastases in 100% of cases. In our study, we evaluated the prognostic significance of amplifications stemness genes in primary BC depending on the NAC response. Methods: The study included 104 patients with stage II-III luminal B (Her2Neu -) breast cancer. All patients received 4-8 courses of NAС followed by surgery and hormone therapy. The follow-up period was 4-10 years. Amplifications in primary tumor DNA were determined using Affymetrix high density microarrays. Metastasis-free survival was estimated using the Kaplan-Meier method. Results: Zero or only 1 amplification was identified in tumor tissue of 42 patients (41%) (group 1). Two or more amplifications were identified in tumor tissue of 60 patients (59%) (group 2). We evaluated metastasis-free survival separately in each group, depending on the NAС response. It was found that in group 1, the median survival time was 122 months in cases with partial or complete regression (PR + pCR, and 63 months in cases with stable disease or disease progression (S + P), p > 0.05. In group 2, the median survival of patients with PR + pCR was not reached, and it was 63 months in patients with S + P, p = 0.025. Conclusions: Achievement of partial or complete regression in breast cancer patients, whose primary tumors displayed 2 or more amplifications of stemness genes, was associated with the increased rates of metastasis-free survival and can be considered as a positive prognostic criterion. However, the response to NAC did not impact survival of patients with 0-1 amplification of stemness genes.
Thyrointegrin αvβ3 nano targeted delivery of chemotherapy into solid tumors and its microenvironment.
Authors: Bharali Dhruba J. , Sudha Thangirala Institute , Godugu Kavitha , Darwish Noureldien H.E , Davis Paul Joseph , Fujioka Kazutoshi Institute , Mousa Shaker A.
Published: May 2019

e14661

Background: Cancer cells and rapidly dividing endothelial cells relevant to tumors primarily express the αvβ3 integrin. Conjugation of tetraiodothyroacetic acid (tetrac) as diamino-tetrac to a poly (lactic-co-glycolic acid) (PLGA) polymer for the formation of Nano DAT was used to target a specific cell surface receptor on the αvβ3 integrin. PLGA prohibits cell entry and the nano shell could be loaded with a generic cancer chemotherapeutic. Without a payload, Nano DAT has anticancer and anti-angiogenesis properties. Methods: Xenografts of human urinary bladder cancer (263JBV) cells, human breast cancer (SUM149PT) cells, and human pancreatic cancer (SUIT-2) cells were established. Tumor growth and tumor content of cisplatin (263JBV xenografts), doxorubicin (SUM149PT xenografts), or of paclitaxel (SUIT-2 xenografts) were compared in the following daily treatment animal arms of cohorts for 3 weeks: (1) controls, (2) void PLGA Nanoparticle (NPs), (3) chemotherapeutic agent (cisplatin 1 mg/kg, doxorubicin 1 mg/kg, or paclitaxel 0.3 mg/kg), (4) Nano DAT 0.3 mg/kg, and (5) chemotherapeutic agent encapsulated into PLGA NPs and into Nano DAT. Results: Tumors in animals treated with Nano DAT bearing a payload of cisplatin, paclitaxel, or doxorubicin were associated with decreased tumor weight by 50%-60% (P < 0.01) with > 90% loss of cancer cell viability. Mean chemotherapeutic agents content of tumors (ng/gm of tissue) was 5-fold that of tumors from animals treated with chemotherapy, alone, and 3-fold that of tumors exposed to chemotherapy encapsulated into PLGA NPs, measured with an established LC/MS/MS method. Animals receiving cisplatin, alone, developed neurotoxicity (inability to use the hind limbs) in comparison to an animal group treated with Nano DAT bearing a payload of cisplatin, and was confirmed histopathologically. Conclusions: The payload capacity of Nano DAT for cancer chemotherapeutic agents and tumor-specific delivery of cancer chemotherapeutic agents significantly increases bladder, breast and pancreatic cancer content of, respectively, cisplatin and paclitaxel.