bluuebunny/crossref_metadata_2025_split huggingface dataset:
PD-L1 expression in soft tissue sarcomas and its prognostic implication.
Authors: Kelany Mohamed Reda , Barth Thomas , Salem Dina , Mosaad Marwa 
Published: May 2019

e14261 Background: The expression rate of PD-L1 in human malignant tumors paid a lot of attention and has been reported to vary from 19% to 92%, and the expression of PD-L1 was associated with poor prognosis of various human and may predicted the response to immune checkpoint inhibitors. The purpose of this study to investigate the expression of PD-L1 and its clinic-pathological feature in soft tissue sarcomas (STS). Methods: We collected Paraffin embedded tissue of 50 Patients with STS retrospectively from the archives of Pathology and oncology Department, Ain Shams University Hospitals from 2011-2017.then we correlated between PD-L1 expression and the clinico-pathological features. For PD-L1 expression we followed the Cologne 6-step proportional scoring system, using the rabbit monoclonal antibody (E1L3N 13684) and Tumors with > /10% membranous stained cells were considered to be positive for expression. The differences among variables were calculated by chi-square test. Results: PD-L1 expression was found in 12 (24%) of cases. Of all sarcoma subtypes , desmoid tumors had the highest prevalence of PD-L1 expression noted in 2/3 (66%) of samples followed by GIST 2/4(50%), then liposarcoma 3/11(27%). In addition, there were 2 rhabdomyosarcoma cases with tumor positivity for PD-L1 expression. We found that STS patients with PD-L1 expression have shorter survival with a median OS 11 vs 19 months (p-value = 0.1) as well as a mean PFS 6 vs 11 months (p-value = 0.1) in PD-L1 positive and negative respectively; this finding considered as clinically significant, but not reached to statistical significant . Conclusions: We report here that PD-L1 expression is as prognostic factor for poorer outcome. This finding may be clinically significant but does not reach the statistically significant levels due to small number of samples included. Its role beyond that of a prognostic biomarker remains to be established in the context of larger clinical trials. Clinical trial information: 31/2017.
Evaluation of combined biomarkers for tumor response to immunotherapy (I/O) in patients with advanced non-small cell lung cancer (NSCLC).
Authors: Ramdani Hayat Oum El Kheir , Falk Markus , Schatz Stefanie , Tiemann Markus , Heukamp Lukas , Schuuring Ed , Groen Harry J.M. , Griesinger Frank 
Published: May 2019

e14269 Background: Immune checkpoint inhibitors have revolutionized NSCLC treatment. At present, the only established predictive biomarker for I/O-therapy stratification are PD-L1 expression and MSI status. However, the expression of PD-L1 is limited by heterogeneous expression and even high expressors not always respond to I/O therapy. The aim of the study is to evaluate the value of combinations of positive (Tumor Mutational Burden, PD-L1) and negative (a.o. CD73 expression and inactivating STK11 mutations) predictive markers in patients (pts) with advanced NSCLC on I/O therapy. Methods: A retrospective study was performed on a cohort of 54 pts with advanced NSCLC that have been treated with I/O between 2015 and 2017. Pts were selected by the availability of tumor tissue and based on tumor response evaluated by RECIST v1.1 criteria: only patients with durable tumor response (CR,PR ≥ 6 months) and patients with no tumor response (PD as best response) were analyzed for biomarkers: hybrid capture NGS assay for TMB (New Oncology) including STK11 mutations and IHC tests for PD-L1, CD73 and VISTA. Adjusted Cox regression and ROC analysis will be performed to evaluate the predictive value of the different biomarkers. Results: 43/54 pts received nivolumab, 11/54 pembrolizumab in different therapy lines (from 1st to 6th line). 24 pts were defined as having a durable tumor response (median PFS 20 months, median OS not reached) 30 pts as primary progressors (median PFS 2 months, p > 0.0001), median OS 12 months, p > 0.0001). In 30/54 pts enough material was available for TMB testing. The median TMB-value is 11.42 mutations/Mb. In 13 durable responders median TMB-value was 13.28 mutations/Mb versus 11.00 mutations/Mb in 17 primary non-responders. Additional analyses of PD-L1, CD73, STK11 and VISTA will be presented at the meeting as well as correlative data of the parameters analyzed. Conclusions: Our results suggest that integrating several biomarkers including positive and negative predictive markers may correlate better with responses to I/O than PD-L1 and TMB alone.
Correlation between K-RAS mutant subsets, TP53 mutation, and PD-L1 status in non-small cell lung cancer (NSCLC).
Authors: Abdel Karim Nagla Fawzy , Onuoha Chisom , Ahmad Imran , Eldessouki Ihab , Ma Patrick C. , Feldman Rebecca , Mamdani Hirva , Portnoy David Craig , Spira Alexander I. , Liu Stephen V. , Naqash Abdul Rafeh 
Published: May 2019

e14272 Background: K-RAS is a non-targetable mutation with no established predictive value. However, PD-L1 is the only approved predictive marker for immunotherapy in NSCLC. K-RAS mutation like PD-L1 has been associated with smoking. TP53 and K-RAS mutations have been identified in aggressive neoplasms. We hypothesized that K-RAS mutant NSCLC has higher PD-L1 expression suggestive of improved response to immunotherapy. Methods: The Caris database from 2016 - 2018 was queried and patients with NSCLC were identified. ≥1% staining for PD-L1 (22c3 antibody) was considered positive. PD-L1 expression as well as K-RAS and TP53 mutation status were analyzed and correlation between different variables were identified using ANOVA. Results: We identified 8,471 patients with NSCLC, where 66% had TP53 mutation and 26.9% had K-RAS mutation; both mutations were identified in 12% of the patients. In the subset of combined K-RAS and TP53 mutations there were 71.48% having positive PD-L1 expression with female predominance 1.4:1. Of the eight main K-RAS mutation subsets, G12C subset was the most common. Compared to other K-RAS subtypes, G12C was associated with the higher occurrence of PD-L1 positivity (62.68%,p < 0.04; Table). Conclusions: In comparison to other subsets of K-RAS mutation, G12C had the highest occurrence of PD-L1 expression, suggestive of improved response to immunotherapy. However, the subset of patients with combined K-RAS and TP53 mutations had a higher occurrence for the PD-L1 positive status of 71.48%. [Table: see text]
Biomarkers of Chinese advanced cancer patients based on real-world data: Actionable genomic alterations and tumor mutational burden.
Authors: Wang HaiTao , Wang Huina , Guo Rongyun , Li Mingwei , Zhang Yanrui , Lou Feng , Cao Shanbo 
Published: May 2019

e14280 Background: Biomarkers would enrich patients(pts) with responsiveness to both targeted treatments and immunotherapy which have become a priority. However, molecular heterogeneous in actionable gene alterations and mutational loads need to be explored. In this study, based on a real world setting, Cancer Gene Panel (CGP） analysis was performed in a series samples of Chinese pts with advanced solid tumors, to delineate the landscape of actionable mutations and tumor mutational burden (TMB). Methods: 176 advanced pts were enrolled encompassing 19 common tumor types. All tissue samples were analyzed using next-generation sequencing with Acornmed panel including 808 genes. Results: The frequencies of genetic alterations among the most common driver genes were comparable to those reported by MSK-IMPACT (2018) ( TP53: 51.7% vs 44.8%; APC: 9.7% vs 9.8%; EGFR: 12.5% vs 7.7%; KRAS: 16.5% vs 13.6%; PIK3CA: 4.6% vs 12.0%; VHL: 4.0% vs 6.7%). 58.3% of pts with refractory solid tumors had at least one actionable mutation. Among those pts, 16.7% of them including CDK4, CDK6 or CDKN2A/B could benefit from palbociclib, and 32.1% of them including mTOR, PIK3CA, PTEN or STK11 could benefit from everolimus, and 61.9% of them including BRCA2, ARID1A, MSH1/2/6 or ATM could benefit from olaparib. Across all the specimens, the top 20% of TMB was 17.23 mutations/Mb, with a range of 0-48 mutations/Mb. The top 20% of TMB for each tumor type was 21.67(Bladder cancer), 17.23(Lung cancer), 16.45(Colorectal cancer), 11.04 (Renal cell cancer), 16.25 (Prostate cancer) , 19.70 (Hepatobiliary cancer), 14.78 (Esophagogastric cancer), 7.80 (Pancreatic cancer), 25.31 (undefined tumor) mutations/Mb respectively. Conclusions: This study indicates that most of pts with advanced refractory solid tumors have at least one actionable mutation, and matched therapies may confer clinical benefit. TMB fluctuated wildly across different cancer types, illustrating the unequal objective response rate of immunotherapy across various cancer type. Furthermore, CGP analysis in advanced pan-cancer pts can provide opportunities for targeted therapies and immunotherapy, especially in those with refractory cancer.
Utilization of novel highly multiplexed immunofluorescence microscopy technology to understand immunological tumor microenvironments in small cell lung carcinoma patients receiving combination PD-L1 and PARP inhibition therapy.
Authors: Trindade Christopher Julius , McDonough Elizabeth , Hanson Jeffery , Walter Rodriguez Beatriz , Roper Nitin , Gasmi Billel , Roque Claire , Gebregziabher Makda , Ylaya Kris , Fetsch Patricia , Abdul Sater Houssein , GINTY FIONA , Hewitt Stephen M. , Thomas Anish 
Published: May 2019

e14289 Background: Immune checkpoint inhibitors have changed the way we treat most malignant tumors especially lung carcinomas. While PD-L1 is the only FDA approved companion diagnostic used to predict response, its accuracy and specificity is lacking. Thus, new biomarkers and mechanisms of checkpoint inhibitor need to be elucidated. A major limitation with the current approved method, immunohistochemistry, is that it can typically only measure one parameter per tissue section. Currently new multiplexing microscopy techniques are being developed that allow us to see multiple parameters at the cell level, which can answer new questions regarding tumor immune microenvironments (TIME). In this study we used a novel multiplexed immunofluorescent (MxIF) microscopy technique, Cell DIVE™ (GE Healthcare, Issaquah, WA), to analyze formalin fixed paraffin embedded (FFPE) tissue samples from small cell lung carcinoma (SCLC) patients treated with a PD-L1 inhibitor, durvalumab (MEDI4736), in combination with a PARP inhibitor, olaparib. Methods: Biopsies from patients enrolled in a phase II expansion cohort clinical trial (NCT02484404) treated with durvalumab and olaparib were analyzed. Tumor immune response from a cohort of 3 responders and 3 non-responders, before and after treatment, underwent MxIF analysis using biomarkers including CD3, CD4, CD8, CD20, CD39, CD45RA, CD45RO, CD56, CD57, CD103, FOXP3, GATA3, LAMP1, PD-L1 and T-bet. Our panel was able to effectively discern T-cells (including subsets, maturation, and function), B-cells, and NK cells and their interaction with tumor cells. The results were validated for accuracy and consistency using immunohistochemistry and Vectra Polaris Imaging System. Results: Spatial analysis of TIME showed responders (3/3) were associated with an inflamed CD8+ T-cell tumor microenvironment while non-responders (3/3) displayed an excluded or desert CD8+ T-cell tumor microenvironment. MxIF/Cell DIVE™ allowed us to further characterize the immune response. Conclusions: Analyzing the type and pattern of immune response using multiplexed immunofluorescent and single cell characterization microscopy may better predict prognosis than PD-L1 immunohistochemistry in SCLC patients treated with immune checkpoint inhibitors. Clinical trial information: NCT02484404.
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.