bluuebunny/crossref_metadata_2025_split huggingface dataset:
A RNA signature predicts outcomes in immune checkpoint blockade treated gastrointestinal cancer patients.
Authors: Lu Zhihao , Chen Huan , Li Shuang , Jiao Xi , Wu Lihong , Yu Jianing , Shen Lin , Zhang Henghui 
Published: May 2019

e14071 Background: Cancer therapy has been greatly revolutionized in recent years by the conceptual developments in the field of cancer immunology. Growing evidence support the utility of immune checkpoint inhibition (ICB) in gastrointestinal (GI) cancer. However, a central question lies in understanding how therapeutic responsiveness is predicted. Methods: To address this, we evaluated tumor FFPE specimens from 97 patients who received ICB treatment. All patients were randomly assigned into discovery (60%) and validation (40%) cohorts. Tumor RNA before ICB treatment was analyzed on a multiplex RNA immune oncology (RNA IO) profiling sequencing panel. Results: We show that four immune-related gene expression signatures were upregulated in responders versus non-responders in the discovery cohort. Three of the four signatures showed significant correlation with clinic response and disease control rates. However, two previously reported RNA signatures, PD-L1 expression and MMR status revealed less predictive values in GI cancers. More importantly, we identified that higher levels of a 19-gene signature were remarkably associated with favorable overall survival (OS) and progression-free survival (PFS) when compared to patients with lower levels of signature in both the discovery and validation cohorts. Of note, a joint biomarker of tumor mutation burden (TMB) and the 19-gene signature may better stratify responders from non-responders in GI cancer patients. Conclusions: Our data provide evidence that a responsive feature, defined by a multi-gene expression pattern across different GI cancer types, can be obtained via a RNA quantitative strategy and may be explored as a future pan-cancer biomarker.
Efficacy and safety of PD-1 inhibitors in combination with chemotherapy versus chemotherapy as first and second line treatment in advanced gastric and gastroesophageal junction cancer: Preliminary data from a real-world setting.
Authors: Hu Yi , Li Tao , Zhang Fan , Zhao Lei , Zhao Xiaochen , Cai Shangli , Zhao Jing , Jiao Shun Chang 
Published: May 2019

e14079 Background: Unresectable locally advanced or metastatic gastric and gastroesophageal junction (G/GEJ) cancer is an aggressive disease with poor outcomes. Although pembrolizumab monotherapy has been approved as third-line therapy for selected G/GEJ tumors expressing programmed death ligand 1 (PD-L1), the combination regimens of PD-1 inhibitor with chemotherapy are rarely studied. Our study explored the efficacy and safety of PD-1 inhibitors combined with conventional therapy as first and second line treatment in advanced G/GEJ cancer. Methods: Patients with stage IV G/GEJ cancer treated with PD-1 combination therapy or chemotherapy alone in the Cancer Center of the Chinese People’s Liberation Army from January 2016 to January 2019 were screened for eligibility. Patients with third-line treatment and beyond were excluded. Primary endpoints were objective response rate (ORR) and progression-free survival (PFS). Secondary endpoints included overall survival (OS) and safety profile. Kaplan-Meier estimates and Cox regression were performed in the analysis of PFS and OS. Results: 60 patients were included in our analysis, including 20 patients with PD-1 inhibitors plus chemotherapy and 40 patients with chemotherapy alone. ORR was achieved in 7 of 20 (35%) patients in combination group versus 7 of 40 (17.5%) in chemotherapy group. In the first-line setting, ORR was 70% in combination group versus 16.1% in the chemotherapy group. Combination group showed significant favorable PFS compared with chemotherapy alone (median PFS, not reached versus 4.95 months; HR, 0.41; 95% CI, 0.48 to 0.93; P = 0.03). Preliminary data of OS showed a trend of superiority of combination group but did not present statistically significance (HR 0.33, 95% CI 0.08-1.33, P = 0.10). Incidence of grade 3 or worse treatment-related adverse event was similar between groups (3 of 20 [15%] in combination group, 7 of 40 [17.5%] in chemotherapy group). Conclusions: Addition of PD-1 inhibitor into chemotherapy could be effective and tolerable as first and second line treatment in advanced G/GEJ cancer. These findings need further evaluation by randomized controlled studies. Survival follow-up of present cohort is ongoing.
A clinical prognosis model for Asian advanced melanoma patients receiving immunotherapy.
Authors: Wang Xuan , Yan Xieqiao , Chi Zhihong , Si Lu , Sheng Xinan , Kong Yan , Mao Lili , LIAN BIN , Tang Bixia , Zhou Li , Cui Chuanliang , Guo Jun 
Published: May 2019

e14081 Background: Immunotherapy PD-1 inhibitor therapy shows relative lower efficacy in Asia especially in acral and mucosal subtypes. The identification of predictive factors of immunotherapy remains a crucial but unmet clinical need. The objective of this study was to evaluate advanced melanoma patients treated with anti-PD-1 in order to identify risk factors for PFS, OS and develop a prognostic scoring system for immunotherapy. Methods: Patients with unresectable melanoma treated with PD-1 inhibitor enrolled on trials between 2015 and 2017 at Peking University Cancer Center were included. A nomogram to predict survival was developed based on a multivariable Cox model. The predictive performance of the model was assessed according to the C-statistic, Kaplan–Meier curve and calibration plots. Results: The discovery cohort comprised 133 patients with unresectable melanoma. 38.3% acral and 21.8% mucosal melanomas were included, 26.3% with liver metastases, 31.6% with an elevated serum LDH, 20.3% harbored BRAF mutations. The median PFS was 4.8 months, based on the Cox model, four factors were selected for the nomogram and assigned specific scores: tumor metastases number≥3, 1; tumor size≥80 mm,1; LDH level, 1 (higher limit of normal range); liver metastases,1. The model achieved relatively good discrimination and calibration, with a C-statistic of 0⋅804 (Table). BRAF mutations were associated with shorter PFS in univariate analysis but not in multivariate analysis. Subtypes were also not related to PFS in this cohort. The median OS was 22.8 months. Univariate analysis identified eight factors were associated with significantly worse OS among 21 factors ( BRAF and subtype included, which not found as risk factors). Based on the Cox model, five factors were selected for the nomogram and assigned specific scores: ECOG > 1, 0.6; Hemoglobin < 120g/ml,0.6; tumor size≥80 mm,1.4; LDH level, 0.5; liver metastases, 1. C-statistic was 0⋅85, with extremely strong predictability (Table). The overall survival rate for patients with a higher score was significantly worse than lower cohort (Score: < 0.6 vs. 1-2 vs. 2-4.1; OS: not reached vs. not reached vs. 8.3m; P < 0⋅001). Conclusions: The nomogram facilitates personalized assessment of prognosis for Asian patients with advanced melanoma with PD-1 inhibitor. [Table: see text]
Safety and tolerability of immune checkpoint therapies and related adverse effects at a tertiary care hospital in Saudi Arabia.
Authors: Al Nuhait Mohammed , Al Awlah Yousef , Bajnaid Eshtyag 
Published: May 2019

e14082 Background: Immunotherapies associated with many toxicities with a potential immune-mediated cause and has been associated with many adverse events in the literature. As the incidence of emergency room (ER) visits in adult patients receiving immune checkpoint therapies and most frequent immune-related adverse events are not yet established well for our population since this class of medications is newly introduced in the oncology field. This research is aimed to shed the light on this new class of medications. Methods: This is a single-center retrospective cohort study to determine incidence of ER visits in adult patients receiving immune checkpoint therapies and to explore most frequent related adverse events. The study involved adult patients who were treated at King Abdulaziz Medical City. Study participants were identified by identified using our electronic health care system to identify patients who were treated with immunotherapies during the study period (January 2016 to December 2018). Inclusion criteria was patients aged more than 18 years who had received immunotherapies. Results: A total of 53 patients met the specified inclusion criteria for our study. The number of patients in each treatment group were as follows: Nivolumab 37, Atezolizumab 10 and Pembrolizumab 6. Average age was 59 years. The percentages of cancer patients presenting to the ER with various related adverse effects after beginning immune checkpoint therapy were (65%) Nivolumab, (80%) Atezolizumab and (83%) Pembrolizumab. The average number of ER visits after beginning immune checkpoint therapy was 3 visits (SD = 2.8). Renal adverse events were occurred following the immunotherapy use, 9 patients (17%) and none of cases experienced a grade≧3 event. 13 patients (24.5%) experienced hepatic adverse event. Only one patient experienced a grade≧3 event that lead to discontinuation of treatment. For diarrhea, among all patients received the immunotherapies, 14 (26%) experience diarrhea and five of them experience grade≧3 event. Thyroxine abnormalities occurred in 7 patients (13%) after use of immunotherapies. (7.5 %) of patients had pneumonitis with immunotherapy. Other adverse events were noted with immune therapies (skin reaction, nausea, vomiting, thrombocytopenia, neutropenia and neurological adverse events). All others adverse events that is reported had a grade 1-2 adverse events. Conclusions: Patients treated with immunotherapies may have a spectrum of adverse drug events that might lead to discontinue the treatment and increase ER visits.
Differences in prescribing and patient demographics of cki agents among United States patients < 65 and 65+ years old.
Authors: Angel William H , Franceschetti Alessandra 
Published: May 2019

e14097 Background: Since FDA approval, immune checkpoint inhibitors (CKIs) have become increasingly important in treating NSCLC, particularly among mutation-negative patients who did not benefit from biomarker testing. Because clinical trials typically recruit healthy patients, little information is available to understand the role of CKIs in treating older patients, who also face immunosenescence. This study explores differences in prescribing behavior of CKIs for mutation-negative NSCLC patients < 65 y/o and 65+ y/o in the US and satisfaction with results. Methods: The Ipsos Global Oncology Monitor: an online multi-center medical chart review study of stage IIIb-IV NSCLC patients currently receiving drug treatments seen in consultation from June – November 2018. 170 US physicians provided de-identified data on 1484 patients negative or untested for EGFR, ALK, ROS1 and BRAF. Results: Compared to patients < 65 y/o (n = 539), those 65+ y/o (n = 945) were prescribed a CKI significantly more often, 63% vs 70% (p < 0.01), driven by CKI monotherapy (CKIm) use, 47% vs 55% (p < 0.01). This trend was seen among patients on 1L therapy (n = 1015), with 42% of patients < 65 y/o and 50% of patients 65+ y/o on CKIm (p < 0.05), and on 2L therapy (n = 337), with 62% of patients < 65 y/o and 76% of patients 65+ y/o on CKIm (p < 0.01). In both lines, this was due to more use of nivolumab among 65+ y/o patients (p < 0.01), while among 2L patients < 65 y/o there was also greater use of pembrolizumab (p < 0.05). Physicians’ stated satisfaction with 1L CKI results was similar in both cohorts but, at 2L, greater among patients 65+ y/o (μ = 8.45; σx̅= 1.26) vs patients < 65 y/o (μ = 8.01; σx̅= 1.38) (p < 0.05). Older 2L CKIm patients were more likely to be ECOG 2+ (18% vs 5%; p < 0.01) and to have 2+ concomitant conditions (60% vs 36%p < 0.01). Conclusions: Satisfaction with 2L CKIs is higher in older vs younger patients, despite the former’s association with poorer outcomes. Potentially, lower expectations at treatment initiation caused higher satisfaction for similar treatment success, but this may also be due to immunosenescence, one study suggesting CKIs are more effective in older melanoma patients ( https://dx.doi.org/10.2147%2FOTT.S165368 ). The role of age in CKIs’ efficacy in NSCLC merits further investigation.
Anti-PD-1 therapy combined with chemotherapy in patients with advanced pancreas cancer in a real-world clinical setting.
Authors: Sun Danyang , Ma Junxun , Wang Jinliang , Han Chun , Qian Yuanyu , Chen Guangying , Li Xiaoyan , Zhang Juan , Cui Pengfei , Du Wushuang , Wu Zhaozhen , Chen Shixue , Zheng Xuan , Yue Zhichao , Song Jia , Cai Shangli , HU YI 
Published: May 2019

e14103 Background: Pancreatic cancer (PC) is a highly lethal disease and characterized by a strong resistance to current radiotherapy and chemotherapy. As PC has the presence of a microenvironment filled with immunosuppressive mediators and a dense stroma which involved in immune system control, the immune system has been hypothesized to play an important role in PC. However, there was no response in patients who received immune checkpoint inhibitors (ICIs) monotherapy. Though small sample studies revealed that ICIs combined with chemotherapy is effective, a head-to-head comparison of ICIs plus chemotherapy and chemotherapy is limited. Methods: Advanced PC patients treated with chemotherapy alone or plus ICIs were retrospectively screened for eligibility. Patients previously treated with any agent targeting T-cell co-stimulation or checkpoint pathways was excluded. The primary outcome was overall survival (OS). Secondary outcomes were progression-free survival (PFS), overall response rate (ORR) and safety. Results: In total, 58 patients were included (combination, n = 22; chemotherapy, n = 36). Combination group presented significantly longer OS than chemotherapy group (median, 18.1 vs 6.1 months, HR 0.46 [0.23-0.90], P = 0.021). Median PFS was 3.2 months in the combination group and 2.0 months in the chemotherapy group (HR 0.57 [0.32-0.99], P = 0.041). The ORR was similar between the combination group and the chemotherapy group with no significant difference (18.2% vs 19.4%, P = 0.906). And all the patients, who reached partial response, accepted a two-chemotherapic-drugs regimen regardless of combinating with ICIs. Adverse events of grade 3 or higher occurred in 31.8% of the patients in the combination group and in 16.9% of those in the chemotherapy group. Though the incidence rate of serious treatment-related adverse events (TRAEs) was higher in the combination group than the chemotherapy group, no statistical significance existed (P = 0.183). Conclusions: Combination of ICIs plus chemotherapy is effective and tolerable for advanced PC. Accepting ICIs combined with a two-drug chemotherapy regimen might be the better choice.
Gene expression profiles of peripheral blood mononuclear cells from patients with advanced non-small cell lung cancer treated with anti-PD-1 monoclonal antibodies.
Authors: Wu Jie , Cheung Yee Him , Huang Weihua , Yin Changhong , Fallon John T , Dimitrova Nevenka , Fanucchi Michael Paul 
Published: May 2019

e14107 Background: Anti-PD-1 monoclonal antibodies have improved the outcome for patients with advanced non-small cell lung cancer (NSCLC). The goal of this study is to characterize the longitudinal gene expression profiles of peripheral blood mononuclear cells (PBMCs) in patients with advanced NSCLC treated with anti-PD-1 monoclonal antibodies and to evaluate the potential of this technology to predict response to therapy. Methods: PBMCs were collected using density centrifugation from patients with stage III/IV NSCLC before the first (T0) and second (T1) treatments, and, for responding patients, before the third (T2), fourth (T3), fifth (T4) and sixth (T5) treatments. Total RNA was extracted, and libraries were prepared using TruSeq Stranded mRNA LT Sample Prep Kit and sequenced by Illumina NextSeq. The paired-end reads were mapped to human reference hg38 using STAR and gene expressions were calculated using RSEM. Longitudinal differential gene expression with pathway analysis and principal component analysis (PCA) was performed across all time points. Genes with Bonferroni-adjusted p values < 0.05 were selected for pathway enrichment analysis with DAVID. Results: Nine of 15 patients have been enrolled. Six patients had a PR by RECIST 1.1, 2 patients have had stable/PD, 1 patient too early. Differential gene expression (DE) is available for the 8 patients with response assessment. There was differential expression of certain genes between T0 and T1 in the following pathways in responders but not in stable/PD: T cell receptor complex (p = 3.1E-6), regulation of immune response (p = 2.5E-5), T cell costimulation (p = 3.9E-3) were upregulated. CD24 is downregulated, while C4B is upregulated. Using PCA analysis we detected strong signal from the beta-hemoglobin HBB transcript. We observed HBG1 and HBM consistently upregulated at T1 (adjusted p = 7.9E-19 and p = 2.3E-10 respectively) through to T4 (adjusted p = 8.8E-27 and p = 3.8E-18 respectively). Conclusions: Anti-PD-1 monoclonal antibodies induce DE of genes in PBMCs from patients with advanced NSCLC. This technology may provide a predictive test for response to anti-PD-1 monoclonal antibodies.
Eosinophilia during treatment of immune checkpoint inhibitors (ICIs) to predict succeeding onset of immune-related adverse events (irAEs).
Authors: Kizawa Rika , Miura Yuji , Oda Yasuhiro , Nagaoka Yukiko , Ozaki Yukinori , Kondoh Chihiro , Moriguchi Shuhei , Takahashi Yui , Ogawa Kazumasa , Tanabe-Hashimoto Yuko , Taniguchi Shuichi , Okaneya Toshikazu , Kishi Akiko , Hayashi Nobukazu , Kishi Kazuma , Takano Toshimi , Masuda Jun 
Published: May 2019

e14110 Background: ICIs such as anti-PD-1/-L1 Inhibitor and anti-CTLA-4 Inhibitor have been used in many types of cancer, and irAEs occur in a considerable proportion of patients. Predictive biomarkers could help us to manage irAEs promptly. Methods: We retrospectively analyzed the consecutive patients treated with nivolumab, pembrolizumab, atezolizumab or ipilimumab, not used as investigational drugs, between March 2015 and December 2018 based on the electric medical records in our institution. We evaluated the relationship between clinical and laboratory factors (gender, age, body mass index, lymphocyte-to-monocyte ratio and eosinophilia) and the occurrence of irAEs using univariate and multivariate analyses. Eosinophilia was defined as absolute eosinophil count over 500/mm3 at least once between initiation of treatment and the occurrence of irAEs. We graded irAEs according to CTCAE v. 5.0. Results: Among 139 patients analyzed in this study, 136, 13 and 6 patients were treated with PD-1, PD-L1 and CTLA-4 inhibitors, respectively (cumulative total of 155 patients). This study included non-small cell lung cancer (n = 78; 56.1%), renal cell carcinoma (n = 17; 12.2%), melanoma (n = 16; 11.5%), gastric cancer (n = 15; 10.8%), Hodgkin lymphoma (n = 7; 5.0%), urothelial carcinoma (n = 3; 2.2%), head and neck carcinoma (n = 3; 2.2%) and mesothelioma (n = 1; 0.7%). Any grade and grade 3-5 irAEs occurred in 60 (38.7%) and 23 (14.8%) cumulative patients, respectively. The most common irAEs in any grade were endocrine disorders including thyroid dysfunction and adrenal insufficiency (n = 21) and skin disorders (n = 20). Eosinophilia occurred in 43 cumulative patients (27.7%). Eighteen patients out of them had eosinophilia from baseline. Among the clinical and laboratory factors, only eosinophilia was significantly associated with the occurrence of any grade of irAEs in both univariate (p = 0.0193) and multivariate (p = 0.0464) analysis. Notably, endocrine irAEs were significantly related to eosinophilia (p = 0.0287). Conclusions: Eosinophilia after the initiation of treatment with ICIs predicts succeeding onset of irAEs.
Real-world use and survival outcomes of immune checkpoint inhibitors in patients with non-small cell lung cancer.
Authors: Youn Bora , Trikalinos Nikolaos , Mor Vincent , Wilson Ira , Dahabreh Issa 
Published: May 2019

e14111 Background: Little is known about the real-world use and survival outcomes of immune checkpoint inhibitors among elderly patients with non-small cell lung cancer (NSCLC). Methods: Using the SEER-Medicare data, we identified 1,338 patients who were diagnosed with pathologically confirmed stage 1-4 NSCLC between 2002 and 2015 and initiated nivolumab or pembrolizumab in 2016. We examined the association of patient and disease characteristics, and treatment history with overall survival, from initiation through December 31, 2017. We estimated survival curves using the Kaplan-Meier method and identified predictors of survival using multivariable Cox proportional hazards regression. Results: The median age at immune checkpoint inhibitor initiation was 74.8 years. The majority of patients were initially diagnosed with stage 4 disease (42.7%). Median time from diagnosis to initiation were 13.9 and 19.0 months for those initially diagnosed with stage 4 and 1-3 disease, respectively. Median overall survival was 9.5 months. In multivariable analyses, multiple comorbid conditions, squamous histology, history of non-platinum doublet systemic therapy, recent radiation therapy, and shorter time from initial diagnosis to initiation were statistically significantly associated with increased hazard of death (Table). Demographics, stage at initial diagnosis, and prior oral targeted therapy were not significantly associated with the hazard of death. Conclusions: Real-world data show that factors that are generally related to poor prognosis remain predictors of survival in elderly patients treated with immune checkpoint inhibitors.[Table: see text]