bluuebunny/crossref_metadata_2025_split huggingface dataset:
Risk factors for emergency room and hospital care for patients with advanced solid tumors on immune checkpoint inhibitor therapy.
Authors: Parikh Anish B , Mellgard George , Qin Qian , Patel Vaibhav G. , Wang Bo , Zhong Xiaobo , Leiter Amanda , Gallagher Emily J. , Galsky Matt D. , Oh William K. , Clinton Steven K. , Mortazavi Amir , Monk Paul , Folefac Edmund , Yin Ming , Yang Yuanquan , Tsao Che-Kai 
Published: May 2020

e15142 Background: Immune checkpoint inhibitors (ICIs) are increasingly utilized across cancer types. Risk factors for emergency room (ER) and inpatient (IP) care in this patient (pt) population remain poorly defined. Methods: We retrospectively reviewed charts for pts with (w/) advanced solid tumors who received more than 1 ICI dose at Mount Sinai from 1/1/11 – 4/28/17. Demographics, medical history, cancer diagnosis and therapy (tx) details, and outcomes were recorded. Descriptive data detailing ER/IP care during ICI tx (from first dose to 3 months after last dose) were collected. Fisher’s exact test and multivariable regression analyses were used to study differences between pts w/ versus w/out ER/IP care during ICI tx. Significance level was set at 0.05 for all tests. Results: 345 patients met the inclusion criteria for this study. Mean age was 64 years. Common tumor types were non-small cell lung cancer (n = 87), melanoma (n = 78), hepatocellular carcinoma (n = 53), and urothelial carcinoma (n = 38). 83% of patients had metastatic disease. Median duration of ICI tx was 2 months. During ICI tx, 50% received ER care and 43% received IP care, resulting in 369 total episodes of ER and/or IP care. 12% of episodes were attributed to ICI toxicity; 6% required intensive care. Median time to ER/IP care was 111 days. Median IP length of stay was 2 days. Several factors were found to be significant predictors of risk for ER or IP care on multivariable analysis (Table). African-American race and Hispanic ethnicity were each predictive of increased risk for both ER and IP care. Conclusions: ER/IP care is common among pts w/ advanced solid tumors on ICI tx. Understanding demographic and clinical risk factors can help prospectively identify higher-risk pts to inform preventive programs aimed at reducing such care. [Table: see text]
Tolerability of single agent nivolumab in cancer patients—A meta-analysis.
Authors: Huang Judy , Carvajal Alejandro Ramon , Wu Shenhong 
Published: May 2020

e15146 Background: Nivolumab, a PD-1 immune checkpoint inhibitor, is being widely utilized in a number of cancers as a single agent. Adverse events, including those that are immune mediated, have been reported that resulted in discontinuation of the drug. We conducted a meta-analysis of published clinical trials to further investigate the tolerability of nivolumab in cancer patients. Methods: Databases, including PubMed and abstracts presented at American Society of Clinical Oncology annual meetings from 2015 to December 2019 were searched to identify relevant studies. This included randomized controlled trials and single arm trials that reported a discontinuation rate due to adverse events. Incidences and relative risks were calculated based on the heterogeneity of included studies. Results: Seventeen studies published between 2015 and 2019 were selected, which included a total of 4216 patients. Overall, the discontinuation rate of nivolumab due to adverse events was 6.7% (95% CI 4.7-9.5%). The rate varied significantly with the type of cancer (p < 0.001). The lowest discontinuation rate was in NSCLC of 2.1% (95% CI 1.3-2.3%), and the highest discontinuation rate was in melanoma of 15.2% (95% CI 6.8-30.6%). In addition, significantly higher intolerability is associated with the fixed dose of nivolumab at 240 mg than 3 mg/kg (P = 0.004). In comparison with chemotherapy controls, the intolerability in the nivolumab group was not significantly different, with a relative risk of 0.97 (95% CI: 0.36-2.6). Conclusions: The intolerability of nivolumab as monotherapy may be similar to chemotherapy, and can be improved with dose adjustment.
Blood-based gene expression profiling to reveal potential response biomarkers for immunotherapy in advanced lung cancer.
Authors: Wu Jie , Huang Weihua , Yin Changhong , Cheung Yee Him , Abrams Debra , Fallon John T , Dimitrova Nevenka , Fanucchi Michael Paul 
Published: May 2020

e15155 Background: Novel immunotherapies are becoming a viable option for advanced lung cancer treatment. High-throughput gene expression profiling (GEP) has enabled better understanding of patient responsiveness to targeted immunotherapy. However, non-invasive blood-based signatures are needed to monitor and predict response. Methods: To evaluate the predictive and prognostic role of blood-based GEP, we designed a longitudinal study by enrolling 15 patients with advanced lung cancers. A total of 65 samples were collected for RNA sequencing, ~4 blood specimens per patient, before and during anti-PD-1 treatment. We used multiple analyses, including time-course differential gene expression, principal component, lymphocyte compartment deconvolution, and genetic mutation, to search for and assess potential predictive and prognostic aspects. Results: Of 15 patients, 11 were classified as Responders (partial responders) and four were Non-Responders (one stable and three progressive diseases). Our analyses demonstrated: 1) By comparing baseline GEPs from Responders vs. Non-Responders before the first treatment, we identified potential markers (e.g., LY6E is significantly lower expressed in Responders, with Log2 Fold change = -3.44 and p = 1.83E-04) that can be used as predictors of responsiveness of the patients; 2) Immunoglobulin subunits- and T cell receptor complex-related genes were differentially expressed in Responders (DAVID analysis, p = 6.7E-3 and 2.1E-2, respectively), but not in Non-responders; 3) γδ T cells in the lymphocyte compartment were relatively increased in Responders; 4) Despite a different set of genes differentially expressed at different time points, the biggest GEP changes were at ~ week 6, after the second treatment. Additionally, we observed certain genes consistently up- or down-regulated through the whole course of treatment. Furthermore, after the first treatment, genes in the immune response pathway were regulated to different directions in Responders and Non-Responders. For example, interleukin receptor genes, such as IL18R1 and IL18RAP, and CD24 were down-regulated in Responders, but up-regulated in Non-Responders (p = 0.042, 0.023 and 0.044 respectively, t-test for the differential expression in these two groups). Conclusions: The utility of blood GEP to identify predictive and prognostic factors for precision immunotherapy is encouraging. Nevertheless, these results, predictive of the anti-PD-1 clinical response, are preliminary and need to be validated in a larger cohort.
Correlation of immunity-related adverse events with survival and response to anti-PD-1 treatment in patients with metastatic melanoma.
Authors: Cybulska-Stopa Bozena , Lugowska Iwona , Zietek Marcin , Dawidowska Anna , Czarnecka Anna Malgorzata , Piejko Karolina , Galus Lukasz , Ziolkowska Barbara , Kieszko Stanislaw , Kosela-Paterczyk Hanna , Switaj Tomasz , Kozak Katarzyna , Rogala Pawel , Kempa-Kaminska Natasza , Calik Jacek , Teterycz Pawel , Staroslawska Elzbieta , Suwinski Rafal , Mackiewicz Jacek , Rutkowski Piotr 
Published: May 2020

e15164 Background: Immunotherapy has become a standard treatment option for metastatic melanoma patients, and the use of anti-programmed cell death-1 monoclonal antibodies (anti-PD-1) has significantly improved the outcomes of this group of patients. Immune related adverse events (irAEs) during anti-PD-1 treatment may present a significant problem. However, irAEs' relationship with overall survival although suggested in single studies was not confirmed in real world data. Methods: Consecutive patients starting treatment between March 2016 and April 2019 with fist line anti-PD-1 (nivolumab or pembrolizumab) for unresectable or metastatic melanoma in 6 comprehensive cancer centers in Poland were enrolled in the study. Baseline patients characteristics and irAEs development during treatment were evaluated to identify predictors of progression-free (PFS) and overall (OS) survival in Cox model. PFS and OS were assessed using Kaplan–Meier method. Results: Overall, 410 patients were included in the present analysis and 107 patients experienced irAEs. Response rate (RR) and disease control rate (DCR) were 36% (148 pts) and 65% (267 pts) respectively. Median PFS and OS were 7.6 (2.8–21.6) and 21.6 (6.7–38.2) months, respectively. In univariate analysis normal LDH level, no brain metastases, ECOG 0 or 1, ≤ 2 number of metastases locations were positive prognostic factors for both OS and PFS. At the same time irAEs occurrence was correlated with longer PFS, OS, RR and DCR (all p < 0.001); moreover high LDH level correlated with irAEs (p = 0.027) development. There was no correlation between irAEs and the number of cycles of anti-PD-1 patients received. Conclusions: Our study showed an association between irAEs and longer survival on anti-PD1 therapy in patients with advanced or metastatic melanoma. An association with irAEs and response to therapy has also been demonstrated.
Pre-existing interstitial lung abnormalities are risk factors for immune checkpoint inhibitor-induced interstitial lung disease in non-NSCLC cancers.
Authors: Shimoji Kiyofumi , Masuda Takeshi , Nakanishi Yu , Yamaguchi Kakuhiro , Sakamoto Shinjiro , Horimasu Yasushi , Nakashima Taku , Miyamoto Shintaro , Iwamoto Hiroshi , Fujitaka Kazunori , Hamada Hironobu , Hattori Noboru 
Published: May 2020

e15171 Background: Immune check point inhibitor (ICI) induced interstitial lung disease (ICI-ILD) is a clinically serious and life-threatening toxicity. Pre-existing ILD has been reported to be a risk factor for ICI-ILD in patients with non-small cell lung cancer (NSCLC). In addition, we have previously reported that interstitial lung abnormality (ILA) is also a risk factor for the ICI-ILD. Therefore, we investigated whether any patient characteristics, including ILA, were risk factors for ICI-ILD in patients with non-NSCLC cancers. Methods: Head and neck cancer, malignant melanoma, oral cavity cancer, renal cell carcinoma or gastric cancer patients who received anti PD-1 antibody (Nivolumab or Pembrolizumab) at Hiroshima University Hospital from December 2015 to May 2019 were enrolled. Information on patient characteristics before anti-PD-1 antibody administration, including chest CT findings and laboratory data, were obtained. Results: Two hundred patients were enrolled, and 20 (10%) developed ICI-ILD. Grade1 was observed in 15 patients, grade2 in 3, and grade3 and 5 in 1. There was no significant difference in the background factors between patients with and without ICI-ILD. On the other hand, the proportion of patients with ILA was significantly higher in the patients with ICI-ILD than those without (P < 0.01). Furthermore, univariate logistic regression analysis revealed ILA was the risk factor for ICI-ILD (p < 0.01), and multivariate logistic regression analysis showed that GGA or reticulation in ILA was an independent risk factor for ICI-ILD (p = 0.016, 0.011). Conclusions: Pre-existing ILA is a risk factor for ICI-ILD, and GGA or reticulation in ILA is an independent risk factor for ICI-ILD in patients with non-NSCLC cancers. Therefore, we should pay more attention to the development of ICI-ILD in patients with ILA, especially GGA or reticulation.
Lung cancer immunochemotherapy: Codelivery of EGFR tki and PTX via an immunostimulatory dual functional nanocarrier.
Authors: Diao Dingwei , Cai Kaican , Liu Xiguang , Yang Jianjun 
Published: May 2020

e15177 Background: Immuno-target therapy combines a target therapy agent with an immune modulating agent and represents an attractive approach to improve cancer therapy.However, the success of it is hampered by the lack of a strategy to effectively co deliver the two therapeutics to the tumours.Here we report an improved dual functional nanocarrier (PEG5k-Fmoc-NLG2) to load Gefitinib for improved cancer Immuno target therapy.PEG5K-Fmoc-NLG2 is a prodrug that can inhibited IDO enzyme activity in vitro,while IDO1 inhibition reversed T cell suppression mediated by IDO expressing mouse cancer cells. Methods: Gefitinib loaded in carrier was prepared via a film hydrationmethod,the physicochemical properties of micelles was determined by TEM and particle size test.The cytotoxicity of the drug was detected by MTT assay. 3LL lung cancer was inoculated in mice and different drugs was injected through the tail vein to compare the anti tumor effect of drug loading micells with existing targeted drug gefitinib and CTLA4 antibody; tumor tissue proteins were extracted to clarify changes in pEGFR expressionexpression; flow cytometry will be finished to observe tumor immune microenvironment changes. Results: 1. Gefitinib loaded micelle maintain the similar size with blank PEG5k-fmoc-NLG2 micelles that is around 20nm.The drug-loaded micelles produced uniformed size and morphology. which further confirmed the size of micelles was around 20nm. 2. PTX and Gefitinib loaded in PEG5k-fmoc-NLG2 exhibited significantly enhanced tumor cell killing effect than the free drug on both A549 and 3LL cell lines. 3. The antitumor efficacy of different drugs loaded in the carrier were tested in a murine lung cancer model (3LL). All treatment showed significant better antitumor activity compared to the control group, Gefitinib/PEG5k-Fmoc-NLG2 plus CTLA4 antibody exhibited the best antitumor effect. Antitumor activity of gefitinib loaded in carrier was comparable with free gefitinib alone. 4. With various treatments the expression of p-EGFR protein level varied. Basically, compare with free gefitinib alone, the carrier loaded gefitinib was more effective in the inhibition of EGFR phosphorylation. Conclusions: We have shown that targeted delivery of PTX and Gefitinib via a immunostimulatory nanocarrier effectively improved drugs antitumor activity. More study about tumor immune microenvironment are required. Such strategy can be employed in novel therapy combining chemotherapy drugs and immunemodulating agents such as PD-1 and CTLA4.
Modulating tumor immune microenvironment by the STK11/LKB1 signaling in breast cancer.
Authors: Hsu Hui-Ping , Wang Chih-Yang , Kuo Yao-Lung , Lee Kuo-Ting , Chen Pai-Sheng , Cheung Chun Hei Antonio , Shen Che-Hung , Chang Chih-Peng , Chen Yi-Ling , Lai Ming-Derg , Shen Meng-Ru 
Published: May 2020

e15185 Background: Standard treatment for breast cancer patients includes surgery, chemotherapy, radiotherapy, target and endocrine therapy. Immune checkpoint inhibitors are newly developing medications. The theoretical basis of immunotherapy is the interaction between cancer cells and tumor-infiltrating immune cells. Cancer cells secrete cytokines and create a specific tumor immune microenvironment (TIME) to attract or modulate immune cells. Further, genetic mutations or copy-number variations in cancer cells contribute to immunosuppression. Liver kinase B1 (LKB1) protein ( STK11 gene) is the upstream of AMP activated Protein Kinase (AMPK)/mammalian Target of Rapamycin Complex 1 (mTORC1) signaling pathway. STK11/LKB1 is one of the possible pathways modulating TIME. Methods: Twenty-seven breast cancer patients who developed recurrence within postoperative 24 months and 22 control cancer patients without recurrence were enrolled from National Cheng Kung University Hospital in Taiwan. Targeted deep sequencing was performed to assess the mutations among individuals with breast cancer using a panel of 143 cancer-associated genes. Bioinformatics and public databases were used to predict the protein functions of the STK11 genes. Immunohistochemical staining of LKB1 protein was performed in clinical specimens. Immune-related molecules were analyzed by RNA sequencing and cytokine array after suppression of STK11. Results: Mutations of STK11 gene were detected in recurrent patients and associated with poor prognosis of patients. From immunohistochemical study, the patients with low LKB1 expression had a worse survival. We utilized CRISPER/Cas9 system to transfect sgRNA into three mouse cell lines, including M158, NF639 and PY8119. RNA sequencing was performed in parental and Stk11-sgRNA cells. Immune-related pathways were ranked in the top 10 networks. Increased mRNA expression of Csf3 (protein G-CSF), Cxcl5, and Ccl2 was detected. The results are confirmed by cytokine array. The expression of G-CSF (gene Csf3) and CXCL5 (gene Cxcl5) proteins was increased in Stk11-sgRNA cells. The results were similar with RNA sequencing. Conclusions: Our findings suggest that suppression of STK11/LKB1 is correlated with early recurrence of breast cancer patients and contributes to modulate TIME. The STK11/LKB1 and downstream AMPK/mTORC1 pathways may be potential targets for immunotherapy.
Evidence for persistent radiation-related injury to the immune system in patients with local breast cancer.
Authors: Athale Janhavi , Broderick Kristen , Wu Xiaojun , Grossman Stuart A. 
Published: May 2020

e15189 Background: Clinical data in multiple tumors has demonstrated that the inadvertent radiation of circulating lymphocytes causes grade III-IV lymphopenia which is associated with worse outcomes in cancer patients and failure to respond to immunologic interventions. Murine data from our lab demonstrated that radiation to the brain results in striking changes in the anatomy and cellularity of distant unirradiated lymph nodes. This study was designed to understand the relationship between local radiation and the depletion of distant unirradiated lymph nodes in humans which has not been previously studied. Methods: Adult women with breast cancer who had undergone prior mastectomy with pathology, labs, and radiation data available at our institution were enrolled at the time of their deep inferior epigastric perforator artery (DIEP) flap reconstruction. During reconstruction, a single abdominal lymph node was extracted, and subsequently formalin fixed. The pre- and post-treatment lymph nodes of radiated and non-radiated patients were presented in a blinded manner to the hematopathologist. The pathologist described each lymph node and graded the lymph node density as (1) low, (2) low-normal, (3) normal, or (4) high. Results: Seven women have been enrolled (median age 50; range 31-55) with AJCC tumor stages from 1a – 3b (five are hormone positive, and two are triple negative). The reconstruction was completed on average 488.71 + 224.57 days after initial mastectomy. Three of the women received neoadjuvant chemotherapy, and five received adjuvant chemotherapy. Five of the seven women had received radiation (mean 50.9 + 5.6 Gy). The baseline median LN density score in all patients was 4 (range 1-4), with a post mean LN density of 1.2 + 0.4 in the radiation group compared to a mean score of 3 + 1.4 in the control group. Conclusions: Systemic lymphocyte counts remain relatively stable but lymph node density is markedly lower than baseline in 80% of patients who received chest wall irradiation consistent with data from animal model studies. It is important to note that this effect on the nodes is seen long after the radiation has been completed. [Table: see text]
Tumour immune characterization in adenoid cystic carcinoma identifies prognostic and immunotherapeutically relevant messenger RNA signatures.
Authors: Dou Shengjin , Chen Di , Li Rongrong , Yang Yining , He Ning , Jin Ge , Li Jiang , Zhu Guopei 
Published: May 2020

e15191 Background: Here, we profiled genetic hallmarks of Chinese adenoid cystic carcinoma (ACC) patients and immune cells infiltration levels by gene expression-based computational methods to investigate the correlation with immunotherapy. Methods: 54 patients with pathologically confirmed ACC admitted from January 2016 to October 2019 were included. Mutation and expression profiles were obtained by whole-exome sequencing (WES) and RNA-seq, respectively. A nomogram that integrated clinicopathological features with the immune signature to predict recurrence or distant metastasis probability was constructed by multivariate Cox regression. Results: As expected, we observed MYB fusion and somatic mutations in our cohort (57%, 31/54), strengthening the role of these aberrations as critical events in ACC. Mutations in NOTCH1 were also found in our cohort (19%, 10/54). Median tumour mutational burden (TMB) of these patients is 0.85 Muts/Mbp (0-11 Muts/Mbp). Analysis of WES data showed that all patients were microsatellite instability (MSI)-negative, and 17 of them were confirmed by conventional MSI-PCR testing. Lack of PD-L1 expression is 96.0% (n = 46/48) at a tumour proportion score 0% and 22.9% (11/48) of cases showed more than 10% CD8+ prevalence. We compared cancer types using an immune infiltration score (IIS) and an antigen presenting machinery expression (APM) score and find that ACC is among the lowest for both scores. Statistically significant correlations were found between IIS and distant metastasis-free survival (univariate analysis, HR = 2.64, 95% confidence interval [CI], 1.134 to 6.145, p = 0.023). Patients with higher IIS had shorter distant metastasis-free survival time (log-rank p = 0.020), and patients with higher T cell infiltration score (TIS) had shorter locoregional recurrence-free survival time (log-rank p = 0.050). In addition, we investigated the pretreatment immune profile of five ACC patients treated with PD-1 checkpoint inhibitors, and found that both TIS and APM were elevated in responding patient (with a partial response to camrelizumab) whereas they were in the lowest for patients with progressive disease on camrelizumab or pembrolizumab. Conclusions: Our study highlights the immune infiltration patterns and unravels mRNA signatures with prognostic utility and immunotherapeutic biomarker potential in ACC.