bluuebunny/crossref_metadata_2025_split huggingface dataset:
Incidence and risk of colitis with programmed death-1 versus programmed death-ligand 1 inhibitors for the treatment of cancer.
Authors: Miyashita Hirotaka , Mikami Takahisa , Satoi Sera , Cruz Christina , Galsky Matt D. 
Published: May 2020

e15087 Background: Programmed death 1 (PD-1) inhibitors and Programmed Death-Ligand 1 (PD-L1) inhibitors are immune checkpoint inhibitors (ICIs) approved for treatment of several different cancers. Colitis is a major immune-related adverse event associated with ICIs, but the risk of colitis with PD-1 versus PD-L1 inhibitors is not well characterized. Methods: We performed a meta-analysis for the incidence of all grade and grade 3-4 colitis with PD-1 inhibitor (nivolumab, pembrolizumab, and cemiplimab) or PD-L1 inhibitor (atezolizumab, avelumab, and durvalumab) monotherapy using a fixed effects model. We also conducted subgroup meta-analyses of non-small cell lung cancer (NSCLC) or urothelial carcinoma (UC) trials, and a network meta-analysis of randomized trials comparing PD-1 or PD-L1 inhibitors with docetaxel for NSCLC. We analyzed Food and Drug Administration Adverse Event Reporting System (FAERS) database to estimate the reporting odds ratio (ROR) of each medication, which provides the estimated relative risk most valid in spontaneous report database. Results: We identified 88 studies that met inclusion for the analysis. PD-1 inhibitors were associated with higher incidence of all grade and grade 3-4 colitis compared to PD-L1 inhibitors in the analysis of all cancer types (1.49% vs 0.83%, relative risk (RR); 1.80, 95% confidence interval (CI); 1.22-2.67 for all grade colitis, and 0.85% vs 0.34%, RR; 2.52, 95% CI; 1.46-4.37 for grade 3-4 colitis). The meta-analyses on NSCLC and UC, and the network meta-analysis on NSCLC also showed the tendency that PD-1 inhibitors are associated with higher risk of all grade and grade 3-4 colitis, though only the analysis on UC for all grade colitis showed a significant difference. (1.95% vs 0.64%, RR; 3.05, 95% CI; 1.18 - 7.88) Retrospective analysis showed ROR of 16.78 (95% CI; 15.8-17.8) for PD-1 inhibitors, and 12.93 (95% CI; 10.74-15.42) for PD-L1 inhibitors. We found that ROR of PD-1inhibitors was 1.17 (95% CI; 0.97-1.43) compared to PD-L1 inhibitors. Conclusions: Our study showed that PD-1 inhibitors have higher risk of colitis than PD-L1 inhibitors.
Risk factors for myocarditis associated with immune checkpoint inhibitors using real-world clinical data.
Authors: Jain Prantesh , Bugarin Jahir Gutierrez , Guha Avirup , Jain Chhavi , Shen Tingke , Stanevich Ilya , Margevicius Seunghee P , Fu Pingfu , Liu Fang , Nikore Vipan , Mangla Ankit , De Lima Marcos J.G. , Velcheti Vamsidhar , Barnholtz-Sloan Jill , Dowlati Afshin 
Published: May 2020

e15100 Background: Immune checkpoint inhibitors (ICIs) can cause unique, high-grade immune-related adverse events. Although rare, ICI related myocarditis has the highest fatality rate (~50%). Cardiovascular monitoring is not routinely performed in patients on ICI treatment, thus risk factors remain unknown. Characterizing rare but fatal cardiac toxicities requires integration of real-world data. Methods: U.S claims data (IBM MarketScan) of over 30 million commercially insured individuals was leveraged to identify 2,687,301 cancer patients between 2011-2018. Patients ≥18 years of age treated with ICIs (targeting CTLA4 (ipilimumab) and/or the PD1 (nivolumab, pembrolizumab)/PDL1 (atezolizumab, avelumab, durvalumab) alone or in combination with ICI and/or chemotherapy were identified and followed until disenrollment. Myocarditis, comorbidities, and treatment details were identified using diagnosis and billing codes. Analyses included descriptive statistics and Cox proportional hazards regression. Results: 16,541 ICI treated cancer patients were included (median age 60; 58% male). Myocarditis was identified in 252 (1.5%) patients, majority (90%) ≥50 years old (median 63) with 12,040 person-years of follow up. 62% received anti-PD1 monotherapy, 12% anti-CTLA4, and 15% received combination treatment with other ICIs and/or chemotherapy. Most common cancer types were lung (48%), melanoma (25%), and renal cancer (14%). Cumulative incidence of myocarditis at 1 year was 2.06%; 95% CI (1.78-2.37), median onset of 80.5 days, 42% occurring within 60 days of treatment. By univariate analyses, age, cancer type, diabetes (DM), hypertension (HTN), kidney, liver disease, atrial fibrillation (AF) were related to myocarditis. Risk was lower in patients who received anti-CTLA4 monotherapy (HR: 0.490; 95% CI: 0.26-0.92; p = 0.0251). On multivariable regression analyses only age, cancer type (renal, lung cancer), comorbidities DM and liver disease were significantly associated with myocarditis (Table). Conclusions: This is the largest real-world longitudinal study for ICI associated myocarditis showing higher than reported incidence and identifiable risk factors. [Table: see text]
Thyroid dysfunction and immune checkpoint inhibitor outcomes.
Authors: von Itzstein Mitchell S. , Lu Rong , Ali Sadia , Xie Donglu , Cai Jennifer , Xie Yang , Gerber David E. 
Published: May 2020

e15103 Background: Immune checkpoint inhibitors (ICI) frequently cause thyroid dysfunction. We performed a longitudinal analysis of thyroid function tests in a large, single-center cohort of patients with multiple cancer types receiving ICI. Methods: We performed a retrospective medical records review of consecutive patients treated with ICI from 1/1/2005 to 12/31/2018. We collected demographic and clinical data, including serial thyroid function tests. We compared overall survival between patients with normal and abnormal thyroid stimulating hormone (TSH) at baseline and after ICI initiation using Kaplan-Meier curves, log-rank tests, and multivariate Cox proportional hazards model. Results: A total of 910 patients were included: 63% male, 82% white, median age 67. The most common cancer types were lung (26%), kidney (18%), and melanoma (17%). ICI types were anti-PD1/L1 (78%), anti-CTLA-4 (7%), and combination ICI (15%). Normal baseline TSH and abnormal post-treatment TSH was associated with longer overall survival (median survival 26 months) compared to all other TSH permutations (median survival < 10 months) ( P< 0.001). This finding persisted after multivariate Cox regression adjustment for age, gender and cancer type (P < 0. 001), and also after sensitivity analysis censoring patients who died within 2 months after starting ICI. Conversely, abnormal TSH at baseline was associated with lower overall survival (median 8 months) compared to normal TSH at baseline (median 18 months) ( P< 0.001), which also persisted in multivariate analysis ( P< 0.001). Kidney and head and neck cancers (71% and 69%) were associated with increased development of thyroid dysfunction compared to melanoma, lung and other urological cancers (52%, 50% and 35%) ( P< 0.01). Conclusions: Although abnormal thyroid function after ICI initiation was associated with improved overall survival, pre-treatment thyroid abnormalities were associated with worse overall survival. Given the prevalence of thyroid abnormalities in the general population, further research into these observations is warranted.
Retrospective analysis of immune checkpoint inhibitor-associated myocarditis from 12 cancer centers in China.
Authors: Wang Feng , Qin Shukui , Lou Fang , Chen Feng Xiao , Shi Meiqi , Liang Xiaohua , Jiang Hua , Jiang Yu , Chen Yu , Du Yingying , Xue Jun , Zhu Hong , Ren Wei 
Published: May 2020

e15130 Background: Immune checkpoint inhibitor(ICI) -associated myocarditis is rare, but it could account for a very high mortality rate. This study reviewed the occurrence of ICI-associated myocarditis in Chinese cancer patients. Methods: A retrospective analysis was made on the occurrence of ICI-associated myocarditis in cancer centers of 12 3A-grade hospitals in China from January 1, 2018 to December 31, 2019. More than 100 patients were treated with ICIs in each center. Results: A total of 2373 patients were treated with ICI alone or in combination. The incidence of ICI-associated myocarditis was 1.05% (25/2373). Of all the data elicited from 16 patients in this study, the tumor types were listed, including: melanoma, lung cancer, renal cancer, urothelial cancer, liver cancer, gastric cancer, colorectal cancer, etc. The 16 patients included 8 male and 8 female with a median age of 65 (36-80). 3 of them had coronary heart disease. The ICI drugs included nivolumab, pembrolizumab and toripalimab, camrelizumab, sintilimab, tislelizumab, atezolizumab. Among them, there were 10 cases of PD-1 inhibitor, 1 case of PD-L1 inhibitor, 5 cases of PD-1 inhibitor combined with chemotherapy or molecular targeted drug. ICI-associated myocarditis occurred in a median of 38 days (2-420) after treatment during which 81.2% (13/16) of them received ICI 1-2 infusions. The common clinical symptoms were palpitation, chest distress and dyspnea, in addition to 8 cases with asthenia, 4 cases with respiratory failure, 2 cases without symptoms. ECG abnormality accounted for 87.5% (14/16). The common abnormalities included: 6 cases of atrial premature contraction, 4 cases of ventricular premature contraction, 3 cases of sinus tachycardia, 1 case of Grade 3 atrioventricular, 1 case of complete right bundle block, and 1 case of acute myocardial infarction. 15 cases of abnormal troponin I or T were observed, followed by CK, CK-MB, MYO and BNP increased. 14 patients were treated with glucocorticoid. 6 patients died with the mortality rate 37.5%(6/16) and 66.7% (4/6) were over 70 years old. Conclusions: The incidence of ICI-associated myocarditis in Chinese patients is low, but the mortality rate is high. Regular monitoring of cardiac biomarkers and ECG is helpful for early diagnosis.
Weighing the role of concomitant medications during PD-1/PD-L1 checkpoint blockade: A preliminary analysis.
Authors: Cortellini Alessio , Mallardo Domenico , Vitale Maria Grazia , Bracarda Sergio , Macrini Serena , Di Marino Pietro , De Tursi Michele , Petragnani Nicola , Natoli Clara , Nigro Olga , Tuzi Alessandro , Patruno Leonardo Valerio , Porzio Giampiero , Cannita Katia , Fargnoli Maria Concetta , Ficorella Corrado , Ascierto Paolo Antonio 
Published: May 2020

e15132 Background: The role of concomitant medications, such as steroids, antibiotics and proton pump inhibitors, during immunotherapy has already been investigated, without conclusive results. Methods: This is a multicenter retrospective study, of advanced cancer patients (any histology) treated with anti-PD-1/PD-L1 immunotherapy. Baseline concomitant medications were collected. Results: From June 2014 to November 2019, 277 consecutive patients were evaluated. Median age was 69 years; male/female ratio was 190/87. Primary tumors were: NSCLC (41.9%), melanoma (40.1%), renal cell carcinoma (11.9%) and others (6.1%). 63 patients (22.7%) had ECOG-PS ≥ 2. 120 patients (43.3%) had ≥ 2 metastatic sites. Conclusions: Cancer-related steroids administration, systemic antibiotics, proton pump inhibitors, anticoagulants, opioids, oral anti-diabetics and insulin therapy seem to significantly affect survival in patients receiving PD-1/PD-L1 inhibitors. In interpreting such data, it is important to consider the prevalent role of poor clinical condition. Our preliminary results warrant further investigation in a larger cohort of patients and in a perspective way. [Table: see text]
Comparative efficacy, safety, and tolerability of immune checkpoint inhibitors (ICIs) in cancer.
Authors: Al-Showbaki Laith , Nadler Michelle , Desnoyers Alexandra , Almugbel Fahad , Cescon David W. , Amir Eitan 
Published: May 2020

e15151 Background: Multiple ICIs have been approved, and in some diseases there is a choice of more than one ICI. The comparative safety, efficacy, and tolerability are not known. Here we report on a network meta-analysis comparing different ICIs targeting PD1 or PDL1. Methods: Randomized trials (RCTs) supporting the registration of a single agent anti-PD1 or anti-PDL1 inhibitors between 2015-2019 were identified. We extracted the hazard ratio (HR) for overall survival (OS) and calculated the odds ratio (OR) for commonly reported safety and tolerability outcomes. We then performed a network meta-analysis including only disease sites in which more than one ICI has been approved. Multiple pair-wise comparisons were then performed. When more than 2 comparisons were available for a pair of ICIs these were pooled into a single estimate. Analyses were performed in Microsoft Excel and RevMan 5.3. Results: Of 16 RCTs included, 10 in non-small-cell lung cancer, 2 in melanoma, 2 in head and neck squamous cell carcinoma and 2 in urothelial cancer. There was a total of 10673 patients in the analysis. Compared to pembrolizumab, efficacy was similar for nivolumab (HR 1.06, 95% CI 0.97-1.16) and for atezolizumab (HR 1.05, 95% CI 0.93-1.20). However, avelumab appeared inferior (HR 1.29, 95% CI 1.07-1.57). Pembrolizumab showed similar odds of serious adverse events (SAEs) as nivolumab (OR 1.12, 95% CI 0.56-2.27) and atezolizumab (OR 1.05, 95% CI 0.55-2.04). However, compared to nivolumab, atezolizumab was associated with more SAEs (OR 2.14, 95% CI 1.47-3.12). Avelumab had the lowest odds of grade 3-4 adverse events compared to pembrolizumab (OR 0.42, 95% CI 0.24-0.74), nivolumab (OR 0.38, 95% CI 0.24-0.62) and atezolizumab (OR 0.21, 95% CI 0.14-0.33). Atezolizumab was associated with more grade 3-4 adverse events than nivolumab (OR 1.84, 95% CI 1.37-2.47). The odds of treatment discontinuation without progression were similar between nivolumab and atezolizumab (OR 1.20, 95% CI 0.73-2.00), but higher with pembrolizumab compared to nivolumab (OR 1.35, 95% CI 0.83-2.17) and atezolizumab (OR 2.56, 95% CI 1.29-5.00). Pembrolizumab was associated with higher OR of immune related adverse events (IRAEs) compared to nivolumab (OR 2.12, 95% CI 1.49-3.03) and atezolizumab (OR 1.63, 95% CI 1.09-2.43), while the OR of IRAEs was almost similar between nivolumab and atezolizumab. Conclusions: Pembrolizumab, nivolumab, and atezolizumab have similar efficacy. Avelumab appears efficacious. Safety and tolerability seem better with avelumab, but worse with atezolizumab and pembrolizumab.
Cancerbiome: Defining a healthy microbiome for therapeutic targeting.
Authors: Babu Hari S , Mason Robert , West Nicholas P , Gunawan Ben , Cox Amanda J , Nelson Tiffanie M , Zhang Ping , Cripps Allan W , Sanmugarajah Jasotha 
Published: May 2020

e15152 Background: The gut microbiome has been shown to modify the efficacy of cancer immunotherapy. Currently, there is little understanding of how the microbiome in advanced cancer patients responding to immunotherapy compares to healthy individuals. The aim of this study was to characterise the intestinal microbiome in patients with advanced solid organ tumours that have a durable response to programmed-death-protein-1 inhibitors (PD-1) with healthy individuals. Methods: Ten patients (mean age 69 ± 11; 60% female) with metastatic melanoma, renal cell carcinoma or non-small cell lung cancer and durable response for greater than one year to anti-PD-1 antibodies and ten healthy age and sex matched individuals (mean age 69 ± 9.2; 60% female) were recruited. Clinical data and a three-day diet diary were collected, with faecal sample analysed via shallow shotgun sequencing (CoreBiome, Minneapolis, USA). Results: Duration of response to immunotherapy was 786 ± 282 days. Responders had a significantly higher body mass index (28 ± 5.5 kg/m2 v 23.3 ± 2.65 kg/m2, p = 0.005; mean ± SD) than the healthy group. There was a significantly higher intake of total fat and fibre in the healthy group. The responder group had significantly higher diversity metrics, exhibiting a greater diversity in the number (OTUs) and the richness of species than the healthy group. At the phylum level, the microbiome in the responder group was significantly abundant in proteobacteria and had a significantly lower abundance of Bacteroidetes compared to the healthy group. At the genus level, the microbiome in the responder group was significantly enriched in Desulfovibrio, Acideminococcus, Klebsiella, Enterococcus and Faecalitalea compared to Ruminococcus, Veillonella and Roseburia in the healthy group. Species that were abundantly higher in the cancer group were associated with glycolysis, the TCA cycle, sugar metabolism and amino acid metabolism. Five Kyoto Encyclopedia of Genes and Genomes (KEGG) orthologues were significantly enriched in the responder group, mostly relating to transport systems for minerals and nitrogen fixation, but also mismatch repair proteins and cell cycle activity. Conclusions: Our findings suggest that compositional and functional differences in the faecal microbiome exist between advanced cancer patients responding to immunotherapy and healthy individuals, suggesting not only potential mechanisms of durable response but also targets for future therapy.
The frequency of HPD gene mutation profile in solid tumors with PD-L1 expression positive.
Authors: Tang Sanyuan , Zhao Shunli , Liu Zhiqi , Zhao Huiping , Gao Caixia , Tian Minqi , Zhang Xing , Qi Chuang , Song Chao 
Published: May 2020

e15175 Background: Program death-ligand (PD-L1) expression and tumor mutational burden (TMB) are the promising predictive biomarkers in immunotherapy for solid tumors. Immunotherapy could be harmful in patients harboring hyper-progressive disease (HPD) gene mutations. Nevertheless, the distributions of HPD gene mutation profile in patients with PD-L1 positive solid tumors especially in East Asian populations have not been well characterized yet. Methods: In this study, tumor tissues from 354 patients using 539 genes panel based on next generation sequencing were performed. Single nucleotide variants (SNVs) of DNMT3A gene and copy number variants (CNVs) of M DM2, MDM4, C CND1, F GF3, F GF4 and F GF19 genes were evaluated as HPD mutations. The protein expression of PD-L1 was divided into three groups as g1 (TC < 1%), g2 (1% ≤ TC < 50%) and g3 (TC ≥ 50%) via the percentage of positive tumor cells (TC value) identified by immunohistochemistry (IHC) method. The ratios of patients with or without HPD mutations in different PD-L1 expression groups were calculated by χ2 test using program SPSS v22.0. Results: In 354 patients with solid tumors, 33 of 354 (9.3%) were found harboring HPD mutations. The ratios of patients with HPD mutations in three PD-L1 expression groups were 8.6% in g1, 10.4 % in g2 and 8.7% in g3, respectively. Meanwhile, the ratios of patients without HPD related mutations in three PD-L1 expression groups were 91.4%, 89.6 % and 91.3%, respectively. There were no significant differences of HPD frequency between different PD-L1 expression groups via χ2 test (χ2 = 0.323, p = 0.851). Conclusions: The frequency of HPD gene mutations was not significantly heterogeneous between different PD-L1 expression groups and indicated that immunotherapy for patients with PD-L1 expression positive needed to test HPD related gene mutations. Our study provided meaningful information to the precise administration of immunotherapy in cancer clinical practice. As a retrospective study with a relatively small population, the conclusions of this study needed to be verified with a larger sample.
Multi-omic single-cell analysis of antigen-presenting compartment reveals a unique functional signature for head and neck squamous cell carcinoma.
Authors: Barber Brittany , Prlic Martin , Mair Florian , Erickson Jami 
Published: May 2020

e15179 Background: Immune studies in head and neck squamous cell carcinoma (HNSCC) are lacking. Studies in the past decade have highlighted the biological significance and the distinct functional properties of immune cell subsets that are resident in non-lymphoid tissues. While tissue-resident memory T cells (TRM) have been well characterized, much less is known about the human myeloid compartment in HNSCC, which includes professional antigen-presenting cells (APCs) such as dendritic cells (DCs) and macrophages, both of which are critical for shaping the local T cell response. This is particularly relevant in the context of anti-tumor immune responses, which are currently a major focus for therapeutic intervention in HNSCC by either checkpoint inhibitory blockade or adoptive T cell therapy. Methods: A combination of multi-omic single cell RNA sequencing (sc-RNAseq) and 30-parameter fluorescent flow cytometry were used to define the APC compartment in 7 human head and neck squamous cell carcinoma (HNSCC) samples and 4 normal gingival tissue samples as references. Importantly, we performed parallel profiling of the adaptive and innate T cell compartment to elucidate the relationship between APCs and local TRM cells that have been designated as critical players for immune responses in solid tumor tissue. Results: Several novel myeloid phenotypes and an altered composition of the APC compartment in HNSCC relative to normal gingival tissues. APCs expressing pro-inflammatory cytokines such as IL-1b and IL-6 showed reduced abundance, while previously unknown APC subsets defined by the expression of a unique chemokine profile were found to infiltrate HNSCC tissue. Furthermore, our multi-omic approach allowed for profiling of the protein surface phenotype in these transcript-defined clusters, opening up avenues for future therapeutic targeting of tumor-specific antigen-presenting cells. Conclusions: A novel myeloid phenotype and APC compartment were observed in HNSCC when compared to normal gingival tissues. A multi-omic assay identified tumor-specific APCs that may represent future therapeutic targets.
Metabolism of tumor cell in tumor micro environment assist immune escape.
Authors: He Ning , Wang Jianfei , Wang Lingyu , Jin Ge , Lin Rongbo , Yang Yadong 
Published: May 2020

e15181 Background: Tumor cell’s metabolism has been identified assisting immune evasion in tumor micro environment (TME), and it is very different from that of immune cells. Previous studies mostly focus on bulk or cell lines transcriptome; we aim to find the specific metabolic model of tumor cell based on vast single cell RNA-seq data. Methods: Public transcriptome of 7186 cells (SMART-Seq2) from 33 melanoma tumors in Benjamin’s study were collected from Single Cell Portal of Broad Institute, and metabolic genes were obtained from Human Metabolome Database (HMDB). Raw count data was preprocessed and analyzed using Seurat R package. Statistical analysis and data visualization were all carried out using R software. Results: Metabolic signature genes of malignant cells (Mals), CD8+ T cells, CD4+ T cells, B cells, natural killer (NK) cells, macrophages, cancer associated fibroblasts (CAFs), and endothelial cells (Endos) were extracted using Seurat. Mals, CAFs, Endos and macrophages shared similar metabolism patterns (high-level glycolysis, pyruvate metabolism, purine metabolism and specific proteoglycans profile compared to immune cells, p < 0.01). Glutathione metabolism activity in Mal was higher than that in immune cell, especially GPX1, GPX4 and GSTO1 genes were highly expressed in Mal ( fc > 2, p < 0.01). Compared to immune cells, genes participate in glycolysis, PFKL, ADH5, ENO2, G6PC3, PGM1, ALDH1B1, PFKM, ALDH7A1, GAPDHS, TPI1, PGK1, LDHA, GPI, PKM, LDHB, ENO1, ALDOA and GAPDH were highly expressed in Mals, CAFs and Endos ( fc > 2, p < 0.01). Noteworthily, LGALS1, an inducer of T-cell apoptosis, was highly expressed in Mals and CAF ( fc > 2, p < 0.01). Otherwise, proteoglycans (PGs) in cancer, which contribute to cancer pathogenesis, exhibited high variation from immune cells. Conclusions: We firstly highlight the differential metabolism between tumor and immune cells in TME. Mals, CAFs, endothelial cells and macrophages can assist in evading immune surveillance through reshaping their metabolic patterns at cell level. This study is helpful for exploring new target of metabolic based anti-cancer immunotherapy.