bluuebunny/crossref_metadata_2025_split huggingface dataset:
Macrophage determines immnophenotype and predicts anti-PD-L1 response of urothelial cancer: Results from phase II clinical trial.
Authors: Zeng Dongqiang , Ye Zilan , Wang Gaofeng , Fan Xinxiang , Wu Jiani , Huang Yiqiang , Li Nailin , Shi Min , Liao Wangjun 
Published: May 2020

e15093 Background: Immune-checkpoint blockades (ICBs) are revolutionizing treatment of advanced or metastatic urothelial cancer (mUC) whereas the promising response merely occurred in a subset of patients. To dig into underlying determinants, we investigated the comprehensive tumor microenvironment (TME) of 348 tumor samples derived from a large phase II trial (IMvigor210: NCT#02108652). Methods: Based on the 348 pre-treatment samples, the LASSO-Bootstraping algorithm were applied to figure out the optimal predictive biomarker. Assessment of immune-cell proportions, pathway activity, and tumor purity used CIBERSORT algorithm, ssGSEA methodology, and ESTIMATE algorithm, respectively. Unsupervised clustering methods were applied to identify TME infiltrating patterns. Moreover, the predictive value of M1 infiltration in mUC were systematically explored, as well as its correlation to integrative molecular subtypes, tumor intrinsic mutation and metabolic pathways. An additional TCGA dataset was applied to validate the results. Results: Bootstrapping and ROC curve analysis indicated that M1 was non-inferior to TMB in predicting ICBs response (M1: AUC = 0.706; TMB: AUC = 0.728; Delong test: P = 0.333), but surpassed more-than-10,000 counterparts covering TME-infiltrating cells, metabolic pathways, tumor intrinsic pathways and hallmarks of cancer. Kaplan-Meier survival analysis (M1: P < 0.0001, Hazard Ratio = 0.25, 95% CI: 0.14 − 0.44) supported its promising prognostic value. Moreover, study into TME patterns demonstrated its role in determining immunophenotypes (AUC = 0.785). M1 frequency is positively correlated with CD8+ T cells fraction (P = 7e-04), whereas the Treg cell, neutrophil and monocyte infiltration which refer to suppressive immune microenvironment were negatively correlated (P = 0.0066, P = 7e-04, P = 2e-04, respectively). Furthermore, significant correlation was observed between M1 and tumor intrinsic characteristics, including TMB, neoantigen and PD-L1 level of tumor (P = 3.83e-5, P = 1.69e-7, and P = 0.0018, respectively). The TCGA data reproductively supported the majority of aforementioned results. Conclusions: Our study lend statistical power to the notion that Macrophage independently contribute to anti-tumor immune function in the context of ICB therapy. Nonetheless, these findings provide important insight into the role of M1-Macrophage, macrophage polarization and innate immune machinery in therapeutic responses to ICB. Clinical trial information: NCT02951767 .
Neurotoxicity associated with immune checkpoint inhibitors: Systematic review and meta-analysis.
Authors: Farooq Muhammad Zain , Ba Aqeel Sheeba Habeeb , Lingamaneni Prasanth , Banskota Shristi Upadhyay , Pichardo Rayli , Siddiqui Mahrukh , Shrivastava Trilok , Mangla Ankit 
Published: May 2020

e15096 Background: Immune checkpoint inhibitors (ICI) are associated with multiple immune related adverse events (irAE). Moderate to severe neurotoxicity is reported in less than 1% of all patients treated with ICI. We performed a systematic review and meta-analysis to assess neurotoxicity associated with anti-PD-1/PD-L1 and anti-CTLA4 therapy. Methods: The Embase, Ovid, Pubmed and Scopus database were comprehensively searched by two independent reviewers, from inception to 2019, to include Phase II and III clinical trials reporting neurotoxicity with the combination of, or monotherapy with anti-PD-1/PD-L1 and/or anti-CTLA4 therapies. Our primary outcome was assessment of neurologic irAE of all grades. We divided neurotoxicity into two groups: peripheral nervous system (PNS) including peripheral neuropathy (PeN), fatigue, Guillain-Barre syndrome (GBS), myelitis; and central nervous system (CNS) including stroke, myasthenia gravis (MG), encephalopathy/encephalitis, altered mental status (AMS), decreased appetite and headache. Statistical heterogeneity was quantified using I2 statistics and publication bias was assessed with Eggers regression test. The estimates were reported as odds Ratio (OR) with 95% confidence intervals (CI) using random effect model. Results: A total of 2,876 full text articles retrieved in the initial database search were analyzed according to PRISMA guidelines. The final analysis included 39 trials, evaluating 10,595 patients in the control arm and 13,110 patients in the immunotherapy arm. All-grade neurotoxicity events with ICI were significantly lower compared to placebo or standard of care (OR 0.55, 95% CI 0.38-0.81, I2 96.82%, P < 0.001). Only significant CNS irAE observed was fatigue (OR 0.82, CI 0.71-0.96, I2 81.75%, P < 0.001). Other CNS irAE including AMS (OR 1.318, 95% CI 0.86-2.0, I2 0%, P = 0.442), encephalopathy/encephalitis (OR 1.36, 95% CI 0.38-4.96, I2 0%, P = 0.82) and seizures (OR 1.96, 95% CI 0.64-6.02, I2 0%, P = 0.56) had statistically non-significant increased risk in ICI group. Only one case of myelitis was reported in placebo group. The ICI arm had statistically significant lower rates of PeN (OR 0.28, CI 0.16-0.49, I2 87.31, P < 0.001). One trial reported 1 patient with MG and 5 trials reported 1 patient each of GBS in the ICI arm. Conclusions: Our meta-analysis concludes that use of ICI is associated with lower rate of neurotoxicity overall. Fatigue and PeN are lower with ICI compared to standard of care or placebo. Although, CNS irAE are increased with ICI, they do not reach statistical significance.
Clinical efficacy of immunotherapy for the treatment of solid tumors in patients with chronic kidney disease.
Authors: Ganta Teja , Jun Tomi , Qin Qian , Patel Vaibhav G. , Wang Bo , Mellgard George , Gogerly-Moragoda Mahalya , Leiter Amanda , Gallagher Emily J. , Oh William K. , Galsky Matt D. , Tsao Che-Kai 
Published: May 2020

e15109 Background: Regulatory T cells play a key role in protecting kidney cells from ischemic injury. Immune checkpoint inhibitors (ICIs) may increase the risk of acute kidney injury via inhibition of regulatory T cells [1, 2]. Prospective clinical trials have largely excluded patients with chronic kidney disease (CKD); thus, we have limited knowledge of the safety and efficacy of ICI in these patients. Herein, we hypothesize that patients with CKD receiving ICIs have worse clinical outcomes. Methods: This single-institution retrospective cohort study included adult patients with solid tumors who were treated with ICIs at The Mount Sinai Hospital between 2011 and 2017. Clinical endpoints [response to treatment, progression of disease (POD) on treatment, mortality] were compared between patients with and without CKD using multivariate logistic regression. Odds ratios were controlled for demographics, primary tumor type, presence of cardiovascular comorbidities, smoking status, incidence of renal adverse events, and a composite of stage of illness with indication for treatment [localized—neoadjuvant, localized—adjuvant, regionally advanced, metastatic disease]. Data were analyzed using R version 3.5.1 with the following packages: readr, dplyr, broom, lubridate, tableone. Results: 420 patients met inclusion criteria: 399 patients without CKD and 21 patients with CKD. Cohorts are well matched for demographics, smoking status, stage/indication for treatment. The CKD cohort has a higher proportion of patients with urothelial cancer compared to patients without CKD (33% vs 11%) as well as a higher proportion of patients with HTN (81% vs 53%), HF (14% vs 3%), and DM (48% vs 21%). There was no statistical difference in odds of response to treatment [OR 0.76, 95% CI 0.26-2.23], POD [OR 0.42, 95% CI 0.15-1.17], or mortality [OR 2.05, 95% CI 0.71-5.96] between the CKD and non-CKD cohort. Conclusions: The data suggest the presence of CKD is not associated with worse clinical outcomes in cancer patients treated with ICIs. As a small retrospective study, the conclusions are hypothesis-generating but support continued use of immunotherapy in CKD in clinical practice and the inclusion of patients with CKD in immunotherapy clinical trials to further clarify safety and efficacy. [Table: see text]
The pattern of time to onset and resolution of immune-related adverse events caused by immune checkpoint inhibitors in cancer: A pooled analysis of 23 clinical trials and 8,436 patients.
Authors: Tang Si-Qi , Xu Cheng , Tang Ling-Long , Mao Yan-Ping , Li Wen-Fei , Chen Lei , Zhang Yuan , Guo Ying , Liu Qing , Sun Ying , Ma Jun 
Published: May 2020

e15110 Background: Immune checkpoint inhibitors (ICIs) yield remarkable clinical efficacy in the treatment of cancer. With the increasing use of ICI therapies, the dissemination of immune-related adverse events (irAEs) data is essential. This study aimed to investigate the pattern of onset and resolution of ICI-induced irAEs in cancer. Methods: Phase II–III clinical trials with single or multiple arms studying ICI-based treatments in cancer published between January 2007 and December 2019 were included. The pooled median time to onset (PMT-O), resolution (PMT-R), and immune-modulation resolution (PMT-IMR) of irAEs were analyzed based on irAE categories and severity grades using the metamedian package of the R software. Subgroup analyses were performed based on different ICI drugs, ICI doses, and cancer types. Results: Twenty-two eligible studies involving 23 clinical trials and 8,436 patients were included. On average, irAEs occurred at 6.1 weeks (95% confidence interval [95% CI], 5.7–7.4) after the initial ICI-based treatment. The first four irAEs with the shortest PMT-O were hypersensitivity/infusion reaction (3.1 weeks), neurological (4.0 weeks), skin (4.1 weeks), and gastrointestinal (6.1 weeks) events. IrAEs were resolved within 4.5 weeks (95% CI, 4.0–6.1), with the shortest and longest PMT-R for hypersensitivity/infusion reaction (0.1 weeks) and endocrine events (28.7 weeks), respectively. The application of immune-modulation drugs prolonged the general resolution time to 5.9 weeks, with the shortest and longest PMT-IMR for hypersensitivity/infusion reaction (0.2 weeks) and endocrine events (56.6 weeks), respectively. Grade ≥ 3 irAEs showed a significantly longer PMT-O (7.9 vs. 6.1 weeks; P < 0.01) compared with all grade irAEs. Nivolumab + ipilimumab had a significantly shorter PMT-O than nivolumab alone (6.0 vs. 8.2 weeks; P < 0.01). A significantly shorter PMT-O was observed for lung cancer compared with that for melanoma (4.7 vs. 6.1 weeks; P = 0.02). Conclusions: This study revealed the pattern and kinetics of the time to onset and resolution of irAEs in pan-cancers, which will promote the comprehensive understanding, timely detection, and effective management of ICI-induced irAEs.
Effect of STK11 mutations on efficacy of PD-1 inhibition in non-small cell lung cancer (NSCLC) and dependence on KRAS mutation status.
Authors: Ricciuti Biagio , Arbour Kathryn Cecilia , Lin Jessica Jiyeong , Vokes Natalie , Vajdi Hoojghan Amir , Li Yvonne Y. , Cherniack Andrew D. , Recondo Gonzalo , Lamberti Giuseppe , Venkatraman Deepti , Rizvi Hira , Egger Jacklynn V. , Plodkowski Andrew J. , Khosrowjerdi Sara , Digumarthy Subba R , Nishino Mizuki , Sholl Lynette M. , Gainor Justin F. , Hellmann Matthew David , Awad Mark M. 
Published: May 2020

e15113 Background: STK11 mutations ( STK11m) have been associated with resistance to ICI in KRAS-mutant ( KRASm) NSCLC. Whether STK11m status also impacts clinical outcomes to ICI in KRAS wild-type (wt) NSCLC is unknown. Methods: We analyzed clinical outcomes of patients (pts) with NSCLC treated with ICI according to KRAS and STK11 mutation status in independent discovery (DFCI+MGH) and validation (MSKCC) cohorts. TCGA and xCell data were interrogated to identify differences in tumor gene expression and tumor immune cell subsets, respectively, according to KRAS/ STK11 co-mutation status. Results: Of 1195 pts with advanced nonsquamous NSCLC treated with ICI, 447 (37.4%) had a KRASm, 252 (21.1%) had pathogenic STK11 mutations, and 128 (10.7%) had concurrent KRASm and STK11m. ICI outcomes for the discovery and validation cohorts in KRASm and KRASwt cases by STK11 mutation status are shown in Table. In the combined cohort (discovery+validation), STK11m was associated with significantly worse outcomes to ICI among KRASm cases: ORR 10.2% vs 30.7%, P < 0.001; median progression-free survival (mPFS): 2.0 vs 4.8 months (mo), HR:0.49 [95%CI:0.39-0.61], P < 0.0001; median overall survival (mOS): 6.1 vs 16.9 mo, HR:0.50 [95%CI:0.39-0.63], P < 0.0001. In multivariable analysis, STK11m was associated with significantly shorter PFS (HR:0.56, P = 0.002) and OS (HR:0.57, P = 0.006). By contrast, STK11m had no impact on ICI outcomes among KRASwt cases: ORR 24.2% vs 19.2%, P = 0.21; mPFS: 2.5 vs 2.8 mo, HR:0.98 [95%CI:0.79-1.21], P = 0.89; mOS: 12.0 vs 11.5 mo, HR:1.06 [95%CI:0.85-1.33], P = 0.57. Among KRASwt cases, STK11m had no impact on ICI outcomes among both smokers and never smokers, when analyzed separately. Gene ontology analysis from TCGA revealed that among KRASm but not KRASwt NSCLC, STK11m was associated with the downregulation of MHC class II-related genes (P = 0.02). Cell subset transcriptome analysis showed significantly lower proportions of M1 macrophages among KRASm/ STK11m but not among KRASwt/ STK11m NSCLCs (P < 0.01). Conclusions: STK11m are associated with resistance to ICI in KRASm but not KRASwt NSCLC. STK11m/ KRASm vs STK11m/ KRASwt NSCLC have distinct immunophenotypes. [Table: see text]
Ophthalmic immune-related adverse events following anti-CTLA-4 or PD-1 therapy recorded in the American Academy of Ophthalmology IRIS Registry.
Authors: Sun Michel M. , Kelly Scott P. , Mylavarapu Apoorva Lakshmi , Coleman Anne L. , Holland Gary N. , Yu Fei , Singh Sukhminder , Hsu Stephen , Lum Flora , Gordon Lynn K. 
Published: May 2020

e15124 Background: The detailed study of ophthalmic immune-related adverse events (OirAEs) is of integral importance in the evolving field of cancer immunotherapy to inform management and treatment guidelines. This study seeks to quantify the differences in incidence and recurrence rates of OirAEs by immune checkpoint inhibitor (ICI) status in a longitudinal big-data registry in patients who are seen in ophthalmic clinics. Methods: This retrospective registry study examined patients newly diagnosed with OirAEs between January 1, 2013 and December 31, 2017 in the American Academy of Ophthalmology’s IRIS Registry. The primary exposure of interest was prior initiation of ICIs. Incidence of OirAEs within 1 year following initiation of ICIs, including anti–PD-1 or anti-CTLA-4 therapy was determined. Incidence rate ratios (IRR) were derived by comparing incidence of OirAEs after ICIs versus rates of non-drug related ocular complications in the entire registry population. Rates of OirAEs in patients with a past history of ocular inflammation or other specific ophthalmic condition prior to initiation of ICIs were further examined. Results: A total of 3,123 patients were identified to have received anti-CTLA-4, anti-PD-1, or anti-PD-L1 therapy, 111 of whom developed an OirAE (3.6%). All OirAE patients had a documented initial pre-drug cancer ICD code, when available, of malignant metastatic melanoma or choroidal melanoma, with the exception of one patient. Incidence rates for anterior uveitis, the most common OirAE, were found to be 3,736 per 100,000 among all ICIs. Rates of all analyzed OirAEs among patients on ICI therapy were elevated compared to baseline ocular complication rates (IRR = 3.5 - 43.0). Time to development of OirAE was drug dependent, with anti-CTLA-4 monotherapy demonstrating rapid onset of OirAE, with most cases within 20 days of starting drug administration. Patients with a prior history of uveitis or other ocular inflammation demonstrated extremely high recurrence rates of OirAEs after initiating ICIs (51.1% for intermediate/posterior/panuveitis, 38.9% for anterior uveitis). Conclusions: Patients initiating ICI therapy are at risk of a number of ocular complications. Rates of OirAEs following ICI therapy are as high as 50% in specific patient populations, including those with a previous history of any uveitis or autoimmune ocular disease. Early coordination with ophthalmic subspecialist care, possibly before ICI is initiated, is critical for optimal care of these high risk populations.
Immune toxicity and flow cytometry of circulating blood cells in cancer patients receiving immune therapy.
Authors: Khan Saad A. , Sorrelle Noah , Brekken Rolf A. , Lu Rong , von Itzstein Mitchell S. , Xie Donglu , Hsieh David , Gloria-McCutchen Yvonne , Saltarski Jessica , Watters Mary , Bleiberg Benjamin Aaron , Popat Vinita , Ahmed Murtaza , Zhang Yuqing , Fattah Farjana , Khan Shaheen , Park Jason , Gerber David E. 
Published: May 2020

e15126 Background: The mechanisms by which immune checkpoint inhibitors (ICI) cause immune related adverse events (irAE) are not clear. No current blood tests predict which patients will suffer irAEs. Methods: 70 cancer patients had blood drawn prior to ICI and then 4-6 weeks later. 63 had lung cancer; median age was 69 yrs; 21 were female and median ICI treatment duration was 142 days. Patient blood samples were analyzed using flow cytometry for over 50 lymphoid and myeloid markers to determine levels of circulating white blood cells, as well as their changes over time. Medical records were reviewed for irAE’s grades in 8 groups: rash, colitis, hypothyroidism, hyperthyroidism, hypophysitis, hepatitis, adrenal insufficiency, and pneumonitis. To determine association between toxicity and cell counts we used logistic regression and random forest for the univariate and multivariate analysis. We included a random permutation of the baseline age (which is associated with higher toxicity rates) as the analytical control in the random forest model to help identify the threshold of association strength of a random noise and to identify only those cell subsets that were statistically significant (reported below). Results: Patients with elevated baseline levels of specific subsets of T-cells were more likely to develop irAE’s, and elderly patients were more likely to develop Grade 2 irAE’s. T-cell populations associated with any toxicity included CD3+CD8+PD1+; CD3+CD8+; CD25+CD127lowFoxP3+ and CD3+CD8+Ki-67+. Also, patients who developed any irAE’s demonstrated changes in the following cell types after 2 doses of immune therapy compared to their baseline readings. These included changes in the percentage of circulating cells that were CD3+CD8+PD1+; CD3+CD8+HLA-DR+; CD3+CD4+HLA-DR+; CD3+CD8+CCR7-; CD56+; CD3-CD19-; CD3+CD8+; CD16+CD56dim. Patients with grade ≥2 toxicities, or organ specific toxicities demonstrated statistically significant differing levels of T-cells subsets, though the number of patients in each group was limited. Patients with > median baseline expression of CD3+ CD8+ PD1+ cells had greater survival compared with those that had < median levels. Conclusions: Flow cytometry analysis of patients receiving immune therapy at baseline and 6 weeks after initiating therapy may predict which patients are at greater likelihood of any/organ specific irAEs, potentially leading to an improved understanding their mechanisms. Responding to leukocyte changes by substitution of drugs or shortening of treatment duration may reduce irAEs.
Pre-treatment predictors of immune-mediated hepatitis in non-small cell lung cancer patients treated with immune-checkpoint inhibitors: A retrospective study.
Authors: Shek Dmitrii , Read Scott A. , Carlino Matteo S. , Nagrial Adnan , Gao Bo , Ahlenstiel Golo 
Published: May 2020

e15136 Background: Immune-checkpoint inhibitors (ICIs) have become standard of care for patients with non-oncogenic driven metastatic non-small cell lung cancer (NSCLC); a feat that has dramatically changed prognosis for these patients. Nevertheless, ICIs can cause immune-related adverse events (irAEs) requiring steroid administration or treatment cessation. This cohort study aimed to examine the incidence of ICI related hepatitis and determine potential predictors of immune-mediated hepatitis. Methods: We retrospectively collected clinicopathological data from 139 patients with metastatic NSCLC treated at Westmead and Blacktown Public Hospitals between 2017 and 2019. Blood tests results were collected longitudinally with a particular focus on liver function tests (LFTs). Further, parameters associated with acute or chronic liver hepatitis were statistically analyzed regarding their association with toxic elevation of LFTs. In particular we were interested in body weight, liver fibrosis (measured by AST to Platelet Ratio Index [APRI] and Fib-4 score), AST/ALT ratio, albumin, globulin, direct/indirect bilirubin, gamma-glutamyl transferase, ratio of serum protein (SP) to total bilirubin (TB) and C-reactive protein. Results: ICIs were more effective in terms of overall (p = 0.0001) and progression-free (p = 0.007) survivals compared to chemotherapy. Pre-treatment blood tests revealed no abnormalities in LFTs, however, at week 9 we first detected elevated LFTs in 29% (n = 18) and 6.5% (n = 5) of ICI and chemotherapy groups, respectively (p = 0.0003). Multivariate regression found that abnormal transaminases at week 9 significantly correlated with high pre-treatment ratio of SP/TB (p = 0.001) in the ICI group only. Specifically, a pre-treatment SP/TB ratio of was > 5 associated with increased ALT at week 9 (odds ratio 92%; positive and negative predictive values: 74% and 97% respectively; sensitivity 94%; specificity 86%). Interestingly, no other significant correlations with elevated transaminases at week 9 were established. Conclusions: In this real-world cohort, we confirmed that ICI therapy results in improved PFS and OS comparing to chemotherapy alone. Moreover, a pre-treatment ratio of SP/TB > 5 was significantly associated with elevated LFTs at week 9 suggesting that it may have a predictive role.