bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intestinal microbiota to predict risk for immune-related diarrhea in patients with lung cancer patients.
Authors: Liu Tian , Hu Yi 
Published: February 2018

132 Background: Anti-programmed cell death 1 (PD-1) inhibitors, which enhance cellular immunity via blockade of PD-1, represent an effective option for the treatment of lung cancer and have shown some impressive efficacy. However, the inhibitors can also result in immune-related adverse events, such as immune-related diarrhea. Researches have shown that intestinal microbiota plays a vital role in gastrointestinal dysregulation. Whereas, the relationship between PD-1 inhibitors and immune-related diarrhea is still elusive. In our study, we aim to identify the correlation of intestinal microbiota and immune-related diarrhea, and hope to find specific bacteria as potential biomarkers of immune-related diarrhea. Methods: Twenty-six lung cancer patients who were treated with PD-1 inhibitors from 301 hospital were enrolled for retrospective analysis. And the fecal samples were obtained from patients before the first dose of PD-1 inhibitor. Based on whether they develop diarrhea or not, the patients were subgroup into progressed to diarrhea(PtD) group and diarrhea-free(D-F) group. Immune-related diarrhea was graded according to the National Cancer Institute Common Toxicity Criteria (CTC, version 4.0). And 16S rRNA sequencing was used to profile fecal bacterial composition. Results: There was no significant difference in baseline characteristics, such as microbial richness between PtD group and D-F group (P > 0.05). However, At the phylum level, Bacteroidetes were richer in D-F group, while Firmicutes were poorer, than that in PtD group. At the genus level, two families of the Bacteroidetes phylum ( Bacteroides and Parabacteroides) and a family of the Firmicutes phylum (Phascolarctobacterium) were more abundant in D-F group. Veillonella from Proteobacteria phylum was lower in D-F group than that in PtD group (all P < 0.05). Conclusions: Our study indicates that microbiota variation probably participates in the onset of immune-related diarrhea. Identifying these biomarkers may help us to diagnose the side effect earlier, and provides a novel treatment for immune-related diarrhea due to PD-1 inhibitors.
Characterization of progressive multifocal leukoencephalopathy (PML) in patients treated with rituximab, brentuximab and ibrutinib: A report from the Southern Oncology Network on Adverse Reactions (SONAR).
Authors: Kommalapati Anuhya , Tella Sri Harsha , Bennett Charles L. 
Published: February 2018

133 Background: Since the advent of Rituximab (R) in 1997, cancer immunotherapy is increasingly used for management of lymphoproliferative disorders. Unexpected cases of PML have been reported in HIV-negative patients in 2005 receiving Rituximab ( R) and subsequently in 2012 and 2014, who received brentuximab vedotin ( B) or ibrutinib ( I), respectively. We sought to compare and contrast clinical characteristics and outcomes of PML in HIV-negative patients who were treated with R, B or I therapy. Methods: Retrospective analysis of the FDA adverse event reporting system (FAERS) and previously published data by our group with confirmed cases of PML associated with R (1997-2008), B and I therapy (2009-2015). Results: PML develops early during the therapy with B and I, compared to that of R group. Confirmation of the diagnosis of PML by MRI in conjunction with JC virus identification in the cerebrospinal fluid or brain biopsy using objective criteria was found only in 40-60% of the cases. Among confirmed cases of R, I, or B-associated PML, mortality was > 90%, usually occurring within weeks to months following diagnostic confirmation. Rare cases of survival were associated with return of immunologic function, including in one case development of an immune reconstitution syndrome. Conclusions: This is the first study that compared the clinical characteristics of PML in R, B and I. PML cases can occur early during the therapy using B and I, while usually occurs late with R. Additional research is needed to quantify the risk factors of PML and to know if this association is causal or incidental. Meanwhile, physicians and patients should be vigilant in detecting and reporting this rare AE to minimize future fatalities [Table: see text]
Immune-related adverse events requiring inpatient management: Spectrum of toxicity, treatment, and outcomes.
Authors: Balaji Aanika , Zhang Jiajia , Marrone Kristen , Elmariah Hany , Yarchoan Mark , Holdhoff Matthias , Zimmerman Jacquelyn W. , Hajjir Khalid , Armstrong Deborah Kay , Laheru Daniel A. , Mehra Ranee , Ho Won Jin , Reuss Joshua E. , Heng Joseph , Vellanki Paz , Naidoo Jarushka 
Published: February 2018

138 Background: Immune checkpoint inhibitors (ICIs) are anti-cancer agents now in routine clinical practice, and may cause immune-related adverse events (irAEs). The proportion of inpatient admissions for irAEs, spectrum of toxicities, management and outcomes are not well described. Methods: Patients with solid tumors admitted to the inpatient oncology service at a tertiary academic center over 3 months, were identified. Patient demographics, treatment details, irAE event and management data, were collected for those who received ICIs, in an IRB-approved database. The diagnosis of irAEs was confirmed by the treating physician and oncologist. Associations between clinical details and irAEs were evaluated using Fisher's exact test. Results: We identified 240 inpatient oncology patients: 53 (22.1%) had received ICIs, and 25% (13/53) were admitted for irAEs. The majority of irAEs requiring admission were high grade (CTCAE grade 1-2: 6/13, 46%; grade 3+: 7/13, 54%), and included: colitis (31%), pneumonitis (23%), skin rash (8%), fever (8%), pancreatitis (8%), fatigue (8%), and renal transplant rejection (8%). Treatment for irAEs included: ICI withhold (2/13, 15%), oral/IV corticosteroids (10/13, 76%), and infliximab (1/13, 8%); with 85% of patients requiring subspecialty consultations. Those with irAEs had a shorter median length of stay vs. other inpatients (5 vs. 6 days). Most irAEs resolved/improved (11/13, 85%), while 15% worsened (1/13) or resulted in patient death (1/13). There was a numerically higher risk of any/grade3+ irAEs for those: treated with combination vs monotherapy (33% vs 23%; 100% vs 40%), age > 65 vs < 65 (33% vs 15%; 56% vs 50%), and former/current vs. never smokers (31% vs 19%; 63% vs 40%), however differences were not statistically significant. Conclusions: Patients with irAEs constitute a notable proportion of inpatient oncology admissions, with a higher incidence than in reported clinical trials. Initial data suggest that patients treated with combination ICIs, aged > 65, and former/current smokers may be more likely to be admitted for irAEs. The majority of irAE admissions require subspecialty consultations, signifying a growing need for multidisciplinary irAE management.
Consideration of the concordance rate of 22C3 and 28-8 antibody in NSCLC and its relation to the effect of nivolumab.
Authors: Kibata Kayoko , Kurata Takayasu , Takeyasu Yuki , Niki Maiko , Satsutani Naoko Murakami , Ogata Makoto , Yoshioka Hiroshige , Saito Tomohito , Murakawa Tomohiro , Tsuta Koji , Nomura Shosaku 
Published: February 2018

143 Background: Anti-PD-1 antibodies (Abs) have improved survival significantly in patients (pts) with advanced non-small cell lung cancer (NSCLC). Depending on the extent of PD-L1 expression, these drugs have become the standard care of initial treatment and 2nd line therapy. However, PD-L1 expression has not yet been recognized as a robust biomarker. Currently, two Anti-PD-1 Abs (Nivolumab, Pembrolizumab) are commercially available in Japan, but have each diagnostic immunohistochemical (IHC) assays (22C3 and 28-8Ab), respectively. The concordance rate of these assays is not yet well understood and the effect of these agents in concordance and inconsistency cases are also unknown. Based on these background, we explored the concordance rate of 22C3 and 28-8 Ab and its relation with the effect of Nivolumab (Nivo). Methods: We investigated the concordance rate of 22C3 and 28-8 as well as treatment effect and response of 24 advanced NSCLC pts treated in Kansai Medical University Hospital from December 2015 and May 2017. All pts had been tumor biopsy for pathologically immunostained and received Nivo at least once. We compared the PD-L1 expression levels of two IHC assays with 22C3 and 28-8Ab measured in different laboratories independently. Results: Pts’ characteristics included adenocarcinoma in 12 pts, squamous cell carcinoma in 11, and others in 1 pts, respectively. In IHC reaction with 22C3Ab, 58.3% and 29.2% of pts expressed PD-L1 on ≥1% and ≥50% of tumor cells and with 28-8Ab, 37.5% and 16.7% of pts expressed PD-L1 on ≥1% and ≥50% of tumor cells, respectively. Of 24 cases, 1 case experienced CR, 5 cases PR. In CR case, expression level was dissociated at 50% with 22C3 and 5% with 28-8. In PR cases, 2 cases had high expression in both, and 2 cases had moderate expression in both assays. However, the remaining one was dissociated as moderate in 22C3 Ab and negative in 28-8. All PD pts expressed 0% with both of the two Abs. Conclusions: Although the number of cases is small, the concordance rate of the two Abs in advanced NSCLC cases is not necessarily high, but the agreement rate in response cases was likely to be high. As both 0% cases were ineffective, measuring with two Abs may be useful for forecasting invalid cases.
Targeting CD38 to improve anti-PD-1/CTLA-4 combination therapy in lung cancer.
Authors: Chen Limo , Li Yanli , Yi Xiaohui , Gibbons Don Lynn 
Published: February 2018

144 Background: The combination of anti-PD-1 and anti-CTLA-4 is a promising strategy that is being clinically explored to treat a variety of cancer types. Some patients display primary resistance to this combination treatment, while others relapse after treatment. Although some cancer patients have long-term durable responses to the combination therapy of anti-PD-1 and anti-CTLA-4, physicians have been looking for biomarkers that predict response. Methods: Using multiple immunocompetent syngeneic and K-rasLA1/+p53R172H?g/+ spontaneous animal models of lung cancer, we have explored the mechanisms of resistance to anti-PD-1/CTLA-4 combination therapy by evaluating the molecular and cellular immune profiles of the tumor microenvironment. Antibody-mediated cell depletion assays were also conducted to validate the mechanisms. Lastly, to determine the applicability to patients, we analyzed 791 lung cancer patients’ specimens with immunohistochemistry staining and mined many immune markers in multiple large independent patient databases (~1900 tumors). Results: We observed that tumor bearing mice treated with combined PD-1 and CTLA-4 blocking antibodies developed resistance through the up-regulation of CD38, and that targeting CD38 abolished the resistance in a manner dependent on B7-costimulation. Additionally, combined PD-1 and CTLA-4 blockade eradicates CD38-deficient tumors in mice. Further study revealed that control of tumors by triple blockade of CD38, PD-1, and CTLA-4 depended on improved functionality of CD4+/CD8+ TILs, which were reactivated by enriched CD103+ dendritic cells in the tumor microenvironment. Pathologic analysis revealed positive immunohistochemical staining for CD38 on tumor cells in 15-23% of cases and bioinformatic analyses revealed a strong correlation between CD38 expression and an immune inflammatory signature. Conclusions: Targeting CD38 improves the efficacy of anti-PD-1/CTLA-4 combination therapy in lung cancer. CD38 on tumor cells could potentially serve as a novel biomarker of resistance for immune checkpoint inhibition.
Monitoring PD-L1 expression on circulating tumor cells (CTCs) in patients with NSCLC treated with PD1 inhibitors.
Authors: Guibert Nicolas Marie , Delaunay Myriam , Lusque Amellie , Gouin Sandrine , Boubekeur Nadia , Rouquette Isabelle , Clermont Estelle , Fourtoul Aurélien , Favre Gilles , Pradines Anne , Mazieres Julien 
Published: February 2018

147 Background: Inhibitors of the immune checkpoint PD-1/PD-L1 have become a standard of care in NSCLC. Patient selection, currently based on PD-L1 expression in tumor tissue, is limited by its temporal and spatial heterogeneity. We hypothesized that monitoring PD-L1 staining of circulating tumor cells (CTCs) could represent a valuable non-invasive biomarker. Methods: Up to 3 blood samples were prospectively collected from patients with advanced NSCLC: i) pretreatment (nivolumab), ii) first follow-up, iii) progression. CTCs were isolated from 10 mL of blood using cell size-based technology (ISET, Rarecells). PD-L1 expression was assessed by immunofluorescence on CTCs and immunohistochemistry on tissue. Results: 162 samples from 96 patients were collected. PD-L1 expression could be assessed pretreatment on tissue and CTCs in 72% and 93%, respectively; and was ≥1% in 37% and 83%; ≥5% in 35% and 79%, respectively. No correlation between tissue and CTCs PD-L1 expressions was observed (Spearman coefficient correlation = 0.04, p = 0.77). At baseline, each 10/7.5 ml increase in CTCs count was associated with increased risk of death and progression (HR[95%CI]: 1.06 [1.005;1.117] p = 0.03 for OS and HR[95%CI]: 1.05 [1.01;1.10] p = 0.02 for PFS). The presence of PD-L1(+)CTC (≥1%) had no prognostic impact (OS: p = 0.89 and PFS: p = 0.55), but pretreatment PD-L1(+)CTCs were more frequent in the “non-responders” group (PFS < 6 months) (p = 0.04). Median CTC count was 30 (n = 96), 68.3 (n = 44) and 50.3 (n = 22) pretreatment, at the first follow-up and at progression, respectively. The changes in CTC count at the first follow-up had no impact on PFS (p = 0.45) or OS (p = 0.68). 96% of patients had PD-L1(+)CTCs at progression. Further analyses are ongoing to assess the prognostic value of the persistence of CTCs and PD-L1(+)CTCs at the first follow up and at progression. Conclusions: Analysis of PD-L1 expression on CTCs is highly feasible. PD-L1 expressions on tissue and CTCs are discordant, CTCs being more likely positives, suggesting false negatives occurring in small biopsies. Further analyses of the kinetics of this biomarker throughout ICI treatment, along with other circulating biomarkers, are ongoing. Clinical trial information: NCT02827344.
Clinical impact of 22C3 PD-L1 expression in non-small cell lung cancer.
Authors: Okabe Naoyuki , Takagi Hironori , Suzuki Hiroyuki 
Published: February 2018

149 Background: Immune checkpoint inhibitors has been widely applied in the field of non-small cell lung cancer (NSCLC). Immunostaining of PD-L1 using 22C3 was carried out as a companion diagnosis for Pembrolizumab. To date, only PD-L1 expression thought to be a predictive biomarker approved in USA and JAPAN. However, clinical impact or characteristic of PD-L1 expression in NSCLC is still controversial. In this report, we tried to analyze the relationship between PD-L1 expression and clinic-pathological parameter in NSCLC. Methods: A total 110 of NSCLC samples (Biopsy tissue and surgical resection specimen) were stained with PD-L1 IHC assays by using 22C3 antibody. The expression rate of PD-L1 was examined and relationship between the PD-L1 expression and clinicopathological factors was statistically analyzed. Results: The frequency of Tumor Proportion Score (TPS) less than 1% was 50%, TPS 1 to 49% was 32.7% and TPS 50% or more was 19%. Compared with the previous clinical trials such as KEYNOTE 001 and the KEYNOTE 010, our data of positivity tended to be low. In comparison between histological subtype, the expression in squamous cell carcinoma was higher than non-squamous histology. Furthermore, in relation to smoking history, higher smoking subgroup tended to be higher than the group with low smoking subset. In addition, the specimen preserved for 3 years or longer had a low positive rate, suggesting the possibility of false negatives due to long term formalin fixation of tissue specimens. Conclusions: We examined the relationship between the expression rate of PD-L1 and clinicopathological factors in 110 tissue samples subjected to PD-L1 staining by 22C3 at our hospital. Our results consistent with recent previous studies. In considering to analyze the archived tissue, we recommend that more fresh sample should be use for PD-L1 testing.
Survival stratification using a baseline inflammatory physiology based scoring system in advanced non-small cell lung cancer (NSCLC) treated with anti-programmed cell death-1 (anti-PD-1) therapy.
Authors: Naqash Abdul Rafeh , Stroud Chipman Robert Geoffrey , Muzaffar Mahvish , Yang Li V. , Walker Paul R. 
Published: February 2018

152 Background: Immune checkpoint blockade (ICB) has shown promise in NSCLC with improved survival and durability in disease control. Despite these advances, the response to ICB remains variable. Thus identifying easily available biomarkers that can assist in the optimal selection of patients for ICB holds paramount importance. Methods: Retrospectively we identified 87 stage III/IV NSCLC patients initiated on anti-PD-1 therapy from April 2015 to March 2017 after progressing on a platinum doublet. These patients were part of an ongoing prospective biomarker-based study at our institution. Follow up cutoff for survival analysis was set at October 1, 2017. Enrolled participants had inflammatory markers (C-reactive protein, absolute neutrophil count, absolute lymphocyte count, serum albumin) measured on the day of first dose of anti-PD-1 administration as well as subsequent doses. Using multivariate Cox analysis, factors demonstrating an association with overall survival after immunotherapy (OSI) were used to develop a composite score to stratify patient survival. Results: The median age was 64 years with predominant histology being adenocarcinoma in 46.0 % followed by squamous cell carcinoma (43.7 %). Stage IV disease was present in 70.1%, with skeletal involvement (54.1 %) and liver (27.9 %) being the most common metastatic sites. In the multivariate Cox regression with backward elimination, factors independently associated with OSI were noted to be: CRP, neutrophil-lymphocyte ratio, and prognostic nutritional index. A composite inflammatory biomarker score was developed using the B-coefficients from the Cox multivariate regression. A score > 1 demonstrated inferior OSI compared to a score of ≤ 1 [1.7 vs. 9.3 months; P < 0.001, HR 4.00, 95% CI (2.21-7.25)]. Conclusions: This study provides preliminary evidence in favor of a composite inflammation based score that can aid in survival stratification of these patients. Validation of this score in prospective NSCLC trials to elucidate its potential utility as a predictive or prognostic tool in facilitating optimal patient selection for ICB is required.
The effect of chemotherapy on the tumor immune microenvironment in non-small cell lung cancer (NSCLC): A single-institution retrospective analysis.
Authors: Devitt Michael Edward , Gade Kristine E , Hall Richard Delmar , Horton Bethany J , Stelow Edward B , Bullock Timothy , Gentzler Ryan D. 
Published: February 2018

155 Background: Platinum-doublet chemotherapy (chemo) is routinely used for treatment of early stage and metastatic NSCLC. Immunotherapy is a proven treatment in these patients as well. The presence of tumor infiltrating lymphocytes (TILs) has been shown to be prognostic of this disease; however, the effect of chemo on TILs and the tumor immune microenvironment in NSCLC has not been well studied. We tested the hypothesis that chemo results in a decrease in the presence of TILs in NSCLC. Methods: We retrospectively identified patients treated with neo-adjuvant platinum-doublet chemo who underwent surgical resection from 2007-2015 at the University of Virginia. The specimens were sectioned and IHC stained for CD8, FoxP3, and PD-L1. Two independent investigators assessed a central and a peripheral high power field of tumor for number of CD8 and FoxP3 positive TILs. An independent pathologist assessed tumor cell PD-L1 expression. The nonparametric Wilcoxon Mann Whitney test was used to compare measurements of TILs in chemo-exposed tissue to a control cohort from a database of NSCLC surgical specimens that had not received pre-operative therapy. Results: Of the 17 patients who met eligibility criteria, 11 had sufficient tissue for evaluation. Results are shown in Table 1. There was a significant decrease in CD8 and FoxP3 TILs in both the center and periphery in patients exposed to chemo. There was no difference in PD-L1 expression. Conclusions: These data suggest that platinum-doublet chemo significantly decreases the presence of cytotoxic and regulatory subsets of TILs without effecting PD-L1 expression. This study is limited by the lack of pre-treatment tumor samples to compare pre- and post-treatment TILs in individual patients. Further studies are warranted to evaluate the impact of decreased TILs in the setting of concurrent or sequential immunotherapy treatment with chemo in NSCLC. [Table: see text]
Simultaneous, single cell, flow cytometric quantification of PD-L1/TILs/cell cycle in non-small cell lung cancer tissue biopsies: Concordance of PD-L1 expression detection between flow cytometry and immunohistochemistry.
Authors: Young Stephen , Griego-Fullbright Christen , Wagner Aaron , Chargin Amanda , Patterson Bruce Kendrick 
Published: February 2018

159 Background: Tumor cell expression of PD-L1 leads to the inhibition of immune responses specifically inactivation of cytotoxic T-cells. PD-L1 expression on tumor cells by immunohistochemistry does not provide the complete picture of therapeutic (PD-L1) and prognostic (TILs, aneuploidy) markers. Here, we report a clinical assay that quantifies tumor infiltrating lymphocytes (TILs), cell cycle/DNA content as well as PD-L1 expression on tumor and aneuploid tumor cell populations. Methods: Punch biopsies were taken from 19 fresh tissues specimens and were processed into single cell suspensions using the IVD/CE-IVD IncellPREP Single Cell Preparation Kit. Cells were fixed and permeabilized in 1 mL IncellMax. Cells were tested with the OncoTect iO Lung Assay which contains antibodies directed against PD-L1 (clone 28-8), CD45, CD3, and CD8, and a cell cycle dye. Concordance to IHC was tested by the Dako PD-L1 IHC 28-8 PharmDx Kit. Immune cell populations were quantified and aneuploidy was determined using a DNA index > 1.05. Results: The number of CD8+ CTL were significantly increased (P = 0.02) in tumor compared to normal lung tissue (37.4% to 28.2%). The number of CTL in aneuploid tumors was twice the number of CTL in diploid tumors. The percentage of antigen presenting cells (CD45+, high SSC) was decreased in the tumor cell samples relative to the normal lung tissue (P = 0.01). PD-L1 expression varies in cells depending on the cell cycle. Conclusions: In this study, the concordance between Oncotect iO and IHC was 95% (NPA-97%, PPA-89%). PD-L1 expression varies with DNA content, PD-L1 expression decreases with increasing DNA content. Though CTL are increased in aneuploid tumors, PD-L1 expression decreasing with DNA content may contribute to the association of aneuploidy with distant metastases. PD-L1 expression is a powerful determinant of treatment and aneuploidy is a powerful prognostic factor that combined yield important clinical information.