bluuebunny/crossref_metadata_2025_split huggingface dataset:
Serum microRNAs to predict the response to nivolumab in patients with esophageal squamous cell carcinoma.
Authors: Sudo Kazuki , Kato Ken , Matsuzaki Juntaro , Kawauchi Junpei , Takizawa Satoko , Miyamoto Takahiro , Shoji Hirokazu , Iwasa Satoru , Honma Yoshitaka , Takashima Atsuo , Hamaguchi Tetsuya , Takeshita Fumitaka , Sakamoto Hiromi , Boku Narikazu , Ochiya Takahiro 
Published: September 2018

e14511 Background: A phase II study demonstrated that nivolumab (Nivo), a PD-1 inhibitor, had a meaningful activity for patients with esophageal squamous cell carcinoma. Although several biomarkers, including PD-L1 expression levels in tumor tissue, are explored to predict the efficacy of Nivo, further investigation is needed. Here we evaluated whether serum levels of microRNA (miRNA) could be a candidate of predictive markers. Methods: Among 65 patients who participated in the phase II study (JapicCTINo.142422) and received Nivo 3 mg/kg IV Q2W, 19 patients were treated at our institution. Patients were classified into responder and non-responder by investigators based on modified ir-RECIST. Serum samples were stored before and during treatment in the National Cancer Center Biobank. Comprehensive miRNA microarray analyses were performed using a 3D-Gene Human miRNA Oligo Chip (Toray Industries, Inc.), which was designed to detect 2565 miRNA expression levels. miRNA were compared between responders and non-responders using Fisher’s linear discriminant analysis, and then we calculated the area under curve (AUC) values of receiver operating characteristic curve. We explored the miRNA that showed AUC values of more than 0.8 and difference by 0.5 in the average log2 value of miRNA levels (log2miRNA) between responders and non-responders, and investigated their relation to progression-free survival using Kaplan-Meier curves and log-rank tests. Results: Among 19 patients, 5 responded (CR/PR, 1/4) to Nivo. We identified 3 miRNAs in the serum before treatment that were related to response to Nivo with AUC of 0.84 (log2miRNA of non-responder/responder: 13.16/12.47), 0.90 (8.65/10.20) and 0.81 (7.18/6.57), respectively. In the serum after the first treatment, 5 miRNAs were related to response to Nivo with AUC of 0.93 (11.93/11.09), 0.93 (11.87/11.13), 0.85 (7.92/8.53), 0.92 (6.61/5.82) and 0.93 (7.77/ 7.09), respectively. Among these 8 miRNAs, 4 miRNAs were significantly associated with progression-free survival. Conclusions: We identified miRNA candidates that could predict the response to Nivo. Further validation is warranted to confirm the results of our explorative research.
Tumor cell-free DNA copy number instability compared to CA19-9 as an early predictor of response to systemic therapy in pancreatic ductal adenocarcinoma (PDAC).
Authors: Kundranda Madappa N. , Koenig Alexander , Beck Julia , Bornemann-Kolatzki Kirsten , Coats Jessica , Bergelin Jana , Waypa Jordan , Mitchell William Marvin , Urnovitz Howard , SchÃ¼tz Ekkehard , Dragovich Tomislav , Ellenrieder Volker , Weiss Glen J. 
Published: September 2018

e14524 Background: Humoral tumor markers are used clinically for real-time assessment of therapeutic efficacy. In pancreatic ductal adenocarcinoma (PDAC) the predominant marker is CA19-9, which is not expressed by 10 to 30% of patients depending on race. We compared plasma cell-free DNA (cfDNA) copy number based assay with changes in serum CA19-9 levels and radiological responses to predict responses to systemic therapy. Methods: In a laboratory blinded, prospective multicenter pilot study, 40 non-resectable PDAC patients, treated with (m)FOLFIRINOX, CAPIRI, or gemcitabine +/- nab-paclitaxel) are currently enrolled. CA19-9 was determined in the local center’s laboratory. Tumor cfDNA was measured with a copy-number instability (CNI) scoring assay, determined by next generation sequencing in a centralized laboratory. The CNI score assesses the amount of cfDNA with somatic macro-alterations originating from malignant neoplasms. The difference of the values before commencing therapy (baseline) and prior to cycle 2 (either rising or falling) was calculated as a predictor of standardized radiological evaluation of chemotherapeutic efficacy. Results: 37 patients (3 drop-outs) had data for baseline and cycle 2, of which CA19-9 was elevated and evaluable in 29 patients. The direction from baseline to cycle 2 of CA19-9 and CNI scores were in agreement in 18/29 patients. 9 of 11 cases with discordant CNI score and CA19-9 had treatment response data, and CNI correlated with 7/9 (78%); in contrast 7/9 had rising CA19-9, when response was stable disease or better (22% concordance). In the 27 patients with available imaging, CNI predicted better (n = 18) than CA19-9 (n = 10) (p = 0.03 Fisher’s exact). Conclusions: This comparative study on cfDNA versus CA19-9 suggest that cfDNA CNI quantitation is a potentially more reliable blood based marker for early real-time assessment of efficacy in systemic PDAC therapy than CA19-9, compared to standard of care imaging. The better prediction after the first cycle might be due to the very short in vivo half-life of cfDNA ( < 1hr) compared to about one week for CA19-9. These results justify a larger prospective validation trial.
Evaluation of CD73 in lung cancer.
Authors: Yu Hui , Amar Maya , Rivard Christopher J , Ellison Kim , Rozeboom Leslie , Suda Kenichi , Brovsky Kristine , Hirsch Fred R. 
Published: September 2018

e14525 Background: Immunotherapy has shown promising results in multiple forms of cancer including lung cancer patients. Treatment targeting alternative immune checkpoints may demonstrate value for specific cancers or in combination therapy with other immunotherapies or chemotherapeutic agents. While adenosine has physiological importance in preventing excess inflammatory reactions and inhibiting autoimmunity, it is generated through an enzymatic cascade in the tumor microenvironment whereby AMP is ultimately dephosphorylated to adenosine by CD73 on tumor cells. Previous studies have shown that increased tumor CD73 expression correlated with increased metastasis, worse prognosis and chemotherapy resistance. Methods: Genomic data from the CCLE and TCGA database were evaluated for CD73 expression in lung cancer. The specificity of an anti-CD73 antibody (Cell Signaling) was confirmed by Western blotting in lung cancer cell lines. Immunohistochemistry (IHC) was performed for FFPE lung cancer cell lines and a NSCLC patient cohort. CD73 expression data was correlated with patient demographic data including outcomes. Results: CD73 mRNA was expressed in lung cancer cell lines (70/126, 55.6%) and did not correlate with other immune checkpoint ligands including PD-L1, GAL-9, and B7H4 in NSCLC. Review of the TCGA database identified CD73 expression is highest in thyroid carcinoma and significant in lung cancer. The prevalence of CD73 protein expression by IHC in NSCLC cell lines was 84.8% (39/46) and 15.4% (6/39) in SCLC cell lines. We also evaluated CD73 protein expression in a NSCLC cohort with a prevalence of 32.1% (36/112), with no significant correlation to patient clinical characteristics or outcomes. Conclusions: We evaluated the expression of the immune checkpoint, CD73, in lung cancer cell lines and tissues. Both genomic data and protein expression by IHC demonstrated CD73 was significantly expressed. However, there was no correlation with other immune biomarkers or patient demographics or outcomes. CD73 is a new target for immunotherapy and current clinical studies with CD73 inhibitors may prove beneficial to lung cancer patients.
Feasibility of cancer vaccine therapy using dendritic cells generated from induced pluripotent stem cells expressing carcinoembryonic antigen.
Authors: Ojima Toshiyasu , Kitadani Junya , Iwamoto Hiromitsu , Nakamori Mikihito , Nakamura Masaki , Yamaue Hiroki 
Published: September 2018

e14538 Background: We investigated whether genetically modified human dendritic cells (DCs) derived from induced induced pluripotent stem cells (hiPSDCs) expressing carcinoembryonic antigen (CEA) could induce the CEA specific cytotoxic T lymphcytes (CTLs) against cancer cell lines endogenously expressing CEA in vitro model using healthy volunteers. Furthermore, we established in vivo tumor model using the CEA transgenic mice (TGM) as a preclinical experiment. Methods: Human model; we differentiated hiPSDCs from iPSCs of three healthy donors and transduced the CEA cDNA into DCs. Mouse model; we differentiated miPSDCs in CEA TGM and transduced the CEA cDNA into DCs. Results: Human model; the surface marker expression, cytokine secretion, and migratory capacity of hiPSDCs were equivalent to human monocytes derived-DCs (hMoDCs). After 3 cycles of stimulation to autologous peripheral blood mononuclear cells (PBMCs) by genetically modified hiPSDCs, the cytotoxic assay was performed using a 51Cr release assay. The CTLs induced by hiPSDCs-CEA exhibited CEA specific cytotoxic activity against the target cells expressing. Mouse model; in the CEA transgenic mice model, the CTLs generated in mice immunized with miPSDCs-CEA showed CEA specific cytotoxic activity against MC38-CEA. Moreover, in the subcutaneous tumor model, vaccination with miPSDCs-CEA achieved significantly high growth inhibitory effect for the MC38-CEA. No adverse events were observed. Conclusions: This vaccine therapy using genetically modified iPSDCs is promising for clinical application for patients with gastrointestinal cancer patients.
Defining an allogeneic CAR-T approach by shRNA-mediated knockdown of the T-cell receptor.
Authors: Suhy David , Garcia Patty , Strings-Ufombah Vanessa , Suhy Natalie , Roelvink Peter , Kilfoil Georgina 
Published: September 2018

e14551 Background: An allogeneic approach for CAR T-Cell therapy can significantly streamline manufacturing, provide more accessible options to patients as well as enhance safety by reducing the possibility of graft-versus-host-disease. The T-Cell Receptor (TCR) is comprised of multiple subunits and functions to activate T-cells by a signal transduction cascade that is initiated upon antigen binding. Eliminating expression of the endogenous TCR on modified CAR-T-Cells may eliminate the ability to recognize major and minor histocompatibility antigens in the recipient. This study assessed if simultaneous expression of multiple short hairpin RNAs that knockdown levels of individual TCR subunits could result in the loss of TCR expression and TCR-mediated T-Cell activation. Methods: Recombinant DNA producing short hairpin RNAs against the TCR complex was transfected into T-cells. Cell surface TCR was analyzed by FACS. Following CD3 activation or co-culture with B-cells, T-Cell activation was quantified by measuring the levels of IL-2 by ELISA and QPCR. Results: When expressed individually, each shRNA inhibited it’s cognate TCR subunit by up to 93% of the endogenous levels. However, upon simultaneous expression of the shRNAs against the different subunits from the same vector, we observed a near complete depletion of the TCR complex from the cell surface ( > 99%) as measured by FACS analyses. Furthermore, TCR functionality was inhibited when treated cells were stimulated with either CD3 or in B cell co-cultures with Staphylococcal enterotoxins. IL-2 secretion was inhibited to undetectable levels by ELISA by the multi-shRNA treatment and > 98% by qPCR. Conclusions: Though knockdown of any single component of TCR never exceeded 93%, simultaneous knockdown of several TCR subunits abrogated surface TCR and downstream activation suggesting that disruption of stoichiometric expression the subunits prevented TCR formation. The small size of the shRNA expression cassette ( < 2 Kb) permits co-expression from the same lentiviral vector as the CAR. Altogether, these data point to a viable strategy towards generating a single vector approach for the production of allogeneic T-Cells for immunotherapies against certain cancers.
Anti-PD-1 therapy in patients with end-stage renal disease on dialysis: A single-center case series.
Authors: Park Soo , Daniels Gregory A. 
Published: September 2018

e14553 Background: Anti-PD-1 monoclonal antibodies (PD1) have clinical activity in several solid tumors. However, experience treating dialysis pts with PD1 is limited. Dosage adjustments are not recommended for renal impairment but PK studies did not include pts with ESRD on dialysis. Two case reports have described objective responses and a tolerable AE profile. We sought to explore the safety and efficacy of PD1 in such pts. Methods: In this single-center case series, we identified 4 pts with ESRD on dialysis who were treated with PD1 between 10/2014 to 11/2016. Data regarding clinical history, PD1 dosing, dialysis regimen, treatment (tx) response, and toxicity were collected. Results: Four pts were evaluable for data collection. Two pts had metastatic renal cell carcinoma (mRCC) and 2 others had unresectable cutaneous squamous cell carcinoma (cuSCC). Age at tx ranged from 66 to 71; all 4 pts were male. Number of doses ranged from 4 to 8. Two pts with mRCC received nivo 3 mg/kg q2wk after dialysis. Two pts with cuSCC received pembro 2 mg/kg q3wk after dialysis; dosing was extended to q4wk for 1 pt due to persistent grade (G) 2 fatigue. Three pts were on hemodialysis 3 times a wk and 1 pt was on peritoneal dialysis. Time to progression was 3 months for 1 mRCC pt and could not be determined for the other mRCC pt who had a PR but died from possible tx-related causes. Two cuSCC pts are still receiving pembro with PR at time of analysis. Immune-related AEs were seen in all 4 pts, including 2 incidences of G2 fatigue and 1 incidence each of G2 rash and G3 pneumonitis.One pt developed acute encephalitis after 4 doses of nivo that improved with steroids but was ultimately fatal. Conclusions: This single-center case series highlights the efficacy and AE profile of PD1 for pts with ESRD on dialysis. While this is a small series, there was significant anti-tumor activity in this group of pts. Despite the reported favorable AE profile of PD1, one pt had a serious and mortal AE that may have been related to tx. This should be considered in future studies. High molecular weight of PD1 suggests these agents are not removed by dialysis but we were limited by lack of PK data. Our experience adds to the 2 cases in the literature. Further studies are warranted in larger cohorts.
Increased risk of liver toxicity secondary to nivolumab therapy in the treatment of cancer.
Authors: Zarrabi Kevin , Wu Shenhong 
Published: September 2018

e14559 Background: Nivolumab, a humanized immunotherapy targeting PD-1, is approved for the treatment of a number of solid and liquid cancers and is associated with liver toxicity. This meta-analysis was conducted to determine the overall risk of hepatotoxicity with nivolumab therapy in cancer patients. Methods: An analysis from all phase I, II, and II clinical trials up to December 2016 examining the role of nivolumab in a variety of cancers was conducted. Eligible trials included those in which patients received nivolumab. Data on all-grade and high-grade (grade 3 and 4) elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were extracted from the safety profiles of each clinical trial. Incidence and relative risk (RR) were calculated using random - or fixed - effect models with 95% confidence intervals. Results: The data from 27 eligible trials were included for analysis. A total of 5,287 patients were evaluated (Nivolumab: n = 3515, Control: n = 1772). The incidences of all-grade and high-grade elevations in AST were 5.4% (95% CI: 3.2% - 9.1%) and 1.60% (95% CI: 0.9% - 3.0%), respectively. The incidences of all-grade and high-grade elevations in ALT were 4.9% (95% CI: 2.9% - 8.2%) and 1.5% (95% CI: 0.9% - 3.1%), respectively. Elevations of both laboratory markers were significantly increased when compared to control (P < 0.001). Nivolumab increased the RR of AST/ALT elevations; RR of all-grade AST elevations was 1.58 (95% CI: 1.1 - 2.2), all-grade ALT elevations was 1.62 (95% CI: 1.2 - 2.3). Subgroup analysis of all-grade AST elevations revealed melanoma patients exhibited a significantly higher rate compared to other solid tumors with an incidence of 8.7% (95% CI: 4.3 - 18.2%). All-grade ALT elevations in melanoma patients revealed the same incidence rate. Of note, renal cell carcinoma patients exhibited a particularly low incidence of all-grade transaminitis with AST 1.6% (95% CI: 0.6 - 11.1%) and ALT 1.8% (95% CI: 0.6 - 14.6%). Conclusions: Nivolumab is associated with significantly increased risk of all-grade and high-grade elevations in AST and ALT. Therapy should include careful monitoring of hepatotoxicity.
Correlation between PD-L1 expression level and clinical benefit in 204 patients across malignancies at a single institution.
Authors: Byrd Kenneth , Nagahawatte Panduka , Martin Michael Gary , Stein Matthew K , Patel Kruti , Schwartzberg Lee Steven , Vanderwalde Ari M. 
Published: September 2018

e14573 Background: The utility of PD-L1 expression levels in predicting response to anti-PD-1 agents in many malignancies is uncertain. In this study, we describe outcomes of patients treated with anti-PD-1 agents by PD-L1 expression level. Methods: Molecular profiling of tumors in patients with newly diagnosed metastatic cancer was performed at West Cancer Center starting late 2014. Most profiling was performed by Caris, which in addition to NGS also reports PD-L1 expression (IHC, reported as percent expressed). Patients were included in this retrospective analysis if they were treated with an anti-PD-1 antibody and had available results from PD-L1 testing between 11/2014 and 11/2016. Time to treatment failure (TTF) was defined as time from first dose to documented progression, intolerance or death. Those without treatment failure were censored at the date of last contact. Pending formal retrospective RECIST review, clinical benefit rate (CBR) is reported. Results: 204 patients with reported PD-L1 expression started treatment with anti-PD-1 agents. Of these, 125 had non-small cell lung cancer, 31 had melanoma, 12 had renal cell carcinoma, and the remainder had other malignancies. 110 patients (54%) had PD-L1 expression level of 0%, 22 patients (11%) between 1-4%, 37 patients (18%) between 5-49%, and 35 patients (17%) >50%. Median TTF and CBR by PD-L1 overall and by malignancy are shown in the table below. Conclusions: Higher PD-L1 expression does appear to be associated with increased clinical benefit rate and time to treatment failure, though the highest levels of PD-L1 did not follow this pattern. Based on these surrogate endpoints, there appears to be substantial benefit with PD-1 inhibitor treatment even with 0% PD-L1 expression. Objective response rate will be presented. [Table: see text]
Neoadjuvant chemoradiotherapy to induce the expression of programmed death-ligand 1 of tumor cells and the infiltration of CD8+ lymphocytes in patients with rectal adenocarcinoma.
Authors: Nakagawa Akio , Yamashita Kimihiro , Hasegawa Hiroshi , Yamamoto Masashi , Kanaji Shingo , Matsuda Yoshiko , Matsuda Takeru , Oshikiri Taro , Nakamura Tetsu , Sumi Yasuo , Suzuki Satoshi , Kakeji Yoshihiro 
Published: September 2018

e14577 Background: In recent years, immune checkpoint inhibitors have attracted attention and a lot of studies on PD-L1 (Programmed death-ligand 1) have been reported, but their anti-tumor effects are limited to colorectal cancer in which the expression of PD-L1 is infrequent. On the other hand, radiation therapy has been suggested to be closely related to the antitumor effect derived from the immune response. So we report the histological and clinicopathological examination about the relationship between the expression of PD-L1 and CD8 and irradiation in rectal cancer cases in which operation was performed after preoperative chemoradiotherapy (neoadjuvant chemoradiotherapy, NACRT) to clarify the indication for immune checkpoint inhibitors. Methods: Immunohistochemical staining of PD-L1, CD8 as immune related factors was performed on 34 cases in which operation was performed after NACRT(UFT/LV:300mg/m2/day and 75mg/body/day, respectively +RT(45Gy)) was done for locally advanced rectal cancer from January 2005 to December 2014, and we evaluated their preoperative biopsy specimens and resected specimens to examine the relationship between their evaluations and clinicopathological factors. Results: The 5-year survival rate and relapse-free survival rate of 34 patients were 84.4% and 65.5%, respectively, and there were 4 pathological CR cases. In 30 patients excluding CR cases, the expression of PD-L1 in tumor cells was enhanced or emerged in 5 cases(16.7%) and the infiltration of CD8+TIL(tumor infiltrating lymphocyte) was also enhanced in 13 cases(43.7%) after NACRT. Also, patients with PD-L1 expression had significantly poor prognosis (p = 0.0023) than others, and the prognosis tended to be further poor in CD8+TIL noninvasive cases. Conclusions: NACRT for locally advanced rectal cancer induced PD-L1 expression in tumor cells and also induced the infiltration of CD8+TIL.
Immune related adverse events (irAEs): A unique profile based on tumor type.
Authors: Sharma Nitika , Atluri Prashanti , Stroud Chipman Robert Geoffrey , Walker Paul R. , Cherukuri Sulochana Devi , Cherry Cynthia R. , Gibbs Paul , Parent Teresa , Hardin Jessica 
Published: September 2018

e14606 Background: Immune checkpoint blockade(ICB) has revolutionized the treatment of a growing number of malignancies. Real world administration of oncolytics is often associated with increased adverse event rates versus what is demonstrated in clinical trials. Whether the tumor biology, site of disease burden or underlying organ dysfunction dictates the differing immune side effect profile in various malignancies remains to be understood. Methods: The incidence of grade 2-4 irAE was abstracted from medical records of all patients (pts) treated with ICB (ipilimumab and/or nivolumab) from 2011 to 2016 at a single institution. Results: Of the 126 pts reviewed, 82 pts had metastatic lung cancer, 31 pts had unresectable or metastatic melanoma, 13 pts had metastatic renal cancer(RCC). In the melanoma cohort, concurrent or sequential PD-1 and CTLA4 blockade was used in 10/31 pts. All of the lung cancer and RCC patients received anti-PD-1 alone. In the patients with lung cancer: pneumonitis was identified in 24%, SIRS in 16%, thrombosis in 11%, cerebritis in 9%, colitis in 4%, hepatitis in 4%, thyroiditis in 5%. In RCC, 8% pts experienced pneumonitis and 8% had thyroiditis. In the melanoma population, colitis was identified in 19%, SIRS in 10%, pneumonitis in 3%, thrombosis in 6%, adrenalitis in 6%, hepatitis in 3%. Colitis was seen in 2/13(15%) pts who got ipilimumab alone and 4/10(40%) pts who got both ipilimumab and nivolumab. Conclusions: Pneumonitis, SIRS and cerebritisappear to be the most prevalent irAEs in lung cancer as compared to melanoma or RCC. The incidence of pneumonitis was higher in RCC compared to melanoma. Colitis appears to have a higher incidence in melanoma, the incidence of which further increases when CTLA4 inhibitors are used in conjunction with anti-PD-1. The majority of the RCC patients tolerated ICB with no major irAEs. With the expanding use of ICB in advanced malignancies, increased awareness of these clinically significant and potentially serious irAEs is indispensable. Future trials designed to distinguish the incidence of irAEs in relation to specific tumor types would be informative. [Table: see text]