bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis of the relationship between ratio N/L and survival in lung cancer patients treated with immunotherapy.
Authors: De Dios Alvarez Noemi , Costa Rivas Marinha , Agraso Busto Sara , Pereiro Corbacho Diego , Alonso Herrero Ana , García Benito Carmé , Villanueva Silva Maria Jose , Huidobro Vence Gerardo , Lázaro Quintela Martín Emilio , Castellanos Diez Javier , Casal Rubio Joaquín 
Published: May 2019

e14247 Background: The neutrophil-lymphocyte (N / L) ratio is a marker of general immune response in different stress situations, having shown a relationship between the quotient and the evolution of patients treated with immunotherapy (IT), emphasizing the importance of inflammation in these patients. Methods: In order to evaluate this relationship in a context of usual clinical practice, we performed a retrospective review of patients with pulmonary neoplasia who received IT treatment in the first line or successive, between November 2015 and December 2018, excluding those who received treatment within of clinical trial. Data were collected from the clinical history of each patient, with special attention to baseline neutrophil and lymphocyte numbers, objective response to therapy by criteria iRECIST 1.1 after 3 months of treatment and overall survival (OS) defined from the beginning of treatment until death by progression of the disease. Results: 92 patients (29 women and 63 men) with a median age of 64 years (44-79) were analyzed. 15 (16,3%) patients (p) received immunotherapy as first line treatment, 65.2% (60 p) received it as 2nd line and 18,5% (17 p) as 3rd or succesive lines. The average number of cycles received was 14 (1-52). Regarding the type of IT, 54 p (58,7%) received treatment with Nivolumab, 33 patients (36%) with Pembrolizumab and 5 patients (5.3%) were treated with Atezolizumab. Two stretches of baseline N / L ratios ≤5 (low) and > 5 (high) were defined. Low ratio N / L (≤5) was identified in 62p (67.4%) of the patients treated with IT and high ratio N/L ( > 5) in 30p (32,6%). Of the 62 patients with a low ratio: 41p (66.1%) had some type of response or stabilization of their disease, 13 patients (21%) had progression and 8 patients (12.9%) received less than three months of treatment, 6 patients for PS deterioration and the other 2 patients continue with the treatment and are pending reevaluation. Among the 30 patients with high N / L quotient: 7p (23.3%) presented response or stabilization of the disease, 23 patients (76,7%) presented progression or treatment was interrupted due to deterioration of the ECOG. The average survival in the group with a low N / L ratio (≤5) was 213 weeks compared to the group with a high N / L ratio ( > 5) 144 weeks (p < 0.05). Conclusions: The N / L ratio has been identified in some studies as an adverse prognostic factor in patients treated with IT. Our data from the usual clinical practice support this theory. If these findings are confirmed in future studies, it could be used as a response biomarker for better patient selection.
Treatment outcome and safety of anti-PD-1 antibody against elderly non-small cell lung cancer.
Authors: Sakatani Toshio , Saihara Aya , Ikushima Hiroaki , Takeshima Hideyuki , Taniguchi Yuri , Hojo Masayuki , Usui Kazuhiro 
Published: May 2019

e14249 Background: The anti-PD-1 antibodies, Pembrolizumab (Pem) and Nivolumab (Nivo), have become available for practical clinical use in Japan, and many patients are benefiting from them. Lung cancer is predominantly a disease of the elderly people. However, the validity and safety of anti-PD-1 antibodies against the elderly are insufficient. Methods: From February 2016 to November 2018, 66 patients with non-small cell lung cancer who received anti-PD-1 antibody therapy (23 Pem and 43 Nivo) were evaluated for progression-free survival (PFS), overall survival (OS), and safety were compared between groups between the aged ≥75 years (≥75 yrs) and < 75 years ( < 75 yrs). Results: The median age (width) was 67 years (46-87 years). 46 patients were < 75 yrs and 20 patients were ≥75 yrs. PFS was 3.3 months (m) vs. 4.4 m ( < 75 yrs vs. ≥75 yrs)(p = 0.214). OS was 11.7 m vs. 16.7 m ( < 75 yrs vs. ≥75 yrs)(p = 0.212). Similar analysis was carried out for each anti-PD-1 antibody. In Pem, 15 patients were < 75 yrs and 8 patients were ≥75 yrs, and there was no significant difference between PFS and OS (p = 0.46, p = 0.17, respectively). In Nivo, 31 patients < 75 yrs, 12 patietns > 75 yrs, and there was no significant difference in PFS and OS (p = 0.49, p = 0.44, respectively). Immunity-related adverse events (irAE) was expressed in 25 patients (37.9%). Among 66 patients, 19 in 46 (41%) were < 75 yrs, 6 in 20 (30%) were ≥75yrs. There were not many irAEs even in the elderly people (χ2= 0.757, p = 0.384). Conclusions: Pem and Nivo proved to be effective and safe for the elderly patients even in the clinical setting.
New generation of oncolytic herpesviruses embodying immunotherapeutic genes encoding IL-12 and anti-PD-1 antibody.
Authors: Zhou Grace , Ni Dongyao , Yan Runbin , Chen Xiaoqing , Liu Xianjie , Ma Jie , Tang Yuxin 
Published: May 2019

e14250 Background: Systemic administration of checkpoint inhibitors alone and especially concurrent with intratumoral administration of oncolytic herpes simplex viruses (oHSV) have a major impact on cancer therapy marred by rare failures of healthy organs. Methods: We constructed 3 families of recombinant oHSVs expressing no immunomodulatory genes (T1 series), murine or human IL-12 (T2 series) and murine or human IL-12 and anti-PD-1 antibody (T3 series). We compared the oncolytic effects of a single or multiple intratumoral injection(s) of T1, T2 and T3 series oHSVs. We also compared the effectiveness of intratumoral injection of T3 oHSV with systemic administration of anti PD-1 ab and IL12 alone or in combinations with T1. Results: Insertion of the gene encoding PD-1 Ab significantly augmented the oncolytic activity of oHSV bereft of immunostimulatory genes (T1 series) or expressing IL-12 alone (T2 series). In syngeneic mice the T3 series oHSV expressing murine IL-12 and PD-1 Ab was effective against a variety of murine tumors. Concurrent with enhanced cytolytic activity the T3 oHSV induced the production and significant intratumoral accumulation of IL-12, PD-1 Ab and IFN-γ. Consistent with an earlier report we noted an inverse correlation between the volume of the tumor and the quantity of retained IFN-γ. The most effective oncolytic effect resulted from the administration of T3855 expressing both IL12 and anti PD-1 antibody or T2850 concurrently with intraperitoneal administration of anti PD-1 antibody alone. The least effective were single intraperitoneal administration of IL12 or PD-1 antibody. Intratumoral injection of T3 oHSV was most effective against murine tumors in comparison of either systemic administration of anti PD-1 ab and IL12 or intratumoral injection of T1 in combinations of systemic administration of anti PD-1 ab and IL12. Conclusions: We report the marriage in a single therapeutic agent of three distinct cancer therapies: the targeting of cancer cells by oncolytic viruses, the stimulation of immune system by IL12, and the production of immunotherapeutic antibodies against PD-1. The significant finding reported in this article is that the anti-tumor responses remain concentrated in the tumor environment.
Immunotherapy-induced endocrinopathies: A multi-center experience.
Authors: Ronan Karine , Che Othman Elly Hanis , McKenna Susan , Anderson Cian , Sheehan David , Griffin Margaret , McDermott Ray , Westrup Jennifer 
Published: May 2019

e14251 Background: Endocrinopathies account for approximately 10% of immune-related adverse events.1 Methods: We carried out a retrospective review of 100 patients who received immunotherapy at two hospital sites between 2012 and 2019. Our aim was to ascertain the overall rate of immunotherapy-induced endocrinopathy and assess the impact of immunotherapy on pre-existing diabetes and thyroid dysfunction. Results: 28 out of 100 patients had pre-existing thyroid dysfunction, 36% of these experienced further thyroid dysfunction on immunotherapy. 41 patients had a diagnosis of renal cell cancer, and had treatment with a tyrosine kinase inhibitor prior to treatment with Nivolumab. Eighteen of these patients had a pre-existing thyroid dysfunction. Of these 18 patients, 44% experienced further thyroid dysfunction following immunotherapy. Of the 23 patients who received a tyrosine kinase inhibitor, who had no pre-existing thyroid dysfunction, 17% developed thyroid dysfunction on Nivolumab. 15% of patients without a pre-existing thyroid dysfunction developed a new thyroid dysfunction while on immunotherapy. Seven patients had diabetes mellitus prior to commencing immunotherapy, diabetes control did not disimprove during treatment. One case of diabetes was diagnosed on immunotherapy(1%). One case of adrenalitis(1%) and two cases of hypophysitis(2%) were diagnosed on immunotherapy. The adrenalitis occurred on Nivolumab (1.35%). Both cases of hypophysitis occurred on ipililumab(14%). The overall rate of new immunotherapy-induced endocrinopathy was 15%. Conclusions: The rates of endocrinopathy observed de novo are in line with published rates.1,2,3,4 In this small study, an increased rate of thyroid dysfunction was observed in patients with pre-existing thyroid dysfunction. Prior treatment with a tyrosine kinase inhibitor did not cause an increase in the rate of thyroid dysfunction. Ipilimumab was observed to be a risk factor for development of hypophysitis. [Table: see text]
Absolute lymphocyte count (ALC) as predictor of Pneumocystis Jiroveci Pneumonia (PCP) infection in patients on immune checkpoint inhibitors (ICPi).
Authors: Joshi Krishna Prasad , Atwal Dinesh , Siegel Eric R , Jillella Anusha , Konda Manojna , Parikh Richa , Ananthula Aneesha , Bano Kulsum , Arnaoutakis Konstantinos , Schafer Liudmila , Milojkovic Natasa , Mahmoud Fade , Govindarajan Rangaswamy 
Published: May 2019

e14255 Background: Checkpoint inhibitor pneumonitis (CIP) is an uncommon but serious immune related adverse event needing treatment with prolonged steroids. PCP prophylaxis is recommended for patients on daily prednisone equivalents of 20 mg or greater for at least 1 month. Known risk factors for PCP infection in general population are glucocorticoid use and defects in cell-mediated immunity. We conducted a retrospective study to evaluate the association between ALC and development PCP infection in the patients with CIP treated with steroids. Methods: A retrospective analysis of subjects who received ICPi for any type of cancer from 2011 to 2018 at a single institution was conducted. PCP was diagnosed by PCR of bronchioalveolar lavage. In patients with CIP, ALC at the beginning of steroid treatment, dose and duration of steroids and development of PCP infection was recorded. The median ALC was compared between the patients with PCP infection and without PCP infection via Welch’s t- test at 5% alpha. Results: Out of 515 patients who received ICPi, there were 429 (83.3%) Caucasians, 79(15.3%) African Americans, 7(1.3%) others. CIP developed in 23 (4.38 %) patients. There were 15(65%) males, 8 females (35%), 20(86.9%) Caucasians and 2(8.6%) African Americans. Median age was 67 Yrs. (range 29-80). Six out of 23 (26%) patients with CIP developed PCP infection. Median ALC in the patients with PCP infection was 0.75 K/uL (range 0.2-0.83) compared to 1.14 K/uL (range 0.18 - 1.76) in those without PCP infection (p = 0.0182). Conclusions: In patients with CIP, low ALC and prolonged steroid therapy are more likely to result in PCP infection as opposed to steroid therapy alone. Low ALC and prolonged steroid therapy may select patients who require PCP prophylaxis. [Table: see text]
Defining tissue requirements for a reliable detection of tumor mutational burden (TMB) in clinical FFPE samples.
Authors: Schildhaus Hans-Ulrich , Herold Thomas , Worm Karl , Stoss Oliver 
Published: May 2019

e14265 Background: In the context of immuno-oncology related cancer treatment, tumor mutational burden (TMB) is currently explored as a predictive biomarker for several human malignancies. Several sequencing assays are increasingly commercially available. Established methodologies require rather large amounts of DNA input (in the range of 100 ng) which, however, are frequently not available from small biopsies. We aim to investigate how tissue size and DNA input influence TMB scores. Methods: DNA from 20 specimens (12 biopsies of non-small cell lung cancer (NSCLC); 8 surgical resection specimens from NSCLC, colorectal cancer and endometrial carcinomas) was manually extracted by using the Qiagen GeneRead DNA FFPE kit. Cases were selected to provide a wide range of relative tumor cell content (from < 10% to > 50%) and to include microsatellite-stable and –instable (MSI) cases. Samples were analyzed in triplicates from predefined numbers of unstained sections of a standardized tissue size. DNA quantification was done fluorometrically and by qPCR. Up to 40 ng of DNA were analyzed with the QIASeq TMB Panel (incl. MSI primer boosters; Qiagen). Sequencing was done on an Illumina NextSeq platform, TMB scores and MSI status were determined by using the CLC workbench 5.0.1 (Qiagen). Results: Biopsy samples generated less numbers of DNA molecules (as detected by unique molecular identifiers, UMIs) and less overall reads compared to resection samples. UMI coverage was > 500x in all samples with > 15 ng DNA input. TMB scores were highly reproducible among all samples with > 15 ng DNA but differed significantly among samples with limited DNA input. Interestingly, TMB scores were inversely correlated with DNA input among those samples with < 15ng. Thus, valid TMB scores could also be obtained from only one slice of 1 cm2 tissue from tumor resections or 3 slices of an endoscopic biopsy (each of 5µm thickness). All pre-characterized MSI carcinomas could be detected correctly. Conclusions: We provide first evidence that TMB can be reliably determined also in small biopsies yielding limited DNA content. However, false high TMB scores can occur in samples with < 15ng DNA input. Our results contribute to the definition of minimum requirements (tissue size and DNA input) for valid TMB measurement on clinical FFPE samples.
A landscape analysis of immunotherapy-related biomarkers across solid tumors.
Authors: Kujtan Lara Ann , Morris Scott , Masood Ashiq , Subramanian Janakiraman 
Published: May 2019

e14268 Background: Checkpoint inhibitor-based immunotherapy has varying success among tumor types and patients. Predictive biomarkers are in high demand to assist with patient selection. Responses to these agents are correlated with programmed cell death ligand 1 (PD-L1) expression, microsatellite instability (MSI), and tumor mutational burden (TMB). Here we evaluated PD-L1 expression, MSI status and TMB in a variety of solid tumors to determine their relationships. Methods: A total of 109 specimens were identified in patients diagnosed with solid tumors that underwent a Paradigm Diagnostic Cancer Test. MSI scores were determined by the number of indels present in runs of 6 homopolymer bases per megabase, with a cut-off of 6 to distinguish between MSI-high (MSI-H) and MSI-stable (MSI-S). TMB scores greater than or equal to 10 muts/Mb were designated as high (TMB-H). Results: Of all tumors, 19.3% were MSI-high. PD-L1 testing was performed in 71.5% of all samples; of these, 21.8% were PD-L1 positive. TMB scores of PD-L1 positive tumors (mean = 10.3 muts/Mb) and PD-L1 negative tumors (mean = 8.6 muts/Mb) did not differ significantly (p = 0.57). All MSI-H tumors were TMB-H, and MSI-H tumors had higher mean TMB scores than MSI-S tumors (57 muts/Mb versus 7.6 muts/Mb; p = 0.06). Among TMB-H tumors, MSI-H status was associated with higher TMB scores compared to MSI-S tumors (55.2 muts/Mb versus 22.1 muts/Mb, p = 0.18). Of the both MSI-S and TMB-H tumors, 68.8% were lung cancers and 18.8% were breast cancers. Tumors both MSI-H and TMB-H were 47.6% gastrointestinal carcinomas and 33.3% endometrial carcinomas. Conclusions: In our analysis, TMB was independent of PD-L1 status. All MSI-H tumors were also TMB-H; these were primarily gastrointestinal and endometrial carcinomas whereas TMB-H tumors that were MSI-S consisted predominantly of lung cancers. This difference may be due to the different mechanisms of acquiring mutations during carcinogenesis in these two tumor types. These data also highlight the need for integrated PD-L1, MSI and TMB testing to identify potential responders to immunotherapy.
Preliminary effects on the innate immune system with the combination of cetuximab and durvalumab in metastatic/ relapsed head and neck squamous cell carcinoma in a phase II trial.
Authors: Gulati Shuchi , Vachon Rachel , Desai Shireen , Steele Aubrey , Palackdharry Sarah , Takiar Vinita , Wise-Draper Trisha Michel 
Published: May 2019

e14273 Background: Cetuximab is a recombinant chimeric monoclonal IgG1 antibody which binds specifically to the epidermal growth factor receptor (EGFR) and stimulates an innate immune response by promoting natural killer (NK) cell mediated antibody-dependent cell-mediated cytotoxicity (ADCC). Cetuximab is approved as a single agent in relapsed/metastatic head and neck squamous cell carcinoma (R/M HNSCC). PD-1 check-point inhibitors which release the inhibition of the adaptive immune response, are also approved as single agents in this setting. However the response rates with these drugs, when used individually range from 10-20%. We hypothesized that adding a PD-L1 inhibitor, durvalumab to cetuximab would cause anti-tumor synergy by activating the innate as well as adaptive immune systems without compromising safety in this phase-2 trial in R/M HNSCC patients who have progressed on platinum based therapy. Methods: Blood samples were collected from the first six enrolled patients prior to starting treatment and 4 weeks after the first combined dose of cetuximab and durvalumab. PBMCs were isolated, stained with a live/dead stain as well as CD3, CD4, CD8, CD56, CD16 and NK2GD (natural killer group 2 member D activation receptor) antibodies and analyzed by flow cytometry. Cytokine levels in plasma were measured using standardized ELISA assay kits. Results: Compared to pre-treatment levels, post-treatment samples showed an increase in activated cytokine producing NK cells (CD56bright/CD16-) in all but one patient. Activated cytotoxic NK cell subpopulations (CD56dim/CD16+) showed variable results post-treatment. CD8+ T cells were similar pre and post-treatment in 5 patients. TGF-b levels increased in 5 patients and decreased in 1 patient post-treatment. Interestingly, the patient with decreased TGF-b levels post-treatment had an almost doubling of CD8+ T-cells and an increase in activated cytokine producing NK cells (CD56bright/CD16-). Conclusions: The clinical trial is ongoing and therefore, comparison to clinical response has not yet been analyzed. However, these findings support the combination of cetuximab and durvalumab in R/M HNSCC given the activation of an NK-cell mediated innate immune response in these patient samples. Clinical trial information: NCT03691714.
Comprehensive analysis of immune indicators provides prognostic markers for early stage non-small cell lung cancer.
Authors: Ding Xiao , Cui Jiuwei 
Published: May 2019

e14276 Background: Adjuvant chemotherapy has been established as a standard for patients with early stage NSCLC after complete tumor resection, but the 5-year survival rate can only increase by about 5%. Given its high morbidity and mortality, new biomarkers are needed to predict clinical response and prognosis of resected NSCLC. The expression of MHC-I, PD-L1 and CD8+ TILs were detected in this study to investigate the potential prognostic markers in patients with early stage NSCLC. Methods: Tissue of 125 patients with surgically resected NSCLC (stage I-III) were obtained from the First Hospital of Jilin Universtiy. MHC-I, PD-L1 and CD8+ TILs were detected with immunohistochemistry. The association between their expression levels and patients’ prognosis was analyzed. Results: MHC-I was down-expressed, and PD-L1 was up-expressed in NSCLC tissues compared with the para-cancer tissues. CD8+ TILs could be seen in tumor stroma and nest. PFS and OS was poorer in MHC-Ilow group compared with MHC-Ihigh group (P < 0.05). PFS and OS in PD-L1− group tended to be longer than the PD-L1+ group, but the difference was not significant (P > 0.05). For CD8+ TILs, PFS and OS of the CD8inflamed group were longer than the CD8non-inflamed group (P < 0.05). With multivariate analysis, we found that MHC-I and CD8+ TILs might be independent prognostic factors of NSCLC (P < 0.05). Based on the PD-L1 and CD8+ TILs expression, we divided the patients into four subgroups: PD-L1+/CD8inflamed, PD-L1+/CD8non-inflamed, PD-L1−/CD8inflamed, and PD-L1−/CD8non-inflamed. Statistical differences were achieved both in PFS and OS (P < 0.05). PFS and OS of the PD-L1+/CD8inflamed and PD-L1−/CD8inflamed group were longer than the other two groups. Patients with PD-L1+/CD8non-inflamed experienced the worst PFS and OS. Besides, we divided the patients into four subgroups according to their MHC-I and CD8+ TILs expression conditions: MHC-Ihigh/CD8inflamed, MHC-Ihigh/CD8non-inflamed, MHC-Ilow /CD8inflamed, and MHC-Ilow/CD8non-inflamed. Statistical differences were achieved both in PFS and OS of these subgroups (P < 0.05). PFS and OS of the MHC-Ihigh/CD8inflamed group were longer than the other three groups. Patients in MHC-Ilow/CD8non-inflamed group experienced the worst PFS and OS. Conclusions: It was reported for the first time that the combination of PD-L1 and CD8+ TILs, MHC-I and CD8+ TILs suggested impressive prognostic values in early stage NSCLC in this study. The comprehensive analysis of immune indicators may provide prognostic markers for early stage NSCLC.