bluuebunny/crossref_metadata_2025_split huggingface dataset:
Assessment of extracellular matrix and tissue derived metabolites in a liquid biopsy for identifying endotypes of metastatic melanoma patients with differential response to immune checkpoint inhibitor treatment.
Authors: Willumsen Nicholas , Bager Cecilie Liv , Jensen Christina , Karsdal Morten Asser , Madsen Daniel Hargbøl , Hansen Morten , Schmidt Henrik , Svane Inge Marie 
Published: May 2019

e14050 Background: The extracellular matrix (ECM) is a major component of tumors. Several recent findings link ECM composition with outcome in cancer patients treated with immune checkpoint inhibitors (ICIs). The aim here was to explore circulating ECM- and tissue-derived metabolites to enable clustering of patients with metastatic melanoma (MM) into putative endotypes and evaluate patient characteristics and outcome when treated with Ipilimumab accordingly. Methods: Serum was collected from MM patients prior to treatment with Ipilimumab (n = 64). Wards hierarchical clustering of patients was based on 15 ECM- and tissue-derived metabolites measured in serum by ELISA. Identified clusters (endotypes) were compared to clinical characteristics and evaluated for associations with disease control rate (DCR), progression free survival (PFS) and overall survival (OS). Results: Three putative endotypes (cluster A, B, C) were identified including 14, 30 and 20 patients, respectively. Overall a stepwise increase in ECM metabolite median levels were detected from C-B-A with the largest absolute change seen from B-A. There was no difference between A, B, and C according to age, gender, lactate dehydrogenase levels, number of metastasized organs and whether patients were treated previously. At follow-up, the DCR was 0%, 60% and 45% in A, B, and C, respectively. Likewise, patients with endotype A had a median PFS/OS time of 69/85 days versus 174/520 and 165/589 days for endotype B and C. In support, endotype A predicted for poor survival outcomes (PFSAvsB+C:HR = 3.9, 95%CI:2.0-7.6, p = 0.0001; OSAvsB+C:HR:2.5, 95%CI:1.2-4.9, p = 0.0108). Conclusions: Hierarchical clustering of MM patients based on 15 ECM- and tissue-derived metabolites measured in a liquid biopsy identifies 3 putative endotypes. One endotype (A) seems to reflect patients with an overall high and differentiated ECM turnover profile. These patients experience poor outcome when treated with Ipilimumab. If validated, this supports a link between ECM remodeling and outcome in cancer patients treated with ICIs.
GLS-010, a novel anti-PD-1 mAb in Chinese patients with relapsed or refractory classical Hodgkin’s lymphoma: Preliminary result of a phase II clinical trial.
Authors: Song Yuqin , Zhu Jun , Lin Ningjing , Zhang Chen , Zhang Mingzhi , Bai Hai , Cui Jie , Liu Hui , Ke Xiaoyan , Jiang Yongsheng , Zhang Zhihui , Zhang Ying , Liu Lihong , Zang Aimin , Chen Chris , Li Jing , Du Hong , Meng Baotong , Xu Kehui , Meng Haijin 
Published: May 2019

e14072 Background: GLS-010 is a novel fully human anti-PD-1 mAb. Previous Phase 1 study exhibited favorable result of tolerance, preliminary efficacy and 240mg fixed dose q2w was selected as Recommended Phase 2 Dose (RP2D). This Phase 2 clinical trial is aimed to further evaluate the safety and efficacy profile of GLS-010 in Chinese patients(pts) with relapsed or refractory classical Hodgkin’s Lymphoma( r/r cHL). Here we reported the preliminary result. Methods: All pts enrolled received GLS-010 240mg every 2 weeks. Tumor response was assessed by Lugona 2014 every 8 weeks. Adverse events (AEs) were graded by NCI CTCAE v4.03. Results: Until Jan 30th 2019, 39 pts were enrolled in this ongoing study. The median dosing number was 4 (range: 1~12). 17 pts received response evaluation. Of 17 evaluable subjects, an objective response was reported in 15 patients (88.3%), including 4(23.5%) pts with a complete response(CR) and 11 pts(64.7% )with a partial response(PR), 1 patient(5.9%) with stable disease(SD)and 1 remaining patient(5.9%) with unconfirmed progressive disease(PD)(observed stable disease(SD) in the first assessment).The most common treatment related AEs included Neutrophil count decreased (10/32), White blood cell count decreased (7/32), Fever (6/32), Alanine aminotransferase increased (4/32), etc. Treatment–related grade 3-5 AEs include Neutrophil count decreased (2/6), Interstitial lung disease (1/6), Influenza like illness (1/6). Conclusions: GLS-010 showed impressive therapeutic activity and an acceptable safety profile in Chinese r/r cHL patients. Current evidence support further development of GLS-010 in this and more indications. Clinical trial information: NCT03655483.
Efficacy and safety of nivolumab monotherapy as the late line for patients with advanced gastric cancer in the real-world.
Authors: Kusumoto Tetsuya , Hashimoto Kenkichi , Yoshinaga Keiji , Kusumoto Eiji , Sakaguchi Yoshihisa , Ikejiri Koji , Oki Eiji 
Published: May 2019

e14074 Background: The ATTRACTION-2 study found that nivolumab showed a significant survival benefit for the patients with unresectable metastatic or locally advanced gastric cancer (AGC) following more than 2 regimens. Based on this trial, nivolumab was currently proved to be one of the most effective regimens for the patients with AGC as the 3rd-line treatment in Japan. We herein examined the clinical significance and validation of nivolumab as late line chemotherapy in patients with AGC. Methods: In October 2017 to December 2018, 26 patients received nivolumab monotherapy in our institute. We conducted a retrospective review of the data of 23 patients with AGC who received more than 2 cycles of nivolumab following the standard chemotherapy regimens including fluoropyrimidines, platinum derivatives and taxanes. Adverse events, tumor responses, and survival data were analyzed. Results: Only 2 patients enrolled here showed ECOG performance status (PS) 2 in the study. The time to treatment failure of them were shorter than those of the other patients with PS 0/1. Four patients quitted the continuation of nivolumab except for the progressive disease, due to non-hematological toxicities higher than grade 3 including myositis, hypothyroidism, dermatitis and liver dysfunction. The rate of hematological toxicities, which showed severe anemia of higher than grade 3 was 21.7%. The ORR and the DCR were 4.3% and 52.3% for the patients in this study. The survival data showed that the median PFS and the OS after nivolumab administration were 75 days and 274 days, respectively. Conclusions: Nivolumab monotherapy might be one of the best regimens for Japanese patients with AGC as the late line treatment following the standard chemotherapy.
Prognostic score for second or further line immunotherapy in advanced non-small cell lung cancer (aNSCLC): An external validation.
Authors: Prelaj Arsela , Lo Russo Giuseppe , Proto Claudia , Signorelli Diego , Ferrara Roberto , Galli Giulia , De Toma Alessandro , Randon Giovanni , Zilembo Nicoletta , Trevisan Benedetta , Montrone Michele , Longo Vito , Pesola Francesco , Varesano Niccolò , Del Bene Gabriella , Pizzutilo Pamela , Galetta Domenico , Garassino Marina Chiara , Di Maio Massimo , Catino Annamaria 
Published: May 2019

e14077 Background: Beyond PD-L1, nowadays oncologists can only use clinical characteristics to candidate patients for immunotherapy (IO). Previously, a clinical prognostic score composed by ECOG performance status (PS), sex, histology, stage, uses of platin-based therapy at first-line (1L) and response to 1L categorized 3 different prognostic groups for patients treated with second-line (2L) chemotherapy (CHT) (Di Maio, EJC. 2010 Mar;46(4):735-43.). The aim of this study is to assess if the same score is able to discriminate the outcome of aNSCLC pts treated in 2L or further-line IO, potentially helping decision making. Methods: We recorded data of patients collected from two institutional databases: Istituto Nazionale Tumori of Milan and IRCCS Oncologico Giovanni Paolo II of Bari, Italy. Overall survival (OS) was the primary endpoint and also progression-free survival (PFS) was assessed. Prognostic score was generated, and pts were divided into 3 prognostic groups: best (B: < 5), intermediate (I:5-9), worst (W: > 9). Results: Overall, 347 pts were included in the analysis (193 from Milan and 154 from Bari). Median age was 66 years (y) (30 – 88y), most were < 70 y (67.5%), male (70.7%), smokers (79.5%) and adenocarcinoma (74.6%). ECOG PS was: 0 (23%), 1 (54.5%) and 2 (22.5%). Pts distribution was: 28%, 51% and 21% in the B, I and W groups, respectively. Median OS was 18.0 months for B group, 8.5 months for I group (HR vs B 1.83, 95%CI 1.35 – 2.47, p < 0.001) and 2.6 months for W group (HR vs B 5.77, 95%CI 3.99 – 8.33, p < 0.001). Median PFS was 3.4 months for B group, 3.7 months for I group (HR vs B 1.35, 95% CI 1.03 – 1.77, p = 0.032) and 1.9 months for W group (HR vs B 2.51. 95% CI 1.80- 3.50, p < 0.001). Similar results were obtained stratifying the model by Institution. Conclusions: This clinical prognostic score, that was generated in patients treated with second-line chemotherapy, is able to highly predict outcomes of patients treated with IO. These results demonstrated that in pre-treated aNSCLC pts, the worst category has a dismal absolute life expectancy, and probably would not benefit from any active systemic therapy (independently if CHT or IO). Perhaps for these pts best supportive care could be the best choice.
A comprehensive meta-analysis of endocrine immune-related adverse events of immune checkpoint inhibitors and outcomes in head and neck cancer and lung cancer.
Authors: Gomes-Lima Cristiane Jeyce , Kwagyan John , King Fred , Fernandez Stephen J , Burman Kenneth D , Veytsman Irina 
Published: May 2019

e14096 Background: Immune checkpoint inhibitors (ICPi) have emerged as an effective treatment for a variety of cancers. However, important immune-related adverse events (irAEs) can occur. The aim of this study was to determine the prevalence of endocrine irAEs in patients with head and neck cancer and lung cancer that have used a ICPi and outcomes. Methods: A systematic literature review was performed within PubMed and EMBASE databases. Search terms included “durvalumab”, “atezolizumab”, “nivolumab”, “pembrolizumab”, “ipilimumab”, “head & neck cancer”, “lung cancer”. Studies published before September 2018 were included. The search was limited to randomized controlled trials (RCTs) phase III written in English. Data were extracted about patient characteristics, interventions, overall survival (OS), progression free survival (PFS), and endocrine irAEs. A summary hazard ratio (HR) and 95% confidence interval were calculated using the software Comprehensive Meta-Analysis and a scatter plot was generated. Results: Twelve RCTs comprising 7060 patients were reviewed; 3815 used an ICPi (treatment arm). The mean follow-up time of 12.2 months ± 7.1 SD. The survival rate of the treatment arm was enhanced (HR, 0.75; 95% CI, 0.70-0.80), compared to the alternate arm. Similarly, the PFS of the treatment arm was improved (HR, 0.77; 95% CI, 0.72-0.81) but with a higher incidence of endocrine irAEs. The most common endocrine irAE reported was hypothyroidism;193 patients in the treatment arm vs. 29 in the alternate arm (p < 0.001); grade 3/4 AE was observed in 10 patients vs. 1 patient, respectively. Other endocrine irAEs were reported in 168 patients in the treatment arm vs. 26 patients in the alternate arm (p < 0.001); grade 3/4 AE was observed in 28 patients vs. 3 patients, respectively. A significant positive correlation between endocrine irAEs and OS was observed (p = 0.019). Conclusions: ICPi are a powerful tool in the treatment of cancer. The prevalence of endocrine irAEs in this meta-analysis was 9%. There is evidence of improved overall survival in patients who developed endocrine irAEs. Further studies are needed to correlate the development of irAEs and OS advantage.
Real-world Merkel cell carcinoma outcomes from a tertiary care center.
Authors: Canavan Theresa N , Doudican Nicole Adell , Stevenson Mary , Pavlick Anna C. , Carucci John 
Published: May 2019

e14098 Background: Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine carcinoma of the skin that is highly immunogenic. Checkpoint inhibitors (CPI) have recently revolutionized the treatment of advanced MCC. In this study we sought to better understand how CPI are used in an outpatient setting and to better define MCC outcomes associated with their use. Methods: We conducted a retrospective chart review of MCC patients seen in the New York University Hematology and Oncology Department from 2012-2018. Patient characteristics and treatment regimens were compared between those with and without disease progression at any point during follow-up. Results: Fifteen patients were identified, 46.7% of whom presented with nodal or distant disease (Table). Nine patients experienced relapse during follow-up. There were no MCC-specific deaths, and 92.3% of patients were without evidence of MCC at the end of follow-up. Ten patients were treated with one or more CPI (pembrolizumab, nivolumab, ipilimumab) either in the setting of first line systemic therapy (71.4%) or after experiencing disease progression (28.6%). There was a trend toward improved relapse free survival with CPI use (P = 0.054). Conclusions: Although recurrences were common, overall outcomes at the end of follow-up were very good. CPI were well tolerated and were associated with a trend toward improved relapse free survival. Patients with advanced stage MCC would benefit from consideration of CPI as part of their treatment options. [Table: see text]
Bone metastases treated with immune checkpoint inhibitors: A single center experience.
Authors: Grover Punita , Karivedu Vidhya , Zhu Zheng , Jandarov Roman , Wise-Draper Trisha Michel 
Published: May 2019

e14105 Background: We conducted a retrospective study to analyze the overall survival (OS) and progression free survival (PFS) among patients with bone metastases (BMs) from Non Small Cell Lung Carcinoma (NSCLC), Melanoma, Head and Neck Squamous Cell Carcinoma (HNSCC) and others (including genitourinary carcinoma) treated with immunotherapy (Nivolumab, Pembrolizumab, Ipilimumab or a combination). Methods: We retrospectively evaluated patients with BMs treated at our institute from 2012-2017 who received either immunotherapy alone or in combination with other therapies for BMs including: medical therapy (zoledronic acid or denosumab), radiation or surgery. Univariate analysis was utilized to analyze OS and PFS. Results: A total of 58 patients were identified, median age at diagnosis of BMs was 61 years (range 29 – 94). 39 patients were male (67.2%) and 47(81%) patients had good performance status (KPS 70-100) at the time of immunotherapy initiation. The median time to diagnosis of BMs was 11.4 months. 20 patients had a single BM, 16 had 2-4 BMs and 22 had ≥5 BMs. Axial-only BMs were seen in 27 patients, appendicular-only in 8 and both in 23 patients. 40 patients were symptomatic and 28 patients had skeletal events (pathological fractures, spinal cord compression or hypercalcemia). 51 patients had other metastatic sites at the time of initiation of immunotherapy. 25 patients received nivolumab, 20 patients received pembrolizumab and 4 patients received combination immunotherapy. 41 patients received additional treatments for BMs. The median OS from the start of immunotherapy was 5.15 months and median PFS was 3 months. On univariate analysis male sex (p = 0.03) and combination immunotherapy (p = 0.06) were associated with better OS. Patients who received additional treatments for BMs (p = 0.04) and combination immunotherapy (p = 0.02) had better PFS. Conclusions: Combination immunotherapy and use of additional treatment modalities for BMs is associated with better survival. Further analysis is required to validate these results. [Table: see text]
Major lab abnormalities as biomarkers in patients treated with immune checkpoint inhibitors: A single institution study of 1044 patients.
Authors: Laukamp Kai , Liput Joseph , Smith Daniel Arnold , Nelson Ariel Ann , Ramaiya Nikhil H. , Hoimes Christopher J. 
Published: May 2019

e14108 Background: Over the past decade, immune checkpoint inhibitors (ICI) have gained increased importance in modern cancer treatment. In this study we investigate the relationship between major lab abnormalities and ICI treatment duration. Methods: 1044 patients receiving ICIs between 2010-2018 were included in this retrospective study. The following parameters were analyzed: gender, age, race, cancer type, lab abnormalities for kidneys, pancreas, liver and thyroid, and treatment duration. Lab abnormalities were grouped and used in a scoring-system (0: no lab abnormalities, 1: one abnormal parameter, and 2: two or more abnormal parameters). For statistical analysis, Likelihood Ratio Chi-Square and Mann-Whitney U tests were applied. Results: The patient cohort included 386 female and 473 male patients with a mean age of 67.8±12.5 years. Primary cancer distribution included lung cancer (n = 439), melanoma (n = 253), head and neck cancer (n = 72), renal cancer (n = 53), lymphoma (n = 33), bladder cancer (n = 42), breast cancer (n = 28), and other malignancies (n = 124). Patients received one (n = 875) or a combination (n = 169) of ICIs for a mean of 152.2±215.8 days, with highest counts for nivolumab (n = 465), pembrolizumab (n = 275), ipilimumab (n = 95), and nivolumab & ipilimumab (n = 130) and others (n = 79). Patients with higher values in the scoring-system or more lab abnormalities had significantly longer treatment duration (Score 0: 107±170, 1: 159±199, 2: 244±282 days, p < 0.001). Furthermore, patients treated with ICI combination therapy demonstrated higher scores (1.1±0.8 vs. 0.5±0.7, p < 0.001) and longer treatment durations (236±304 vs. 127±175 days, p < 0.001). Patients with scores of ≥1 in the scoring system had improved overall survival (451±475 vs. 369±526 days, p < 0.001), and patients treated with two or more ICIs lived longer (563±524 vs. 377±496 days, p = 0.003). Therapy duration was also positively correlated with survival (Spearman’s rho correlation r = 0.64, p < 0.001). Conclusions: Our current exploratory study demonstrates associations between major lab abnormalities and both treatment duration and overall survival in patients treated with immune checkpoint inhibitors.
Effect of smoking on the efficacy of immune checkpoint inhibitors in advanced cancers: A systematic review and meta-analysis.
Authors: Lee Chia Ching , Tham Ivan Weng Keong , Soon Yu Yang , Tey Jeremy Chee Seong 
Published: May 2019

e14109 Background: The association between smoking history and benefit from treatment with immune checkpoint inhibitors (ICIs) was unclear. We performed a meta-analysis to assess the efficacy of ICIs in advanced cancers according to smoking status (never-smokers vs ever-smokers). Methods: We searched MEDLINE and EMBASE for randomized controlled trials (RCTs) comparing immunotherapy with standard-of-care in the treatment of advanced cancers which reported overall survival (OS) as the outcome, stratified by smoking status. We calculated pooled hazard ratios (HRs) and 95% confidence interval (CIs) for OS using random-effect models and assessed the differences in OS between the two estimates (never smoker (vs) ever smoker). using a test of heterogeneity. We also performed prespecified subgroup analyses based on disease site, line of therapy, proportion of never-smokers in the trials and trial conclusion to assess the potential association of oncologic and methodologic factors in effect modification of smoking status with the efficacy of ICIs. Results: We identified ten RCTs on non-small cell lung cancer, head and neck, and urothelial cancers, including 4,245 ever-smokers and 972 never-smokers. The difference in the effects of ICIs on OS between ever-smokers (HR, 0.74; 95% CI, 0.66-0.84) and never-smokers (HR, 0.79; 95% CI, 0.61-1.02) was not statistically significant (interaction P-value = 0.69). There were no significant differences in the effects of ICIs on OS between ever-smokers and never smokers in the pre-specified subgroups. Conclusions: There was no significant association between smoking status and improved survival outcome with ICIs in the treatment of advanced cancers. Smoking status should not be used as a biomarker for guiding treatment with immunotherapy.
Expression of PD-L1 and IDO in hormone receptor negative DCIS.
Authors: Phadke Sneha Deepak , Clamon Gerald H. , Bashir Amani , Keeney Matthew , Ginader Timothy 
Published: May 2019

e14116 Background: Although outcomes from ductal carcinoma in situ (DCIS) are generally excellent, hormone receptor (HR) negative DCIS is associated with a higher rate of recurrence. There is no chemopreventative agent that has been effective in this subgroup. The aim of our study was to evaluate expression of PD-L1 and IDO (Indoleamine 2,3-Dioxygenase) in HR negative DCIS, in an effort to identify a possible target for prevention using immunotherapy. Methods: Using pathology databases at the University of Iowa, we identified 60 cases of HR negative DCIS from 1995-2017, and 41 of these cases had adequate DCIS tissue for immunostaining. Immunohistochemical staining with antibodies against PD-L1 and IDO was performed on slides prepared from formalin-fixed paraffin-embedded tissue blocks retrieved from pathology archives. IDO was assessed by IHC using the mouse monoclonal antibody clone 10.1 (Millipore Sigma). An initial assessment for PD-L1 (M3653 mouse monoclonal antibody clone 22C3, DAKO) was negative. A repeat assessment for PD-L1 on a smaller sample in a different laboratory was also negative. Clinical data was abstracted from the medical record of each patient. Results: Of the 41 subjects with enough tissue for staining, the median age at diagnosis was 56.76 years, and median BMI was 26.59 kg/m2. Most common method of DCIS detection was screening mammogram (80.5%) versus a patient detected breast finding (19.5%). Most subjects had high grade DCIS (92.7%) and none had low grade DCIS. Six subjects (16.7%) had an ipsilateral in situ recurrence while another 6 subjects developed ipsilateral invasive cancer. Most of the subjects had HER2+ DCIS (63.9%). None of the 41 cases stained positive for IDO or PD-L1, thus no statistical analysis was done to analyze associations with clinicopathologic characteristics. Conclusions: Our sample of HR negative DCIS tumors did not express PD-L1 or IDO, making these receptors unlikely targets for immunopreventative efforts. It is still possible that tumor mutation burden, expression of PD-L2, PD-L1 or IDO expression on TILs, or expression of CTLA-4 may be future considerations for work in the DCIS microenvironment.