bluuebunny/crossref_metadata_2025_split huggingface dataset:
A new nodal classification based on log odds and location of involved lymph nodes in lung cancer.
Authors: Zhou Rui , Zhang Jingwen , Sun Huiying , Zeng Dongqiang , Liao Wangjun 
Published: September 2018

e20069 Background: To explore the prognostic effect of log odds of positive lymph nodes (LODDS) in node-positive non-small cell lung cancer (NSCLC) patients, and evaluate whether a model incorporates the pN and LODDS is a more reliable prognostic determinant in these patients. Methods: Data of 9557 NSCLC patients (pT1-pT3, pN1-pN2, M0) with lymphadenectomy recorded in the Surveillance Epidemiology and End Results database between 2004 and 2009 were retrospectively studied. Results: In adjusted analyses, LODDS value was an independent prognostic factor for patients with node-positive NSCLC, as well as pN classification and MLN count. However, the LNR value lost its significance in multivariate regression model. Next, we established the pN-LODDS (N-L) classification model and observed that it had better discriminatory ability, monotonicity, and homogeneity for prognostic stratification, as well as more accurate time point OS prediction than either of pN, MLN and LODDS classifications alone. Moreover, besides the pN classification, the N-L model could serve as a referential indicator designing postoperative treatment in node-positive NSCLC patients. Analyses stratified by the N-L classification showed that postoperative radiotherapy was independently linked to prolonged survival in patients with N-L 3 classification, N-L 5 classification, and in pN2 subgroup of N-L 4 classification. Conclusions: Our findings indicated that the N-L classification model could serve as the optimal scheme for prognostic assessment in patients with node-positive NSCLC. Incorporating N-L classification into the staging system will enable clinicians to more accurately predict the prognosis and to guide the decision of regional therapy regiment.
Automated brightfield multiplex immunohistochemistry to quantify biomarkers related to immune senescence: Relationships with survival in non-small cell lung cancer patients.
Authors: Hofman Paul , Beaulande Mélanie , Ben Hadj Saima , Erb Gilles , Pomerol Jean-François , Lassalle Sandra , Butori Catherine , Long Elodie , Washetine Kevin , Guerin Olivier , Guigay Joel , Mouroux Jerome , Leroy Sylvie , Marquette Charles Hugo , Hofman Veronique , Ilie Marius 
Published: September 2018

e20500 Background: Elderly patients have an eroded immune characterized by a progressive decline in immune surveillance that favors infection and cancer development. Tumor cells can escape immune surveillance by upregulating inhibitory immune checkpoint such as PD-L1. High expression of PD-L1 was reported in association with CD8+T-cell exhaustion and increased levels of CD33+ myeloid-derived suppressor cells. Although low CD4/CD8 ratio is associated with increased mortality, the status of the CD4+T-cells as a clinical marker of immunosenescence is less well characterized in the field of aging. The aim of this study was to determine the presence of immunosenescence biomarkers according to age in non-small cell lung cancer (NSCLC) patients and to evaluate them as predictive biomarkers of patients’ outcome. Methods: One hundred NSCLC patients, matched by age (50 patients < 70 years, 50 patients ≥70 years) were included. An automated 4-Plex optical IHC assay was developed on the Discovery ULTRA automated stainer using monoclonal antibodies PD-L1 (SP263), CD4, CD8, and CD33. The stained slides were scanned with Nanozoomer HT 2.0 Scanner, and analyzed with Calopix software. Results: The CD4/CD8 ratio and PD-L1 expression in tumor and immune cells were significantly lower in elderly NSCLC patients ≥70 years than in age-paired patients, while absolute count of CD33+ was increased. Patients with CD4/CD8 ratio higher than two, high PD-L1 density and low CD33+ frequency achieved increase in median disease-free survival. Conclusions: Distribution of PD-L1, CD4, CD8, and CD33 cells was influenced by age in NSCLC patients. The proportion of CD8 + CD28- T cells, CD4+ T cells and CD4/CD8 ratio may be used as predictive biomarkers of anti-PD-L1 therapy efficacy in NSCLC patients. The automated 4-Plex IHC assay together with its respective digital analysis could serve as a tool for further characterizing tumors and their microenvironment and provide a better understanding of which patients may benefit from immunotherapy.
Population pharmacokinetic and pharmacodynamic analysis of osimertinib.
Authors: Johnson Martin , Schmidt Henning , Sunnaker Mikael , Nash Anthony F , Nayak Suman , Tomkinson Helen , Vishwanathan Karthick 
Published: September 2018

e20536 Background: Osimertinib is an oral, potent, irreversible, CNS active EGFR-TKI, selective for sensitizing (EGFRm) and T790M resistance mutations, indicated for the treatment of patients with T790M positive advanced non-small cell lung cancer who have progressed on or after EGFR-TKI therapy. Osimertinib pharmacokinetics (PK) were evaluated using a population approach and pharmacodynamic (PD) relationships using appropriate modeling approaches. Methods: To understand the impact of covariates on osimertinib PK, a population PK analysis was performed using data from patients who received osimertinib (20–240 mg) during the AURA studies. Exposure metrics were derived from a PK model and used to assess the exposure-response (safety/efficacy) relationship. Efficacy analysis included patients who were T790M positive (n = 710) and safety analysis included all dosed patients (n = 1088). The impact of covariates on exposure-response was assessed. Models accounting for rare safety events were applied to quantify the association between events and exposure. Results: Population PK analyses supported dose- and time-independent PK of osimertinib with no clinically meaningful covariates identified. Patients in the highest exposure quartile (Q4) had a numerically shorter median progression-free survival (8.3 months [95% CI 6.9, 10.5]) compared with patients in Q1, Q2 and Q3 (all 11.2 months [95% CIs 9.7, 12.7; 8.5, 15.6 and 8.7, 13.7, respectively]). A model-based analysis indicated that this effect is likely due to a larger number of patients in Q4 with poor prognostic features, i.e. worse performance status (WHO 1 or 2) and lower baseline serum albumin compared with Q1, Q2 and Q3, rather than to osimertinib exposure. Model-predicted probability of a relationship between osimertinib exposure and LVEF changes was not evident. Model-based analysis predicted that, compared with the median probability (0.03), the probability of a patient experiencing interstitial lung disease may increase with increasing osimertinib exposure (Q1 probability 0.01 [steady-state AUC 6361 nM*h] vs Q4 0.06 [24460 nM*h]) at the 80 mg dose. Conclusions: Population PK and PK-PD analysis is supportive of 80 mg as an appropriate dose for osimertinib. Clinical trial information: NCT01802632; NCT01802632; NCT02094261; NCT02151981.
Epidemiology of PD-L1 and ALK expression and EGFR mutational status in Argentinian patients with lung cancer.
Authors: Salanova Ruben , Calderazzo Pereyra Julio C , Leguina Laura , Bena Asuncion , Barberis Mariana , Vargas Rosana , Jimenez del Toro Rocio , Kreimberg Kevin , Powazniak Yanina 
Published: September 2018

e20565 Background: Until now, the results of the correlation between PD-L1, ALK expression and EGFR mutations remain controversial. We prospectively evaluated patterns among EGFR mutant, ALK positive and PD-L1 positive lung cancer patients. Methods: PD-L1 and ALK expression was evaluated in 342 adenocarcinomas (AD) of the lung using inmunohistochemestry (anti-PD-L1 22C3, anti-ALK D5F3), and EGFR mutations using real time PCR (therascreen EGFR RGQ PCR Kit version 2). PD-L1 was also evaluated in 36 squamous (SQ) cell carcinomas. Results: 181 of 342 patients with AD were positive for PD-L1. 108 were positive with a TPS value between 1 and 49, and 73 were positive with a TPS value higher than 50 (p = 0.002). 25 of 36 patients with SQ were positive for PD-L1. 17 were positive with a TPS value between 1 and 49, and 8 were positive with a TPS value higher than 50. 133 samples with AD PD-L1 positive and 97 PD-L1 negative were tested for EGFR and ALK, 33 and 14 respectively were positive for EGFR mutations (p = 0.15), with 45% for exon 19 deletions (p = 0.003), 5 and 0 respectively were positive for ALK translocations (p = 0.053). 210 of 342 patients were men and 132 were women, 117 and 64 were positive for PD-L1 expression respectively (p > 0.1). Conclusions: NSCLC with EGFR mutation showed a trend for higher frequency of positive PD-L1 expression and NSCLC harboring ALK rearrangement was significantly associated with PD-L1 expression. These findings might contribute to the understanding of the regulation of PD-L1 expression in lung cancer and its relation to ALK expression and EGFR mutation.
Efficacy and safety of endostar in the treatment of advanced lung squamous cell carcinoma.
Authors: Hu Weiheng , Fang Jian , Nie Jun , Dai Ling , Zhang Jie , Chen Xiaoling , Ma Xiangjuan , Tian Guangming , Wu Di , Han Jindi , Han Sen , Wang Yang , Long Jieran 
Published: September 2018

e20574 Background: From the early 2000s, many advances in non-small cell lung cancer (NSCLC) have been made with the emergence of targeted therapies. However, because of safety concerns and a lower prevalence of relevant therapeutic targets, patients with squamous NSCLC have been excluded from many of these breakthroughs. Endostar is a novel inhibitor of tumor angiogenesis that acts specifically on neovascular endothelial cells. This study is to explore the clinical efficacy and safety of endostar in advanced squamous NSCLC patients. Methods: We performed a retrospective analysis of 259 newly diagnosed advanced squamous NSCLC patients who had received platinum-based doublet chemotherapy (PBDC) between September 2009 and March 2016. Of these patients, 116 received Endostar combined with PBDC, and 143 received PBDC only. Clinical tumor responses, progression-free survival (PFS), overall survival (OS), and toxicity profiles were recorded and analyzed. Results: After a median follow-up of 13.5 months, a improvement in PFS was observed in the Endostar group, the median PFS was7.7 months compared with 5.4 months in the control group (HR, 0.745; P= 0.034). The median OS was 19.0 months in the Endostar group versus 14.3 months in the control group, but the difference was not significant (HR, 0.780; P= 0.094). Multivariate analysis demonstrated that in patients with advanced squamous NSCLC, anti-angiogenesis therapy with Endostar, radiotherapy of primary tumor and Ⅲb stage were significant and independent predictors of improved PFS ( P< 0.05). For both arms, hematologic and gastrointestinal toxicities were the most common adverse events. Patients treated with Endostar had slightly higher rates of cardiac disorder and thromboembolic event, as compared with the control patients, but there were no statistically significant differences in toxicities overall between the 2 treatment groups. Conclusions: The current study indicates that Endostar as an anti-angiogenesis therapy combined with PBDC is able to provide further survival benefits with satisfactory toxicity in previously untreated squamous NSCLC patients, which merits further evaluation in randomized trials.
The efficacy and toxicity of osimertinib in T790M-positive NSCLC with acquired resistance to EGFR-TKI in clinical practice.
Authors: Sonoda Tomoaki , Yanagitani Noriko , Saiki Masafumi , Ariyasu Ryo , Koyama Junji , Takano Natsuki , Kawashima Yosuke , Oguri Tomoyo , Nishikawa Shingo , Kitazono Satoru , Ohyanagi Fumiyoshi , Horiike Atsushi , Nishio Makoto 
Published: September 2018

e20575 Background: A Phase III study (AURA3) demonstrated that osimertinib prolonged PFS compared to platinum doublet in patients with T790M-positive non-small-cell lung cancer (NSCLC) exhibiting acquired resistance to epidermal growth factor receptor- tyrosine kinase inhibitor (EGFR-TKI). Although the patients in the study had good PS and only one prior EGFR-TKI treatment, most practical patients had multiple prior EGFR-TKI and poor PS. Moreover, several patients exhibited symptomatic central nervous system (CNS) metastasis in clinical practice. In this study, we evaluated the efficacy and toxicity of osimertinib in clinical practice. Methods: We retrospectively analyzed 30 patients who were treated with osimertinib at our hospital from April 11th 2016 to September 30th 2016. The efficacy and toxicity was compared between the patients with matched and unmatched AURA3 eligibility criteria. Efficacy was evaluated according to RECIST ver.1.1 and toxicity was evaluated using CTCAE ver.4.0. Results: A total of 9 out of 30 patients matched the AURA3 eligibility criteria (PS ≤ 1 and one prior EGFT-TKI) and 21 patients were unmatched (PS ≥ 2 or two or more EGFR-TKI or symptomatic CNS metastasis). The overall response rate(ORR) of osimertinib was 78% and 67% for the matched and unmatched patients, respectively. The disease control rate (DCR) was 100% and 90% for the matched and unmatched patients, respectively. In addition, the response rate of symptomatic CNS metastasis was 67%. Regarding toxicity, grade 3/4 toxicities were observed in 22% of the matched patients and 33% of the unmatched patients. In the matched patients, the most frequent AE was a rash (89%) and the frequent grade 3/4 toxicities were a rash (22%) and pneumonitis (11%). In unmatched patients, the most frequent AE was also a rash (57%), but the frequent grade 3/4 toxicities were pneumonitis (14%), rash (10%), and neutropenia (10%). Conclusions: Both the ORR and DCR in the unmatched patients were slightly lower than the matched patients; however, osimertinib was still found to be beneficial in clinical practice.
Impact of EGFR mutation status on clinical outcome of nintedanib plus docetaxel in patients with previously treated non-small cell lung cancer (NSCLC): Retrospective analysis of Korean nintedanib named-patient usage (NPU) program in NSCLC (KCSG LU14-2).
Authors: Hong Sook-hee , An Ho Jung , Lee Yun-Gyoo , Kim Hoon-Kyo , Lee Seung-Sei , Kang Jin Hyoung 
Published: September 2018

e20638 Background: Anti-angiogenic agents have been reported to have clinical activity for NSCLC harboring EGFR mutation (mutEGFR) with/without EGFR Tyrosine kinase inhibitor (TKI). We report clinical outcomes of nintedanib plus docetaxel for refractory NSCLC patients conducted by virtue of Korean NPU program. Methods: Patients with NSCLC were eligible if they failed at least one prior systemic treatment. Docetaxel was administered with 75 or 60mg/m2 on D1 or 37.5mg/m2 on D1, D8 every 3 weeks plus nintedanib 200mg orally twice daily. Nintedanib treatment was continued until disease progression or unacceptable toxicity after 4-6 cycles of combination therapy. Results: Of 62 patients enrolled, 23 patients had activating EGFR mutations (14 in exon19 deletion, 7 exon21 L858R/L861Q, 1 exon20 duplication, and 1 in both exon19 deletion and exon20 T790M) and progressed during prior EGFR-TKI treatment. Of 23 patients, 22 had progressed during or after platinum doublet chemotherapy. Only for 2 patients, EGFR mutation status was unknown. The majority of patients were heavily pretreated, with 43.7% received nintedanib plus docetaxel as ≥ 4th line therapy. 4 patients had prior bevacizumab treatment. Objective response rate (ORR) was 22.9%. Median PFS and OS were 3.9 months (95% CI 3.1-4.6) and 9.5 months (95% CI 5.3-13.7), respectively. Depending on EGFR mutation status, ORR in mutEGFR group was higher than wtEGFR group (30.4% vs 20%, p= 0.50) and median PFS in mutEGFR group was significantly longer than wtEGFR group (6.1 vs 3.3 months, p= 0.008). No treatment related death was reported. Common grade 3/4 adverse events were neutropenia (58.3%) and reversible elevated liver enzyme (18.8%). Conclusions: Taken together, nintedanib plus docetaxel showed meaningful clinical activity with good tolerability for refractory NSCLC patients. Our data suggest that this combination may be a recommendable regimen for EGFR-TKI-resistant mutEGFR NSCLC.
Molecular analysis of cell-free DNA to identify distinct molecular mutational burden and its effect on first-line chemotherapy in patients with NSCLC from a phase III trial.
Authors: Zhou Caicun , Li Xuefei , Jiang Tao , Ren Shengxiang , Su ChunXia , Zhao Chao , Han Wenbo , Wang Jianfei , Zhang Henghui , Du Bo 
Published: September 2018

e20660 Background: To investigate the predictive significance of molecular mutational burden via genetic analysis of circulating cell-free DNA (cfDNA) in NSCLC patients treated with first-line platinum-based chemotherapy. Methods: Eligible patients were enrolled in a phase III trial (NCT01560195). Blood samples were collected at baseline, every two cycles of chemotherapy and at disease progression. Both cfDNA fragment and genomic DNA were isolated and subjected to enrichment for a 1.15M size panel covering exon regions from 1,086 genes. The captured sequencing data was further processed to identify somatic mutations, including single nucleotide variants (SNV) and short insertions/deletions (indels). Results: Forty-eight patients were enrolled. 17 genes alterations were frequently found from 15 patients (training set). Patients with partial response (PR, n = 3) had significantly lower total mutational burden of these genes than that with stable disease (SD, n = 9) and progression disease (PD, n = 3) (P < 0.05). Based on these results, we further developed a predictive model including 6 genes ( PIK3CA, KIF5B, CD74, XRCC1, MTHFR and KRAS) in the validation set (n = 33). The results showed that the mutational burden of 6-genes panel had the promising predictive yield in patients with PR (n = 7) vs. SD+PD (n = 25) (AUC = 0.962, P = 0.000), PR vs. SD (n = 18) (AUC = 0.960, P = 0.000) and SD vs. PD (n = 8) (AUC = 0.964, P = 0.003). Notably, there was no significant difference in the baseline cfDNA concentration among patients with PR, SD and PD (P > 0.05). Patients with PR experienced a reduction of molecular mutational burden of cfDNA while patients with SD or PD experienced no change or increased molecular mutational burden of cfDNA after two or four cycles of chemotherapy. However, it did not reach the statistically significant difference. Conclusions: The current study demonstrated that molecular characteristics of cfDNA was significantly associated with the effect of first-line platinum-based chemotherapy in patients with NSCLC. The mutational burden of six-genes panel had the promising predictive value in NSCLC patients treated with first-line chemotherapy.
The changing paradigm of management in melanoma brain metastases.
Authors: Ladwa Rahul , Atkinson Victoria 
Published: September 2018

e21027 Background: Brain metastases (BM) are a frequent complication in patients with metastatic melanoma (MM). We aimed to explore the outcome of these patient with modern therapeutic options. Methods: We retrospectively analysed 142 patients diagnosed with BM at a single site in Brisbane, QLD, Australia during 2009-2016. Basic clinico-pathological parameters, treatments used and mortality data were collected. Results: Patient characteristics included a median age of 57(17-82) years, presence of seizures (N = 18), dexamethasone use (N = 106) and BRAF mutant mm (N = 117). BM were categorised as solitary (N = 45), 2-6 (N = 65), more than 6 (N = 28) and leptomeningeal only (N = 4). BM were found on systemic treatment in 62 patients. Tyrosine kinase inhibitor (TKI) was used after the diagnosis of BM (N = 50). Management of BM included surgical resection (N = 39), Stereotactic radiosurgery (SRS) (N = 33) and Whole Brain Radiotherapy (N = 45). Immunotherapy with Ipilimumab (N = 35), Pembrolizumab (N = 36) and Nivolumab (N = 21) was used. With a median follow up of 8 months, 115 patients had died, 112 from MM. Death occurred due to progressive disease in the brain (N = 66), systemically (N = 13) or both (N = 33). The number of patients dying of mm were statistically higher on dexamethasone, increasing number of BM, BRAF mutants, absence of surgical resection or SRS and absence of immunotherapy use. Statistically Improved OS were found with solitary BM, treatment naive patients and surgical management of BM. In BRAF mutant patients who were TKI naïve at diagnosis of BM the mean OS was 14.7 versus 6.5 months in patients on TKI treatment (P < 0.05). In BRAF wild type patients mean OS was 11.7 months with PD1 use versus 8.3 months without PD1 use (Not Significant). Conclusions: Despite improvements in systemic treatment for mm the outcomes of those with BM remains poor. Solitary BM amenable to resection or ablation provides optimal treatment. The use of TKIs in BRAF mutant mm post BM diagnosis and the use of immunotherapy are effective treatment options.
NRAS-mutated melanoma patients have similar response rates to therapy with checkpoint inhibitors as other cohorts.
Authors: Kirchberger Michael Constantin , Ugurel Selma , Mangana Joanna , Heppt Markus , Eigentler Thomas , Berking Carola , Schadendorf Dirk , Schuler Gerold , Dummer Reinhard , Heinzerling Lucie 
Published: September 2018

e21035 Background: About 20% of metastatic melanomas harbor NRAS mutations which constitutively activate the MAPK pathway, driving cell proliferation and inhibiting apoptosis. The response of patients with NRAS-mutated melanoma to checkpoint inhibitor therapy is so far unknown. A previous study suggested a higher response rate of NRAS-mutated melanoma to anti-PD-1/anti-PD-L1 with an objective response in 7 out of 11 (64%) patients compared to 35% and 21% in BRAF wildtype or BRAF V600-mutated melanoma, respectively. Methods: In total, 224 patients with NRAS-mutated melanoma were analyzed. Of these, 180 patients received ipilimumab, 98 anti-PD1 monotherapy, and one patient combined ipilimumab and anti-PD1 therapy. We evaluated overall response rate (ORR), disease control rate, progression-free survival (PFS) and overall survival to checkpoint inhibitor therapy in these patients. Results: In this patient cohort with NRAS-mutated melanoma, 27% had brain metastases, 62% an elevated LDH and 22% an ECOG > = 1. ORR was 15% for treatment with ipilimumab and 34% for anti-PD1 therapy. Disease control rates were 27% for ipilimumab and 52% for anti-PD1 therapy. PFS was 4.5 months for ipilimumab and 11.4 months for anti-PD1 therapy. Overall survival of all patients was 29 months. Conclusions: The efficacy data of ipilimumab or anti-PD1 therapy in NRAS-mutated melanoma patients were similar to the known response rates of NRAS wildtype melanoma patients.