bluuebunny/crossref_metadata_2025_split huggingface dataset:
Camrelizumab in the treatment of patients with advanced lung cancer: A multicenter, prospective, cohort study.
Authors: Wang Rong , Ji Mei , Shi Meiqi , Hua Dong , Liu Lianke , Lu Kaihua , Shen Hua , Chen Meng , Cai Wei , Chen Bi , Gao Chao , Yu Changhua , Shu Yongqian 
Published: May 2020

e21650 Background: Camrelizumab is a humanized PD-1 monoclonal antibody. The efficacy of camrelizumab monotherapy or combined with chemotherapy in the treatment of advanced NSCLC had been demonstrated with promising anti-tumor activity in previous studies. However, in the real-world clinical practice, the activity of camrelizumab in patients with advanced lung cancer is poorly characterised. We sought to analyse the antitumour activity and toxicity of camrelizumab in advanced lung cancer to explore benefit subgroups and optimal treatments. Methods: This is a multicentre, prospective cohort study of advanced lung cancer in Jiangsu province, China. Eligibility required patients with histologically confirmed advanced lung cancer who couldreceive treatment regimen based on camrelizumab. No other restrictive inclusion criteria were applied. Data were captured with electronic uniform database templates to ensure consistent data collection. Primary endpoint is progression-free survival (PFS), Secondary endpoints are adverse events (AE), objective response rate (ORR), disease control rate (DCR), and overall survival (OS). Results: 97 pts with advanced lung cancer were enrolled from August 7, 2019 to December 20, 2019. Median age was 64, male 82.5%, adenocarcinoma 50.5%, squamous carcinoma 29.9%, SCLC 14.4%. 30.9% were treated as first-line therapy, 24.7% were second-line treatment, 44.4% were third-line and above treatment. Treatment regimens included camrelizumab monotherapy 13.4%, combination chemotherapy 52.6%, combination anti-angiogenic therapy 24.7%. 52 pts were accessable for efficacy analysis. 11 (21%), 37(71%), and 6(8%) patients showed partial response (PR), stable disease (SD), and progression disease (PD), respectively. The ORR, DCR was 21.2%, 92.3%. 72 pts had experienced the safety assessment. This was an early stage of data analysis, PFS has not yet reached. Major AE was reactive cutaneous capillary hyperplasia (RCCEP) (20/72), no Grade≥3 RCCEP occurred. Other common AEs were eutrophil count decreased (14/72), nausea (12/72), fatigue (11/72), white blood cell decreased (10/72). No treatment-related deaths occurred. Conclusions: This Real-world research showed current treatment status of advanced lung cancer and provides preliminary evidence for camrelizumab treating with advanced lung cancer, and we expect follow-up data to provide more clues. Clinical trial information: ChiCTR1900026089.
PD-L1, brain metastases, and survival among patients with metastatic non-small cell lung cancer treated with immune checkpoint inhibitors.
Authors: Feisal James , Balakrishna Pragathi , Itani Aleena , King Caleb , Acharya Pawan , Vesely Sara , Aljumaily Raid 
Published: May 2020

e21655 Background: PD-L1 expression is predictive of response to treatment with PD-1/PD-L1 immune checkpoint inhibitors (ICI) among patients with metastatic non-small cell lung cancer (mNSCLC). Brain metastases (BM) are common in patients with mNSCLC and carry significant morbidity. While the use of ICI has significantly improved survival for mNSCLC, it is unclear if patients with brain metastases have the same survival benefit. Methods: In this retrospective study, we reviewed data from all patients treated at our center with mNSCLC who had PD-L1 testing from 2015-2019. Patients with another active malignancy were excluded. Descriptive statistics were calculated using proportions and means using SAS v9.4. We examined the relationship between PD-L1 level ( < 50% vs ≥50%) and BM at diagnosis among patients with mNSCLC using chi-square analysis. We then compared overall survival (OS) and progression free survival (PFS) among mNSCLC patients with and without BM at diagnosis treated with ICI using Kaplan-Meier plots followed by log rank tests. Results: 141 mNSCLC patients with PD-L1 results were identified. 71 (50.4%) were female. Mean age was 63. 71 (50.4%) were current smokers, 53 (37.6%) were former smokers. Histology included 111 (78.7%) adenocarcinoma, 19 (13.5%) squamous cell carcinoma, and 11 (7.8%) other or mixed types. 19 (13.5%) had KRAS mutation, 13 (9.2%) had EGFR mutation, 1 had ALK rearrangement, 3 had ROS1 rearrangement, and 2 had BRAF mutations. 86 (61.0%) were PD-L1 high (≥50%). 57 (40.4%) had BM at diagnosis. Patients with high PD-L1 had a higher rate of BM at diagnosis (47.3% vs 36.0%), but this trend was not statistically significant (p = 0.18). There were significantly more current smokers among those with BM at diagnosis than those without BM (p = 0.01). Among patients treated with first line ICI (n = 78), median OS was 26.5 months for those without BM and 12.2 months for those with BM at diagnosis, although this difference was not significant (p = 0.11). Median PFS was 8.9 months for patients without BM and 8.6 for those with BM (p = 0.58). Conclusions: While a higher proportion of patients with high PD-L1 had BM at the time of metastatic diagnosis, this trend was not significant. Among patients treated with ICI, survival for those with or without BM at the time of diagnosis was not significantly different. Our observations may be limited by the number of patients.
Do herbal drinks augment the cytotoxic effect against different cancer cells? Are they potent stimulators of innate and acquired immunity?
Authors: Adnan Israa , Talib Wamidh 
Published: May 2020

e21657 Background: The herbal drinks are highly prevalent in the Middle East and are consumed in large quantities as daily drinks. Few studies have evaluated the biological activities of the herbal drinks produced from some plants.The current study aims to evaluate the anticancer and immunomodulatory activities of five herbal drinks consumed in the Middle East. These drinks are Palestinian Zhourat, Lebanese Zhourat, Lemon and Ginger combination, Wild Thyme, and Marjoram. Methods: The selected herbal drinks as concentrated water extracts were tested separately for: A. Anti-cancer effect on the cell lines (MCF-7, MDA-MB231, HCT-116, A549, and Vero-normal cells) by assessing: - Antiproliferation activities using MTT assay. Apoptosis (using the caspase-3 assay) and vascular endothelial growth factor (VEGF) expression (using ELISA kit) for the most potent antiproliferative extract. B. Immunomodulatory effect by evaluating: - Splenocytes proliferation using the mitogen proliferation assay. Phagocytosis activity using the nitro blue tetrazolium assay. - Pinocytosis function using the neutral red method. Results: The Lemon and Ginger combination was the most potent against MDA-MB231, MCF-7 and A549l cell lines with IC50 3.5,4, 6.5mg/ml, respectively. Lemon and Ginger combination and Wild thyme separately showed high apoptosis induction and angiogenesis suppression on the MDA-MB231cell line at concentrations 3.5 and 4.4 mg/ml for both extracts, respectively. Wild thyme was the most potent stimulant lymphocyte proliferation (with index 4.7), and Marjoram has the highest percentage (314.4%) in phagocytosis activity, while moderate stimulation by Zhourat was noted. Lemon and Ginger combination, Wild thyme, Marjoram, and the Lebanese herbal drink "Zhourat" were the most active extracts in stimulating pinocytosis with absorbance value 0.5745,0.4645,0.461,0.4575 nm, respectively. Meanwhile, the Palestinian herbal drink "Zhourat" had a moderate effect. Conclusions: The consumption ofthe mentioned herbal drinks has various Anti-cancer and immunomodulatory effects. Lemon and ginger combination exhibits the most potent anticancer activities. Wild thyme and marjoram are potent stimulators of innate and acquired immunity. The result achieved in this study is very optimistic and encouraging to be considered for further clinical trials.
Comparison of treatment outcomes in patients with metastatic lung cancer who did or did not develop EGFR T790M mutation.
Authors: Wang Zhen , Sandler Jason , Shieh Kevin , Mo Lan , Huang Yiwu , Solomon William B. , Becker Kevin Douglas , Xu Yiqing 
Published: May 2020

e21658 Background: First-line treatment of lung cancer patients with EGFR mutation with early generation tyrosine kinase inhibitors (TKIs) renders a median progression-free survival (mPFS) of 11 months (m), and for the patients who subsequently develop the T790M mutation, osimertinib provides an additional mPFS of 10 m. First-line treatment with osimertinib showed mPFS of 18.9 m and none developed T790M at the time of progression (FLAURA trial). We hypothesized that the mPFS for patients who developed T790M mutation might be longer than those who did not and the prognosis and outcome might be different between these two groups. Methods: This is a retrospective study on patients who were diagnosed with metastatic, EGFR-mutated NSCLC and treated at Maimonides Cancer Center between 1/1/2011 and 9/30/2019. Patients were divided into two cohorts: those who did not develop T790M mutation (group 1), and those who did (including 1 patient who had de novo mutation, group 2). Results: Fifty-six patients were identified, with median age of 70 years (range 40-93). All patients had adenocarcinoma. Thirty-nine (70%) were Chinese. There were 31 (55%) exon 19 deletion, 22 (39%) L858R, 1 E709A, 1 G719S and 1 de novo T790M mutations. Forty-five patients (80%) never developed T790M (group 1), 10 (18%) did and 1 had primary mutation (group 2). The median time to developing T790M mutation was 22 m. In group 1, 8 patients received first-line osimertinib, while other 37 received erlotinib (23), gefitinib (4) and afatinib (10). Among the 37 patients, 12 were switched to osimertinib in subsequent lines, 5 due to toxicity and 7 due to progression. In group 2, 8 patients received osimertinib at identification of T790M and 1 for de novo mutation. At 22 m median follow up, the mPFS for group 1 was 14 m (95% CI 9.3-19); the mPFS for group 2 was 21.6 m (95% CI 7.4-49.1) up to the time of identification of T790M, and 31.2 m (95% CI 4.9-45.4) until disease progression after osimertinib. The mPFS of the entire cohort was 17.1 m (95% 11.1-25.9), and mOS was 22.0 m (95% 15.6-29.6). The mOS was 19.0 m (95% CI 11.4 – 25.2), and 39.9 m (95% CI 13.3 – 62.1) for group 1 and 2 respectively. Conclusions: Patients who developed the T790M mutation appeared to have a longer PFS than those who did not and the mean duration to detection of T790M was 22 m. The development of T790M may confer a slower growth pattern and longer PFS. This question should be further explored in larger studies.
LP-300 as a potential first-in-class combination agent with tyrosine kinase inhibitors (TKIs) in non-smoker lung adenocarcinoma.
Authors: Kulkarni Aditya , Parker Aulma , Jair Kamwing , Petluru Pavankumar , Chen Xinghai , Kochat Harry , Hausheer Frederick H. , Kathad Umesh , Bhatia Kishor , Barnhart Kerry , Sharma Panna 
Published: May 2020

e21660 Background: Lung cancer in non-smokers (LCINS) is the seventh leading cause of death among solid tumors. LCINS is more frequent in women, and the histological incidence of adenocarcinoma is higher among non-smokers. The mutation pattern by smoking status in non-small cell lung cancer (NSCLC) is distinct with genomic alterations in EGFR, MET and ROS1 being more frequent in non-smokers. Non-smoking status is the strongest clinical predictor of benefit from the EGFR TKIs. Lantern Pharma is developing LP-300/Dimesna, a non-toxic, well-tolerated, water-soluble disulfide as a combination therapy agent potentially indicated in female never-smokers with adenocarcinoma. Retrospective subgroup analyses of prior phase 3 trial data showed substantial overall survival benefit for LP-300 in combination with standard chemotherapy in patients with advanced NSCLC, especially in the female non-smoker adenocarcinoma subgroup (13.4 months in control arm to 27 months in treatment arm). Purpose of this work conducted at BioNumerik Pharmaceuticals was to determine if LP-300 modulates activity of selected receptor tyrosine kinases relevant to non-smoker NSCLC. Methods: In vitro luminescence-based kinase assays were used to evaluate the effect of LP-300 and LP-300-derived mesna-disulfide heteroconjugates, Erlotinib, and Crizotinib, in combination and as single agents, on EGFR, MET, and ROS1 kinase activity. Results: LP-300 inhibited WT EGFR kinase and MET kinase. LP-300 had a time-dependent inhibitory effect on ROS1 kinase activity. LP-300 and LP-300-derived mesna-disulfide heteroconjugates stimulated Erlotinib-mediated inhibition of WT and T790M EGFR. T790M EGFR is normally insensitive to Erlotinib but when LP-300 was used with Erlotinib, inhibition was more prominent. LP-300 also stimulated Crizotinib-mediated inhibition of MET kinase and displayed time-dependent stimulation of Crizotinib-mediated inhibition of ROS1 kinase. Conclusions: LP-300 is a multi-targeted modulator of enzymatic activities of EGFR, MET and ROS1, and potentiates the activity of Erlotinib and Crizotinib. EGFR family members contain conserved extracellular structures that are stabilized by disulfide bonds. Compounds that disrupt extracellular disulfide bonds could inactivate EGFR and potentially downregulate EGFR-dependent proliferative signaling in cancer cells. We propose LP-300 as a Disulfide Bond Disrupting Agent (DDA) that may complement existing EGFR-targeted agents functioning through alternate mechanisms.
Preclinical evaluation of SIM1803-1A, a small molecule Trk/ROS1 dual inhibitor for wild and mutate NTRK/ROS1 fusion solid malignancies.
Authors: Wang Jianfei , yu xiaohong , Zhu Shunwei , Chen Qingying , Sun Jikui , Xia Yuanfeng , Zhang Yang , Chan Chi-Chung , Li Jian , Chen Shuhui 
Published: May 2020

e21663 Background: Fusions and rearrangements of NTRK1/2/3 and ROS1 genes are oncogenic drivers in multiple solid malignancies. Drugs targeting tyrosine kinases TrkA/B/C and ROS1, such as larotrectinib and entrectinib, are proven highly efficacious in diverse adult and pediatric tumor types (ORR > 75%). However, the treatment-related drug resistance, including S.F. mutations, G.K. mutations and DFGx mutations, has been identified in clinical trials. The use of second generation of TKI, such as repotrectinib to against these acquired resistance mutations, has been explored in clinical trials and reported unsatisfied efficacy in patients under acceptable dosages, which might due to its broader inhibition of multiple kinases. Here we report a novel potent Trk/ROS1 dual inhibitor SIM1803-1A, targeting both the wild type and multiple clinical mutations of Trk and ROS1 with clean selectivity profile and expected in vitro and in vivo efficacy for wild and mutant NTRK/ROS1 fusion solid tumors. Methods: Kinase inhibiting potency was determined with Reaction Biology kinase assays. Kinase selectivity was screened on Eurofins Kinase Profiler panel. Cellular anti-proliferative potency was evaluated on relevant fusion cell lines. Antitumor efficacy was evaluated in the related CDX and PDX mice models shown in results. Results: SIM1803-1A displayed high kinase inhibiting potency with IC50 3.64/1.24 /4.45 nM on TrkA( WT/G595R/G667C) kinase, 0.07/5.03/5.68 nM on TrkC( WT/G623R/L686M), and 0.08/0.10 nM on ROS1( WT/G2032R) respectively. A clean selectivity profile was also identified in 112 enzymes from TK and TKL family at 0.5 µM. The proliferation inhibition IC50 of SIM1803-1A in following cell lines were: 0.3 nM on KM12 TPM3-NTRK1, 2.2/0.9/5.7/5.6 nM on Ba/F3 LMNA-NTRK1( WT/F589L/G595R/G667A), 2.9/6.2 nM on Ba/F3 ETV6-NTRK3( WT/G623R), and 7.3/15.0 nM on Ba/F3 SLC34A2-ROS1(WT/G2032R) respectively. SIM1803-1A showed high antitumor efficacy in the subcutaneous colon cancer KM12 TPM3-NTRK1 CDX model with 68% and 80% TGI at 1 and 3 mg/kg (bid) dosing, and similar high efficacy in the subcutaneous NSCLC LU-01-0414 SDC4-ROS1 PDX model with 60% and 74% TGI at 1 and 3 mg/kg (bid) dosing. Conclusions: Collectively, these studies have shown SIM1803-1A is a potent Trk/ROS1 dual inhibitor with better safety potentially from improved kinase selectivity. SIM1803-1A is currently at IND submission stage and represents a promising clinical candidate for the treatment-naïve and acquired-resistance NTRK/ROS1 fusion-positive malignancies.
RB1 mutation had influenced on bone metastases in advanced treatment-naïve lung cancer.
Authors: Zhou Chengzhi , Xu Ying , Lin Xinqing , Wang Fei , Deng Huojin , Xie Xiaohong , Liu Ming , Xie Zhanhong , Zhang Jiexia , Ouyang Ming , Li Shiyue , Chen Rongchang , Qin Yinyin , Chen Rongrong , Xia Xuefeng 
Published: May 2020

e21668 Background: RB1 is one of the most vital cancer suppressor genes in various cancer types. RB1 mutation always occurs in treatment-naïve small cell lung cancer (SCLC) patients or in resistance to EGFR TKI therapy of non-small cell lung cancer (NSCLC) patients. However, we observed a group of clinical NSCLC patients, and found that RB1 mutations also occurred in treatment-naïve patients. Methods: RB1 is one of the most vital cancer suppressor genes in various cancer types. RB1 mutation always occurs in treatment-naïve small cell lung cancer (SCLC) patients or in resistance to EGFR TKI therapy of non-small cell lung cancer (NSCLC) patients. However, we observed a group of clinical NSCLC patients, and found that RB1 mutations also occurred in treatment-naïve patients. Results: Nonsense and frame-shift mutations were the major pathogenic mutations found in RB1 gene, which predicted RB1 protein-deficient in these mutational patients. Furthermore, we found these RB1 mutation patients had TP53 mutations at the same time. Patients with RB1 mutation had a higher smoking prevalence than patients who had wildtype RB1 genes (P < 0.0001). Gene testing showed RB1 mutations patients also developed EGFR driver mutations, while the mutation frequency was significantly lower than RB1 wildtype patients ( P = 0.0368). Eight RB1 mutated patients diagnosed with actionable EGFR mutations, including exon 19 del, L858R, L861Q, G719S and S768I, while no patients diagnosed with EGFR exon 20 insertion. 10 (62.5%, 10/16) patients in RB1 mutated group, and 25(32.1%, 25/78) patients with RB1 wildtype had bone metastases. The proportion of bone metastases in patients with RB1 mutation was significantly increased than others ( P = 0.0216). Conclusions: This study demonstrates that the function of tumor suppressor gene RB1 in advanced stage of NSCLC. From the results, we considered RB1 mutation had influence on bone metastases. Although loss-of-function mutations in tumor suppressor gene (TSG) RB1 always had no targets therapeutic drugs, it also suggested that some other clinically treatment can be performed as soon as possible.
The prognostic value of neutrophil-to-lymphocyte ratio in patients with epidermal growth factor receptor mutated advanced non-small cell lung cancer (NSCLC).
Authors: Yun Nicole , Rouhani Sherin Juliet , Gilmore Brendan , Ritz Ethan M. , Bestvina Christine M. , Tarhoni Imad , Batus Marta , Borgia Jeffrey Allen , Bonomi Philip D. , Fidler Mary J. 
Published: May 2020

e21675 Background: An elevated neutrophil-to-lymphocyte ratio (NLR) indicates a poor prognosis across multiple cancers, including non-small cell lung cancer (NSCLC). Our study aims to validate these findings in EGFR-mutated NSCLC patients receiving tyrosine kinase inhibitor (TKI) therapy, and to evaluate other factors that may impact NLR. Methods: We retrospectively analyzed 95 patients with advanced EGFR-mutated NSCLC treated with TKIs at Rush University Medical Center and The University of Chicago Medical Center from August 2011 to August 2018. The prognostic value of NLR was assessed at the start of therapy, and after 6 and 12 weeks of treatment. The median progression free survival (mPFS) and median overall survival (mOS) were calculated by the Kaplan-Meier method and compared with the log rank test. Spearman rank correlation was used to correlate number of disease sites with NLR at diagnosis. T test analysis compared mean NLR between patients with high grade (≥ 3) toxicity versus low or no (grades 0-2) toxicity. The relationship between NLR and body mass index (BMI) changes were analyzed using Pearson correlation. Results: At therapy start, patients with NLR < 5 (n = 57) had a mPFS of 15.3 months and a mOS of 56.7 months, while those with NLR ≥ 5 (n = 35) had a mPFS of 13.8 months ( p= 0.024) and mOS of 40.0 months ( p= 0.0056). After 6 weeks of treatment, patients with NLR < 5 (n = 69) had a mPFS of 14.6 months and mOS of 56.2 months, while those with NLR ≥ 5 (n = 23) had a mPFS of 10.0 months ( p= 0.052) and a mOS of 37.74 months ( p= 0.049). After 12 weeks of treatment, patients with NLR < 5 (n = 66) had a mPFS of 14.2 months and mOS of 54.8 months, while those with NLR ≥ 5 (n = 17) had a mPFS of 3.0 months ( p= 0.0016) and a mOS of 22.4 months ( p= 0.0012). Patients who had a decrease in NLR did not have significantly better mPFS or mOS compared to patients whose NLR increased at either 6 or 12 weeks. Baseline number of disease sites and BMI did not correlate with NLR at diagnosis. Changes in BMI did not correlate with a change in NLR at 6 weeks or at 12 weeks. There was no significant difference in NLR between patients with high grade (≥ 3) versus no or low grade (0-2) drug toxicities. Conclusions: NLR can be used as a prognostic factor to predict which EGFR mutated NSCLC patients on TKI therapy may have worse PFS or OS outcomes. Closer monitoring and potential therapeutic escalation may be beneficial in patients with elevated NLR ≥ 5. Further work studying NLR in patients being treated with a larger osimertinib cohort is ongoing.