bluuebunny/crossref_metadata_2025 huggingface dataset:
Downregulation of CPA4 to suppress NSCLC proliferation by inducing apoptosis and G1 arrest.
Authors: Fu Yangyang , Huang Xiaoying , Wang Liangxing
Published: September 2018

e20074

Background: Carboxypepidase A4 (CPA4) is a member of the metallocarboxypeptidase family. Previous study discovered that CPA4 may participate in cell growth and differentiation of prostate epithelial cells. Meanwhile, CPA4 is a printed gene and thought to be involved in prostate cancer aggressiveness. As is reported, CPA4 was increased in NSCLC tissues compared to normal lung tissues and high expression of CPA4 was correlated with poor prognosis of NSCLC patients. However, the role of CPA4 play in lung tumorigenesis is still unclear. Methods: We examined the mRNA and protein expression level of CPA4 via real-time PCR and immunohistochemistry in NSCLC tissues and adjacent tissues. Growth assays both in vitro and in vivo were performed to elucidate the role of CPA4 may play in lung cancer and Fluorescence Activated Cell Sorter was conducted to uncover the putative mechanism. Results: CPA4 expression was increased both in mRNA and protein levels in NSCLC tissues compared to adjacent tissues. MTT and colony formation assays showed that downregulation of CPA4 in H1299 and A549 cells inhibited lung cancer cells proliferation. We further confirmed this result by using cellomics and celligo. Depleting CPA4 also suppressed tumor growth in mice. Mechanically, we found that suppressing CPA4 expression in lung cancer cells could induce apoptosis and G1 arrest. We supposed that CPA4 expression may be associated with caspase family and it needs further studies. Conclusions: Collectively, we demonstrate that decreased CPA4 inhibits NSCLC proliferation via inducing apoptosis and G1 arrest.
Histological features and survival in NSCLC patients treated with surgery with curative intention.
Authors: Cárdenas Quesada Nuria , Ortega Granados Ana Laura , Márquez Lobo Bélgica , Vivo Molina María Carmen , Rosa Garrido Carmen , Piedra Fernández Inmaculada , Sevilla López Sebastián , Cerro Antonio Bravo , Lacárcel Bautista Celia , Pérez Chica Gerardo , Nieto Serrano José , García Verdejo Francisco José , Luque Caro Natalia , Fernández Garay David , Moreno Jimenez Miguel Angel , Plata Fernández Yessica , Núñez Torres María Isabel , Sánchez Rovira Pedro
Published: September 2018

e20080

Background: New classification of adenocarcinomas and better typing of histological characteristics of lung tumors leads us to wonder if these histological data could have a prognostic repercussion in the NSCLC who were into curative intent surgery Methods: We followed 95 patients with stage I-III NSCLC underwent surgery in a 4 year period (2010-2013), until August 2016. Most patients were male (82%), smokers (90%, 44% exsmokers and 56% active , median age at diagnosis was 64 years, 47% had a previous COPD, and 52% were diagnosed of NSCLC without any symptom of lung cancer. 79% patients had lobectomy or sleeve resection, and 21% pneumonectomy. 47% patients had adjuvant chemotherapy (CT) Results: We found no significant differences in age of diagnosis between men (64.95 y) and women (58.65 y) (p = 0.066) nor in survival time. Median disease-free survival (DFS) is 15 months and overall survival (OS) is 49 months. If we analyze DFS from surgery to the first relapse, most happen at first 2 years (80%). By stage, OS at 5 years is 73% in stage IA, 58% stage IB, 46% stage IIA, 36% stage IIB, 24% for stage IIIA and 9% in IIIB. We had 49% adenocarcinomas (most frequent, 53%, acinar subtype), and 51% squamous, and we found no significant difference between histologies, nor between subtypes. But there was a significant difference between DFS, favorable for mild lymphoid response (20 months) with respect to moderate or intense response (11 months) Conclusions: We found that we are underusing adjuvant CT. In our group there is no difference in survival for tumor size, linfovascular invasion, histological grade or histology, but we found a better DFS for mild lymphoid response vs moderate-intense pattern. This finding may be related to the antitumor activity of the immune system, and we want to validate it prospectively, and its relationship with subsequent immune therapy response.
Apatinib to enhance antitumor activity of gefitinib in non-small cell lung cancer.
Authors: Li Fang , Zhu Tengjiao , Zhu Xiang , Wang Jiadong , Liang Li
Published: September 2018

e20086

Background: Gefitinib, an oral EGFR-TKI, is recommended as the first-line therapy for non-small cell lung cancer (NSCLC) patients with EGFR mutations. Apatinib is an oral TKI against VEGFR-2 and is effective as third- or later-line treatment in advanced NSCLC. EGFR and VEGF/VEGFR pathways are interrelated. We conducted this study to explore the effect of gefitinib plus apatinib therapy in NSCLC and the possible mechanism. Methods: Cell viability assay was performed on 4 NSCLC cell lines (A549, H1975, H1650 and HCC827) to determine IC50 of gefitinib, apatinib and their combination for growth inhibition. The nude mice were injected i.h. with H1975 cells to establish EGFR mutated NSCLC xenograft tumor. Tumor volume was recorded every three days. Immunohistochemistry for Ki67 and PCNA expression was performed to detect tumor cell proliferation in mice. In addition, the expression levels of key proteins were detected by immunohistochemistry and western blot, respectively. Results: The H1975 cells were the most susceptible to the combination of gefitinib and apatinib, with lowest IC50 value of 0.44 ± 0.09, compared with other cells. In H1975 xenograft model, gefitinib plus apatinib showed markedly higher inhibiting effect on tumor volume than both gefitinib and apatinib mono-therapy. Moreover, the expressions of both Ki67 and PCNA significantly decreased in mice after combined therapy than either gefitinib or apatinib alone, indicating that the combined therapy was superior to mono-therapy of gefitinib or apatinib in suppressing cell proliferation in mice. Additionally, there was an obviously higher expression of EGFR, pho-EGFR, VEGFR, pho-VEGFR, VEGFA, p-mTOR, t-mTOR, p-AKT, t-AKT, p-Erk, and t-Erk in mice treated with gefitinib plus apatinib than mono-therapy. Furthermore, the much stronger inhibitory effect on angiogenesis of gefitinib plus apatinib therapy was revealed, as more expression of CD31 than both gefitinib and apatinib mono-therapy. Conclusions: Apatinib significantly potentiated the antitumor effect of gefitinib in NSCLC both in vivo and vitro. These findings support a great therapeutic potential role for the combination of apatinib and EGFR-TKI in the treatment of NSCLC in clinic.
Priming PD-L1 expression by chemotherapeutic agents in non-small cell lung cancers.
Authors: Lin Emily Pei-Ying , Yang Ching-Yao , Lin Ching-Wen , Huang Bo-Tsang , Lai Wei-Yun , Tseng Yi-Ting , Yang Pan-Chyr
Published: September 2018

e20087

Background: Immunotherapy targeting PD-1/PD-L1 axis has yielded fruitful results in non-small cell lung cancers (NSCLCs). Evidences showed that treatment responses are likely correlated with tumor PD-L1 expression levels, which is especially true in the first line setting. Results from Keynote-021 suggested that pembrolizumab plus platinum-pemetrexed doublet came out with better overall response rate and progression free survival as compared to chemotherapy alone even in the PD-L1 low-expression group. Nevertheless, grade III and IV toxicities were much frequently observed in the combinational arm. The aim of the current study is to investigate the effect of chemotherapeutics on PD-L1 priming in NSCLCs so as to provide a better option in the chemo-immunotherapy combinational setting. Methods: NSCLC cell lines CL1-5, CL141, and H1299 were treated with a platinum-based drug (cisplatin), microtubule-targeted agents (paclitaxel or vinorelbine), or antimetabolites (pemetrexed or gemcitabine) for 24 to 72 hrs. The concentration of each drug selected for experiments was stepping-down titrated from the IC50s, with the maximum concentration allowed being 10 μM. The priming effects of chemotherapeutics on PD-L1 expression were evaluated with RT-qPCR, Immunoblotting and FACSCalibur flow cytometer. The functionality of the induced PD-L1 was examined by the T cell cytotoxic assay and the IL-2 production ability, done with co-cultured systems containing chemo-primed tumor cells and activated T cells. Results: The results showed that pemetrexed or gemcitabine, but not cisplatin, paclitaxel or vinorelbine, effectively induced PD-L1 expression at concentrations below the IC50s. Membranous distribution of the induced PD-L1 was observed. Addition of anti-PD-L1 blocking antibody in the co-cultured system increased T cell cytotoxic ability and promoted IL-2 production, implicating the biological functionality of the induced PD-L1. Conclusions: The data suggested that pemetrexed or gemcitabine effectively primed the expression of biologically functional PD-L1 in NSCLC cells. The results implicate that pemetrexed or gemcitabine alone may be a good combinational candidate for PD-L1-targeted therapy in NSCLCs.
Distant outcomes of chemoimmunotherapy with recombinant interferon-gamma for acinar-type adenocarcinoma of the lung.
Authors: Pyltsin Sergey P. , Lazutin Yuriy N. , Ayrapetova Tamara G. , Chubaryan Anna V. , Anistratov Pavel A. , Leyman Igor A. , Shogenov A. S. , Gappoeva M. A. , Afaunov M. Kh.
Published: September 2018

e20090

Background: We performed a comparative analysis of disease-free survival (DFS) after adjuvant chemoimmunotherapy (ACIT) with recombinant interferon-gamma in combination therapy and standard adjuvant chemotherapy (ACT) of patients with acinar-type adenocarcinoma of the lung. Methods: The study included 63 patients who received radical surgery for stage I-IIIA adenocarcinoma in 2009-2012. Group 1: 33 patients with ACIT after radical pneumonectomy, carboplatin AUC = 5 on day 1 and etoposide 100 mg/m2 on days 1, 3 and 5; i.v. ingaron 500 000 IU/m2 but no more than 1 million IU for one injection on days 2, 4 and 6. Carboplatin was replaced by cisplatin 100 mg/m2 in ACIT after lobectomy. Group 2: 30 patients with similar ACT without ingaron. The interval between courses was 21 days. Survival was estimated by Kaplan-Meier method, and differences were compared using log-rank test. Results: Group 1: 28 (84.8%) patients received 3 ACIT courses, 5 (15.2%) – 2 courses. Group 2: 27 (90%) patients received 3 ACT courses and 3 (10%) – 2 courses. Analysis of the Kaplan-Meier curves showed a tendency to a 8% increase in 5-year DFS that was 58% in Group 1 and 50% in Group 2 (p = 0.064). Conclusions: 5-year DFS increase by 8% demonstrates the expediency of further studies involving more patients which will allow revealing statistically significant differences in long-term results of treatment.
Veristrat based stratification of responses to immune checkpoint blockade (ICB).
Authors: Walker Paul R. , Sharma Nitika , Stroud Chipman Robert Geoffrey , Muzaffar Mahvish , Cherry Cynthia R. , Cherukuri Sulochana Devi , Parent Teresa , Hardin Jessica
Published: September 2018

e20512

Background: Veristrat (Biodesix, Boulder, CO) is a blood based proteomic assay that is dominated by inflammatory proteins and is prognostic and predictive in metastatic NSCLC after treatment with platinum based chemotherapy (Gregorc et al, Lancet 2014). Smoldering inflammation in the tumor microenvironment regulates and escalates cancer invasion, angiogenesis and immune surveillance escape (Balkwill and Mantovani, Lancet 2001). There is preclinical evidence to suggest that the tumor microenvironment can be altered with immunomodulatory interventions (Martino et al, 2016). While immune checkpoint blockade has shown durable benefit in metastatic NSCLC, the response rates still hover around 20%. As a result, identification of predictive biomarkers are of critical importance. The predictive value of the Veristrat assay with respect to ICB is poorly defined. Methods: At our institution, 83 pts with metastatic lung cancer pts were treated with nivolumab between 6/2015 to 12/2016. The following clinicopathologic characteristics were abstracted from medical records: tumor histology, Veristrat status, no. of doses of nivolumab, irAEs and overall survival. Results: Of the 83 pts, 65 pts were found to have NSCLC. Veristrat status was available for 17/65 of these pts. Nine pts were identified to have “Veristrat good” and seven pts were “Veristrat poor”. Median number of nivolumab doses was 4. Median survival for all patients was 30 weeks. Median survival was 20 weeks for “Veristrat poor” and 26 weeks for “Veristrat good”(p = 0.68). Grade 3-4 irAEs were noted in 5/9 patients with “Veristrat good” and 5/7 patients with “Veristrat poor”. Conclusions: “Veristrat poor” pts treated with ICB have a lower median survival as compared to “Veristrat good” pts. Our study did not meet statistically significant end point due to limited sample size. Further studies are needed to identify poorly immunogenic tumors and develop novel treatment approaches to optimize outcomes. [Table: see text]
EGFR status evaluation by liquid biopsy during first-line therapy in patients with advanced NSCLC.
Authors: Zanelli Francesca , Pagano Maria , Bonelli Candida , Casali Bruno , Cavazza Alberto , Farnetti Enrico , Gnoni Roberta , Larocca Mario , Nicoli Davide , Pinto Carmine
Published: September 2018

e20524

Background: over the past decade, personalized management based on the molecular features of tumours in patients with advanced non small-cell lung cancer (NSCLC) has entered routine clinical practice. The poor performance of many advanced NSCLC patients may limit invasive biopsies. The liquid biopsy is a diagnostic procedure performed on cancer-derived material obtained in blood samples. In this abstract, we will describe our experience with liquid biopsies. Methods: In the Reggio Emilia Clinical Cancer Centrefrom March 2016 to December 2016, 42 patients with advanced NSCLC were analyzed that had had or had already started first line therapy. The liquid biopsy was repeated at each imaging response evaluation by thoracic-abdominal compound tomography (CT) scan performed every 3 months. In the liquid biopsy, the mutational status of EGFR was analyzed with real time PCR (KIT cobas EGFR mutation test v2 CE-IVD Roche); in tissue, it was evaluated by pyrosequencing. Results: 21/42 liquid biopsies were EGFR-mutated (12/21 eson 19 and 9/21 eson 21). In 3/21 (14.3%) cases, the tissue biopsies showed wild type (WT) EGFR. 6 liquid biopsies were also performed at time 0 (diagnosis). All liquid biopsies of EGFR WT remained WT during treatment and imaging evaluation. The median number of liquid biopsy tests for patients was 2 (range 1-3). In 4/21 cases, T790M was performed: 3 cases in both liquid biopsies and tissue, and 1 case in tissue but not in liquid biopsy. TKi therapy was ineffective in this patient with T790M mutation detected in tissue, but not in liquid biopsy. In all patients, the disappearance of the T790M mutation during TKi therapy was related to disease progression. In 11 cases, modification of EGFR mutation status during treatment anticipated CT scan evidence of disease progression (median = three months). Conclusions: the liquid biopsy is an excellent resource. In our experience the liquid biopsy is the sensitive method of choice during treatment of advanced NSCLC patients. EGFR modification status during TKi therapy showed advanced disease progression.
Differential expression proteins in lung adenocarcinoma with bone metastasis: Correlation of ALDH2 and ENO1 with prognosis.
Authors: Yang Mengdi , Sun Jing , Wang Zhiyu , Zhang Rui , Gu YIfeng , Zhao Hui
Published: September 2018

e20534

Background: The prognosis of lung adenocarcinoma (LUAD) with bone metastases (BM) is still poor. It is increasingly demanded to find key proteins to solve the problem. Methods: First, we collected three groups of bone tissues: normal, osteosarcoma, and LUAD with BM from Shanghai Sixth People's Hospital. Each group had five patients. Two-dimensional gel electrophoresis (2D-E) was used to find proteins with significant differences, then Maldi-tof-tof mass spectrometry was used to identify the proteins. Second, immunohistochemical (IHC) was used to check the expression of proteins in 28 BM patients and 9 LUAD patients. Real-Time PCR (QPCR), western boltting (WB) were further used to check the expression of para-LUAD, LUAD and BM. Last, we downloaded RNA-seq and clinical datas from the Cancer Genome Atlas(TCGA) database to further verify differentially expressed genes using ‘DESeq’ package and explored their relationship with survival using ‘survival’ package in R. Kaplan-Meier survival plot and the hazard ratio and logrankp was calculated (www.kmplot.com/lung). Results: We got 26 matched proteins from 2D-E, then selected Aldehyde Dehydrogenase 2 Family (Mitochondrial) (ALDH2) and Enolase-1 (ENO1). In IHC analysis, strong-stained ALDH2 showed OR = 0.568 (95 % confidence interval [CI], 0.317-1.019), p= 0.036, strong-stained ENO1 OR = 1.929 (95% CI, 0.915-4.066), p= 0.023, were associated with bone metastastic incidences in LUAD with statistically significantly difference. QPCR, WB validated that ALDH2 had lowest expression in BM, followed by LUAD samples, and para-LUAD highest. However, ENO1 displayed the opposite tendency . In TCGA LUAD RNA-seq, ALDH2 had low expression ( p= 3.83E-12, log2Foldchange = 1.158), and ENO1 was up-regulated ( p= 0.0004, log2Foldchange = 1.210 ). ALDH2 is correlated with better survival (HR = 0.47, 95% CI (0.37-0.61), logrankP = 6.5E-10), while ENO1 was inversely associated with better prognosis (HR = 1.67,95% CI (1.32-2.12), logrankP = 1.9E-05) in K-M Plotter. Conclusions: In this study, we discovered new differential expression and prognosis related proteins, ALDH2 and ENO1, and they are worthy of further exploration into the underlying mechanism.
Retrospective review of concurrent chest radiation and chemotherapy (CRT) in newly diagnosed stage IV non-small cell lung cancer (NSCLC) with oligometastatic disease (OM) treated with stereotactic radiation.
Authors: Narayan Preeti , Yeung Anamaria R , Ogunlari Olushola , Morris Chris G , Gopalan Priya Kadambi
Published: September 2018

e20539

Background:The primary treatment for patients (pts)with stage IV NSCLC is palliative chemotherapy (CT), with a median OS of approximately 10-12 months, and 5-year survival of ~2%. Several studies have demonstrated that pts with a lung nodule with a solitary brain or adrenal metastasis can achieve relatively high 5-year survival rates with resection of the metastasis and the lung nodule. Studies have also demonstrated that OM can be effectively treated with stereotactic body radiation (SBRT) or stereotactic radiosurgery (SRS) to the brain. We hypothesize that treatment of OM with SBRT and/or SRS and treatment of the thoracic disease with CRT will improve survival over palliative chemotherapy alone. Methods:A retrospective review of charts in the RADTRACS database at the Univ of Florida was conducted between 1/1/2010 - 6/30/2015 to identify pts with newly diagnosed stage IV NSCLC with 5 or less OM at diagnosis that were treated with concurrent CT and definitive RT (60-66 Gy) to the primary lung mass in addition to SRS and/or SBRT to the OM. Date and site of first progression, and date of death/last follow-up were noted. Endpoints included median progression free survival (PFS) and median overall survival (OS). Results:26 pts met these criteria. 20 pts (77%) had recurrence of disease after treatment with CRT + SRS/SBRT. Median PFS was 6 months, and median OS was 14.4 months. Of the 20 recurrences, 10 (50%) were in the brain, while 10 (50%) were in non-CNS sites. One year OS was 60% and 3-year survival was 33% in our patients. When pts with CNS OM at diagnosis were compared to non-CNS OM, PFS (5.5 vs 5.8 months, respectively, p > 0.05) and OS (16.6 vs 13.8 months, respectively, p > 0.05) were similar. 8/12 CNS OM pts progressed in the brain while only 3/9 non-CNS OM progressed in the brain. Of the 5 patients with no progression, 4/5 had non-CNS OM at diagnosis. Conclusions:When compared to standard palliative CT where median OS 10-12 months, median OS was 14.4 months in our pts treated with CRT + SBRT/SRS. This data suggests a possible role for more aggressive treatment of stage IV NSCLC pts with SBRT/SRS to OM and definitive chest CRT.
LuCaS (Lung Cancer Surveillance) study: Surveillance models for advanced lung cancer patients.
Authors: Fraser Sarah Anne
Published: September 2018

e20546

I hope to present the trial protocol as a poster at ASCO with co design work commencing 2017. Background: Lung cancer is the leading cause of cancer death in NZ.1 85% of registrations annually are stage four at diagnosis, presenting a significant burden on resources. Despite novel therapies, survival is poor and quality of life is a key consideration in patient management .2,3 Currently the aim of surveillance is to detect for disease progression and follows a three monthly pattern. There is little literature around benefits of surveillance on survival, and quality of life in these patients. 4-6 Alternative approaches to surveillance should be evaluated to ensure safe, convenient, economical care. Lung cancer outcomes for Maori patients sit significantly lower than those for New Zealand Europeans. Maori patients are twice as likely to present with locally advanced disease and four times less likely to receive curative treatment (multivariate analysis). There are significant barriers for Maori patients to attending health care including time off work, health literacy, costs, child care, language barriers, and transport. 19 Ministry of Health data describes poor outcomes for Maori lung cancer patients with rate of death sitting at 3.4 times that of non-Maori. Co-Primary End Points To determine if there is a reduction in health services utilisation (ED visits, hospital visits, unplanned clinic visits, GP visits, and Nurse Specialist contact) with the end point identified at progression, lost to follow up, or death. To compare the impact of a novel virtual surveillance model (VSM) versus usual follow-up care on patient anxiety measured using the HADS-A tool. Methods: LuCaS is a Randomised Controlled trial in patients with advanced lung cancer randomised to virtual model or standard care. Results: recruitment begins this year. Conclusions: Hypothesis:A virtual follow up model for advanced stage non-small cell lung cancer patients, extensive stage small cell lung cancer patients, and mesothelioma patients will reduce health care utilisation and patient experienced anxiety defined by reduction in Hospital Anxiety and Depression Scale (HADS-A) score, while maintaining effectiveness detecting recurrence and survival.
The efficiency of apatinib plus S-1 as second-line or laterline chemotherapy for advanced non-small-cell lung cancer.
Authors: Wu Zhiyong , Wu Jianyu , Dai Guanghai , Si Haiyan , Wang Yanrong , Zhao Haiqing , Wang Guanqing , Cao Hongli
Published: September 2018

e20549

Background: There is no standard treatment strategy for patients with advanced non-small cell lung cancer (NSCLC) who experienced progression with three or more lines of chemotherapy. Apatinib, a new tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2 (VEGFR-2), has been shown confirming antitumor activity and manageable toxicities in breast and gastric cancers. Clinical trials of apatinib on non-small cell lung cancer show that progression-free survival is improved, but the objective response rate is still low. However, It remains to be explored whether the combined treatment of apatinib plus S1 could be further effective on NSCLC. Methods: We retrospectively assessed the efficacy and safety of apatinib plus S1 in patients with advanced NSCLC after the failure of second or third-line chemotherapy. The study group comprised 12 patients who received oral apatinib, at a dose of 250 mg daily, and S1, at a dose of 40-60mg bid D1-14, repeat every 3 weeks, for progression after the failure of second or third-line chemotherapy for advanced NSCLC. Treatment was continued until disease progression. Results: Between Mar 30, 2016 and Feb 1, 2017, 12 patients were enrolled. In 12 patients, there were 10 patients available for efficacy and safety evaluation. 4/10 (40%) patients experienced dose reduction during treatment. Followed up to Feb 1, 2016, the median during time of treatment was 3 months. According to RECIST criteria, the disease control rate was 80%, 8/10 (partial response 50%, 5/10 and stable disease 30%, 3/10). The most frequent treatment-related adverse events were secondary hypertension (40%, 4/10), oral mucositis (40%, 4/10), hand-foot syndrome (30%, 3/10) and fatigue (30%, 3/10). Main grade 3 or 4 toxicities were hypertension (20%, 2/10), oral mucositis (10%, 1/10) and fatigue (10%, 1/10). Conclusions: Apatinib plus S1 exhibits superior activity and acceptable toxicity for the heavily pretreated patients with advanced non-small cell lung cancer.
Smoking cessation counseling in advanced non-small cell lung cancer (aNSCLC).
Authors: Radtchenko Janna , Feinberg Bruce A.
Published: September 2018

e20551

Background: Lung cancer is the leading cause of cancer mortality, with smoking the major risk factor1. Advances in treatment (tx) are lengthening survivorship increasing the importance in smoking cessation among diagnosed pts. Barriers to counseling include: time, skill, patient motivation, prognosis and short survival2. This study analyzed smoking status and cessation counseling in better prognosis aNSCLC patients (pts) defined as those who completed at least two lines of systemic therapy (2L). Methods: Using Inovalon’s MORE2 Registry®claims data for July 2013–2014, pts with aNSCLC identified by ICD-9 codes and treated with chemotherapy (chemo) or targeted therapy (TT; erlotinib, ceritinib, afatinib, or crizotinib) were selected. Pts >18 years of age and treated with 1L therapy within 6 months of diagnosis and who completed 2L were eligible. Pts with small cell lung cancer or secondary malignancies, or pts enrolled in a trial, were ineligible. Smoking history was assessed based on ICD-9 codes (305.1, 649.0, 989.84, V15.82), cessation drug use (bupropion, varenicline, nicotine gum or patches), counseling procedure codes (99406, 99407, G0436, S9453). Results: Of 5,319 pts, 2,198 completed 2L; of those 241 (11%) received 1L TT and 1,957 (89%) 1L chemo. 1L TT had a higher proportion of females (66% vs. 52%, p<0.0001) and a lower smoking rate (33% vs. 58%, p<0.0001) compared to chemo. Cessation rates (counseling or drug) were 9% for 1L TT and 13% for 1L chemo. Conclusions: RWE assessment of smoking incidence and cessation counseling is feasible. Despite methodological limitations one third pts on 1L TT had smoking documentation. Evidence of smoking cessation was present in 12% of pts irrespective of 1L tx choice. Our findings warrant increased focus on smoking cessation in aNSCLC. [Table: see text]
Lymphocytes and neutrophils count after two cycles and TTF1 expression as early outcome predictors during immunotherapy (IT) in stage IV non-small cell lung cancer (NSCLC) patients.
Authors: Baraibar Iosune , Oroz Ricardo , Roman Marta , Martin Patricia , Ponz-Sarvisé Mariano , Rolfo Christian Diego , López-Picazo José María , Perez-Gracia Jose Luis , Gurpide Alfonso , Sala Elarre Pablo , Gil-Bazo Ignacio
Published: September 2018

e20553

Background: NSCLC therapeutic paradigm has changed with immune checkpoint blockers. Biomarkers predicting clinical benefit are still lacking. As previously shown in melanoma, changes in absolute lymphocytes and neutrophils count (ALC and ANC) during IT (PD-1/PD-L1 inhibitors) may be related to response in NSCLC (Nakamuta et al, Oncotarget 2016). TTF1 expression has been associated with PD-L1 expression (Vieira et al, Lung Cancer 2016). We aimed to investigate TTF1 expression and changes in ALC and ANC after 2 cycles and their potential association with clinical outcomes to IT. Methods: We retrospectively analyzed 26 consecutive patients with stage IV NSCLC treated with IT at Clínica Universidad de Navarra (Spain) during 2016. Radiological response was evaluated according to RECIST v1.1. The potential correlation between ALC and ANC changes during the first two cycles and response to treatment [disease control rate (DCR) vs progression] was evaluated using Student’s T-test. Fisher’s exact test was used to study the association between changes in ALC ( < 1,000 vs > 1,000) and ANC ( < 4,000 vs > 4,000) after 2 cycles and response to IT. TTF-1 expression was correlated with treatment response. Overall survival (OS) was assessed with Kaplan-Meier analysis and Log-rank test according to ALC and ANC. Results: An ALC increase after 2 cycles was significantly associated with DCR compared to progression (192 vs -155; p = 0.043). ALC > 1,000 after 2 cycles was more frequent among patients experiencing DCR compared to progression (87% vs 50%; p = 0.07). ALC > 1,000 after 2 cycles was more frequently observed among patients with TTF1+ tumors (93% vs 55%; p = 0.03). Patients with ANC < 4,000 showed a longer median OS (NR vs 19.25 months; p = 0.03). TTF1 expression in adenocarcinoma (n = 18) was associated with response to IT (83% vs 16%, p = 0.01). Conclusions: Despite this retrospective small series’ limitations, our results show that ALC and ANC changes during IT and TTF1 expression may act as early predictors of clinical benefit in stage IV NSCLC patients treated with PD1/PD-L1 blockers. Our results warrant further investigation in larger prospective series.
FDG-PET in the assessment of metabolic response in patients with NSCLC treated with nivolumab: Preliminary results.
Authors: Goldfarb Lucas , Duchemann Boris , Chouahnia Kader , Gomez Lea , Pop Gabriel , Zelek Laurent , Soussan Michael
Published: September 2018

e20554

Background: Immunotherapy becomes a standard treatment in non-small-cell lung carcinoma (NSCLC), locally advanced or metastatic, after prior chemotherapy. Because of systemic involvement and heterogeneity of the tumoral disease, methods of assessment are complex and the role of PET-FDG is not well established. The objective of the present study is to describe the results of FDG-PET in the evaluation of patients with NSCLC treated with checkpoint inhibitor (OPDIVO®, Nivolumab) in our academic center. Methods: A retrospective analysis of FDG-PET’s data was performed in 16 patients (performance status: 1), with NSCLC (13 adenocarcinoma, 2 squamous cell carcinoma and 1 large cell neuroendocrine carcinoma) and progression after at least one line of treatment, and treated with Nivolumab. All patients had an FDG-PET before and at 2 months (M2) of treatment. Patients showing progression at M2 had a third PET at M3 to confirm disease progression. Disease responses were assessed according to PERCIST criteria. Patients were considered as responders to Nivolumab treatment, if the treatment was pursued at least 6 months, or as non-responders if the treatment was pursued less than 6 months. Pseudoprogression was defined as a disease progression at M2, which was not confirmed on FDG-PET control at M3. Results: Assessment by FDG-PET after 2 months of treatment showed 8/16 partial metabolic responses (PMR), 6/16 progressive diseases (PD), 1/16 stable disease (SD) and 1/16 complete metabolic response (CMR). Among the patients with PMR, SD or CMR at M2 (n = 10), 90% (9/10) were considered as responders and 10% (1/10) as non-responder. Nivolumab was discontinued in patients with PD. One patient showed a pseudo progression at M2 (PMR at M3), and was eventually classified as non-responder. Conclusions: These results show an association between the metabolic response at M2 and the continuation of the treatment with Nivolumab in NSCLC patients. 90% of patients with early metabolic response showed a sustained response with Nivolumab. FDG-PET could be helpful in the therapeutic strategy of these patients and deserves to be assessed in prospective trials including a cost/benefit evaluation.
Immuno-related cutaneous adverse events (IRcutAEs) of anti-PD-1/anti-PD-L1 therapy in patients (p) with advanced non-small cell lung cancer (NSCLC): A single-institution prospective study.
Authors: Felip Eudald , Garcia Juan Jose , Rivera Noelia , Angelats Laura , Moran Teresa , Erasun Carlos , Vilà Laia , Hardy Max , Gil Maria de los Llanos , Boada Aram , Carcereny Enric
Published: September 2018

e20556

Background: Despite the impressive benefits of the immune checkpoint blockade in NSCLC, its use can be hampered by the occurrence of serious adverse events. IRcutAEs are underestimated and poorly described according to data from the clinical trials. We sought to characterize the IRcutAEs and their treatment in p with NSCLC. Methods: Before starting immunotherapy, all NSCLC p were prospectively referred to the Dermatology Department. Periodic monitoring visits were also scheduled for each p, in order to describe the IRcutAEs and their treatments. The study included data from all consecutive NSCLC p treated with immunotherapy in our institution. Results: Since May 2016, 50 p were recruited for the present study. According to clinical characteristics; 18 p had squamous histology, 43 p received treatment as second line or further, and 36 p were treated with nivolumab. During the follow-up period, 15 p (30%) developed IRcutAEs. Lichenoid reactions were the most common AE (9 p, 60%), but some specific conditions were also observed, such as a cutaneous lupus (1 p, 6.6%) or an eruptive pseudoangiomatosis (1 p, 6.6%). Conclusions: IRcutAEs are common during antiPD1-PDL1 therapy. By offering a dermatological follow-up, the diagnosis and management of this type of toxicity can be provided to NSCLC p initiating immunotherapy.
The comparison of 18F-alfatide PET/CT and 18F-FDG PET/CT in predicting chemoradiotherapy sensitivity in patients with advanced non-small cell lung cancer.
Authors: Luan Xiaohui , Huang Yong , Liu Ning , Gao Song , Zheng Jinsong , Yu Qingxi , Zhao Shuqiang , Hu Chen , Yu Jinming , Yuan Shuanghu
Published: September 2018

e20558

Background: Both 18F-alfatide positron emission tomography/computed tomography(PET/CT) and 18F-fluorodeoxyglucose (18F-FDG) PET/CT were potential in predicting thearapy sensitivity, in this study,we recruited patients with advanced NSCLC to detect and compare the potential predictive vaue of them on the CRT sensitivity of patients with advanced non-small cell lung cancer (NSCLC). Methods: According to the design of Natural Science Foundation ofChina (NSFC) 81372413, twenty-four patients with advanced NSCLC accepted 18F-alfatide PET/CT before radiotherapy (T1), another thirty-nine patients underwent 18F-FDG PET/CT at both T1 and during CRT (40Gy of radiotherapy, T2). Logistic regression analyse was used to evaluate the correlations between PET parameters and CRT sensitivity providing an odds ratio (OR), 95% confidence interval (CI) and p value. Propensity score matching (PSM) approach was used to control confounding. Results: Logistic regression analyse showed that Karnofsky Performance Status (KPS) score was correlative with CRT sensitivity. After PSM, controlling KPS scores, twenty-four pairs of patients were matched. The results showed that SUVmax obtained from baseline 18F-alfatide PET/CT was associated with CRT sensitivity in both univariate and multivariable logistic regression analysis (OR: 0.532, 95% CI: 0.305–0.927, p = 0.026; OR:0.376, 95% CI: 0.165-0.860, p = 0.021), but the baseline 18F-FDG PET/CT was not. Univariate analyses showed that the percent change in MTV of 18F-FDG PET/CT between T1 and T2 was correlative with CRTsensitivity (OR: 1.039, 95% CI: 1.003-1.077, p = 0.036). When patients’ KPS score was considered simultaneously, it was still related to CRT sensitivity (OR:1.038, 95% CI: 1.001-1.077, p = 0.045). Conclusions: 18F-alfatidePET/CT may be better than 18F-FDG PET/CT in predicting CRT sensitivity, and 18F-FDG PET/CT is potential in monitoring the tumor response to CRT in patients with advanced NSCLC.
The real-world experience with nivolumab in previously treated patients with advanced non small cell lung cancer (NSCLC): A Galician Lung Cancer Group clinical practice.
Authors: Areses MC , Campelo Rosario Garcia , García González Jorge , Afonso Francisco Javier , Lazaro Martin Emilio , Campos Begoña , Azpitarte Cristina , Amenedo Margarita , Santomé Lucía , Ron David Arias , Alonso-Jaudenes Guillermo , Baron Francisco , Vilchez Rocio , Casal Joaquin , Fernandez Natalia , Carou Iria , Mosquera Joaquin , Anido Urbano , Garcia Mata Jesus , Firvida Jose-luis
Published: September 2018

e20564

Background: Nivolumab, was the first checkpoint inhibitor to show a survival benefit in previously treated patients with advanced NSCLC in two randomized trials (CheckMate 017 and 057). Experience in routine clinical practice may differ from that seen in a controlled clinical trial. This is an observational study that represents the real-world experience. Methods: Elegibility criteria included, histologically confirmed NSCLC stage IIIB vs IV, evaluable disease and at least one prior therapy. Patients received nivolumab 3 mg/kg IV (60 min) every 2 weeks until progressive disease or unacceptable toxicity. The aim of the study was to report the efficacy and safety profile of Nivolumab in pretreated patients with advanced NSCLC of our everyday clinical practice. The exploratory assessments include response rate (RR), progression-free survival (PFS), overall survival (OS) and treatment related adverse events (AEs). Results: From August 2015 to January 2017, with a median follow time of 18 months, 188 patients were enrolled from 9 different centers. Patients demographics were: median age 62 years, 44 female and 144 male; 17 never smoker and 171 former or current smoker; 105 adenocarcinoma, 7 large-cell carcinoma, 66 squamous, 3 adenosquamous and 7 NSCLC; 61 stage IIIB and 129 stage IV; 42 with central nervous system metastasis; and 70 received 2 or more prior therapy lines. Among 156 patients evaluated, 1,3% had CR, 28,2% PR, 29,7% SD and 40,8% PD. At the time of database lock, the median of PFS was 2.9 IC 95% (2,3-3.4) and OS was 12,8 IC 95% (9,2-16,4). The evaluation of PFS and OS by baseline characteristics doesn´t revealed statistical significance. Grade 1-2 treatment related adverse events (AEs) occurred in 58% of the patients: asthenia (22%), rash (14%), diarrhea (8%), anorexia (7%), endocrine (6%) and neumonitis (1,5%). Grade 3-4 AEs occurred in 5 patients; (3) diarrhea and (2) neumonitis and there were 3 treatment-related deaths. Conclusions: This study represents the real-word experience with nivolumab and the results are consistent with those previously reported in the CheckMate 017 and 057 trials.
Whole genome and transcriptome sequencing of lung cancer: Options for personalized cancer treatment.
Authors: Chooback Negar , Ho Cheryl , Shen Yaoqing , Tsang Erica S , Zhao Yongjun , Mungall Andrew J. , Moore Richard , Lim Howard John , Renouf Daniel John , Gelmon Karen A. , Yip Stephen , Jones Steven , Laskin Janessa J. , Marra Marco
Published: September 2018

e20567

Background: Targeted therapy against driver mutations has revolutionized lung cancer management. The Personalized OncoGenomics (POG) program uses whole genome and transcriptome derived information to build pathways and identify potential therapeutic targets. We examined the lung adenocarcinoma (LUAD) patients enrolled in POG in order to identify novel cancer drivers and correlate the findings with clinical characteristics. Methods: Patients with advanced LUAD and survival > 6 months were eligible. Blood, archival and fresh tumour specimens were subjected to comprehensive DNA and RNA sequencing. SNV data were compared to the TCGA-LUAD cohort using the cBioPortal platform. Whole tumor transcriptome data were compared to matched normal blood specimens. Clinical characteristics were collected by chart review. Results: 30 POG LUAD cases were analyzed. Baseline characteristics; 47% female, median age 60, 57% never/light smokers, biopsy site - 50% lung, 50% metastatic lesion. High mutations rates in TP53, KRAS, NF1 were comparable to the TCGA-LUAD cohort. Four genes ( GOLGA6L2, FAM186A, ARMCX4 and RBMXL3), were mutated 17-27% of the time in POG patients, while the rate in TCGA-LUAD was < 1%. Driver mutations ( KRAS and EGFR) and known fusions (ROS1 and RET) were present in 63%.Other potential drivers included ERBB3, ERBB2, SDC:NRG1 fusion were identified. Copy number alterations and expression data revealed variations in cell cycle, mTOR, androgen receptor,HSP90, MET and Wee1 proteins, all potential targets for therapy. PD-L1 over-expression and a strong smoking signature were not mutually exclusive to EGFR copy gain and FGFR3 overexpression. Conclusions: The molecular signature of NSCLC is complex and involves multiple key oncogenic drivers. Whole genome sequencing and transcriptome data should be used together to map out the pathways of carcinogenesis and reliably identify targets for therapy.
Circulating biomarkers and outcomes in advanced non-small cell lung cancer patients treated with anti-PD1 (program death 1 receptor) monoclonal antibodies.
Authors: Fidler Mary J. , Batus Marta , Tarhoni Imad , Sayidine Selina , Fhied Cristina L. , Basu Sanjib , Bonomi Philip , Borgia Jeffrey Allen
Published: September 2018

e20592

Background: Current evaluation of immunohistochemical expression of PDL-1 (program death receptor 1 ligand) can select some non-small cell lung cancer (NSCLC) patients who may benefit from anti-PD1 directed therapy. It is an imperfect marker and there is little information about systemic modulation of the immune system on therapy. In this study we explored the prognostic value of baseline circulating immune checkpoint and inflammatory molecules in advanced non-small cell lung cancer (NSCLC) patients receiving anti-PD1 therapy. Methods: Prospectively collected serum from advanced NSCLC patients receiving nivolumab or pembrolizumab were evaluated with the MILLIPLEX Human High Sensitivity T-cell (17-plex) and ProcartaPlex Human Immuno-Oncology Checkpoint (14-plex) panels on our Luminex FlexMAP 3D. Biomarker level cutoffs were optimized and evaluated against progression-free survival (PFS) and overall survival (OS) using log-rank analysis. Results: 21 cases were enrolled in this pilot study: 72% Caucasian, 61% female, 24% never-smokers. IL-10 was found to have a significant association with both PFS (p = 0.0055) and OS (p = 0.024), with levels below 3.32 pg/mL being associated with a superior clinical outcome. We also found IL-2 and IL-6 to have significant associations with PFS (p = 0.033 and 0.040, respectively), again, with low levels being associated with a superior outcome. Neither of these had significant associations with OS. Low circulating levels of the T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) protein were associated with superior PFS (p = 0.036), and a weak trend (p = 0.19) for OS. Conclusions: In this small exploratory pilot study we identified several circulating molecules associated with inflammation and immune system regulation that may have prognostic value for anti-PD-1 therapy. Notably, TIM-3 is a Th1-specific protein associated with macrophage activation and is also a component of T-cell exhaustion along with LAG3 and PD-1. Additional studies to follow up on these findings in larger cohorts are underway.
Prognostic significance of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) in untreated and treated stage IV non-small cell lung cancer (NSCLC): An Australian cancer centre experience.
Authors: Mandaliya Hiren A. , Jones Mark , Oldmeadow Christopher , Nordman Ina
Published: September 2018

e20630

Background: Baseline high NLR predicts poorer outcome in stage IV NSCLC; post-treatment variation in NLR and potential impact on overall survival (OS) is not clear in this group. Prognostic implications of PLR and LMR are not well studied for stage IV NSCLC. We aimed to assess the prognostic role of NLR, LMR and PLR in stage IV NSCLC at diagnosis and post-treatment. Methods: A retrospective descriptive study of 279 patients with Stage IV NSCLC treated at our centre over five year period (2010 to 2015). NLR, PLR and LMR calculated at diagnosis and post first cycle chemotherapy/targeted treatment. Demographic variables summarized. Estimates of Kaplan-Meier survival distributions for OS were generated. Cox regression used to derive OS hazard ratios of predictive variables. Approval from ethics committee obtained. Results: Baseline NLR, PLR and LMR showed strong association with OS. A five-unit increase at baseline (treatment start date) in NLR was associated with an 11% increase in the hazard of death (HR = 1.115, 95% CI: 1.077-1.148) while the same increase in PLR was associated with 0.5% increase in the hazard of death (HR = 1.005, 95% CI:1-1.005). A five-unit increase in LMR at baseline was associated with a 50% reduction in the hazard of death (HR = 0.50, 95% CI:0.260-0.956). Post-treatment NLR, PLR and LMR were examined in 221 patients. Fitted models incorporating adjustment for baseline values demonstrated that increasing NLR correlated with a shorter OS (HR = 1.574, 95% CI:1.295-1.917) but no statistically significant relationship could be demonstrated for PLR nor LMR. Conclusions: While NLR, PLR and LMR showed significant associations with OS prior to treatment, only NLR showed an association with OS after treatment. OS was shorter for high NLR and high PLR at baseline compared to low NLR and low PLR at baseline. OS was longer for high LMR at baseline compared to low at baseline. An increase in NLR post-treatment correlated with a shorter OS. This is the first study examining the prognostic significance of all three ratios in patients with untreated and treated stage IV NSCLC.
Coexistence of MET exon 14 mutations with EGFR mutations in non-small cell lung cancer.
Authors: Li Wen-Feng , Kang Jin , Zhang Xu-Chao , Jian Su , Chen Huajun , Wang Zhen , Wang Bin-Chao , Zhou Qing , Tu Hai-Yan , Wu Yi-Long , Yang Jin-Ji
Published: September 2018

e20636

Background: Activation of MET oncogene as the result of amplification or activation MET exon 14 mutations represents an emerging molecular target for non-small cell lung cancer (NSCLC) treatment. MET exon 14 mutations account for 1.0% in Chinese NSCLC patients. However, few data have been reported on the coexisting of MET exon 14 mutations and EGFR mutations in NSCLC. Moreover, the clinicopathological characteristics and targeted therapy of these MET/ EGFR-coexisting patients remain elusive. Methods: Next-generation sequencing was performed on the DNA of 969 patients and Sanger sequencing was conducted on cDNA of 621 patients for MET exon 14 mutations in NSCLCs. EGFR mutations were determined by direct DNA sequencing. Results: Fifteen patients harbored positive MET exon 14 mutations. Frequency of concomitant EGFR and MET exon 14 mutations was 0.2%(3/1590). 3 patients with concomitant MET exon 14 mutation and EGFR activating mutation were all female, never smokers and adenocarcinoma. Their stagings were stageⅠB (n = 1) and stage Ⅳ(n = 2). The stage ⅠB patient harboring concomitant MET exon 14 skipping and EGFR L858R mutation did not relapse 2 years after operation. The other two stage Ⅳ patients received first-line gefitinib. Case one harbored concomitant MET exon 14 point mutations (IVS13-36G > A) and EGFR exon 19 deletion, and showed resistance to gefitinib with progression free survival(PFS) of 2 weeks and overall survival(OS) of 1 month. Case two had concomitant MET exon 14 point mutations (IVS13-36G > A) and EGFR L858R mutation. Meanwhile, she also had both METamplification and c-Met overexpression at the baseline. She showed partial response (PR) to gefitinib with 3.8 months PFS. Then she was enrolled in a clinical trial (NCT02374645) to receive volitinib plus gefitinib on December 20, 2016. Initial response was good PR on January 24, 2017. Only grade 1 rash was observed. Conclusions: Coexisting MET exon 14 /EGFR mutation is an uncommon molecular event in NSCLC patients. Such coexisted patients might show relative resistance to EGFR inhibitor. However, combination of MET and EGFR inhibitors will be potentially a good strategy to overcome such a relative resistance for MET exon 14 /EGFR co-mutant patients.