bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic factors and combined histologies in 205 resected small cell lung cancer (SCLC) patients.
Authors: Zhao Xiao-Liang , McCutcheon Justine N , Kallakury Bhaskar , Chahine Joeffrey J , Raffeld Mark , Pratt Drew , Chen Yu-Long , Zhang Bin , Zhang Hua , Zhang Yu-Wen , Wang Chang-li , Giaccone Giuseppe
Published: September 2018

e20009

Background: SCLC accounts for 15%-20% of all lung cancer, 2%-5% of them are combined SCLC. The objectives of this study were to evaluate the prognostic factors in a large series of resected SCLC patients, and to perform genetic analysis of combined forms. Methods: 205 SCLC cases were resected at Tianjin Cancer Hospital between 1/2005 and 12/2015. We analyzed: gender, age, type of resection, cigarette index (CI), tumor markers (CEA, SCC, NSE, Cyfra21-1), R resection type, number of resected lymph nodes (LNs), ratio of metastatic LNs, and pathological stage. All combined SCLC cases were identified by H&E staining and confirmed by immunohistochemistry. The different components were microdissected using an automated dissection system (MillisectTM, Roche Diagnostics) and DNA was extracted and subjected to targeted exome sequencing. Results: The median follow-up time was 24 (2-121) months. Median survival time of all the patients was 24 months; 5-year survival rates were 51.4% overall, and 69.5%, 66.5%, 34.4%, and 0% for pathological stage I, II, III, and IV, respectively. Multivariate analysis indicated age, CI, complete resection, number of resected LNs and the ratio of metastatic LNs as independent prognostic factors. Twelve cases of combined SCLC were identified out of 170 with adequate histological material: 6/12 were combined with squamous cell carcinoma. 1-, 3-, 5-year survival rates were 73.3%, 0% and 0%. There were no significant differences between combined SCLC and pure SCLC with respect to gender, age, pathological stage, LN status and tumor markers. Three cases were successfully sequenced. Around 50% gene mutations were present in both components (10/24; 14/27; 4/5 respectively). TP53 mutations were present in all three cases. One case displayed amplification of 2 genes in both components. Interestingly, there were also gene mutations and amplifications that are unique to one of the components. Conclusions: In this large resected SCLC series we identified CI, complete resection, resected number of LNs and ratio of metastatic LNs to be prognostic. Combined SCLC had worse survival than pure SCLC. The histologically different components had a significant number of common as well as unique genetic alterations.
Method development for detection of PD-L1 in circulating tumor cells in small-cell lung cancer patients.
Authors: Cheng Ying , Li Hui , Zhao Dandan , Liu Yan , Wang Ying , Liu Xianhong , Cui Hongxia
Published: September 2018

e20012

Background: Previous studies showed that circulating tumor cells (CTCs), as liquid biopsy, are the alternative for tumor tissue in small-cell lung cancer treatment and study. Programmed death- ligand 1(PD-L1) is the most commonly used biomarker in immune-targeted therapy. The aim of this study is to develop a method to detect PD-L1 in CTCs in small-cell lung cancer patients. Methods: The anti-PD-L1 antibodies were purchased from both BD (clone MOPC-21) and Cell Signaling (clone E1L3N) Technology. Control cell lines were selected by single clone culturing technique and confirmed by immunecytochemistry and flow cytometry. CellSearch system was used to select and optimize antibodies, and to test CTCs in small-cell lung cancer patients. Results: After single clone culturing selection, the purity of PD-L1 positive H446 cells (positive control) was increased to 95% from 70%, and the purity of PD-L1 negative PC3 cells (negative control) increased from 90% to 95%. The dilution of 1:200 is the optimal antibody titer for CellSearch System with 98% positive rate and 3% negative rate. In all patients (n = 4) with CTCs presenting (n = 2), PD-L1was detected and the ratios of PD-L1 positive cells to CTC counting were 1:1 and 2:5, respectively. Conclusions: We developed the method for PD-L1 detection in CTCs and validated it in small-cell lung cancer patients, which paved the way for automatic detection of PD-L1 in liquid biopsy in the future.
Effect of friend leukemia virus integration 1 on tumorigenesis of small cell lung cancer cells and activation of the miR-17-92 pathway.
Authors: Cui Jiuwei , Li Lingyu , Song Wei , Hu Jifan , Li Wei , Yan Xu
Published: September 2018

e20015

Background: Small cell lung cancer (SCLC) is regarded as the most devastative type of human lung malignancies, mostly due to their rapid and disseminated growth pattern. However, the molecular factors that drive rapid progression of SCLC remain unclear. Friend leukemia virus integration 1( FLI1),an Ets transcription factor family member, was identified as a proto-oncogene in some tumors via regulation of different target genes. In this study, we explored the potential role of FLI1 in SCLC. Methods: FLI1 protein expression was evaluated by immunohistochemistry in 67 primary SCLC, 20 non-small cell lung cancer (NSCLC) and 20 normal lung specimens. Correlation between FLI1 expression and clinical characteristics was evaluated with the logistic regression. Cell proliferation, cell cycle, apoptosis, colony formation assays in vitro and tumorigenesis assay in vivo were used to explore the function of FLI1 in SCLC cells. Use the miR-17-92 promoter/luciferase reporter assay to identify the regulation of FLI1 on miR-17-92 cluster promoter. Results: Immunohistochemical staining data showed that FLI1 was significantly upregulated in SCLC tissues compared to that in NSCLC and normal lung tissues ( p< 0.01). The expression score of FLI1 oncoprotein was associated with the extensive stage of SCLC and the overexpressed Ki67. Knockdown of FLI1 promoted apoptosis and induced repression of cell proliferation, tumor colony formation and in vivo tumorigenicity in highly aggressive SCLC cell lines. Importantly, we discovered that FLI1 promoted tumorigenesis by activating the miR-17-92 cluster family transcritption. Conclusions: This study uncovers that FLI1 is an important driving factor that promotes tumor growth in SCLC through the miR-17-92 pathway, and may serve as an attractive target for therapeutic intervention of SCLC.
Genomic profiling of circulating tumor DNA in small cell lung cancer: comparison of relapsed disease to initial tumor biopsies.
Authors: Bhateja Priyanka , Wildey Gary , Lipka Mary Beth , Sharma Neelesh , Dowlati Afshin
Published: September 2018

e20017

Background: Genomic studies in small cell lung cancer (SCLC) are hampered by the small amounts of biopsy tissue typically available. The emergence of ‘liquid biopsy’ to identify tumor DNA mutations in plasma (circulating tumor DNA or ctDNA) has the potential to overcome this restriction and also facilitates multiple sampling during disease treatment. Here we use ctDNA to compare mutation profiles in SCLC and non-small cell lung cancer (NSCLC)patients and to identify changes that occur post-relapse in SCLC. Methods: Targeted exome sequencing of 73 genes in plasma from 13 SCLC and 17 NSCLC patients was obtained along with matched patient targeted exome sequencingof 315 genes for 6 SCLC and 8 NSCLC tumor biopsies. Only the 70 genes analyzed by both assays were studied. Results: 3 SCLC and 8 NSCLC ctDNA specimens were collected pre-treatment, with the remainder post-relapse. In SCLC, 46 total gene mutations were detected in ctDNA with a mean allelic fraction (mAF) of 16.0%. TP53 (mAF 30.8%, N= 15) and ARID1A (mAF 16.0%, N= 6) were the most frequently mutated SCLC genes. In NSCLC, 53 gene mutations were detected with a mAF of 2.5%. TP53 (mAF 5.9%, N= 13), EGFR (mAF 2.3%, N= 10) and KRAS (mAF 4.4%, N= 5) were frequently mutated NSCLC genes. 44 and 10 gene amplifications were detected in SCLC and NSCLC ctDNA, respectively. 5 SCLC patients with tumor DNA profiles obtained pre-treatment had matching ctDNA profiles obtained post-relapse. TP53 mutation status agreed in 4 of the matched specimens. 6 new gene mutations occurred post-relapse in ctDNA, notably a TSC1 mutation (AF 8.4%) in one patient. 7 tumor gene mutations were lost post-relapse, notably ARID1A and NTRK1 mutations were lost in two patients each. Remarkably, 23 new gene amplifications were detected post-relapse in ctDNA, including PIK3CA ( N= 5) and CCNE1 ( N= 5), whereas only 1 was detected in pre-treatment tumors. Conclusions: SCLC exhibits much greater ctDNA mAF values than NSCLC, although their overall mutation profiles agree with published tumor DNA mutation profiles. Interestingly, the predominant change observed in SCLC ctDNA profiles in relapsed specimens is increased gene amplification.
Immune status parameters in lung cancer patients with various levels of circulating tumor cells.
Authors: Zlatnik Elena Yurievna , Novikova Inna Arnoldovna , Bakhtin Andrey Vladimirovich , Selyutina Olesya N. , Zakora Galina I. , Lazutin Yuriy N. , Pyltsin Sergey P. , Ayrapetova Tamara G. , Leyman Igor A. , Chubaryan Anna V. , Anistratov Pavel A. , Shogenov A. S. , Gappoeva M. A. , Afaunov M. Kh.
Published: September 2018

e20018

Background: The purpose of the study was to evaluate parameters of cellular immunity in lung cancer patients with various levels of circulating tumor cells (CTCs) and different tumor histogenesis. Methods: Blood samples of 28 patients (24 men, 4 women, mean age 62±1.3 years) were studied. 18 (64.3%) patients had neuroendocrine tumors (small cell lung cancer, SCLC), and 10 (35.7%) patients had adenocarcinoma (AC). 11 (39.3%) patients were diagnosed with stage III disease and 17 (60.7%) – stage IV. CTCs were detected in the blood before treatment using the CellSearch System (Janssen Diagnostics, LLC) with iron microparticles coated with antibodies to EpCAM, CD45 and cytokeratins 8, 18 and 19; subsets of lymphocytes, including minor ones, were studied on FACSCantoII flow cytometer (BD). Results: CTCs were found in 25 patients (89.3%); their number ranged 1-6888. 15 (83.3%) patients with SCLC had 0-6888 CTCs, with an average of 655.7, median 38.5. All 10 patients with AC had 1-486 CTCs, with an average of 57.2, median 5.0. The number of CTCs in CTC-positive patients with SCLC was, despite high individual variability, significantly higher than in patients with AC (786.9±474 vs. 57.2±47.9, respectively; p < 0.05). Such differences were accompanied by higher levels of Th-lymphocytes with activation/apoptosis markers (CD3+CD4+CD95+): 84.2±2.7 vs. 72.2±3.7%, and cytotoxic CD16bright/56dim NKcells: 91.4±1.8 vs. 83.4±3.7%. Patients with CTC+ AC had higher levels of IFNγ-producing NK-cells, compared to SCLC patients (15.3±3.8 vs. 7.2±1.6%), as well as levels of Th with the early activation marker (CD4+CD38+) (27.8±3.5 vs. 17.4±2.3%). Presence of CTCs in SCLC patients was associated with lower levels of activated lymphocytes of various subsets: T-cells (CD4+CD38+, CD8+CD38+, CD3+CD8+HLA-DR+) and NК-cells (Granzyme B+ and CD335+). Conclusions: Levels of CTCs were significantly higher in patients with SCLC than in those with AC; immune status parameters had a number of differences in CTC+ tumors with various histogenesis. The presence of CTCs in SCLC was accompanied by reduced blood levels of activated T- and NK-cells. The reported study was partially supported by RFBR, research project No. 16-34-00244mol_a
Phase I study of amrubicin and cisplatin with concurrent thoracic radiotherapy (TRT) in limited-disease small cell lung cancer (LD-SCLC).
Authors: Shimada Midori , Nakatomi Katsumi , Yamaguchi Hiroyuki , Dotsu Yosuke , Ikeda Takaya , Sugasaki Nanae , Yamazaki Takuya , Hayashi Nobuyuki , Nakamura Yoichi , Fukuda Minoru , Mukae Hiroshi
Published: September 2018

e20023

Background: Amrubicin and cisplatin is one of active regimens for patients with extensive-disease small cell lung cancer (ED-SCLC). Combined modality of combination chemotherapy and concurrent thoracic radiotherapy has been recognized as standard treatment for LD-SCLC. This study aimed to determine the maximum tolerated dose (MTD), and dose limiting toxicity (DLT) of amrubicin and cisplatin with concurrent TRT in LD-SCLC. Methods: Patients fulfilling the following eligibility criteria were enrolled: chemotherapy-naïve, PS0-1, age = < 75, LD-SCLC, and adequate organ function. Patients received escalating doses of amrubicin on days 1, 2, and 3, under a fixed 60 mg/m2 of cisplatin on day 1. Four cycles of chemotherapy were repeated every 4 weeks. TRT of once-daily 2Gy/day commenced on day 2 of the first cycle of chemotherapy. The initial doses of amrubicin was 20 mg/m2, and the dose was escalated to 25 and 30 mg/m2. Results: Eight patients (male/female = 3/5; PS 0/1 = 4/4; median age (range) = 68.5 (60-73)) were enrolled at three dose levels. Three patients in 20 mg/m2 and three patients in 25 mg/m2 dose levels did not experienced DLT. Two of two patients in 30 mg/m2 dose level experienced DLTs. The presentation of DLTs included grade4 neutropenia and leukopenia lasting more than four days. Evaluation of responses were 7 partial response and 1 progressive disease (response rate 87.5%) and the median survival time was 24.7 months. The MTD of amrubicin and cisplatin were determined as 30 mg/m2 and 60 mg/m2. A dose of 25 mg/m2 amrubicin and cisplatin 60 mg/m2 was recommended in this regimen. Conclusions: This regimen with concurrent TRT in LD-SCLC is associated with an acceptable tolerability profile, and warrants evaluation in the phase II setting. Clinical trial information: UMIN000005816.
UGT1A1 gene polymorphisms and clinical outcomes in small cell lung cancer (SCLC) patients treated with irinotecan-platinum chemotherapy: The first study from north India.
Authors: Singh Navneet , Bandyopadhyay Ankan , Sharma Siddharth , Behera Digambar
Published: September 2018

e20024

Background: Irinotecan(CPT11) is an important drug for SCLC chemotherapy(CTx). UDP-glucuronosyl-transferase1A1(UGT1A1) polymorphisms can influence CPT11-related toxicity. This study aimed to assess incidence of UGT1A1 polymorphisms and their association with clinical outcomes in SCLC patients on CPT11-CTx. Methods: Observational cohort of treatment-naïve SCLC patients given CPT11-platinum doublet at a referral centre in North India over 3-yrs(January 2013-December 2015). Clinical outcomes assessed were hematological & gastrointestinal toxicity(CTC-AE v3.0), response rates by RECIST & overall survival(OS). Peripheral blood was drawn from all enrolled patients just prior to CPT11-CTx initiation & genomic DNA isolated. Genotyping was done by PCR-RFLP for UGT1A1*7, UGT1A1*6 & UGT1A1*27 & by PCR-DNA sequencing for UGT1A1*28. Patients were classified as homozygous wild-type(WT/WT), heterozygous-mutant(WT/M) or homozygous-mutant(M/M) for each polymorphism assessed. Results: Of 140 patients enrolled, no mutant alleles were found for UGT1A1*27 or UGT1A1*7. Frequency of UGT1A1*6 polymorphisms(n = 111) was 89.2% WT/WT, 8.1% WT/M & 2.7% M/M. For UGT1A1*28(n = 102), this was 41.2% WT/WT, 43.1% WT/M & 15.7% M/M. For UGT1A1*6, 60% WT/WT patients tolerated > 95% predicted CPT11 dose (vs. 25% in WT/M-M/M combined group;p = 0.026). Severe(grade≥3) diarrhea was more common in WT/M-M/M group (44.4% vs. 17.9% in WT/WT,p = 0.06) as was any grade mucositis (55.6% vs. 9.5% in WT/WT,p = 0.002). On multivariate logistic regression analysis, UGT1A1*6 WT/M-M/M status was the only variable associated with(a/w) occurrence of both mucositis[OR = 10.4] & severe(grade≥3) diarrhea[OR = 4.8]. UGT1A1*28 WT/M-M/M patients had better OS[338 days(95% CI = 190-486) vs. 216 days(95% CI = 136-296) in WT/WT group;p = 0.045]. On multivariate Cox proportional hazards analysis, better OS was independently a/w number of CTx cycles, UGT1A1*28 WT/M-M/M status, maximum % dose of CPT11 delivered & inversely with age. Conclusions: UGT1A1*6 & UGT1A1*28 polymorphisms are a/w increased toxicity & improved OS respectively in North Indian SCLC patients receiving CPT11-CTx.
Assessment of EGFR mutation status in matched plasma and tumor tissue of NSCLC patients.
Authors: Feng Qin
Published: September 2018

e20032

Background: Tumor tissue is currently used for EGFR testing non-small cell lung cancer (NSCLC) patients, but the detection of circulating tumor DNA (ctDNA) is being actively investigated as a new method for the detection and longitudinal monitoring of actionable mutations in plasma samples. Around 30% patients with EGFR mutation presented inconsistent status of EGFR mutation between in tissues and plasma. We compared EGFR mutation detection in circulating tumor DNA from blood to that in matched tissue. Methods: EGFR mutation status were assessed by the Human EGFR Gene Mutations Detection Kit (Beijing ACCB Biotech Ltd.) both in tissue and plasma. Retrospective analysis to evaluate the concordance of tissue and plasma EGFR determination for assessing eligibility for EGFR-TKIs therapy in NSCLC patients. 10 mL tubes of blood were collected from patients who never had been treated by EGFR TKI, and plasma circulating tumor DNA were extracted from plasma by Biomark Circulating DNA Kit. Qubit2.0 Fluorometer was used to make plasma circulating DNA tumor quantitation. The concentration of final DNA sample is ≦2ng/μl. Results: A total of 224 NSCLC patients were detected by Amplification Refractory Mutation System (ARMS), with 92 tissue positive and 49 blood positive. Results showed 53.3% sensitivity in overall samples, but 81.4% sensitivity in ⅢB~Ⅲ patients. The specificity is 100%. Conclusions: The high sensitivity and specificity between tissue and plasma EGFR determination supports the blood-based EGFR mutation testing to determinate the eligibility of NSCLC patients for EGFR-TKIs treatment, especialy in ⅢB~Ⅲ NSCLC patients. Blood, in particular plasma, is a good screening substitute when tumor tissue is absent or insufficient for testing EGFR mutations to guide EGFR TKIs treatment in patients with NSCLC. EGFR mutation positivity in blood could be used to recommend EGFR TKIs treatment, but the blood negativity should be confirmed with other sample, biopsy tissue, pleural effusion, etc..
The impact of tumor size on survival in T3 non-small cell lung-cancer with direct extension.
Authors: Kim Clara H. , Salazar Michelle C. , Hoag Jessica R. , Rosen Joshua E. , Arnold Brian N. , Boffa Daniel J. , Blasberg Justin David
Published: September 2018

e20033

Background: Tumor size is an important prognostic variable that affects clinical decision-making in NSCLC including the use of adjuvant therapy. However, the association between tumor size and survival in a subset of patients who have T3 NSCLC with direct extension into nearby structures (T3dx) has not been explicitly characterized. We hypothesize that tumor size impacts survival and prognosis within this cohort. Methods: Patients with T3dxin 2006-2013 who underwent lobectomy or pneumonectomy were identified in the National Cancer Database. Patients who received neoadjuvant therapy or had positive margins were excluded. Tumor size was categorized based on cutoffs used by current staging guidelines and patients were stratified by pathologic N stage (see table). Cox proportional hazard models were used to measure the independent impact of tumor size on survival. Results: Overall, 0.1-3cm tumors exhibit superior 5-year survival compared to 3.1-5cm and >5cm tumors. Tumor size is significantly associated with survival in N0 patients but not in N1 and N2 patients. Use of adjuvant chemotherapy is associated with improved survival in the overall cohort and all subgroups; however, use of adjuvant chemoradiation may be associated with inferior survival in the overall cohort. Conclusions: Larger tumor size is associated with inferior survival in T3dx in the absence of nodal disease. T3dx requires a more tailored approach to adjuvant therapy than other T3 subgroups. Adjuvant chemotherapy appears to benefit all patients with T3dx; however, the role of adjuvant chemoradiation is less clear. [Table: see text]
Management of patients with head and neck cancer (HNC) and synchronic stage I or II lung cancer. SYNCHRON GFPC 15-01 study.
Authors: Saramon Laurie , Paleiron Nicolas , Robinet Gilles , Gervais Radj , Fournel Pierre , Le Caer Hervé , Berard Henri , Bylicki Olivier , Rousset Jean , Valette Gerald , Chouaid Christos
Published: September 2018

e20048

Background: There is few published data’s of the management of patients with a HNC and a synchronic lung cancer. The aim of this observational study was to describe in a multicentric setting the management of these patients. Methods: The study included, consecutively all patients diagnosed between January 2011 and December 2015 in 19 French centers with a HNC and a synchronic lung cancer. Patients were described per the clinical characteristics, management and outcomes. Patient characteristics and treatment information was analyzed descriptively. Kaplan-Meier estimation was used to assess median overall survival. Results: The study included 62 patients: men : 84%; 62 ± 1.3 years old, current smokers: 68%, asbestos exposure: 11%; performans status: 0 and 1 for 22.5% and 66% of the patients respectively; hight rate of comorbidities, cardiovascular: 68%, COPD: 32%. Main histology for HNC was squamous: 98%, in oral cavity: 32%, oropharyngeal: 21%, hypo-pharyngeal: 22.5% and laryngeal: 24%. T classification was T1, T2, T3 and T4 in 18%, 29%, 29% and 16% of cases respectively, and N classification was N0, N1, N2, N3, for 40%, 24%, 21% and 6% of cases respectively. The main treatment was surgery, 47%, and chemo-radiotherapy, 52%. The diagnosis of lung cancer impacts the HNC management in 21% of the cases. Median delay between HNC and first day treatment was 54 ± 6 days. HNC progressive free survival rate was 68% at 2 years. Lung cancers were localized (stages I: 81%, stages II: 19%), squamous: 32%, adeno-carcinomas: 47%, larges cells or sarcomatosis: 7%. Main treatments were surgery: 56%, mainly lobectomy, radiotherapy: 15%, radio-chemotherapy: 10% and chemotherapy alone: 26%. Six patients didn’t receive active treatment. Median delay of treatment was 150 ± 16 days. Lung cancer progressive free survival rate was 28% at 2 years. OS was 55% at 2 years, better for stage I than stage II lung cancers. Conclusions: Synchronic lung cancer at HCN diagnosis impact management and outcomes of HNC with a delay in the management of lung cancer. Specific recommendations should be elaborate to improve the management of these patients.
Prognostic gene signatures for lung adenocarcinoma using digital multiplexed gene expression in formalin-fixed paraffin embedded tissue.
Authors: Wei Ping , Du Xiang
Published: September 2018

e20050

Background: The outcome after resection of non-small-cell lung cancer (NSCLC) patients are poor, even in the early stage, there still has 35-50% recurrence rates. Current staging methods are not inadequate for predicting the outcome of NSCLC patients. Methods: 396 lung adenocarcinoma specimens were obtained for this study, of whom 78 frozen specimens (corhort1) and 223 FFPE specimens (corhort2) were from Shanghai Cancer Center, Fudan University and 85 FFPE specimens (independent corhort) were from Shanghai Pulmonary Hospital. The RNA was extracted from corhort1 and used in the microarray gene expression analysis to derive prognostic associated genes. The digital multiplexed technology (Nanostring) was then used to determine the expression of these genes in FFPE-derived RNA from corhort2. For validation, we used the random patients from the independent corhort. Results: Through microarray assay, the top 18 survival and 19 metastasis associated gene were chosen to digital multiplexed gene expression analysis using FFPE-derived RNA from corhort2. Four genes that correlated with the survival were then identified by risk scores. Kaplan-Meier analysis showed that patients of high risk scores had longer OS and DFS compared with patients of low risk scores in the corhort2. The four-gene signature was an independent predictor of OS and DFS. We validated the four-gene model in the independent corhort. Conclusions: Our results suggest that the four gene signature is a new biomarker for the prognosis of patients with NSCLC, enabling more accurate prediction of prognosis.
RRM1 expression is verified as a biomarker predicting the drug sensitivity for GEM with in vitro 3D drug sensitivity test in non-small cell lung cancer tumor.
Authors: Nakashima Nariyasu , Liu Dage , Nakano Takayuki , Kita Yusuke , Zhang Xia , Tokunaga Yoshimasa , Tarumi Shintaro , Matsuura Natsumi , Nii Kazuhito , Go Tetsuhiko , Kakehi Yoshiyuki , Yokomise Hiroyasu
Published: September 2018

e20054

Background: Ribonucleotide reductase M1 (RRM1) is involved in regulation of cell proliferation and synthesis of deoxyribonucleotides for DNA. It is also a cellular target for gemcitabine (GEM) and overexpression of RRM1 was reported to be associated with the resistance to GEM. Though RRM1 expression has been reported as the biomarkers in predicting the response to chemotherapy clinically, the value of GEM remains inconsistent and controversial. Collagen gel droplet embedded culture-drug sensitivity test (CD-DST) is a newly developed in vitro chemosensitivity test that could directly inspect the anti-cancer drug sensitivity with fresh tumor tissue. With use of CD-DST test, we have verified the predictive value of RRM1 expression to the anti-cancer agent sensitivity for GEM in non-small cell lung cancer (NSCLC) tumor. Here, the predictive value of biomarker RRM1 to GEM was further verified with CD-DST. Methods: Twenty-five patients with primary NSCLC were used in this study. Expression of RRM1 was assessed by immunohistochemistry. For CD-DST test, viable cells were collected from fresh surgical specimen and embed into the collagen gel droplets in 3D condition. Tumor cells were exposed to GEM for 1 hour and further incubated with serum-free culture medium for 7 days. The in vitro sensitivity was expressed as the percentage T/C ratio, where T was the total volume of the treated group and C was the total volume of the control group. Results: 1)Anti-cancer drug sensitivity: The sensitivity for GEM (T/C%) was 76.2 ± 30.5. 2)Expression of biomarkers: RRM1 expression was 39.2 ± 28.2 %. 3) Correlation: The expression of RRM1 significantly correlated with drug sensitivity for GEM (r = 0.446, p = 0.0256). Higher expression of RRM1 indicated worse anti-cancer drug sensitivity for GEM. Conclusions: The significant correlation between the RRM1 expression and sensitivity to GEM was proved with CD-DST in NSCLC tumors. The expression of RRM1 may become a useful biomarker in predicting the drug sensitivity for GEM in NSCLC.
Association of delays in time to surgery for resectable stage IIIA non-small cell lung cancer with survival.
Authors: Combs Susan E , Tullio Katherine , Pennell Nathan A.
Published: September 2018

e20056

Background: Delay in time to surgery (TTS) for early stage non-small cell lung cancer (NSCLC) may impact survival; however the effect of delayed TTS for patients with stage IIIA NSCLC is unclear. Methods: Patients with pathologic stage IIIA NSCLC who underwent curative intent resection with documented days from diagnosis to definitive surgery were identified in the National Cancer Database from 2004 to 2012. Patients with surgery on the day of diagnosis or more than 180 days after diagnosis, and those who received pre-operative systemic or radiation therapy were excluded. Association between TTS as a continuous variable by week and month was assessed by cox regression models. Multivariate cox proportional hazard models estimated the mortality risk associated with TTS as a continuous variable with age, sex, race, comorbidity score, pathologic T and N stage. Overall survival (OS) between immediate and delayed groups was estimated by Kaplan-Meier method and log-rank test. Results: Of patients with NSCLC who underwent definitive resection, 16,033 were confirmed to be pathologic stage IIIA. Median follow-up was 25 months, and 61% of patients died with a median survival of 32 months. Median time from diagnosis to surgery was 37 days. Five-year OS for patients with surgery in the first 37 days was 34.7%, compared to 30.1% in patients who had surgery after the first 37 days (p < 0.001). When grouped by increasing weeks of delay, the earliest significant survival difference was noted in patients resected within three weeks of diagnosis, with 5-yr OS of 35.2%, compared to 31.5% for patients treated more than three weeks later (p = 0.002). For each week of additional TTS, the associated risk of mortality increased by 1.2% (HR 1.012, 95% CI 1.007-1.016, p < 0.001) and 5.0% for each month of delay (HR 1.046, 95% CI 1.026-1.065, p < 0.001). In the multivariate model accounting for confounders, the mortality risk associated with delay to surgery increased by 0.75% with each additional week (HR 1.0075, 95% CI 1.003-1.012, p = 0.002). Conclusions: This analysis suggests that delays in time to curative intent resection for patients with stage IIIA NSCLC decreases the 5-year OS and thus the likelihood of cure.
Chemoradiotherapy (CRT) for locally-advanced (LA) lung cancer patients with interstitial lung abnormalities (ILA).
Authors: Kubo Toshio , Higo Hisao , Ninomiya Takashi , Ichihara Eiki , Ohashi Kadoaki , Sato Akiko , Hotta Katsuyuki , Tabata Masahiro , Makimoto Satoko , Ihara Hiroki , Masaoka Yoshihisa , Katsui Kuniaki , Kiura Katsuyuki
Published: September 2018

e20057

Background: Interstitial lung disease (ILD) is an independent risk factor for lung cancer. The incidence of ILD in lung cancer patients is 5–10%. Although CRT is the standard treatment for LA lung cancer and has potential for long-term disease-free survival or cure, the treatment is avoided in patients with ILD because of the risk of severe radiation pneumonitis or acute ILD exacerbation. ILA has recently been evaluated using high-resolution computed tomography (HRCT) to assess interstitial changes. The aim of this study was to determine the feasibility and efficacy of CRT for LA lung cancer patients with ILA. Methods: Patients who underwent CRT for LA lung cancer at Okayama University Hospital between 2012 and 2015 were reviewed retrospectively. HRCT prior to treatment was evaluated by one pulmonologist and two radiologists using sequential reading. Results: Of 74 patients, ILA was present in 25 (33.8%) and indeterminate ILA was present in 23 (31.1%); 26 patients (35.1%) did not have ILA. Patient characteristics are shown below. Desaturation at rest (SpO2< 95%) and honeycombing on HRCT were not observed in patients with ILA. Only one patient with ILA had a low vital capacity (VC% of predicted, < 80%). Severe radiation pneumonitis (≥ grade 2) occurred in 32.0% of patients with ILA and 19.2% of patients without ILA (P=0.35). All radiation pneumonitis was controllable and grade 4 or 5 was not observed. Using multivariate analyses, treatment > 20 Gy involving > 25% of the lung volume was a predictive factor for severe radiation pneumonitis, but not ILA. The 2-year survival percentages of patients with and without ILA were 56.8% and 72.5%, respectively (hazard ratio, 1.21; 95% confidence interval, 0.76–1.90; P=0.42). Conclusions: Although severe radiation pneumonitis tended to increase, CRT was appropriate for patients with ILA without desaturation, low VC, and honeycombing on HRCT. [Table: see text]
Genomic and transcriptomic profiling of localized sarcomatoid carcinoma of the lung to reveal association between immune activation and a lower risk of recurrence.
Authors: Seth Sahil , Lee Won-Chul , Zhang Jianhua , Fujimoto Junya , Behrens Carmen , McDowell Christina , Kalhor Neda , Weissferdt Annikka , Papadimitrakopoulou Vassiliki , Heymach John , Gibbons Don Lynn , Futreal Andrew , Wistuba Ignacio Ivan , Amit Moran , Kadara Humam , Zhang Jianjun
Published: September 2018

e20058

Background: The sarcomatoid carcinoma of the lung (SCL) is a rare subtype of non-small cell lung cancers (NSCLC). The prognosis of SCL is poor with 5-year survival of ~20%. There have been only a few studies on genomic landscape of SCL. Comprehensive genomic and transcriptomic profiles of SCL have not been systematically studied. Methods: In this study, we performed whole-exome sequencing and ultra-deep targeted sequencing of 400 cancer genes on 21 resected localized SCLs and matched normal lung tissues. RNA sequencing (RNA-seq) was also performed to 17 SCLs and matched normal lung tissues for those with materials available. Results: On average, 688 mutations including 503 non-synonymous mutations were identified per tumor. Canonical cancer gene analysis demonstrated that the most frequently mutated gene in this cohort was TP53 (detected in 11 out of the 21 tumors) followed by KRAS (detected in 6 out of the 21 patients). The recently discovered potentially targetable MET exon 14-skipping mutation was also detected in 3 patients in our cohort. For the 17 tumors, for, whom RNA-seq was conducted, unsupervised clustering analysis using non-negative matrix factorization (NMF) led to two stable clusters of patients in our cohort. Of particular interest, all patients (7/7) in Cluster 1 have relapsed, while only 3 of 10 patients in Cluster 2 relapsed (p-value < 0.01). Further pathway analyses demonstrated that immune activation pathways are significantly up regulated in tumors from Cluster 2 compared to Cluster 1. Conclusions: SCLs seem to have similar genomic landscape and canonical cancer gene mutations compared to other types of NSCLCs such as squamous cell carcinoma and adenocarcinomas. Immune pathway activation may be associated with lower risk of postsurgical recurrence in patients with localized SCL.
A phase II trial of S-1 plus cisplatin with concurrent proton-beam therapy for locally advanced non-small cell lung cancer.
Authors: Akita Kenji , Iwata Hiromitsu , Ogino Hiroyuki , Yamaba Yusuke , Kunii Eiji , Mori Yuta , Yoshihara Misuzu , Horiuchi Minoru , Hattori Yukiko , Hashimoto Shingo , Nakajima Koichiro , Nakamae Katsumi , Baba Fumiya , Shibamoto Yuta , Mizoe Jun-etsu
Published: September 2018

e20070

Background: Concurrent chemo-radiotherapy is the standard treatment for locally advanced (LA) non-small cell lung cancer (NSCLC). Recent phase II studies have demonstrated that S-1 plus cisplatin (CDDP) with concurrent radiotherapy yields promising results against LA NSCLC. Proton-beam therapy (PBT) is an alternative modality that is expected to reduce toxic effects against normal tissues compared with X-ray radiotherapy. We conducted a phase II trial of S-1 plus CDDP combined with concurrent PBT for patients (pts) with LA NSCLC. Methods: The eligibility criteria included unresectable stage III NSCLC, chemo-naïve status, PS 0 or 1, and age < 75 years. Pts received CDDP (80 mg/m2) on day 1 and S-1 (30-40 mg/m2 twice daily) on days 1 to 14, q4w, up to 4 cycles, plus concurrent PBT at a total dose of 70 GyE in 35 fractions for primary lesion and 66 GyE in 33 fractions for lymph node metastasis. PBT was performed using respiratory-gated and image-guided techniques, and adaptive plans were implemented according to a verification plan at 10, 20, and 30 days. Results: Thirty-two pts were enrolled between August 2013 and December 2016. The patient characteristics were as follows: median age, 66 (31-74); male/female, 24/8; PS 0, 26 pts; stage IIIA/IIIB, 19/13; non-squamous histology, 17 (53%). Twenty pts were out of indication for radical chemo-radiation with X rays. All 4 cycles of S-1 plus CDDP could be completed in 24 pts and the median number of cycles was 3.3 (range: 2 to 4). Grade 3/4 toxicities per pt were: neutropenia 28%, anemia 13%, thrombocytopenia 9.4%, fatigue, anorexia, esophagitis, mucositis and enteritis 3.1%, and radiation pneumonitis 0%. One case of febrile neutropenia was observed. PR + CR was achieved in 24 of 28 evaluable pts. The median PFS was 12.5 months, and 2-year OS was 63%, with a median follow-up period of 19.5 (range: 1.5-40.0) months. Conclusions: Concurrent chemo-PBT using S-1 plus CDDP with image-guided and adaptive techniques is considered to be effective and well tolerated for LA NSCLC. Further evaluations in a large randomized controlled trial are warranted.
Special considerations of DMCs for oncology studies.
Authors: Kerr David , Koprowicz Kent
Published: September 2018

e20071

Background: Data Monitoring Committees (DMCs) are an important component of the clinical trial process. They are charged with reviewing interim data and making recommendations to protect the safety of trial participants and ensure the scientific integrity of the study. Oncologists may be involved with the DMC process in a number of ways – as a DMC member, as an investigator, as a sponsor, or in a regulatory role. This presentation will discuss novel aspects of the DMC review process that are particularly relevant for oncology trials. Methods: The authors are leaders of a Contract Research Organization (CRO) that specializes in providing independent DMC services for government and industry sponsored trials. They have worked with hundreds of unique DMCs and facilitated approximately 1,000 DMC meetings. The proposed methodologies for maximizing the efficiency and thoroughness of DMC reviews are based on extensive experience and well-established principles. Results: Topics that will be covered include: Discrepant trends in PFS vs. OS PFS results that are inconsistent between local and central assessment, or are not yet centrally assessed Co-primary endpoints – OS, PFS, ORR, CR Multiple populations of interest – ITT and a biomarker subgroup Interim analyses – overwhelming efficacy and statistical futility Program-wide DMCs – interpreting trends across multiple studies and logistical details Safety assessment in a study with thousands of AEs – novel graphics and tables Laboratory values and vital signs – novel graphics and tables Multiple comparisons and/or multiple p-values Non-standard tables, listings, figures that are particularly useful for DMC review Open-label studies – immediate withdrawals for those randomized to control arm and other potential biases Single-arm studies – how to interpret safety with no control arm Novel therapies – immune-oncology, CAR-T, small sample sizes CIOMS reports or patient narratives Conclusions: DMCs will perform a more thorough and efficient review of accumulating data upon adapting the guidance provided. A more thorough review will enhance the protection of the trial participants while a more efficient review will allow DMCs to focus their efforts appropriately.
A propensity-matched analysis of stereotactic body radiotherapy and sublobar resection for stage I non-small cell lung cancer in patients at high risk for lobectomy.
Authors: Chen Wucheng , Lin Qingren , Sun Xiaojiang , Liu Jinshi , Xu Yaping , Chen Qixun , Mao Weimin
Published: September 2018

e20076

Background: The aim of this study was to perform a survival comparison between stereotactic body radiotherapy (SBRT) and sublobar resection (SLR) in patients with stage I non-small cell lung cancer (NSCLC) at high risk for lobectomy. Methods: All patients who underwent SBRT or SLR because of medical comorbidities for clinical stage I NSCLC from January 2008 to December 2015 were reviewed retrospectively. Propensity score matching was performed to reduce selection bias between SBRT and SLR patients based on age, gender, performance status, tumour characteristics, pulmonary function. Overall survival (OS) and recurrence-free survival (RFS) were estimated with Kaplan–Meier method. Results: Forty-nine patients were matched into each group of SBRT and SLR (include 27 underwent segmentectomy, 22 underwent wedge resection). There were 32 and 30 men with median age of 67 and 69 years, respectively. Median follow-up was 25 months. In terms of treatment-related mortality, the 30- day mortality rates for the SBRT and SLR groups were 0 and 2.0 %, respectively. Patients treated by SBRT had a tendency to increase 3-year OS compared with SLR (94.0% versus 78.1%; P = 0.064).There was no difference between two groups in 3-year RFS (61.8% versus 65.7%; P = 0.864). In a subanalysis, 3-year OS after SBRT was greatly better than wedge resection subgroup (94.0% versus 67.4%; P = 0.026), but there was no significant difference between SBRT and segmentectomy in 3-year OS (94.0% versus 88.0%; P = 0.212). Conclusions: SBRT had a tendency to increase OS compared with sublobar resection in patients who are not medically fit for lobectomy with clinical stage I NSCLC. However, OS after SBRT was better than wedge resection subgroup. SBRT can be an alternative treatment option to segmentectomy for patients who cannot tolerate lobectomy because of medical comorbidities. A randomized prospective study is necessary to determine survival in compromised SBRT and sublobar resection.
A phase I-II clinical trial to evaluate the safety, pharmacokinetics, and efficacy of high-dose intravenous ascorbic acid synergy with mEHT in Chinese patients with stage III-IV non-small cell lung cancer.
Authors: Ou Junwen , Zhu Xinyu , Lu Yimin , Zhao Changlin , Zhang Hongyu , Zhang Xinting , Zhang Tao , Pang Clifford L.K.
Published: September 2018

e20078

Background: Ascorbic acid (AA) infusion and modulated electrohyperthermia (mEHT) are widely used by integrative cancer practitioners for many years. However, there are no safety and pharmacokinetics data in Chinese cancer patients. Methods: Blood ascorbic acid in the fasting state was obtained from 35 NSCLC patients; selecting from them 15 patients with stage III-IV entered the phase I-II study. They were randomized allocated into 3 groups. Pharmacokinetic profiles were obtained when they received solely IVAA at concentrations of 1g/kg, 1.2g/kg, and 1.5g/kg, and when IVAA in combination with mEHT. The process was applied 3 times a week for 4 weeks. Participants in the first group received IVAA when mEHT was finished, in the second group IVAA was administered simultaneously with mEHT and in the third group IVAA was applied first, and followed with mEHT. All patients started the trial doses of 1 g/kg for 8 treatments. When there was no DLT observed, the test dose for patients increased to 1.2 g/kg and 1.5 g/kg. DLT was defined as any reversible grade ≥3 adverse events, whether haematological or non-haematological. Results: Fasting plasma AA levels were significantly correlated with stage of the disease. Peak concentration of AA were significantly higher in the simultaneous treatments than in other combinations with mEHT or in solely IVAAmanaged groups. The average scores for the functioning scales continuously increased and the symptoms gradually decrease over the full cycle of the study.3/7 patients with squamous cell lung cancer were CR, 4/7 were PR. 1/8 patient with adenocarcinoma cell lung cancer was PR, 5/8 were SD, and 2/8 were died. Conclusions: IVAA synergies with simultaneous mEHT is safe and the concomitant application significantly increases the plasma AA level for NSCLC patients. QOL is improved when they receive the above treatments. Patients diagnosed with squamous cell lung cancer were sensitive to the above two treatments. Clinical trial information: NCT02655913.
Long-term survival in patients with NSCLC treated with single fraction vs multi-fraction palliative radiotherapy in the case of lung tumor, brain metastases, and bone metastases.
Authors: Szablewska Sylwia , Adamczak-Sobczak Magdalena , Roszkowska Zofia , Roszkowski Krzysztof
Published: September 2018

e20082

Background: Patients with advanced non-small cell lung cancer (NSCLC) are candidates for different types of treatment, including chemotherapy and radiotherapy or supportive care. Despite the fatal prognosis in advanced disease, many experienced radiation oncologists will apply radiation at low doses with the intention of palliative care. Choosing an effective radiation dose that does not cause significant complications remains under discussion. Methods: We used an extensive database of medical patients diagnosed with NSCLC, treated with palliative radiotherapy at the Oncology Centre in Bydgoszcz, Poland, from June 1998 to December 2013. A group of 3202 patients was divided into subgroups: A) 1762 patients irradiated on the lung tumor (without distant metastases): Total dose: A1) 6 Gy/1 fr.(n = 19); A2) 8 Gy/1 fr.(n = 276); A3) 20 Gy/5 fr.(n = 1349); A4) 30 Gy/10 fr.(n = 118). B) 548 patients irradiated on the central nervous system (CNS) metastases: B1) 20 Gy/5 fr.(n = 476); B2) 30 Gy/10 fr.(n = 72). C) 892 patients irradiated on the bone metastases: C1) 8 Gy/1 fr.(n = 452); C2) 10 Gy/1 fr.(n = 30); C3) 20 Gy/5 fr.(n = 341); C4) 30 Gy/10 fr.(n = 69). Date of death was obtained from medical records. Patients who were alive or whose date of death could not be determined were censored at the date of their last encounter. Survival was calculated from the start of treatment to the date of death or censorship. Results: Overall Survival (in months) for each group was: A1) = 6; A2) = 5; A3) = 7; A4) = 7. B1) = 4; B2) = 4. C1) = 5; C2) = 4; C3) = 4; C4) = 5. There was no significant difference in survival between patients treated with single fraction pRT or multi-fractionation schedules in all groups of patients. Conclusions: The patients who were prescribed single fraction palliative radiotherapy did not have poorer prognoses or experience shorter survival than patients who were prescribed multi-fraction pRT in the case of lung tumor, brain metastases and bone metastases.
A novel MAGE-A1-IgG antibody for lung adenocarcinoma.
Authors: Mao Yuan , Tang Qi , Fan Weifei , Tang Xiaojun , Xu Li , Zhu Jin , Feng Zhenqing , Wang Jun
Published: September 2018

e20085

Background: Melanoma-associated antigen A1 (MAGE-A1) has been reported to perform oncogenically and act as an ideal candidate in tumor immunotherapy. Methods: One-step quantitative real-time polymerase chain reaction (qPCR) test and immunohistochemistry (IHC) analysis were used to detect the relationship between MAGE-A1 expression and the clinicopathological characteristics of lung adenocarcinoma (LAC). Then a novel MAGE-A1 IgG antibody was constructed on the previous MAGE-A1 scFv antibody by eukaryotic expression vectors. CCK-8, wound healing, transwell, matrigel, apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC) and CDC (complement-dependent cytotoxicity) assays were performed to evaluate the inhibitory effects of MAGE-A1-IgG on LAC in vitro. Results: High MAGE-A1 expression was observed in LAC tissues and MAGE-A1 expression was associated with several malignant properties of LAC patients, including overall survival. MAGE-A1-IgG revealed significant roles in inhibiting proliferation, inducing apoptosis and activating ADCC and CDC of LAC in a dose- and time- dependent manner in vitro. Conclusions: MAGE-A1-IgG may provide a promising therapeutic strategy for the treatment of MAGE-A1-positive LAC.