bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preclinical and clinical impact of the GLI2 transcription factor in non-small cell lung cancer (NSCLC).
Authors: Leal Ticiana A.B. , Spiegelman Vladimir S. , Goswami Srikanta , Oettel Kurt R. , Weigel Tracey L. , Huang Wei , Choi Sangbum , Kim KyungMann , Larson Martha M. , Hoang Tien , Campbell Toby Christopher , Traynor Anne M. 
Published: March 2020

e18537 Background: Components of the Hedgehog (Hh) signaling pathway are over-expressed in NSCLC. Hh signaling contributes to tumorigenesis in lung cancer and is under investigation as a therapeutic target. We assessed in vitro characteristics of the GLI2 transcription factor, a primary mediator of Hh signaling, in NSCLC tumorigenesis, and its prognostic impact in early stage NSCLC. Methods: Colony formation, growth in soft agar, and measurement of GLI2 RNA were assayed in A549 NSCLC cells. Changes in tumor growth and proliferation were evaluated using a two-sample t-test. The automated quantitative analysis system (AQUA) was used to assess protein expression of GLI2 in NSCLC specimens from 88 deceased patients (pts) with resected stages I and II NSCLC. Pts did not receive additional pre- or post-operative anti-cancer therapies. Pt age, sex, smoking history, histology, TNM stage, and type of resection were also collected. Progression-free survival (PFS) and overall survival (OS) were estimated per Kaplan-Meier; multivariate Cox proportional hazard analyses were used to determine if the GLI2 AQUA score was an independent prognostic factor. Results: GLI2 knockdown in A549 NSCLC cells using GLI2 shRNA resulted in inhibition of colony formation and in the anchorage-independent growth, compared to A549 cells with intact GLI2 function. Characteristics of our population included median age 73 (43-96), males 62.5%, smokers 96%, adenocarcinoma 46.6%, squamous cell histology 40.9%, and stage I 62.5%. GLI2 AQUA score was not associated with any clinical variable per Wilcoxon analyses. High GLI2 AQUA score was associated with shorter PFS (median PFS 8.6 mo [95% CI 7.0-10.7 mo]) compared to low GLI2 AQUA score (median PFS 17.2 mo [95% CI 15.8-22.6 mo], p=0.001), and with shorter OS (median OS 14.8 mo [95% CI 10.5-23.0 mo]), compared to low GLI2 score (median 25.9 mo [95% CI 20.2-35.7 mo], p<0.001), independent of clinical variables. Conclusions: The GLI2 transcription factor of Hh signaling impacts in vitro models of NSCLC tumorigenicity and is an independent negative prognostic factor in early stage disease. Hh signaling remains a worthwhile investigational therapeutic target in NSCLC.
Rare discrepancy in driving gene mutations between histologically heterogeneous primary lung cancer.
Authors: Zhong Wenzhao , Chen Zhi-yong , Xu Fangping , Yang Xue-Ning , Su Jian , Chen Zhihong , Zhang Xuchao , An Shejuan , Zhou Qing , Yang Jinji , Wu Yi Long 
Published: March 2020

e18547 Background: The mixed subtype adenocarcinomas account for nearly 90%. The driving gene mutations are found with different frequency in various histological subtypes. The role of the intra-tumoral heterogeneity is still controversial. Methods: In order to compare the gene status of the area of different growth patterns, the representative morphologically different tumor areas within the same surgical resected primary tumour were extracted from tissue sections. Driver genes were detected by sequencing, ARMS and FISH methods. Results: During routine clinical genotyping, 79 consecutive surgical resected cases with mixed subtype adenocarcinoma harboring driving gene mutation were selected. The gene statuses of different growth patterns within the same primary tumor were compared. The discrepancies of EGFR mutation were 10 in 65 with direct sequencing, and 1 in 65 with ARMS, among which consistent EGFR mutations were found in all the 5 cases adenosquamous cell carcinoma. The discrepancy of KRAS mutation in direct sequencing was 2 in 10. No discrepancy of EML4-ALK rearrangement in FISH was found in 4 cases. Conclusions: Rare discrepancy of driving gene mutations within histologically heterogeneous primary lung adenocarcinoma was found. It indicated that the different components of the primary lung cancer may have originated from a common ancestor.
Genetic background and risk of lung adenocarcinoma in never smokers.
Authors: Takamochi Kazuya , Oh Shiaki , Suzuki Kenji 
Published: March 2020

e18549 Background: The causative association between tobacco smoking and lung cancer is well-known. However, the mechanism underlying the pathogenesis of lung adenocarcinoma in never smokers remains unclear. Recently, several driver oncogenes, such as EGFR and EML4-ALK, have been identified in lung adenocarcinomas ofnever smokers. Methods: This was a retrospective review of 596 patients with surgically resected lung adenocarcinomas between February 2009 and October 2012. The clinicopathological factors (age, gender, and pathological stage), EGFR and KRASmutation status, past history of any cancer or benign tumor, family history of any cancer, and the presence of multiple primary lung cancers were compared between never smokers (n = 312) and smokers (n = 284). Results: Lung adenocarcinomas in never smokers were more frequently found in females (P < 0.001) and in patients with early stage disease (P = 0.01) than those in smokers. EGFR mutations were detected in 183 (59%) never smokers and in 89 (31%) smokers (P < 0.001). K-ras mutations were detected in nine (3%) never smokers and in 57 (20%) smokers (P < 0.001). The proportion of patients with a past history of any cancer was higher in smokers than in never smokers (28% vs 21%, P = 0.03). This may reflect the fact that tobacco smoking can cause various types of cancers. In contrast, the proportions of patients with any benign tumor and a family history of any cancer were higher in never smokers than in smokers (14% vs 4%, P < 0.001 and 20% vs 13%, P = 0.02). These findings may suggest that a certain genetic background is involved in the pathogenesis of lung adenocarcinoma in never smokers. The frequency of multiple primary lung cancers was not significantly different between never smokers and smokers (6% vs 5%, P = 0.6). In never smokers, the EGFR and KRASmutation status was not associated with the frequency of a past history of any cancer or benign tumor, a family history of any cancer or the presence of multiple primary lung cancers. Conclusions: A certain genetic predisposition is suspected to be involved in the pathogenesis of lung adenocarcinoma in never smokers. Further studies are thus needed to elucidate the genetic alterations associated with the susceptibility to lung adenocarcinoma in never smokers.
Is CT-based selective nodal irradiation safe for clinical stage N0-1 LD-SCLC patients?
Authors: Hu Man , Fan Bingjie , Kong Li , Yu Jinming 
Published: March 2020

e18551 Background: Radiotherapy plays an important role in the management of limited-disease small-cell lung cancer (LD-SCLC). However, volume of irradiation remains unanswered as well as optimal total dose, timing and sequencing of radiation. In this study, we compared the clinical lymph node staging with pathological staging, with the aim of investigating the safety of CT-based selective nodal irradiation for clinical stage N0-1 LD-SCLC patients. Methods: From July 2004 to March 2012, 20 potentially operable patients with clinical stage N0-1 LD-SCLC underwent contrast-enhanced CT scans and other routine initial staging procedures followed by radical resection of primary tumor and systemic intra-thoracic lymph node dissection. The results of reviewing clinical staging for the mediastinal lymph node metastases were compared with pathologic findings. Results: Preoperative nodal staging was compared with postoperative pathological staging, 35% (7 of 20) of patients were under staged by clinical staging. Of all the 7 patients with mediastinal lymph node metastases, 4 patients (57.1%) had subcrinal nodes (station 7) metastases, 1 had right upper paratracheal nodes (station 2R) metastases, 1 had left lower paratracheal nodes (station 4L) metastases, 1 had aortopulmonary nodes (station 5) metastases. Conclusions: CT-based selective nodal irradiation for LD-SCLC may result in geographical miss in clinical stage N0-1 patients. Mediastinal lymph node regions especially the subcrinal nodes should be contained in the clinical target volume for radiotherapy.
Prognostic value of epidermal growth factor receptor gene amplification in surgically resected non-adenocarcinoma lung cancer patients.
Authors: Yang Yaewon , Chang Hyun , Lee Jong-Seok , Kim YuJung , Jheon Sang-hoon , Chung Jin-haeng 
Published: March 2020

e18553 Background: The purpose of this study is to investigate the prognostic role of genomoic gain and expression for epidermal growth factor receptor (EGFR) gene in surgically resected non-adenocarcinoma of non-small-cell lung cancer (NA-NSCLC). Methods: This retrospective study included 115 NA-NSCLC consecutive patients with available tumor tissue and survival data, median follow up period of 6.4 years. EGFR gene copy number and protein expression was evaluated using by fluorescent in situ hybridization (FISH) and immunohistochemistry (IHC) in tissue microarray sections, respectively. Results: Among 115 patients, 99 patients (86.1 %) were with squamous cell carcinoma histology. EGFR gene amplification and high polysomy (EGFR FISH+) were observed in 57 (49.6%) and 45 (39.1%) patients, respectively. Patients with EGFR FISH+ had significantly shorter overall survival [median, 41 months vs. not reached (>70 months), P = 0.011]. Multivariable model confirmed that patients with EGFR FISH+ had a significantly greater risk of death than those with EGFR FISH-negative after adjusting pathologic staging, presence of pleural invasion, venous invasion and adjuvant chemotherapy (hazard ratio = 2.11, 95% confidence interval 1.23-3.61, P = 0.006). EGFR IHC expression did not associate with overall survival in same group. Conclusions: EGFR increased gene copy number is an independent negative prognostic factor in surgically resected NA-NSCLC.
Combination efficacy of mTOR and MEK inhibitor in malignant pleural mesothelioma (MPM).
Authors: Matsumoto Seiji , Orui Hayato , Kuroda Ayumi , Hashimoto Masaki , Yoneda Kazue , Takuwa Teruhisa , Kondo Nobuyuki , Hasegawa Seiki 
Published: March 2020

e18557 Background: Malignant pleural mesothelioma (MPM) is an aggressive tumor and poor prognosis. Active new agents is an urgent priority for patients with MPM. PI3K/AKT/mTOR pathway inhibitors in MPM have reported, but, the results has limited. Because PI3K/AKT/mTOR pathway inhibitors will make signaling feedback loops and cross-talk between signaling pathways. Combining PI3K/AKT/mTOR pathway inhibitors with other inhibitors might improve efficacy. Activation of RTKs stimulates both the PI3K/AKT/mTOR and RAS/RAF/MEK signaling pathways, and some study shows that inhibition of both pathways may be more effective than targeting either alone. We speculated that simultaneous inhibition both of mTOR and MEK by everolimus and selumetinib might improve the treatment of MPM. Methods: At first, we examined the growth inhibitory effects of everolimus or selumetinib alone on MPM cell lines. Next we examined combination efficacyofeverolimus with selumetinib on MPM cell lines, H226 was examined by computer-assisted analysis using the CalcuSyn software. We next confirmed the in vivo efficacy of everolimus or selumetinib alone, and the combination of both compounds in H226 MPM xenograft model. Results: Everolimus inhibited the growth of MPM cell lines with IC50 values 1.19-21.5 μM. Selumetinib also inhibited the growth of MPM cell lines with IC50 values 4.68-88.2μM. Next we examined combination efficacyofeverolimus with selumetinib on MPM cell lines, H226 was examined by computer-assisted analysis using the CalcuSyn software. With H226, the combination index (CI) at fraction (Fa) 0.5 and 0.8 were (0.56 ± 0.30) and (0.76 ± 0.48), respectively, indicating everolimus and selumetinib act synergistic, respectively. Everolimus or selumetinib alone showed significant antitumor activity, and the combination of everolimus and selumetinib enhanced the individual antitumor activity in H226 MPM xenograft model. (p<0.05). Conclusions: These findings indicate that the combination of everolimus and selumetinib is effective in MPM growth inhibition not only in vitro but in vivo and chemotherapy regimens involving the combination of everolimus and selumetinib may be new molecular target therapy for MPM patients
Predictive factors of distant recurrence after surgery in patients with clinical stage IA lung adenocarcinoma.
Authors: Ibuki Yuta , Miyata Yoshihiro , Yoshiya Tomoharu , Mimae Takahiro , Tsutani Yasuhiro , Okada Morihito 
Published: March 2020

e18563 Background:The tumor recurrence after complete surgical resection occurs even in patients with clinical stage IA lung adenocarcinoma. The predictive factors of the distant recurrence have not been determined yet in such early stage lung adenocarcinoma patients. Methods:A total of 610 patients with clinical stage IA lung adenocarcinoma who underwent complete resection in multi-institutions were retrospectively analyzed . The correlation between clinicopathological factors andthe incidence of distant recurrence was examined. Results:Thirty six patients with distant recurrence had significant inferior overall survival. In the multivariate Cox regression analysis, solid tumor size on high resolution computed tomography (HRCT) and maximum standardized uptake (SUVmax) on 2-[18F]fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography (FDG-PET/CT) were found to be independent predictors of distant recurrence. According to receiver operating characteristic analysis, 1.6cm or more of solid tumor size and 3.3 or more of SUVmax were indicated to be an optimal criteria to detect a high risk group for distant recurrence. In fact, distant recurrence and local recurrence were more frequently observed in patients whose solid tumor size and SUVmax met the criteria than the unmet patients (24 of 104 (20.2%) patients v.s. 12 of 506 patients (2.4%)). Conclusions:Solid tumor size on HRCT and SUVmax on FDG-PET/CT were indicated to be predictive factors of distant recurrence for the patients with clinical stage IA lung adenocarcinoma. It is highly possible that neoadjuvant chemotherapy is useful for such a high risk group.
KRAS and EGFR status as predictive markers of response and time to progression in EGFR wild-type stage IV non-small cell lung cancer (NSCLC) patients treated with EGFR tyrosine-kinase inhibitors.
Authors: Domine Manuel , Rojo Federico , Hernandez Tatiana , Zazo Sandra , Serrano Gloria , Chamizo Cristina , Carames Cristina , Madoz Juan , Moreno Irene , Perez-Gonzalez Nuria , Ortega Carolina , Carvajal Nerea , Lobo Francisco , Auz Carmen Laura , Casado Victoria , Rubio Gustavo , Oruezabal Mauro , Lendinez Alberto , Leon Ana , Garcia-Foncillas Jesus 
Published: March 2020

e19000 Background: KRAS mutations on codons 12, 13 and 61 result in the constitutive activation of protein, which may render tumor cells independent of epidermal growth factor receptor (EGFR) signalling and thereby resistant to tyrosine-kinase inhibitor (TKI) therapy in NSCLC patients. This study was aimed to evaluate the associations of KRAS and EGFR copy number alteration and mutations with response and time to progression (TTP) in EGFR TKI-treated patients. Methods: 84 samples from NSCLS patients treated with erlotinib or gefitinib were analyzed for KRAS and EGFR mutation status by cobas KRAS and EGFR Mutation Tests (Roche). EGFR copy number was determined by fluorescent in situ hybridization (FISH, Abbott Molecular) and amplification was defined with three or more gene copies in tumor. Results: KRAS mutation was detected in 15 (17.8%) cases, EGFR mutation in 27 (32.1%) and EGFR amplification in 8 (9.5%). Significant differences were detected in response rates for wild-type (0.2) and mutant KRAS (0.0) (p=0.023), for wild-type (0.12) and mutant EGFR (0.39) (p=0.007), and for non-amplified (0.18) and EGFR-amplified (0.71) patients (p=0.005). Additionally, significant benefit from TKI therapy was observed for KRAS wild-type compared with KRAS-mutated patients (median TTP 7 vs. 3 months, p=0.001), for EGFR-mutated compared with wild-type patients (14 vs. 4 months, p=0.004) and for EGFR-amplification in contrast to non-amplified cases (11 vs. 5 months, p=0.001). KRAS and EGFR mutations or EGFR amplification did not correlated with overall survival (18 vs. 19 months, p=0.406; 16 vs. 21 p=0.094; 25 vs. 17 months, p=0.103, respectively). Combined analysis of favourable status of three biomarkers strongly predicted benefit to TKI therapy (median TTP 15 vs. 3 months, p<0.001). Conclusions: Combined analysis ofKRAS mutation, EGFR mutation and EGFR amplification in EGFR TKI-treated NSCLC might provide superior predictive information than single biomarker study in these patients.
Impact of concomitant use of anti-acid agents on efficacy of gefitinib in EGFR-mutant non-small-cell lung cancer (NSCLC).
Authors: Chikamori Kenichi , Aoe Keisuke , Maeda Tadashi , Kishino Daizo , Oishi Keiji , Hotta Katsuyuki , Matsumoto Tsuneo , Ueoka Hiroshi 
Published: March 2020

e19008 Background: Gefitinib, an EGFR-tyrosine kinase inhibitor, is an essential agent for EGFR-mutant NSCLC. The preclinical studies revealed its reduced area under the curve (AUC) by elevation of pH in GI tract, potentially leading to alteration in the absorption of gefitinib. It, however, has been controversial as to whether and how simultaneous use of anti-acid agents, commonly used in clinical practices, could alter the sensitivity of gefitinib, especially in EGFR-mutant NSCLC. Thus, we conducted a retrospective cohort study to clarify this issue. Methods: We evaluated progression-free survival (PFS) and overall survival (OS) from the medical charts of chemotherapy-naïve patients with EGFR-mutant NSCLC treated with gefitinib monotherapy in our institution. We also identified history of concomitant use of anti-acid agents (proton pomp inhibitors and histamine type 2 receptor blockers) at the time of initiation of gefitinib therapy and assessed its impact on the efficacy of gefitinib using Cox’s proportional hazard model. Results: Between 2006 and 2012, consecutive 83 patients received gefitinib therapy, of whom 29 (34.9%) used anti-acid agents simultaneously. Baseline clinical characteristics between the two groups (use and non-use of anti-acid agents) were well balanced except performance status (PS) of 0: 17.2% vs. 37.0% respectively. Neither PFS nor OS were influenced by concomitant use of anti-acid agents in univariate analysis (hazard ratio: 1.12; 95% confidence interval: 0.66-1.92 and 1.67; 0.86-3.44, respectively). Multivariate analysis also showed no significant effect of anti-acid agent use on PFS and OS (1.18; 0.67-2.06 and 1.66; 0.81-3.38, respectively), whilst poor PS affected OS (2.03; 1.27-3.26). Additionally, no difference in the impact of use of anti-acid agents on the gefitinib sensitivity was observed when stratified by the type of EGFR mutations. Conclusions: Concomitant use of anti-acid agents does not seem to affect efficacy of gefitinib in EGFR-mutant NSCLC. It is unlikely that physicians need to keep in mind the drug interaction of gefitinib and anti-acid agents in daily clinical practices, although further extensive cohort studies are warranted.
A pemetrexed-based genetic study of Chinese Han patients with advanced non-small cell lung cancer (NSCLC).
Authors: Lu Shun , Niu Xiaomin , Li Ziming , Yu Yongfeng , Ye Xiangyun , Liu Yun , Chen Zhiwei , Kan Mengyuan 
Published: March 2020

e19014 Background: Pemetrexed has been approved for ﬁrst- and second-line treatment in patients with non-small cell lung cancer (NSCLC). Two studies have confirmed the role of polymorphisms (SNPs) in reduced folate carrier (SLC19A1) is related with the survival differences in pemetrexed-treated NSCLC in Caucasian population. Considering different genetic backgrounds in different populations, our study was aimed to identify candidate SNPs for pemetrexed-treated NSCLC in Chinese Han population. Methods: Fifty-seven patients with previously treated NSCLC received pemetrexed-based third-line treatment from Shanghai Chest Hospital from Nov 2006 to Jul 2011. Four genes, SLC19A1, gamma-glutamyl hydrolase (GGH), methylenetetrahydrofolate reductase (MTHFR), and methionine synthase (MTR), responsible for pemetrexed transport and activation were evaluated. The five SNPs (rs4819128, rs914232, rs4818789, rs3788189, rs1051298) in SLC19A1, two SNPs (rs3780130, rs3780126) in GGH, two SNPs (rs1801133, rs180131) in MTHER, and one SNP (rs1805087) in MTR were selected based on the HapMap Chinese Han databases. All SNP genotyping was performed by TaqMan PCR using the ABI Prism 7900HT Sequence Detection System. Kaplan-Meier cumulative probability and Cox multivariate analyses were used to evaluate the relationship between genetic variations with survival outcome. Results: Fifty-seven patients received a median of three cycles (range, 1-16 cycles) of pemetrexed-based treatment. Median overall survival (OS) and progression-free survival (PFS) times were 23.0 and 3.2 months, respectively. Patients with AA/AG genotype of SLC19A1 rs1051298 had the better PFS and OS compared with GG genotype (5.5m vs 1.9m for PFS, P=0.047; 45.5m vs 17m for OS, P=0.001). The TT/TA genotype of novel GGH rs3780130 was correlated with better PFS compared with AA genotype (5.8m vs 2.5m, P=0.029). Conclusions: This study in Chinese Han NSCLC patients identified the unique result that novel TT/TA genotype of GGH rs3780130 was related with better PFS for pemetrexed-based treatment. Meanwhile, we obtained the same result with that in Caucasian study, AA/AG genotype of SLC19A1 rs1051298 was related with better PFS and OS.
Clinical observation of next-generation photodynamic therapy (NGPDT) for advanced non-small cell lung cancer.
Authors: Li Li Jun 
Published: March 2020

e19028 Background: Clinical observation of next-generation photodynamic therapy (NGPDT) for advanced non-small cell lung cancer (NSCLC). Methods: Through pathology or cytology diagnosis, 66 cases of advanced non-small cell lung cancer patients were selected and randomly divided into two groups. The Next Generation Photodynamic Therapy (NGPDT) group had 32 patients. Photosensitizer was administered on a dosage of 2 mg per kilogram of body weight, wherein two-thirds via ultrasonic atomization inhalation and one-third via oral intake. After the irradiation target(s) were determined, optical fiber for laser treatment purposes was guided into lung tumor(s) via interstitial procedure, percutaneous puncture under precious laser navigation, irradiation light intensity was 200 J/cm2, irradiation power was 1,000 mw, activation was then started and lasted for eight to ten minutes, laser irradiation into tumor was two to five centimeters in length, irradiation could be performed phase by phase (sub-paragraph treatment) based on tumor size or irradiations could be performed repeatedly. While in the mean time in the chemotherapy/radiotherapy group (external beam radiotherapy + whole body chemotherapy) 34 cases were observed, 15 MV X ray radiation therapy irradiation field covers primary lung tumor lesion(s) and mediastinal lymphatic drainage area, dosage was 65-70 Gy, on every first day in a week of radiotherapy, 20 mg cisplatin was administered via intravenous application. Results: In the NGPDT group and simultaneous radiotherapy/chemotherapy group, one and two years survival rate were 93.75%, 70.60% and 68.75, 32.35% respectively (P <0.05). The complete remission rate and partial remission rate were 56.20% and 21.30%, rate of the NGPDT group was significantly higher than that of the corresponding radiotherapy and chemotherapy group, the difference was statistically significant (P <0.05). Conclusions: NGPDT can prolong survival in patients with advanced NSCLC, improving their quality of life; it is one of the most effective measures for advanced non-small cell lung cancer treatment.