bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of a microRNA (miRNA) based signature for survival in advanced non-small cell lung cancer (NSCLC) patients (pts) treated with cisplatin-vinorelbine: A ELCWP study.
Authors: Berghmans Thierry , Willems Luc , Paesmans Marianne , Ameye Lieveke , Lafitte Jean-Jacques , Meert Anne-Pascale , Scherpereel Arnaud , CsToth Ingrid , Cortot Alexis B. , Mascaux Celine , Leclercq Nathalie , Sculier Jean Paul ,   European Lung Cancer Working Party
Published: March 2020

e18006 Background: Main prognostic factors for survival in NSCLC pts are stage and performance status (PS) while sex, histology and others are reported. However, these variables do not allow predicting individual prognosis, justifying further research. MiRNA are small non-coding RNAs regulating gene expression. As a secondary aim of a prospective study, we looked at the prognostic value of tumour miRNA on survival in NSCLC pts treated by cisplatin (60 mg/m2 D1) and vinorelbine (25 mg/m2, D1+8) 1st line chemotherapy. Methods: During the diagnostic bronchoscopy, a biopsy was lysed into Tripure Isolation Reagent (Roche Diagnostics) on ice, snap frozen and stored at -80°C. MiRNA expression was assessed using TaqMan Low Density Arrays (756 human miRNA panel, Applied Biosystems) and normalized using the delta delta CT method to RNU48 (SNORD48) CT value for every sample. Survival was measured from the registration date. Results: The main characteristics of 38 eligible pts were: median age 60 years, male 27 (71%), 80-100 Karnofsky PS in 26 (68%), adenocarcinoma 20 (53%), stage IV 30 (79%). At time of analysis, 25 pts were dead. After stepwise selection among 756 analysed miRNA, a combination of 4 miRNA including miR-200c, miR-424, miR-29c and miR-124 provided a prognostic signature for survival. Using a linear combination of the miRNA CT values with Cox's regression coefficients as weights, we constructed a prognostic score. With a cut-off of 52, the signature distinguished pts with good (n = 18) and poor (n = 20) prognosis with respective median survival of 47.3 months (95% CI 29.8-52.4) and 15.5 months (95% CI 9.1-22.8) (p <0.001; hazard ratio 21.1, 95% CI 4.7-94.9). The same signature discriminated pts with “good progression-free survival” (median 19.8 months; 95% CI 15.3-33.8) from the others (median 9.1 months; 95% CI 6.3-15.5) (p <0.001; hazard ratio 3.8, 95% CI 1.7-8.7). Conclusions: A 4 miRNA signature is associated with improved survival in patients with advanced stage NSCLC treated with 1st line cisplatin and vinorelbine. These results need confirmation in an independent cohort and the signature has to be compared to conventional prognostic factors.
Differential effect of erlotinib on survival of patients with non-small cell lung cancer in terms of EGFR status: A meta-analysis.
Authors: Tun Nay Min , Nayak Asha 
Published: March 2020

e18024 Background: Erlotinib is a small-molecule tyrosine kinase inhibitor that inhibits the protein kinase activity of epidermal growth factor receptor (EGFR). The primary objective of this meta-analysis is to compare the response of patients with EGFR-positive versus EGFR-negative advanced non-small-cell lung cancer (NSCLC) to erlotinib in terms of overall survival (OS) and progression-free survival (PFS). Methods: A Medline search using the MeSH terms “erlotinib” and “lung” in the title field, filtered by ‘clinical trial’, yielded 108 articles. Clinical trials involving erlotinib with available survival data on EGFR-positive versus EGFR-negative NSCLC were searched for. The intervention effect estimate and standard error of each study was derived from the hazard ratio (HR) and p value. Generic inverse variance method was applied to compute the overall effect size and HR with 95% confidence interval (CI). Fixed or random effects model was used according to the level of between-study heterogeneity. Results: 3 studies including 504 patients were eligible for the analysis. All patients received erlotinib in a single arm. EGFR gene mutation was tested in 326 patients (35 mutation-positive, 188 wild-type, 103 indeterminate). EGFR gene amplification by fluorescent in-situ hybridization (FISH) was studied in 353 patients (100 positive), and EGFR protein expression by immunohistochemistry (IHC) in 368 patients (290 positive). Patients with EGFR gene mutation had significantly longer PFS (HR = 0.4, CI 0.25-0.64, p = 0.0001) but not OS (HR = 0.59, CI 0.18-1.95, p = 0.39). In contrast, EGFR FISH-positivity was associated with better PFS as well as OS (HR = 0.52, CI 0.39-0.71, p < 0.00001 and HR = 0.65, CI 0.47-0.88, p = 0.006, respectively). Conclusions: Results of EGFR gene amplification by FISH rather than EGFR gene mutation by PCR may be a better predictor of survival for advanced NSCLC patients receiving erlotinib. Subgroup analyses of erlotinib's differential effect on NSCLC patients with regard to their EGFR status (as measured by PCR, FISH or IHC) are further warranted in randomized controlled trials.
Activity and safety of CPBev regimen (cisplatinum, pemetrexed, and bevacizumab) as first-line therapy for locally advanced or metastatic adenocarcinoma of the lung: Final results of a phase II study.
Authors: Bordonaro Roberto , Soto-parra Hector , Giannitto-Giorgio Carmelo , Cinieri Saverio , Latteri Fiorenza , Sergi Concetta , Pappagallo Giovanni L. , Cordio Stefano Sergio , Salice Placida , Sambataro Daniela , Potenza Enrico 
Published: March 2020

e18026 Background: During the past five years the paradigms of advanced lung cancer therapy dramatically changed; Bevacizumab and Pemetrexed, when administered separately in association with platinum salts, demonstrated to improve survival in patients with non-squamous histologies. In the aim to investigate activity and safety of a three-drugs-regimen containing both these agents and cis-platinum, we conducted a multi-institutional phase II study started on november 2007. Methods: chemonaive patients with non-squamous non-small cell lung cancer were considered eligible We adopt the two-stage of Simon model as statistical design of the study; activity of the regime, expressed as overall response rate and safety were the main end-points. Administered doses were 75 and 500 mg/p.s.m for cis-platinum and pemetrexed respectively and 7.5 mg./kg for Bevacizumab, for 3 - 6 cycles. G-CSF were administered only after the first cycle of therapy, whereas vitamin supplementation started from day 1 of the first cycle. No maintenance therapy was allowed. Results: We registered 9 partial responses among the first 15 patients treated so, accordingly with the design of the study, we completed the enrollment up to 32 patients. Patients characteristics are: male/female: 20/12, median age (years): 59 (r. 36 - 77), ECOG-WHO/PS 0/1: 21/11. One hundred eighty-three cycles of CPBev were administered: we registered only 13 cases of grade 3 adverse events. No grade 4 toxicities were observed. One case of allergic reaction to cis-platinum were observed. In terms of response rate, we registered 20/32 (62.5%) partial responses, 8/32 (25%) stable diseases and 4/32 (12.5%) progressive diseases, with a clinical benefit rate of 28/32 (87.5%). Results in terms of outcome parameters expressed by progression-free and overall survival will be presented at the meeting. Conclusions: On the basis of our data, CPBev have a good toxicity profile and seems to be extremely active in advanced non-squamous lung carcinomas.
Endostar plus gemcitabine/cisplatin (GP) with maintenance endostar as first-line therapy for advanced non-small cell lung cancer (NSCLC): Preliminary results of a phase II study.
Authors: Lu You , Huang Meijuan , Fan Qingxia , Wu Qi , Wang Jin , Li Lu , Zhang Xi , Guo Chengye , Li Wenhui , Peng Feng , Ouyang Xuenong , Yu Ding , Cai Xiaohong , Xu Yong , Hou Mei , Luo Rongcheng , Zhang Tao 
Published: March 2020

e18033 Background: Endostar is a recombinant human endostatin. We conducted a multi-centre trial to investigate the efficacy and safety of Endostar plus GP with maintenance Endostar as first- line therapy for advanced NSCLC Methods: Chemotherapy-naïve patients with histologically or cytologically confirmed, measurable, stage ‡W NSCLC were enrolled from 11 centers in China. All patients received gemcitabine 1,000 mg/m2 (days 1 and 8) plus cisplatin 25 mg/m2 (days 1-3) every 21 days. Patients achieving objective response or disease stabilization following initial 2 cycles of GP were given Endostar (15 mg) on days 1–14 every 21 days in combination with another 2 cycles of GP. Then, patients who did not progress received maintenance endostar (15 mg) on days 1–14 every 21 days until disease progression or unacceptable toxicity. The primary was progression-free survival (PFS). Secondary endpoints were treatment-related toxicity and median overall survival (OS). Results: Between Oct.2008 and Sep. 2010, we enrolled 85 patients (median age: 52.2 years; median KPS score: 80; stage IV with M1b: 94.1%; adenocarcinoma: 64.6%). 48 (56.5%) patients complete 4 cycles of GP plus 2 cycles of Endostar and 33(38.8%) patients were treated with maintenance Endostar. For 38 patients receiving maintenance therapy, median PFS throughout the study period by independent review was 5.97 month and 1-year survival rate was 75.8%. Median PFS were 3.97 months for all 85 patients, while 1-year survival rate was 64.7%. No treatment related death occurred. 28(32.9%) patients had at least one grade 3/4 adverse events; the grade 3/4 hematologic toxicity included anemia in 32.9%, thrombocytopenia in 25.9%, neutropenia in 4.7% of patients. The grade 3/4 non-hematologic toxicities included nausea/vomiting in 18.8%, rash in 5.9%, hepatic impairment in 3.5%, diarrhea in 1.2%, hemorrhage in 1.2% of patients. Conclusions: This regimen, involving maintenance Endostar, didn’t significantly improve PFS in advanced NSCLC patients as compared to historic control although associated acceptable toxicity has been demonstrated
CEA levels and EGFR mutations associated with patients in nonsmokers lung cancer.
Authors: Han Baohui , Dong Yu , Zhang Yanwei , Jin Bo 
Published: March 2020

e18038 Background: Background: As the non-smoking Asian patients with adenocarcinoma of the EGFR gene tend to have higher mutation rate, and serum CEA levels in patients with lung cancer, especially adenocarcinoma, high expression in many recent years, studies have also found that serum CEA levels in EGFR-changes before and after TKI therapy efficacy and treatment are closely related. However, whether serum CEA level and EGFR gene mutations is a correlation between two biomarkers. This study attempts to explore its relevance between EGFR gene mutations and analysis of serum CEA levels in non-smoking patients with lung cancer and it’s various clinical and pathological features. Methods: 84 cases of histologically confirmed non-smoking history in newly diagnosed lung cancer patients, respectively, serum CEA levels and histological detection of EGFR gene. According to the expression level of serum CEA patients were divided into high expression and did not express two groups were compared in patients with EGFR gene mutations. Results: 58/84 cases were found with activity EGFR gene mutations, the overall mutation rate was 69.0%, serum CEA levels high expression of EGFR gene mutation was significantly higher than non-expression group (serum CEA levels were <5ng/ml, ≥ 5ng/ml <20ng/ml, ≥ 20ng/ml patients with EGFR gene mutations histology were 63.2%, 70.8%, 81.8%). Conclusions: Non-smoking lung cancer patients with serum CEA levels and EGFR gene mutations was positively correlated.
Periodic measurement of N-telopeptides of type I collogen in serum (sNTx) for early diagnosis of bone metastasis in patients with lung cancer.
Authors: Takeda Koji , Tokunaga Shinya , Daga Haruko , Okada Hideaki , Taira Koichi , Miyamoto Natsuko , Hattori Michiyo , Tamiya Motohiro , Kobayashi Masashi , Okamoto Norio , Sasada Shinji , Suzuki Hidekazu , Morishita Naoko , Matsuura Yuka , Hirashima Tomonori 
Published: March 2020

e18042 Background: The bone resorption biomarker sNTx has been previously shown to add value as an aid in the diagnosis of bone metastasis in patients with lung cancer. The objective of this prospective study was to determine if periodic sNTx measurements could lead to early diagnosis of bone metastasis in patients with lung cancer. Methods: Patients with newly diagnosed organ-confined lung cancer were enrolled. sNTx values were determined once each month using the OSTEOMARKTM serum NTx assay (Alere Medical). The presence or absence of bone metastasis was determined by monthly physical examination and by bone scintigraphy every 3 months for 12 months. All patients were required to provide written informed consent. Results: Forty patients were enrolled between June and December 2010. One patient withdrew early and was excluded from analysis. The mean +/- 1 SD baseline level of sNTx was 17.5 +/- 4.4 nM BCE/L. Five patients developed bone metastasis (as characterized by bone scintigraphy) during the study period. The level of sNTx in subjects with bone metastasis was slightly increased (21.6 +/- 3.2 nM BCE/L), however, in these patients, there was no statistically significant difference between sNTx values at baseline (18.2 +/- 4.2 nM BCE/L) and when metastasis was diagnosed. (p=0.176). When a cut-off value of sNTx was set to 22.0 nM BCE/L, the sensitivity and the specificity of detection of bone metastasis were 80.0% and 41.2%, respectively. Using this cut-off, the elevation of sNTx could predict bone metastasis at least one month before diagnosis by bone scintigraphy in all 5 patients, however, the specificity was relatively low for clinical implementation. Additionally, the sensitivity and the specificity of early detection of systematic spread of disease (including bone metastasis) were 70.6% and 45.5%, respectively. Conclusions: Periodic determination of sNTx in patients with organ confined lung cancer did not provide sufficient specificity for it to be used for the early diagnosis of bone metastasis or disease progression.
Metastatic NSCLC: Can molecular biology guide surgical decision making?
Authors: Ulivi Paola , Mattioli Sandro , Puccetti Maurizio , Capelli Laura , Zoli Wainer , Ricci Marianna , Calistri Daniele , Amadori Dino , Milandri Carlo 
Published: March 2020

e18045 Background: Guidelines do not recommend surgical resection of metastatic non-small cell lung cancer (NSCLC), with the exception of single brain or adrenal gland lesions, and further resection in the event of a new lung metastasis is generally not indicated. A different therapeutic approach is used in patients with multiple primary lesions. Can molecular alterations help to distinguish between independent primary tumors and metastatic lesions? Methods: A 74-year old woman underwent bilateral inferior lobectomy in May 2008 for two different synchronous NSCLC (adenocarcinoma and adenocarcinoma in situ, formally known as “bronchioloalveolar carcinoma” – J Thorac Oncol 2011;6:244–285). Three months after surgery the patient developed a single symptomatic brain metastasis. A CT scan also highlighted a suspect lingular lesion of the lung. Stereotaxic brain radiotherapy was carried out followed by systemic platinum-based chemotherapy. The brain metastasis showed very good radiological partial remission (PR) while the lung lesion remained stable after 4 cycles of chemotherapy. After two years’ follow-up the brain metastasis remained in PR whereas the lung lesion had progressed, and fine needle aspirate revealed adenocarcinoma. Results: Molecular analysis showed that EGFR gene status was wild type in all three tumors, whereas K-ras gene status differed. With regard to the two synchronous tumors, a barely visible G12C K-ras gene mutation was found in the bronchioloalveolar carcinoma, while a G12D K-ras mutation was detected in the adenocarcinoma. Moreover, K-ras gene status in the lingular node revealed a G12A mutation. On the basis of these results we hypothesized the presence of a third lung cancer and it was decided to proceed with surgery. The patient underwent laparoscopic lingulectomy which confirmed the diagnosis of adenocarcinoma with the same G12A K-ras mutation. Conclusions: This case highlights the importance of the molecular characterization of tumors in patients with multiple lesions. Different alterations within a single gene in different lesions are indicative of an independent clonal origin and suggestive of separate primary tumors rather than secondary lesions, thus facilitating treatment decision making.
Two genetic polymorphisms of EGFR as useful predictive biomarkers for NSCLC patients receiving EGFR TKIs.
Authors: Kang Jin Hyoung , Shin Jung-Young , Kim Jeong-Oh , Oh Ji-Eun , Zhang Xiang-Hua , Hong Sook Hee , Jeon Eun Kyoung , Cho Eun Kyung 
Published: March 2020

e18050 Background: The EGFR mutation on particular exons has been known as a strong predictive biomarker to EGFR TKIs (tyrosine kinase inhibitors) in NSCLC pts. However, some pts having wild type EGFR do not infrequently show clinically favorable outcome to EGFR TKIs. Accordingly, we hypothesized that clinical outcome and skin toxicity to EGFR TKIs might be related to specific single nucleotide polymorphisms regulating the expression of EGFR gene as well as EGFR sensitive mutation. Methods: In 211 advanced or metastatic NSCLC pts receiving gefitinib or erlotinib, we assayed mutation status of EGFR in paraffin embedded tumor tissue using PNA clamping method and direct sequencing. Six different SNPs in genomic DNA extracted from peripheral blood were analyzed; promoter 191C>A, 216 G>T, CA repeat number, exon 13 R497K, exon 20 2607G>A, and exon 25 D994D. Results: M:F ratio was 106:105 and mean age was 63.2 (35.0-82.0). Histological subtypes are as follows: 175 adenocarcinoma, 32 squamous cell ca. and 3 large cell ca. Objective response (CR+PR) was observed in 78 pts (36.9%) and SD in 69 pts (32.7%). Median PFS and OS were 8.7 ± 11.3 and 15.9 ± 14.8 months, respectively. Of 167 pts in whom EGFR mutation was analyzed, 68 pts (40.7%) had EGFR harboring sensitive mutation. In R497K, wild type (RR) was 35 (21.0%) and K alleles (RK + KK) were 132 (79.0%). In D994D, wild type (GG) was 76 (45.5%) and heterozygote and homozygote variants (GA+AA) were 91(54.5%). Statistically significant differences of PFS and OS were observed between wild and hetero-/homozygote variants of R497K (11.9 m vs. 36.2 m, p=0.037 and 23.7 m vs. 39.1 m, p=0.054, respectively) in the pts harboring mutant type EGFR. Meanwhile, in the pts harboring wild type EGFR, GA+ AA genotype of D994D demonstrated much longer PFS and OS compared with GG genotype (PFS: 18.5 vs. 3.7 m, p=0.013 and 37.6 vs. 15.2 m, p=0.035, respectively). In addition, skin rash showed statistically significant association with R497K polymorphism (P=0.031). Conclusions: Our data suggest that two germline genetic variations of EGFR gene, R497K and D994D, be useful pharmacogenetic biomarker to predict longer PFS and OS for EGFR TKIs in advanced NSCLC pts harboring mutant type and wild type EGFR, respectively.
Impact of EGFR tyrosine kinase inhibitors on skeletal-related events in EGFR mutation-positive non-small cell lung cancer patients with bone metastases.
Authors: Yoshida Tatsuya , Yoh Kiyotaka , Goto Koichi , Umemura Shigeki , Niho Seiji , Ohmatsu Hironobu , Nagai Kanji , Ohe Yuichiro 
Published: March 2020

e18054 Background: Clinical outcome of EGFR mutation-positive non-small cell lung cancer (NSCLC) patients with bone metastases is less well known. The purpose of this study was to evaluate the clinical outcome of EGFR mutation-positive NSCLC patients with bone metastases who were treated with EGFR tyrosine kinase inhibitors (TKIs). Methods: From January 2008 to December 2010, 127 patients received first-line chemotherapy for advanced or postoperative recurrent NSCLC with bone metastasis at our institution. EGFR mutational status was analyzed using a PCR-based assay for EGFR exons 18 to 21. Clinical outcome including the incidence of skeletal-related events (SREs), time to the first SREs from first-line chemotherapy and overall survival (OS) was evaluated by the EGFR TKIs-sensitive mutations status (either exon 19 deletion or L858R in exon 21). SREs were defined as a pathologic fracture, spinal cord compression, surgery to bone, radiation therapy (RT) to bone, other radiological intervention, and hypercalcemia of malignancy. Results: Sixty-two (50%) of the 125 patients were sensitive EGFR mutations positive. 39 of 62 (63%) EGFR mutation-positive patients were treated with EGFR TKIs (gefitinib or erlotinib) as first-line chemotherapy, and most of negative patients received cytotoxic agents such as platinum-based chemotherapy. Zoledronic acid were administered in 50 % of EGFR mutation-positive patients, and in 57 % of negative patients, respectively (P= 0.59). With a median follow-up of 13 months, the incidence of SREs were 21% in EGFR mutation-positive patients, and 38% in negative patients, respectively (P<0.05). Additionally, median time to first SREs from first-line chemotherapy in EGFR mutation-positive patients was significantly longer than negative patients (13 months versus 6 months, P<0.05). Median OS in mutation-positive patients was 26 months, as opposed to 12 months in negative patients (P<0.05). Conclusions: Our study indicated that EGFR mutation-positive NSCLC patients with bone metastases who were treated with EGFR TKIs have favorable clinical outcome on SREs compared with mutation-negative patients.
Utility of nonsurgical diagnostic specimens in cellular differentiation and molecular profiling (EGFR mutation and EML4-ALK detection) of NSCLC.
Authors: Cohen Victor , Levitt Amanda , Kasymjanova Goulnar , Agulnik Jason Scott , Al Banna Amr , Small David I. , Pepe Carmela , Spatz Alan , Brandao Guilherme 
Published: March 2020

e18061 Background: The utility of different non-surgical specimens for the accurate determination of cellular and molecular attributes in NSCLC has yet to be established. The primary objective of this study was to determine and compare the yield of non-surgical specimens for the accurate cellular differentiation of NSCLC and analysis of EGFR and EML4-ALK mutations. Methods: Patients with a histologic diagnosis of NSCLC from January 2004 to September 2010 were included. Diagnosis was based on cytological characteristics and IHC analysis. Fragment analysis and real-time PCR methods were used for EGFR mutation detection. EML4-ALK rearrangements were detected by FISH. Diagnostic specimens were divided into pathology specimens (PS) and cytology specimens (CS). PS included surgical and non-surgical biopsies. CS included FNA (TBNA and TTNA) and body fluid samples. These groups were compared using χ2 analyses. Yield of histologic analysis was compared in a subgroup of patients who underwent both surgical and non-surgical procedures. Results: 715 patients were included in the study. The yield of CS when compared to PS was lower for cellular differentiation (76% vs. 91%, p <0.0001) and IHC (70% vs. 89%, p <0.0001). Among the CS, TTNA provided better yield than TBNA for cellular differentiation (89% vs. 67%, p < 0.0001) and IHC (85% vs. 72%, p = 0.023). 94 patients underwent both surgical and non-surgical procedures. As compared to surgical biopsies, the yield of non-surgical procedures for cellular classification was 81% in body fluid samples, 68% in FNA, and 88% in non-surgical biopsies. 320 patients were tested for both EGFR and EML4-ALK mutations. The yield of CS versus PS was lower for EGFR mutation status (74% vs. 93% p < 0.0001). Among the CS, TTNA provided better yield than TBNA for EGFR mutation analysis (90% vs. 70%, p = 0.045) and body fluid samples were least likely (59%) to provide EGFR mutation status. Three EML4-ALK FISH-positive cases were identified. All samples were PS. All EML4-ALK positive cases tested negative for EGFR mutations. Conclusions: Non-surgical lung biopsy specimens can yield sufficient samples for histologic assignment and mutational analysis.