bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical significance of 22C3-PD-L1 IHC expression in surgically resected non-small cell lung cancer.
Authors: Lin Gen , Li Chao , Huang Cheng , Fang Rong Xi , Xu Peng Hai , Lin Dong xian , Wu Biao , Chen Xiaohui , Xu Chunwei , Mok Tony 
Published: September 2018

e20507 Background: Multiple studies correlated PD-L1 expression with clinicopathologic and survival have reported conflicting results.Methods: We retrospectively collected 185 patients with NSCLC who underwent surgical resection to detect PD-L1 IHC using the clone 22C3 pharmDx kit and evaluated PD-L1 expression along with clinicalpathological characteristics and prognosis.Results: Most of tumors had TNM stage lower than stage III. Adenocarcinoma and squamous carcinoma was accounting for 56.8% and 43.2%, respectively. Heterogeneous distribution of PD-L1 staining was observed, PD-L1 strong-positive and weak-positive staining were detected in 11.4% and 24.3% of patients. In univariate analysis, smokers, squamous carcinoma, central type cancer, larger primary tumor size, metastatic lymphonode, neoadjuvant chemotherapy and TILs present was found associations with higher proportion of PD-L1 positive expression. In multivariate analysis, only primary tumor size, smoking status, TILs status and neoadjuvant chemotherapy were confirmed associations with PD-L1 positive expression. Especially, PD-L1 positive expression rate climbed gradually with the increase of tumor size, T≤3cm 21.0%, 3cm < T≤5cm 32.8%, 5cm < T 50.7%, respectively, p = 0.003. PD-L1 positive expression highly improved with patients with neoadjuvant chemotherapy versus without neoadjuvant chemotherapy, 88.9% vs 33.0%, respectively, p = 0.009. In survival analysis, neither PD-L1 expession/TILs status nor the interaction term between were confirmed as independent prognosis biomarkers . PD-L1 negative group had a tendency of longer OS than PD-L1 positive group, mOS 66.4 months (95%CI, 59.4-73.4) vs. 39.2 months (95%CI, 16.0-62.4), respectively, p = 0.096. Conclusions: PD-L1 expression showed heterogeneous distribution and was highly influenced by tumor size, smoking status, TILs and neoadjuvant chemotherapy.It indicated a strong spatial and temporal variability in the PD-L1 expression, which could be in part to explain the conflicting results in PD-L1 expression and correlation with clinicopathologic in multiple studies. The dynamics of PD-L1 expression may also limit its use as a prognosis biomarker.
Interlaboratory-concordance of PD-L1 IHC for NSCLC.
Authors: Scheel Andreas H. , Bänfer Gudrun , Baretton Gustavo Bruno , Dietel Manfred , Diezko Rolf , Henkel Thomas , Heukamp Lukas C. , Jasani Bharat , Jöhrens Korinna , Kirchner Thomas , Petersen Iver , Reu Simone , Schildhaus Hans-Ulrich , Schirmacher Peter , Tiemann Markus , Warth Arne , Weichert Wilko , Wolf Juergen , Rüschoff Josef , Buettner Reinhard 
Published: September 2018

e20508 Background: Immunohistochemistry (IHC) of the PD-L1 protein has become a mandatory diagnostic test for NSCLC. We conducted a two-step round robin test to analyze interobserver- and interlaboratory-concordance of PD-L1 IHC and to compare four clinical trial assays (CTAs; 28-8, 22C3, SP264, SP142) and laboratory-developed tests (LDTs). Results of step-one showed that reproducible PD-L1 IHC scoring is feasible; here we present the data on interlaboratory concordance Methods: Interlaboratory-concordance was tested by a centrally prepared tissue-microarray containing 21 NSCLC specimens that was stained at ten sites using CTAs and LDTs. Assay-performance was assessed with a second tissue-microarray containing eleven cell-lines with defined PD-L1 expression. Slides were evaluated by central quality-control and image-analysis. Results: The four CTAs yielded reproducible IHC-stainings at all sites while the results of the LDTs were mixed: Six protocols showed appropriate IHC quality with staining patterns similar to 22C3 and 28-8 CTAs, five protocols yielded less DAB-deposits and reduced staining intensity. Interlaboratory-concordance of carcinoma cell scoring using the 6-step system was moderate (κ = 0.43-0.69) while the included cut-offs ≥1% and ≥50% showed substantial concordance for the CTAs (κ = 0.73-0.89) and moderate concordance for the LDTs (κ = 0.50). No significant differences in interlaboratory-concordance were found among the CTAs. However, differences in the resulting staining patterns were noticed: While 22C3 and 28-8 showed similar staining patterns, SP263 showed minor differences in some cases and SP142 showed distinct patterns. Conclusions: The data show that the PD-L1 CTAs can be reproducibly employed and scored at different sites. LDTs with staining patterns similar to the CTAs are possible yet have to be carefully calibrated to match the appropriate intensity-range. The choice of assay and the set-up of the IHC-protocol may strongly influence the resulting staining.
Detecting KRAS and NRAS resistance mutations in plasma of lung cancer patients.
Authors: Potikyan Gary , Falat Magdalena , Duchoud Fabienne , Maland Matthew , Adhikari Sanjay 
Published: September 2018

e20511 Background: Mutations in KRAS and NRAS have been found in a number of malignancies, particularly metastatic colorectal cancer, lung adenocarcinoma, and thyroid cancer. Several studies have shown that specific mutations in KRAS and NRAS are less likely to respond to anti-EGFR therapies. Several diagnostics have been developed to identify such mutations. However, in a large number of cancer patients, tumor biopsy poses a significant health risk thereby limiting the tissue available for current molecular diagnostics. Non-invasive liquid biopsy diagnostics are revolutionizing cancer treatment selection, patient prognosis, and monitoring. Low abundance circulating tumor DNA (ctDNA) is purified from patient plasma and used as an alternative source of genomic material for detecting tumor mutations. Currently available qPCR kits for detecting RAS mutations have a limited sensitivity and coverage since they are not optimized for liquid biopsy purposes. Methods: We have developed a two-step PCR to qPCR method to identify down to single mutant copies of KRAS or NRAS in ctDNA isolated from plasma. The mutant copies are first enriched by a novel multiplexed formula of primers and wildtype (WT) allele blockers. The mutations are then identified by EntroGen’s RAS Mutation Screening Panel or next generation sequencing (NGS). Synthetic mutant DNA was spiked in a background of WT DNA purified from plasma to yield a range of mutant allelic burden over WT background. The dilutions were analyzed to determine the method’s sensitivity. We subsequently used the method to screen 53 non-small cell lung cancer (NSCLC) patient samples. Results: Our two-step method detects single digit mutant copies of 35 clinically significant KRAS and NRAS mutations. Furthermore, NGS experiments demonstrated the two-step method can enrich mutations more than 52-fold. KRAS 12/13 mutations were identified in 6 out of 53 (11%) NSCLC patients. Conclusions: ctDNA-based liquid biopsy tests have been employed by few laboratories but are generally available only as a service. EntroGen’s platform agnostic liquid biopsy RAS assay provides clinicians the tools necessary to determine cancer treatment and monitor patients using most PCR and qPCR instruments.
The value of Fn14, CD44v, and EGFR expression in lung adenocarcinoma patients with and without activating EGFR gene mutation.
Authors: Bryl Maciej , Bednarek-Rajewska Katarzyna , Zalewski Przemysław , Janicka-Jedyńska Małgorzata , Ramlau Rodryg , Barinow Wojewódzki Aleksander , Woźniak Aldona 
Published: September 2018

e20514 Background: Lung cancer is considered the most common cause of death in the world. The prognosis for patients is poor and depends on the clinical stage and the histological type of cancer. There is a need to identify and develop new therapeutic targets that could improve the prognosis of NSCLC patients and may be responsible for development of resistance to TKI therapy. Increased expression of Fn14 or CD44v and EGFR was observed in many tumors and also correlated with the overall survival of NSCLC patients Methods: We analyzed the clinical data and the immunohistochemical expression of Fn14, CD44v and EGFR in tumor tissues from 61 patients with NSCLC divided in two groups according to the presence of activating EGFR gene mutation. The aim of the study was to evaluate the correlation between the expression of the studied molecules and the neoplastic disease course of NSCLC patients. Results: Increased expression of Fn14 was observed in study group (B) compared to expression of this molecule in the control group (K). There were no differences in the intensity of the reaction with anti CD44v and EGFR antibodies in both groups. OS was significantly longer in the study group. Histological grade of tumor correlated with the intensity of CD44v expression in both groups. There was no correlation between the OS and Fn14 expression in any group. Negative correlation was noted between the expression of CD44v and the OS in the study group and between EGFR expression and the OS in both groups. Conclusions: Our observations suggest that the expression of CD44v and EGFR may be useful clinical markers of prognostic value in lung adenocarcinoma patients regardless of the presence of activating mutation in EGFR gene. Simultaneous assessment of Cd44v and EGFR expression may grant a greater prognostic value than the assessment of each receptor separately. Increased expression of Fn14 receptor in patients with EGFR gene mutation may become a new target in therapy allowing to eliminate the problem of secondary resistance to treatment with TKI’s
Prognostic factors for oligometastasis after 1st line first or second generation TKI for EGFR-mutated metastatic NSCLC.
Authors: Lee Victor HF , Choi Cheuk-Wai , Yau Tsz-Yui , Or Dicky , Choy Tim-Shing , Leung Dennis KC , Lau Kin-Sang , Lam Ka-On , Leung To-Wai 
Published: September 2018

e20521 Background: First and second generation TKI (gefitinib, erlotinib, afatinib) is the standard 1st line therapy for EGFR-mutated metastatic NSCLC. Resistance ultimately develops despite initial durable response. Oligometastasis (OM) (defined as ≤5 newly developed metastatic lesions after TKI therapy) can be effectively treated with local ablative therapy so that the original TKI can be continued until further disseminated progressive disease. Methods: 151 patients treated with 1st line TKI for their EGFR-mutated metastatic NSCLC recruited between 2009 and 2013 in our previous study (Lee et al, Journal of Thoracic Oncology 2013) were now included in the training set. Another 263 prospectively recruited patients treated in the same setting between 2013 and 2016 were in the validation set. The factors prognostic of OM-free survival in the training set were re-tested again in the validation set. Results: The OM-free survival for the training set did not differ from that for the validation set (mean 68.4 months vs. 56.1 months; p = 0.961, median OM-free survival were not reached for both sets). 37 (24.5%) and 56 (21.2%) patients in the training set and validation set respectively developed OM. Sex (hazard ratio 0.490, 95% confidence interval 0.257–0.936; p = 0.031) was the only significant prognostic factor of OM-free survival in the training set while it was just borderline significant in the validation set (hazard ratio 0.631, 95% confidence interval 0.366–1.088; p = 0.098). Conclusions: Male patients were more likely to develop OM after 1st line first or second generation TKI. A more closer vigilance should be adopted for them so that effective local ablative therapy can be duly performed to procrastinate the use of 2nd line treatment.
The advantage of pemetrexed combined with platium chemotherapy treatement for advanced nonsquamous non-small-cell lung cancer (NSCLC) patients without drive oncogene.
Authors: Xu Haiyan , Wang Yan 
Published: September 2018

e20527 Background:Platinum-based chemotherapy is the standard first-line treatment for non-squamous NSCLC patients without driver oncogene (EGFR, KRAS, and ALK mutations). However, it remains unknown that from which chemotherapy regimens can those patients get more benefit. Therefore, the study explore whether pemetrexed combined with platinum chemotherapy is superior to the other platinum-based chemotherapy regimens.Methods:We performed a retrospective study on 114 histologically or cytologically advanced IIIB-IV NSCLC patients admitted to Cancer Hospital from 1 Jan 2013 to 30 Dec 2015. The primary endpoint was the median progression free survival (PFS) and the disease control rate (DCR). And objective response was evaluated every two cycles by imaging according to the Response Evaluation Criteria In Solid Tumors (RECIST version 1.0). The multivariate logistic analyses were carried out by SPSS version 16.0. Results:114 patients received platinum-base doublet as first-line treatment. Among them, 59 patients underwent pemetrexed-containing regimens, and 55 patients received non-pemetrexed-containing regimens (38 patients for paclitaxel-containing regimens, 13 patients for gemcitabine-containing regimens, and 4 patients for other regimens.). The baseline characteristics between two groups were comparable ( p>0.05). The median PFS of pemetrexed-containing regimens was significantly longer compared with that of non-pemetrexed-containing regimens (7.2 months [95% CI: 5.3–9.1] vs. 4.9 months [95% CI: 3.2–6.6], p%0.05). DCR of pemetrexed-containing regimens was better than that of non-pemetrexed-containing regimens in the multivariate logistic analysis (89.8% vs.74.5%, p%0.05).Conclusions:Pemetrexed-containing regimens displayed more benefit than the other chemotherapy regimens for non-squamous NSCLC patients without driver oncogene. However, large scale perspective study is warranted in the future.
EGFR-TKI rechallenged treatment combined with apatinib in non-small cell lung cancer with EGFR-TKI resistance.
Authors: Liang Li , Li Fang , Cao Baoshan , Zhang Zhaohui , Zhu Xiang , Wang Jiadong 
Published: September 2018

e20529 Background: Acquired resistance to EGFR-TKIs frequently occurs in non-small cell lung cancer (NSCLC) patients (pts) with sensitizing EGFR mutations. EGFR-TKIs rechallenged therapy is one of the recommended strategies. This study aimed to explore the efficacy and safety of EGFR-TKI combined with apatinib (a TKI against VEGFR-2) in EGFR-TKIs resistant pts. Methods: From Aug 2015 to Nov 2016, we retrospectively screened 16 NSCLC pts who acquired resistance to the EGFR-TKI therapy and chose apatinib plus EGFR-TKI as the second-line treatment in our hospital. All pts signed informed consent before treatment. Results: Pts characteristics and efficacy are shown in the table below. Two pts discontinued on the 4th and 10th day due to side effects, respectively, and thus were excluded from short efficacy analysis. No CR, 4 PR and 10 SD were confirmed, resulting in an objective response rate of 28.6% and a disease control rate of 100%, respectively. At the cut-off date on Feb 7, 2017, 6 pts were still being treated. The median progression-free survival was 4.60 months (95%CI, 2.23–12.52 months). The main adverse events were hypertension, hand-foot skin reaction (HFSR) and diarrhea. Five (31.3%) grade 3 hypertension, 1 (6.3%) grade 3 HFSR and 1 (6.3%) grade 3 diarrhea were observed. Conclusions: EGFR-TKI combined with apatinib may stand for a new option for NSCLC pts with acquired EGFR-TKIs resistance. [Table: see text]
Effect of liquid withdraw technique on the incidence of pneumothorax and tumor tissue amount of CT-guided cutting needle lung biopsy: An expanded retrospective study.
Authors: Li Rutian 
Published: September 2018

e20535 Background: CT-guided cutting needle lung biopsy is important for the diagnosis of lung cancer especially in the area of precision medicine. In ASCO 2015, we reported that “Liquid withdraw” technique (to inject small amount of liquid while withdraw of the needle) can prominently reduce incidence of pneumothorax when combined with co-axial technique in 38 cases. In this reported, we retrospectively studied 90 patients undergoing CT-guided cutting needle lung biopsy to investigate the role of this technique in reducing complications and promoting biopsy effectiveness. Methods: From Jan 1st, 2014 to Nov 30th, 2016, we retrospectively studied 92 CT-guided percutaneous lung biopsies using co-axial and liquid withdraw techniques in 90 patients. The pathologies and complications secondary to biopsy procedure were noted. Pneumothorax and bleeding was graded as mild (mild and very mild), moderate, and severe. Results: 88 cases were diagnosed out of 92 biopsies (95.7%), of which 60 cases were adenocarcinoma. Liquid withdraw technique assured adequate tissue for diagnosis and treatment planning of lung cancer. Among 71cases diagnosed as NSCLC, only 5 (7.0%) were diagnosed as NOS. Among 52 cases of adenocarcinoma who consented EGFR mutation test, only 1 case (1.9%) failed due to insufficient tissue. Among all the biopsies, when acquiring specimens 4-6 times per procedure, the incidence of pneumothorax was in 18 cases (19.6%), among which 13 cases (14.1%) were very mild pneumothorax (lung surface retraction of≤1 cm), mild and moderate pneumothorax accounted for just 4.3%. No severe pneumothorax occurred. 19 cases (20.7%) happened bleeding (18 cases were mild bleeding). No infection, tumor implantation or aeroembolism happened. Conclusions: Compared to lung biopsy without liquid withdraw, the incidence of pneumothorax was reduced from approximately 35% to 19.6%. The liquid withdraw technique also resulted in low rate of other complications and adequate tissue for diagnosis. Next, we are planning to conduct a prospective study to further evaluate the role of this technique in the precision diagnosis and treatment of lung cancer.
The reasons why re-biopsies were not performed after failure with EGFR-TKI.
Authors: Oguri Tomoyo , Horiike Atsushi , Ariyasu Ryo , Koyama Junji , Saiki Masafumi , Sonoda Tomoaki , Takano Natsuki , Nishikawa Shingo , Kitazono Satoru , Yanagitani Noriko , Ohyanagi Fumiyoshi , Nishio Makoto 
Published: September 2018

e20540 Background: Repeat biopsy becomes important to determine subsequent treatment after failure of EGFR-TKI. However, some patients did not receive re-biopsy in real world. Here we retrospectively analyzed the reasons why the patients did not receive re-biopsy. Methods: We reviewed medical records of 235 patients treated with EGFR-TKI at our institution between January 2014 and September 2016 and analyzed the treatment, the progression site after failure of EGFR-TKI and the reasons why they did not receive re-biopsy. Results: 127 of 235 (54%) patients had tumor progression after treatment with EGFR-TKI and 93 (73.2%) of 127 patients received re-biopsy and 34 (26.8%) patients didn’t. The characteristics of 34 patients who did not received re-biopsy were; the median age, 67 years (29-83), male/ female: 12/22, PS0-1/2 ≥:27/7, stage IV/recurrence/other:20/10/4, smoking history never/ex/current: 15/17/2, histology : adeno/other 34/0, EGFR mutation type; 19del/L858R/Other = 13/15/6, prior EGFR-TKI; Gefitinib/Erlotinib/Afatinib/other: 22/9/2/1. The commonest reason why they did not receive re-biopsy was no target lesion to get biopsy (n = 13,38%). CT scans of these patients were retrospectively evaluated and it was confirmed that there were no lesions that could be accessed safely at that time. Central nervous system lesions, multiple small pulmonary lesions and bone metastasis were unaccessible lesions. Although 21 patients had accessible lesions including lung, superficial lymph nodes, pleural effusion, liver, they did not receive re-biopsy because of patient refusal (n = 9), worsening of general condition (n = 3), need for other therapy immediately (ex: chemotherapy, radiotherapy) (n = 3), old age (n = 2), existence of de novo T790M (n = 2), complications (n = 1) and physician’s choice (n = 1). Conclusions: Some patients who did not recieve re-biopsy had some target lesions and it could be increase the re-biopsy rate.
Phase II trial of the c-Met inhibitor tepotinib in advanced lung adenocarcinoma with MET exon 14 skipping mutations.
Authors: Paik Paul K. , Felip Enriqueta , Veillon Remi , Scheele Jürgen , Bruns Rolf 
Published: September 2018

e20541 Background: Approximately 3-4% of lung adenocarcinomas express a truncated form of c-Met (c-Metex14) due to mutation-induced exon 14 skipping. c-Metex14 accumulates on the cell surface and is constitutively active with the ability to drive NSCLC. Data suggest that lung adenocarcinomas harboring c-METex14 are sensitive to c-Met kinase inhibitors. The highly selective c-Met inhibitor tepotinib is well tolerated and active at an oral dose of 500 mg QD. This single-arm phase II trial (NCT02864992) is investigating the efficacy and safety of tepotinib in patients (pts) with advanced lung adenocarcinoma harboring METex14. Methods: Adults with stage IIIB/IV lung adenocarcinoma who have failed 1 or 2 lines of systemic therapy, including a platinum doublet-containing regimen, are eligible. Tumors must harbor mutations that are known to cause exon 14 skipping, confirmed by a central laboratory, but not activating EGFR mutations or ALK rearrangements. Pts receive tepotinib 500 mg QD until disease progression, intolerable toxicity, or withdrawal from treatment for other reasons. The primary endpoint is objective response rate. Secondary endpoints include progression-free and overall survival, safety, pharmacokinetics, and quality of life. Recruitment of 60 patients in Europe, USA, and Japan is planned. Results: Four pts (age 64–77 years; 3 stage IV, 1 stage IIIB, all Caucasian males) have been enrolled. All had received two prior chemotherapy regimens including a platinum doublet. Pts have currently completed 1–5 cycles of tepotinib therapy. The majority of adverse events observed to date have been grade 1/2 in severity; grade 3 disease-related dyspnea, pulmonary embolism, and pleural effusion were observed in one patient and grade 3 tepotinib-related elevated serum amylase in another. Of the 3 pts with post-baseline tumor evaluations, two have had an unconfirmed partial response and the third (with only one post-baseline assessment) stable disease. Conclusions: These initial data suggest that the efficacy of tepotinib 500 mg QD is comparable to that of less selective c-Met inhibitors in pts with c-METex14 NSCLC (ORR > 40%). Tepotinib is also well tolerated. Recruitment to the trial is ongoing. Clinical trial information: NCT02864992.