bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic value of SOX2 and CD8+TIL in limited stage small cell lung cancer.
Authors: Lee Jinsoo , Hong Soon Auck , Hwang Hye Won , Park Se Jun , Shin Kabsoo , Kim Joori , Lee Seung-Hwan , Lee Jieun , Kim In-Ho , Hong Sook-Hee 
Published: May 2020

e21108 Background: SOX2 is a transcriptional factor that drives embryonic stem cell to neuroendocrine cells in lung development and is highly expressed in SCLC. The serum SOX2 antibody in SCLC has been known to mediate neurologic paraneoplastic syndrome. In this study, we evaluated the expression of SOX2 and CD8+ tumor infiltrating lymphocyte (TIL) in LS-SCLC from clinical tumor tissue and their impact on PFS and OS. Methods: Among the total 245 patients with SCLC treated between 2010 and 2018, 75 patients with LS-SCLC with available tumor tissue were enrolled. SOX2 and CD8+ TIL were evaluated by immunohistochemistry. High SOX2 expression was defined as above 100 of H score that was derived from multiplying intensity by the proportion of stained tumor cells. The number of CD8+TILs was counted under high magnification (x400) with four fields in intratumoral area. The cut value for high CD8+TIL was the above the median of total case. Results: 64 patients (85.4%) received etoposide/platinum and definite local therapy (radiation therapy or surgery) and 18 patients (24.0%) received surgical resection. High expression of CD8+ TIL was related to significantly longer PFS (13.9 vs. 8.0 months, P = 0.014) and tended to related to longer OS (32.1 vs. 17.4 months, P = 0.056) than low expression. High expression of SOX2 was tended to related with longer OS and PFS compared to low expression of SOX2 (median, 21.7 vs. 17.1 months, P = 0.118; 12.7 vs. 9.0 months, P = 0.110, respectively) without statistical significance. 29 patients with high CD8+TIL among 52 patients with high SOX2 had significantly longer PFS and OS compared to the other groups (median PFS 19.3 vs. 8.4 months, P = 0.002 and median OS 35.7 vs. 17.4 months, P = 0.004, respectively). Multivariate Cox regression analysis showed that combined high expression SOX2 and CD8+ TIL was an independent good prognostic factor for OS (HR = 0.449, P = 0.018) and PFS of SCLC (HR = 0.481, P = 0.021). Conclusions: In our study, high expression level of combined SOX2 and CD8+ TIL were related to longer OS and PFS, and it could be used as a prognostic biomarker for LS-SCLC. [Table: see text]
Clinical utility of a liquid biopsy diagnostic approach in lung cancer using amplicon-based next-generation sequencing in parallel with allele-specific PCR.
Authors: Choudhury Yukti , Phyo Wai Min , Lim Jing Shan , Gupta Chaitanya , Ho Yiliang , Tay Carina , Sim Yuki , Ng Wei Shuen , Pek Michelle , Tan Min-Han , Chin Tan Min , Tan Yew-Oo , Wong Seng Weng , Hsue Victor , Foo William , Sze Wing Kin , AU Siu Kei , Lam Tai Chung 
Published: May 2020

e21516 Background: The utility of a liquid biopsy test for diagnosis and treatment is determined by its accuracy, molecular target coverage and timeliness to a clinically informative result. We describe our clinical experience of providing comprehensive next-generation sequencing (NGS) plasma testing for advanced lung cancer cases, including parallel testing with allele-specific PCR (AS-PCR) for rapid EGFR mutation detection. Methods: Plasma cell-free DNA (cfDNA) from advanced lung cancer patients (n = 374) underwent real-world testing with an amplicon-based NGS assay, in a CAP and ISO15189 accredited central laboratory. The assay covers 51 genes, including 8 guideline recommended biomarkers- EGFR, BRAF, MET, ALK, RET, ROS1, ERBB2 and KRAS. 168 cases (44.9%) were treatment-naïve (baseline) and 206 cases (55.1%) had received one or more lines of treatment. Parallel testing with AS-PCR for 10 specific EGFR mutations was done for 151 cases (90 baseline, 61 non-baseline). Concordance of EGFR mutation detection by the two methods, and the frequency of detection of clinically actionable (driver) mutations by NGS were assessed. Turnaround time (TAT) was calculated from sample receipt. Results: An overall concordance of 97.4% was observed for EGFR mutations between AS-PCR and NGS. When restricted to baseline cases, concordance was 100%. Among baseline cases which were concordant with AS-PCR for EGFR negativity (n = 63), driver mutations were identified in EGFR (n = 7 rarer mutations), KRAS, ERBB2, MET, NRAS, BRAF and ALK (n = 16 total) by NGS, providing an additional 37% diagnostic yield (23/63 cases). Among all baseline cases tested by NGS, a driver gene mutation was found in 64.28% of cases, including EGFR (36.9%) and KRAS mutations (11.9 %). Among non-baseline cases which were EGFR-negative by NGS and by AS-PCR, added diagnostic yield provided by NGS was 33.3% (10 of 30 cases), and included 16.7% rarer EGFR mutations. Overall, detection rate of ALK, RET, ROS1 fusions was 2.4% (n = 5, 3 and 1, respectively). Median TAT for EGFR results by AS-PCR was 1 day (range 1-2 days), while median TAT for NGS results was 10 days (range 4-13 days). Conclusions: We report excellent real-world performance of blood-based liquid biopsy testing for detecting recommended biomarkers in lung cancers, including an approach combining two orthogonal platforms for quick decision making. Clinically meaningful diagnostic yields can be obtained using a timely comprehensive NGS assay, either individually or in parallel with rapid AS-PCR testing.
Mutational profiles of lung adenocarcinoma subtypes.
Authors: Chang Shuai , Wang Yan , Wang Yi , Zhou Kun , Che Guowei 
Published: May 2020

e21517 Background: Genomic profiling of lung adenocarcinoma has been studied, however, different histological subtypes were not carefully distinguished, especially in patients with mixed subtypes. Methods: Fifty-three invasive adenocarcinoma (IA) FFPE samples from lung cancer patients with detailed histological classifications were panel sequenced and analyzed. Results: Among the 53 IAs, acinar (n = 42), lepidic (n = 34) and papillary (n = 25) were most dominant subtypes and were frequently mixed with other types. Zero to 14 mutations were identified in each sample (median = 4). Thirteen of the 42 (31%) tumors containing acinar subtype harbored TP53 mutations, while none of the 11 (0%) acinar negative tumors harbor TP53 mutation; six of the 42 (14.3%) acinar positive had RBM10 mutations, while 5 of the 11 (45.4%) acinar negative had RBM10 mutations. Three of the 34 (8.8%) tumors with lepidic subtypes harbored TP53 mutations, while 10 of the 19 (52.6%) lepidic negative tumors harbored TP53 mutations; Ten of 34 (29.4%) lepidic positive tumors harbored RBM10 mutations, while 1 of the 19 (5.3%) lepidic negative tumors harbored RBM10 mutations. All papillary tumors were mixed with other subtypes. Conclusions: Different histological subtypes have different mutational features. Acinar subtypes harbor more TP53 and less RBM10 mutations than acinar negative tumors; lepidic subtypes harbor less TP53 and more RBM10 mutations than lepidic negative tumors. Lack of mucinous, micropapillary and solid subtypes requires further study to analyze their mutational signatures.
MMR deficiency of lung cancer patients.
Authors: Ming Zongjuan , Yang Shuanying , Shi Jie , Bai Jun , Wei Xuemei , Lu Qiang , Li Wei , Zhong Yujie , Yang Xia , Lyu Xin , Wei Qingbo , Gu Dejian , Chen Rongrong , Yuan Jingyan , Chen Yang 
Published: May 2020

e21523 Background: DNA Mismatch repair (MMR) plays an essential role in the genetic. The main function of MMR is thought to correct post replication errors since the system could recognizes base exchanges and short DNA insertions or deletions. Somatic mutation of MMR are common detected in lung cancer, and several studies has shown that the presence of MMR mutation may be resistance to EGFR-TKI. Here we retrospectively analyzed the MMR mutation in chinese lung cancer. Methods: We retrospectively analyzed the genetic aberration in 910 Chinese lung patients. All the patients were detected by hybridization capture-based NGS 1021-gene panel. Results: Here is an interesting lung cancer case which was called EGFR T790M, TP53 and MSH2 somatic mutations without any germline mutations, and this patient showed no response to Osimertinib. We retrospectively analyzed the MMR in 910 patients and called 39 patients with MMR mutation.The percence of MLH1, MLH2, MSH3, MSH6, PMS1 and PMS2 mutations rate is as followed: 10.3% (4/39), 33.3% (13/39), 7.7% (3/39), 28.2% (11/39), 5.1% (2/39), and 15.4% (6/39) cases in PMS2 mutation. Also we found that TP53 is the most highly concurrent gene for MRR deficiency the rate is 79.5%(31/39). The rate of EGFR mutation concurrent with MMR deficiency is 27% (10/39). Conclusions: MMR deficiency was found in 4.3% chinese lung cancer and 27% of them concurrent with EGFR. [Table: see text] [Table: see text] [Table: see text]
Measuring PD-L1 mRNA expression using targeted next generation sequencing and correlation with interferon pathway activation genes in lung and colorectal cancers.
Authors: Ma Wanlong , De Dios Ivan , Antzoulatos Spiraggelos , Estella Jeffrey , Albitar Maher 
Published: May 2020

e21534 Background: Expression level of PD-L1 mRNA as determined by next generation sequencing (NGS) is becoming more routinely available in cancer profiling. We explored the relevance of PD-L1 mRNA expression as detected by RNA sequencing in providing information relevant to clinical practice and compared lung cancer with colorectal cancer in activating interferon pathway. Methods: RNA was extracted from 160 non-small cell lung cancers and 53 colorectal cancers (CRC) as well as from 103 samples of various types cancers that were also analyzed for PD-L1 expression by IHC. The RNA sequencing was performed using a targeted panel of 1408 genes. IHC for PD-L1 staining was performed with the FDA-cleared diagnostic assay using the 22C3 antibody. Results: Based on comparing the number of PD-L1 IHC positive tumor cells and CD274 mRNA, significant correlation between the two methodology can be demonstrated as continuous variables (P < 0.0001) as well as when the IHC positivity is grouped as 0 to 1, 2 to 9, 10 to 49, and > = 50 (P < 0.0001). However, cancers with PD-L1 by IHC > 50% had distinctly higher levels of CD274 mRNA, while all other levels of IHC positivity showed significant overlap. Overall lung cancer showed significantly higher levels in STAT1 (P = 0.002), STAT3 (P < 0.0001), STAT4 (P = 0.005), PTPN2 (0.002) as compared with CRC. However, when only CRC cases that show PD-L1 overexpression were considered, there was no significant difference in the expression in any of these genes as compared lung cancer cases that also show PD-L1 overexpression. The only difference is that lung cancer cases with PD-L1 overexpression showed higher levels of IKBKE mRNA as compared with CRC cases with PD-L1 overexpression (P = 0.004). In addition, lung cancer overall showed higher levels of PD-L2 (P = 0.0002), PD-1 (P = 0.0002), CD8A (P < 0.0001), and CD19 (P = 0.0008), but CRC with PD-L1 overexpression showed no difference in the expression of any of these genes when compared to lung cancer cases with PD-L1 overexpression. Conclusions: While CRC shows overall significantly lower RNA levels of PD-L1, PD-L2, PD-1, CD19, CD8A and genes involved in interferon pathway, CRC cases with high expression of PD-L1 mRNA are similar to lung cancer high expressors of PD-L1. Furthermore, PD-L1 quantification using NGS testing can be used to select patient for immunotherapy and might provide valuable information on co-markers that may provide better insight to selecting patients for immunotherapy.
Clinical significance of BIM-deletion polymorphism on chemoradiotherapy in patients with non-small cell lung cancer.
Authors: Wakabayashi Yu , Masuda Takeshi , Nakashima Taku , Fujitaka Kazunori , Yamaguchi Kakuhiro , Sakamoto Shinjiro , Nishimura Yoshihumi , Horimasu Yasushi , Miyamoto Shintaro , Senoo Tadashi , Iwamoto Hiroshi , Ohshimo Shinichiro , Hamada Hironobu , Hattori Noboru 
Published: May 2020

e21536 Background: The standard treatment for locally advanced non-small cell lung cancer (NSCLC) is chemoradiotherapy (CRT) followed by anti-programmed cell death-ligand 1 (PD-L1) drug therapy. BIM deletion induces apoptosis suppression and the effect of epidermal growth factor-tyrosine kinase inhibitor is reportedly attenuated in EGFR-mutated NSCLC patients with BIM deletion. This study retrospectively examined the effects of BIM deletion on CRT or PD-1 treatment in patients with NSCLC. Methods: Among patients with unresectable NSCLC at Higashi-Hiroshima Medical Center and Hiroshima University Hospital between April 1994 and April 2018, we enrolled those treated with CRT or chemotherapy using carboplatin + paclitaxel or cisplatin + vinorelbine, or PD-1 antibody treatment. Results: Of 1,224 patients with unresectable NSCLC, 88, 80, and 79 underwent CRT, chemotherapy, or PD-1 antibody treatments, respectively. Within these treatment groups, 15 (17%), 15 (19%) and 11 (14%) patients, respectively, had BIM deletion. Among patients receiving CRT, the progression-free survival and overall survival were significantly shorter in those with BIM deletion than in those without (150 vs. 254 days, p = 0.003; 429 vs. 710 days, p = 0.03). Moreover, multivariate Cox regression analysis showed BIM deletion to be an independent factor for anti-tumor effect or prognosis (hazard ratio [95% confidence interval] 2.042, [1.112–4.039], p = 0.029; 2.414, [1.063–4.984], p = 0.036). These results were not observed in the chemotherapy and PD-1 treatment groups. To confirm the association between radiation therapy effect and BIM deletion, we performed in vitro experiments using two NSCLC cell lines (A549 and EBC-1). Suppressed BIM expression using siRNA (instead of BIM deletion) in these cells showed significantly suppressed antitumor effect and apoptosis 48 hours after 30-Gy irradiation but not chemotherapy. Conclusions: We showed that BIM deletion is an independent anti-tumor effect or prognostic factor for CRT. The results also indicated that BIM deletion was associated with the effects of radiation but not chemotherapy or PD-1 antibody treatment.
Digital pathology to evaluate PD-L1 IHC scoring as a predictor of outcome with second-line avelumab treatment in patients with non-small cell lung cancer (NSCLC).
Authors: Mrowiec Thomas , Svenson Elena , Gerhold-Ay Aslihan , Wolf Corinna M , Grote Hans Juergen , Otte Marcus , Rolfe P. Alexander , Shah Parantu K. , von Heydebreck Anja , Scheuenpflug Juergen , Ruisi Mary M. , Labarta-Beceiro Violeta , Beeman Glenn , Cai Ti 
Published: May 2020

e21539 Background: Assessment of programmed death ligand-1 (PD-L1) protein expression using immunohistochemistry (IHC)-based tests is currently the only approved biomarker guiding treatment of non-small cell lung cancer (NSCLC) with checkpoint inhibitors. Robust scoring guidelines and suitable cut-offs should be defined specifically for each PD-L1 IHC assay and are critical for appropriate treatment decisions. Methods: We retrospectively applied a novel digital pathology (DP) solution that mimics the conventional tumor proportion scoring (TPS) of PD-L1. The exploratory DP solution was developed and validated using samples from 340 patients enrolled in the first- and second-line (1L and 2L) NSCLC cohorts of the avelumab phase 1 JAVELIN Solid Tumor trial (NCT01772004) and 792 patients with NSCLC enrolled in the avelumab phase 3 JAVELIN Lung 200 trial (NCT02395172). Efficacy analyses were conducted for overall survival (OS) and progression-free survival (PFS) using the full analysis set with evaluable imaging data (n = 136 and n = 544, respectively). Results: Comparison of DP and conventional, semiquantitative pathologist scoring resulted in a high correlation overall (Spearman correlation coefficient, 0.86), with comparable performance for prediction of outcome to treatment with avelumab in 2L NSCLC. Consistent with conventional scoring, median OS and median PFS in avelumab-treated patients increased with higher PD-L1 expression cut-offs: in patients with ≥1%, ≥50%, and ≥80% PD-L1 expression on tumors cells, median OS was 10.0 months (95% CI: 8.6-14.3), 13.8 months (95% CI: 9.6-20.4) and 18.5 months (95% CI: 9.6-not estimable), respectively; median PFS, 3.1 months (95% CI: 2.7-4.9), 5.5 months (95% CI: 2.8-8.3) and 5.6 months (95% CI: 2.8-9.9). Conclusions: Our results demonstrate the technical feasibility, robustness, and utility of DP in scoring PD-L1 IHC in clinical trial samples, achieving comparable performance to conventional, semiquantitative pathologist scoring. Furthermore, our study supports the manual pathologist scoring algorithm (TPS scoring) in NSCLC and the selection of higher cut-offs for the PD-L1 IHC Ab clone 73-10.
Sarcopenia as a negative predictive marker for treatment with pembrolizumab as a second line in patients with metastatic non-small cell lung cancer.
Authors: Petrova Milla , Valchev Gerogi , Conev Nikolay Vladimirov , Dimitrova Eleonora , Robev Bozhil , Boneva Marsella , Pavlov Boian , Minchev Velko , Karanikolova Teodora , Valev Spartak , Gencheva Radostina , Zhbantov Georgi , Ivanova Anika , Timcheva Constanta , Donev Ivan 
Published: May 2020

e21541 Background: In this multicentric retrospective study we evaluated the incidence of clinical benefit rate (CBR) and its relation to Neutrophil-Lymphocyte Ratio (NLR) and psoas major muscle area (PMMA), as well as their dynamics in patients with Non-small Cell Lung Cancer (NSCLC) treated with pembrolizumab (P) as a second line. Methods: Patients with metastatic NSCLC (n = 84) whose tumors expressed PD-L1≥1% were retrospectively analyzed between Apr 2017 and Dec 2019. All patients received platinum-containing chemotherapy (CT) as a first line treatment. Absolute neutrophil, and absolute lymphocyte count enabled calculation of NLR; NLR1 - before CT, NLR2 – before P infusion. ΔNLR was calculated. Area of PMMA was calculated at L3 position on computed tomography. CBR was defined as the proportion of patients with a partial response or stable disease for at least six months since no patients with complete response were recorded. PMMA was calculated before CT and before the P infusion; (% change rate of PMMA = ([1-PMMA before P / PMMA before CT]*100). Patients with the change rate of PMMA≥10% were considered with sarcopenia - 30 (35.7%). Results: CBR was 72.6%. There were not significant correlations between NLR, PMMA and their dynamics. Patients without clinical benefit (CB) had significantly higher values of ΔNLR (1.38±2.2) and ΔPMMA (11.2±10.7) than patients with CB - ΔNLR (0.12±1.88; p = 0.023) and ΔPPMA (8.9±13.5; p = 0.001). ROC analysis revealed that at the optimal cutoff values of all markers, ΔPMMA achieved the greatest AUC = 0.738 (95% CI, 0.77-0.93) and could distinguish between patients with or without CB with sensitivity of 77.3% and specificity of 83.6%. Sarcopenic patients had significantly shorter mean progression-free survival (PFS) – 6.5 months (95%, CI 5.1-8.1) than the rest – 20.8 months (95%, CI 16.7-24.1). Moreover in the multivariable analysis, ΔNLR (HR 1.19, 95% CI 1.05-1.38, p = 0.01) and ΔPPMA ≥10 % (HR 5.4, 95% CI 2.82-10.19, p < 0.001) were found to be independent predictive factors for shorter PFS. Conclusions: Our data suggests that ΔPMMA and ΔNLR are potential predictive markers, which may identify patients appropriate for immunotherapy as a second line treatment.
High neutrophil to lymphocyte ratio as a predictor for hyperprogressive disease in patients with metastatic non-small cell lung cancer treated with pembrolizumab as a second line.
Authors: Petrova Milla , Eneva Mariyana , Arabadjiev Jeliazko Iliev , Conev Nikolay Vladimirov , Dimitrova Eleonora , Koynov Krassimir Dimitrov , Karanikolova Teodora , Valev Spartak , Gencheva Radostina , Zhbantov Georgi , Ivanova Anika , Sarbianova Iva , Penkova Polya , Timcheva Konstanta , Donev Ivan 
Published: May 2020

e21546 Background: In this study we evaluated the incidence of early non-responders (which are potential hyper-progressors (HP)) and its relation to Neutrophil-Lymphocyte Ratio (NLR), Platelet-Lymphocyte Ratio (PLR) as well as their dynamics in patients with Non-small Cell Lung Cancer (NSCLC) treated with pembrolizumab (P) as a second line. Methods: Patients with metastatic NSCLC (n=119) whose tumors expressed PD-L1≥1% were retrospectively analyzed between Apr 2017 and Oct 2019. All patients received platinum-containing chemotherapy (CT) as a first line treatment. Hematological parameters of interest were absolute neutrophil (ANC), absolute lymphocyte (ALC) and platelet (APC) counts, enabling calculation of NLR (ANC/ALC) and PLR (APC/ALC). NLR1 and PLR1 were calculated before CT, NLR2 and PLR 2 – before the first P infusion. ΔNLR (NLR2-NLR1) and ΔPLR (PLR2-PLR1) were calculated. The tumor response was assessed according to the RECIST (version 1.1) at every 3 months. Early progressors (EP) were defined as non-responders at the first computed tomography scan evaluation of the CT. As HP on P were considered patients with time to progression ≤ 3 months, clinical deterioration and appearance of ≥2 new lesions in organ already involved or spread to a new organ. Results: Twelve (10.1%) patients in the CT group were EP. Fourteen (11.8%) patients in the immunotherapy group were assessed as HP. Four patients (3.4%) did not respond either to CT or to P and had clinical aggravation. HP had significantly higher NLR2 (9.1±1.9 vs 4.8±3.2, p<0.001), PLR2 (400±173.8 vs 214.7±117.3, p<0.001), ΔNLR (2.3±1.9 vs 0.3±2.0, p=0.001), ΔPLR (107.9±167.3 vs 0.6±94.9, p=0.012) than the rest of the patients. ROC analysis revealed that at the optimal cutoff values of all markers, NLR2 achieved the greatest AUC=0.855 (95% CI, 0.77-0.93) and could distinguish between patients with or without hyperprogressive disease (HPD) with sensitivity of 85.7% and specificity of 72.4%. HP had significantly shorter mean OS - 12.5 months (95%, CI 10.9-14.1) than the rest – 32.2 months (95%, CI 28.4-36.1). Patients who did not respond either to CT or to P had significantly shorter mean OS – 9.2 months (95%, CI 6.6-11.8) than the rest – 29.8 months (95%, CI 26.4-33.4). NLR was found to be an independent predictive factor for HPD, HR=1.22 (95% CI,1.11-1.35; p<0.001). Conclusions: Our data suggest that the incidence of intrinsic aggressive disease phenotype, irrespective of treatment, is low. NLR is a novel predictive marker for HPD.