bluuebunny/crossref_metadata_2025_split huggingface dataset:
A multicenter real-world study of tumor-derived DNA from pleural effusion supernatant in genomic profiling of advanced lung cancer.
Authors: Guo Renhua , Chen Likun , Zhou Chengzhi , Ai Xinghao , Zhao Jun , Chen Rongrong , Xia Xuefeng 
Published: May 2020

e21584 Background: Pleural effusion (PE) is commonly observed in advanced lung cancer. Researches have suggested molecular profiling of PE represents a minimally invasive approach of detecting tumor driver mutations for clinical decision making. The objective of this study is to investigate the efficacy and precision of detecting gene alterations in PE samples in the real world setting. Methods: 656 metastatic lung cancer patients with pleural effusion were enrolled in this study. Seven hundred and thirty-two samples, including 351 samples of PE supernatant, 224 plasma, 138 tissue, and 25 PE sediments from these patients were collected and subjected to targeted next-generation sequencing (NGS) of 1021 cancer-related genes in a real world setting. The efficacy of pleural effusion in detecting actionable mutations and identifying resistant mechanisms of targeted therapy were analyzed by comparing different samples. Results: Among the 656 NSCLC patients, 413 were in M1a stage and 243 were in M1b/M1c stage, while 272 were newly diagnosed and 384 was previously treated. When comparing different groups of stage and therapeutic history, PE supernatant was preferred as the choice for those patients (46.6% - 48.2% vs 23.3%-34.8% of plasma vs 16.8%-21.2% of tissue and 0.96%-7.3% of PE sediment). While mutant allele frequency (MAFs) of plasma in patients of M1a stage was significantly lower than that of M1b/c stages, MAFs was similar for PE supernatant. EGFR, KRAS, MET, ALK, BRAF, ERBB2, ROS1, and RET actionable mutations were identified in 60, 12, 9, 7, 6, 3, 2, and 1 of the 118 PE supernatant samples at M1a stage taken before treatment. PE-supernatant demonstrated higher sensitivity than plasma of detecting actionable mutations in M1a disease (84.7% of PE-supernatant vs 42.1% of plasma, p < 0.01) but not in M1b/c stages (80.7% of PE-supernatant vs 86.4% of plasma). Seventy-two of the 117 patients who were resistant to 1st or 2nd generation of EGFR-TKI, 22 of the 42 patients resistant to osimertinib, and 9 of the 13 patients resistant to crizotinib had known resistant mutations identified. Remarkably, PE supernatant outperformed plasma in identifying resistant mutations to 1st/2nd generation EGFR-TKI (75.4% vs 29.8%, p < 0.001). Conclusions: This real world large cohort study verified that genomic profiling of PE-supernatant has higher actionable mutation detection sensitivity than plasma. It offers an alternative approach in assessing tumor genomics in advanced lung cancer when tumor tissue is not available.
Neutrophil to lymphocyte ratio and lipi score prognostic value in patients with non-small cell lung cancer in a Mexican population.
Authors: Reyes Eduardo , Martínez-Herrera José Fabián , Andrade Moreno Raul Alejandro , Lara - Torres Cesar , Amador García Geovani , Villalobos Prieto Alberto , Aguayo Alvaro , Serrano Juan Alberto , Gerson Raquel , Olivares Guillermo 
Published: May 2020

e21593 Background: Non-Small cell lung cancer (NSCLC) is the most common type of lung cancer and accounts for most of all cancer-related morbidity and deaths in the World. Recent Evidence shows that inflammatory response is associated with a poor prognostic in several cancers. Evaluating these markers is of great importance to classify patients of solid tumors including NSCLC. Inflammatory markers like, Glasgow Prognostic Score (GPS), Lung Immune prognostic index (LIPI) and C-Reactive Protein (CRP) have been associated with poor prognosis in patients treated with immune checkpoint inhibitors. Neutrophil to Lymphocyte Ratio (NLR) is a biomarker for the general immune response to various stress stimuli in peripheral blood. It can be easily determined, inexpensive and can correlate with poor outcomes. Methods: A review of medical records was performed including patients from January 2013 to December 2018. The clinical characteristics were described, analyzed and the NLR and the LIPI were calculated. Categorical variables were analyzed with Chi-square test and the correlation was analyzed with the Pearson correlation coefficient. Variables were included in the construction of survival models through Cox multivariate regression using statistical software: STATA SE ver11.0 (StataCorp LLC Texas,USA). Results: A total of 175 patients with complete medical record and pathology samples were included. Around half of patients were female. The mean age was 69 years ± 11 years. The most frequent histology was Adenocarcinoma in 87%, Epidermoid 10% and others 3%. The most frequent mutations were KRAS 25%, EGFR 22% and ALK 1%. PDL-1 > 1% was determined in 20% of patients. Clinical stage IV was found in 58% of the cases followed by Clinical Stage I, II and III with 25%, 9%, 8% respectively. The NLR > 4 is associated with a worse prognosis in Stage I and II HR = 5.4 (95% CI 1.73 - 17.17, p = 0.004). LIPI > 2 had predictive capacity for progression in Stage IV HR = 8.2 (IC 95 % 2.39-23.4, p = < 0.001). Conclusions: NLR > 4 showed prognostic value for recurrence in early clinical stages. LIPI score > 2 resulted in higher risk for progression in metastatic stages. Determination of these indexes has the potential as a readily available prognostic indicator for patients.
Factors influencing disease control in metastatic lung cancer with intracranial metastasis post gamma-knife radiotherapy.
Authors: Tam Laura , Pinkham Mark B. , O'Byrne Kenneth John , Ladwa Rahul 
Published: May 2020

e21602 Background: Traditionally, disease control of brain metastases (BM) has dictated the prognosis of those with metastatic lung cancer. Immune check-point inhibitors (ICI) have shown intracranial response but data on the magnitude of such effect in combination with radiation is still evolving. We report the time to progression of intracranial and systemic disease post gamma-knife radiation (GK) and associations with the use of ICI in this cohort. Methods: Patients with metastatic lung cancer with BM treated with GK between 2015 and 2019 were retrospectively analysed in a single institution at the Princess Alexandra Hospital, Queensland. The primary endpoint was time from first GK to death. Results: 104 patients were eligible. Median age was 63 years. BM was seen in 46.7% at diagnosis (versus relapsed in brain). Solitary BM was seen in 37.1% patients. 7.7% had prior whole-brain radiation (WBRT) prior to GK. 45.7% received ICI either at the time of GK or as the next line of treatment immediately post GK. 56.2% received ICI at any time during the study period. Oncogenic driver mutations were seen in 13 cases [EGFR mutant (9.5%), ALK mutation (2.5%)]. 15.2% patients had a high-PDL1 (≥50%) level. Time from GK to death was: 14 (9.7-18.3) months for all patients. Incidence of progressive BM was 46.7%. Time to intracranial PD was 5 months. Systemic PD was seen post GK in 44.8% patients. Survival was improved in those patients with the presence of a driver mutation (p = 0.043) on univariate analysis. Factors which did not impact survival included: the number of BM (solitary vs multiple; p = 0.837), PD-L1 status (PD-L1 < 50% vs ≥50%; p = 0.186), use of ICI (used vs not used; p = 0.307) and previous WBRT (treated vs not treated; p = 0.251). Failure of BM requiring GK on ICI was not associated with a worse outcome (p = 0.707). Conclusions: The presence of driver mutations was associated with prolonged overall survival in select patients undergoing GK for BM. High PDL-1 expressivity and timing of ICI relative to GK do not appear to positively influence outcome in this retrospective study.
Artificial intelligence-assisted CT characterizations and quantitative analysis for differentiating pre-invasive lesions from invasive adenocarcinomas in pulmonary subsolid nodules ≤ 2cm.
Authors: Zhang Bingyu , Yu Fenglei , Peng Muyun 
Published: May 2020

e21614 Background: The use of artificial intelligence (AI) in medical imaging has dramatically improved the quality of segmentation including accuracy, efficiency and reproducibility. This study sought to determine whether AI-assisted computed tomography (CT) features and quantitative analysis of pulmonary subsolid nodules (SSNs) under 2cm could be used to differentiate preinvasive lesions from invasive adenocarcinomas. Methods: Clinical data and CT images of 297 preinvasive lesions and early invasive lung adenocarcinomas confirmed by surgery pathology with CT manifestations of SSNs under 2cm were retrospectively analysed. The nodules were divided into two groups: the preinvasive lesions (PILs, N = 115) including 7 cases of atypical adenomatous hyperplasia (AAH), 30 cases of adenocarcinoma in situ (AIS) and 78 cases of minimally invasive adenocarcinoma (MIA), and the invasive adenocarcinomas (IACs, N = 182). All CTs were processed by AI and the volume, mean CT value, consolidation-to-tumor ratio (CTR), mass and maximum diameter of each SSN were obtained. Results: The volume, mean CT value, CTR, maximum diameter and mass of nodules showed significant difference between the two groups (Table). Multivariate analysis was determined by logistic regression. The regression model between the two groups was logit(p) = -1.439-2.927Volume +0.0005(mean CT value)-0.463(CTR > 0.5) +0.238(maximum diameter)+6.298(mass).The receiver operating characteristic curve (ROC) showed that the mass can do the best prediction among all the independent factors with the areas under the curve(AUC) 0.748 at a cut-off value of 0.154, with the sensitivity of 70.9% and specificity of 70.4% .The AUC of the ROC using the regression probabilities of regression model was 0.769. Conclusions: AI-assisted CT characterizations may be promising tools to predict if SSNs under 2 cm have invaded. [Table: see text]
Disease monitoring and TKI resistance mutations of EGFR mutation-positive NSCLC patients via circulating tumor DNA.
Authors: Woestmann Corinna , Ju Christine , Hinzmann Bernd , Yaung Stephanie J. , Thomas Michael , Heussel Claus Peter , Kriegsmann Mark , Meister Michael , Schneider Marc , Herth Felix , Muley Thomas , Wehnl Birgit , Palma John F. , Jiang Yuqiu 
Published: May 2020

e21627 Background: 15–40% of NSCLC adenocarcinoma patients harbor EGFR sensitizing mutations. Tyrosine kinase inhibitors (TKI) provide significant clinical benefit in this population, yet all patients will develop resistance. Liquid biopsy has been demonstrated to reliably identify tumor associated somatic EGFR mutations. Quantitative assessment of mutated EGFR driven tumors could potentially be used to monitor disease progression, to assess therapeutic response, and to identify resistance mechanisms. Methods: 106 longitudinal plasma samples from 16 NSCLC patients who were treated with osimertinib as either first line or second line therapy were collected. A series of plasma samples collected during treatment and at the time of disease progression were analyzed with the AVENIO ctDNA Surveillance kit*. Mutations at each time point were identified and reported by the AVENIO software v2.0*. The mutation profile of each patient at different timepoints along with the treatment journey was examined in combination with clinical outcome data. Results: EGFR sensitizing mutations were detected in all plasma samples by sequencing except in 3 cases. Patients responsive to anti-EGFR therapy showed a rapid decrease of EGFR driver mutations to non-detectable levels. Meanwhile, patients who had stable disease or rapid disease progression had stable or slightly decreasing ctDNA levels after receiving the treatment. One patient had a MET amplification, FBXL7 SNV, and EGFR T790M detected at the time of disease progression which were not detected at baseline. One patient had both EGFR L858R and T790M mutations. This patient progressed very quickly on erlotinib. Detection of the T790M mutation decreased upon osimertinib administration, however, the L858R mutation level stayed the same. TP53 mutations were elevated in 3 patients at the time of progression, and could potentially be related to anti-EGFR resistance. Conclusions: This study clearly demonstrated that liquid biopsy could identify resistance mutations beyond EGFR prior to clinical progression. Plasma samples collected prior to or at disease progression could facilitate identification of novel resistant mutations to TKI therapy. Further studies to demonstrate the clinical utility of serial blood EGFR testing in NSCLC management are necessary. *For Research Use Only. Not for use in diagnostic procedures.
Poor performance status and front-line pembrolizumab in advanced non-small-cell lung cancer (NSCLC) patients with PD-L1>50%.
Authors: Addeo Alfredo , Metro Giulio , Signorelli Diego , Economopoulou Panagiota , Roila Fausto , Banna Giuseppe Luigi , De Toma Alessandro , Camerini Andrea , Christopoulou Athina , Lo Russo Giuseppe , Galetta Domenico , Jimenez Munarriz Beatriz , Collazo Ana , Calles Antonio , Baxevanos Panagiotis , Linardou Helena , Kosmidis Paris A. , Mountzios Giannis Socrates , Garassino Marina Chiara , Friedlaender Alex 
Published: May 2020

e21651 Background: We retrospectively analysed real-world clinical outcomes of patients with advanced non-small-cell lung cancer (NSCLC) harbouring high PD-L1 expression ( > 50%) and treated with first-line pembrolizumab, following the Keynote 024 regimen. In the recent PePS2 trial and Checkmate 817, we see that some patients with PS2 could benefit from a durable response to checkpoint inhibitors. However, current data does not suggest an improvement in median OS compared to historical data on chemotherapy in this setting. Methods: Data was collected by 16 participating centers. The trial was approved by local ethics committees and patients included signed a general consent form. All patients with NSCLC with PD-L1 expression ≥50%, treated with first-line pembrolizumab were included, from the introduction of first-line pembrolizumab to the present. We collected medical data from patient files, pathology reports and laboratory reports for all patients. Patient characteristics, comorbidities, Eastern Cooperative Oncology Group (ECOG) performance status (PS), and tumor characteristics were reported. Overall survival (OS) was calculated from the date of the first cycle of pembrolizumab to death and estimated through the Kaplan-Meier method. Results: 302 patients were identified, of which 247 with a PS of 0-1, 52 with a PS of 2. Patients (3) with PS3 were excluded. The median age was 69 with a range from 19 to 87 years. There were 193 males and 106 females, 90% were active or former smokers, 19% had brain lesions at diagnosis. Only 14% received brain radiotherapy. Median OS was 7.2 months among patients with PS2, while not reached for those with PS0-1 (HR 3.80, 95% confidence interval 2.49-5.78). Conclusions: Patients with a PS of 2 had significantly worse survival than those with PS0-1. The retrospective nature of our trial and lack of a control arm treated with chemotherapy do not allow us to postulate as to whether PS is predictive or prognostic. Our data suggests worse survival among NSCLC patients with PS2 treated with front-line pembrolizumab. A prospective randomized trial comparing immunotherapy to chemotherapy or chemo-immunotherapy in this population would be welcome.
Hyperprogressive disease during treatment with immune checkpoint inhibitors in patients with advanced non-small cell lung cancer (NSCLC).
Authors: Ayala de Miguel Pablo , López Gallego Javier , Gorospe García Itziar , Rivera Vargas Pablo René , Posada Restrepo Andrea , Aires Machado Jonathan , Alonso Calderón Rubén , Rodríguez García José Manuel , Ceballos Eduardo , Acero Caballero Alfonso , Illán Varella Andrea , Quintana Cortés Laura , Borrega Garcia Pablo 
Published: May 2020

e21664 Background: Hyperprogressive disease (HPD) is a new pattern of progressión during immunotherapy and is described as an acceleration of tumor growth during treatment with immune checkpoint inhibitors (ICI). The rate of HPD in advanced solid tumors remains unknown, but it has been reported in 9% to 29% of patients in two recent series. Our aim was to study prognostic factors of HPD. Methods: We collected data of 104 patients diagnosed of advanced NSCLC and treated with ICI in monotherapy at our institution between December 2015 and December 2019. Several variables as clinical, tumour-related and therapeutical were included in the analysis. The variables were compared by chi-square and Fisher test, then we performed a multivariate logistic regression model to analyse the effects of the covariates, and finally we performed a Kaplan Meier survival analysis. We described HPD as disease progression at first evaluation with an increase in tumor growth rate exceeding 50%, according to Gustave Roussy criteria previously reported. Results: Cohort of 84 men and 20 women, median age of 67 years and 86% with Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1. 89% were active or ex-smokers and 11% had never smoked. 60% of patients had adenocarcinoma histology, 39% scamous and 1% had not otherwise specified (NOS) carcinoma histology. 3% of patients had III-B stage at the moment of start of immunotherapy, 37% M1a, 30% M1b and 30% M1c. 2 patients had driver mutations in EGFR gene. 41% of patients had unknown PDL1 status; 14% had no PDL1 expression, 14% low expression and 31% high expression. 78% of patients had progressed to prior line of treatment, while 22% were treatment-naive. Nine of 104 patients (8.7%) in our population developed HPD during treatment with ICI. HPD occured within the first two months of treatment in all 9 patients, and was associated with worse overall survival in the multivariate analysis by Cox regression (12.6 vs 2.6 months; HR 13.94, p < 0.001). The presence of 2 or more metastatic sites was related to the development of HPD in the multivariate analysis (HR 8.59, p = 0.026). Conclusions: The incidence of HPD in our population is concordant with previous report about this topic. As previously described by Ferrara et al, HPD was significantly associated with a high number of metastatic sites before start treatment with ICI and correlated with poor outcomes in patients with advanced NSCLC.
Population pharmacokinetic (PK) and exposure-response analyses from the pivotal ALTA-1L study: Model-based analyses supporting the brigatinib dose in patients with anaplastic lymphoma kinase (ALK)–positive non–small cell lung cancer (NSCLC).
Authors: Gupta Neeraj , Reckamp Karen L. , Camidge D. Ross , Kleijn Huub Jan , Ouerdani Aziz , Bellanti Francesco , Maringwa John , Hanley Michael J. , Wang Shining , Zhang Pingkuan , Venkatakrishnan Karthik 
Published: May 2020

e21725 Background: Brigatinib is a next-generation ALK tyrosine kinase inhibitor (TKI) with differential activity by dose (90 mg vs 180 mg [with a 7-day lead-in at 90 mg] qd) in the phase 2 post-crizotinib ALTA trial (NCT02094573). Herein, we describe results from population PK and exposure-response analyses of the efficacy and safety of brigatinib 180 mg qd (with a 7-day lead-in at 90 mg) from data in the first-line phase 3 ALTA-1L study (NCT02737501). Methods: Brigatinib plasma concentration-time data were described by a 3-compartment model with transit compartment absorption. Post hoc individual apparent clearance estimates for brigatinib were obtained using Bayesian re-estimation and used to calculate time-averaged area under the concentration-time curve (AUC) values for logistic regression analyses of relationships to response endpoints (confirmed objective response rate [ORR], intracranial ORR) and time-varying AUC values for parametric time-to-event models of relationships to progression-free survival (PFS). Population PK modeling, covariate analysis, and simulations were performed using NONMEM (version 7.3 or higher), running under PsN (Perl-speaks-NONMEM, version 4.6 or higher), while exposure–efficacy and safety analyses were performed using R (version 3.5.2 or higher). Results: Brigatinib PK parameters and estimated systemic exposures for patients in ALTA-1L (ALK TKI–naive setting) were similar to those in the 180 mg qd arm of ALTA. Patient covariates including weight, sex, age, race, and renal function (CrCL ≥30 mL/min) were not found to impact brigatinib exposure, suggesting no dose adjustment based on these covariates. In the exposure-response analyses, brigatinib exposure was not a significant predictor of response (≥partial response) or PFS. This suggests that the efficacy benefit was consistent across the range of exposures achieved with the 180 mg dosing regimen including after dose modifications. There was a significant relationship ( P< 0.05) between exposure and certain laboratory abnormalities (increased amylase and lipase). There was no relationship between exposure and CPK elevation, and brigatinib exposure had no effect on time to first dose reduction. Conclusions: These results support a favorable benefit/risk profile of the proposed 180 mg qd brigatinib dose (with a 7-day lead-in at 90 mg) for the front-line treatment of patients with ALK+ NSCLC. Clinical trial information: NCT02737501.
Single institution experience looking at efficacy of PD-1 inhibitors after progression on PD-L1 inhibitors or vice-versa in metastatic non-small cell lung cancer (NSCLC).
Authors: McGovern Kerri , Seetharamu Nagashree , Sullivan Kevin M. 
Published: May 2020

e21726 Background: The treatment landscape for metastatic NSCLC has changed dramatically with emergence of checkpoint inhibitors (CPI). Even though all currently approved CPI target engagement of PD-1 with PD-L1 and have similar efficacy in NSCLC, there are some differences in their mechanisms of action. Current guidelines do not recommend switching to another CPI after progression of disease (POD) or toxicity on one CPI. For some patients, however, therapeutic options may be limited due to comorbidities, lack of trial prospects, performance status, or reluctance towards chemotherapy making switch to alternate CPI an attractive strategy. We report outcomes of patients who were treated with second CPI after POD on initial CPI for metastatic NSCLC between 2015 and 2019 at our institution. Methods: Data collection included demographics, clinic-pathologic factors, CPI agents, disease control rate (DCR), progression free survival (PFS), and immune-related adverse events (irAE). DCR was defined as response or stable disease based on RECIST. PFS was measured from date of initiation of CPI to POD or death. Results: Of 169 patients with NSCLC treated with CPI (median age 71 years, range 30-93), 26 received 2 lines of CPI. Two patients received first CPI as part of front line chemoimmunotherapy whereas all others received CPI alone. First CPI was PD-1 inhibitor in 20 patients and PD-L1 inhibitor in 6. DCR for first CPI was 88% and median PFS of 5 months (range: 1 –24). There were no irAE over grade 2 with initial CPI. Six patients were treated with PD-1 inhibitors after PD-L1, 16 with PD-L1 after PD-1, and 4 with an alternate agent in same class. Median PFS for 2nd CPI was 3 months (range: 1 - 36) for all patients and DCR for evaluable patients was 63% (n = 16). One patient experienced steroid-responsive grade 2 pneumonitis. Responses with either line of CPI did not correlate with PD-L1 expression. Conclusions: Our data suggests that switching from one CPI to another may be a reasonable, potentially effective option in select patient population. Prospective studies exploring this strategy is warranted.