bluuebunny/crossref_metadata_2025_split huggingface dataset:
Validation of tumor DNA in bronchial lavage as a diagnostic tool in lung cancer.
Authors: Witting Christensen Wen Sara Witting Christensen , Thomsen Caroline Brenner , Hansen Torben , Andersen Rikke Fredslund , Nederby Line , Hager Henrik , Rasmussen Kristian , Jakobsen Anders Kristian Moeller , Hilberg Ole 
Published: May 2020

9020 Background: Diagnosing lung cancer requires invasive procedures with risk of complications for the patient. The HOXA9 gene is highly methylated in lung cancer, and methylated tumor DNA (meth-tDNA) in bronchial lavage has previously shown potential as a diagnostic biomarker. The aim of the present study was to validate these preliminary results. Methods: Patients were referred by the general practitioner on suspicion of lung cancer. The Danish diagnostic package includes chest and abdominal CT scan, bronchoscopy, blood tests, and histopathological or cytological verification. Twelve ml lavage fluid was collected at bronchoscopy for analysis of meth-tDNA based on droplet digital PCR according to our published method. A positive test was defined as ≥ 4 droplets containing meth-tDNA and a ratio between HOXA9 and Albumin of > 0.15%. The analysis was performed blinded to clinical data and meth-tDNA status was compared with the final diagnosis. Results: The study population was 204 consecutively enrolled patients. The material consisted of a discovery cohort (n = 105, presented at ASCO 2019) used for establishing the cut-points, and a validation cohort (n = 99). Six were excluded from analysis due to malignancy other than lung cancer and one due to failed analysis. In the discovery cohort, the sensitivity was 68.7% (95% CI 56.2-79.4%), specificity 88.2% (95% CI 72.6-96.7%), and positive predictive value (PPV) 92.0% (95% CI 80.8-97.8%). In the validation cohort, the same values were 76.9% (95% CI 63.2-87.5%), 77.3% (95% CI 62.2-88.5%), and 80.0% (95% CI 66.3-90.0%), respectively. Analyzing the entire patient material (n = 197) the sensitivity, specificity, and PPV were 72.3% (95% CI 63.3-80.1%), 82.1% (95% CI 71.7-89.8%), and 86.0% (95% CI 77.6-92.1%), respectively. The false positive samples were equally distributed among patients with cryptogenic organizing pneumonia, granulomatous inflammation, and acute inflammatory disease. The false negative samples were mainly from patients with peripheral tumor, no radiologically detectable tumor, and mesothelioma. Conclusions: Meth-tDNA in bronchial lavage holds potential as a supplementary tool in the diagnosis of lung cancer with a clinically relevant sensitivity and specificity. Routine clinical application awaits further validation in a clinical trial. [Table: see text]
Circulating tumor DNA (ctDNA) analysis predicts recurrence following surgery in patients with stage I-IIIA non-small-cell lung cancer (NSCLC): Results of GASTO1035 and GASTO1018.
Authors: Wang Si-Yu , Li Ning , Ou Wei , Cheng Chao , Kuang Peng-Peng , Wu Hui-Qi 
Published: May 2020

9023 Background: Circulating tumor DNA can be detected in the plasma and serum of patients with solid tumors and has emerged as a noninvasive biomarker for dynamically monitoring tumor. Postsurgical ctDNA analysis of early-stage NSCLC may identify patients at high risk of recurrence and facilitate early intervention and personalized cancer therapy. Methods: These studies recruited 123 patients with newly diagnosed resectable stage I-IIIA NSCLC. Preoperative and postoperative plasma and postoperative tissue samples were subjected to next-generation sequencing (Nanjing Shihe Jiyin Biotechnology Inc.) using a 425 cancer-related genes panel. Peripheral blood samples were collected before surgery, postoperatively within 1 month, and every 3-6 months for up to 3 years. Plasma samples with at least 1 variants detected in tissue samples were defined as ctDNA positive. Results: After 4 exclusions, 119 eligible patients were enrolled from June 2016 to February 2019. Presurgical ctDNA was detectable in 31 of 117 (26.5%) patients and was associated with inferior recurrence-free survival (HR, 3.90, 95% CI, 1.44-10.58, P = 0.004). Similarly, ctDNA was detected in 13 of 116 (11.2%) of the first postsurgical samples and was associated with shorter RFS (HR, 3.54, 95% CI, 1.22-10.23, P = 0.002). During surveillance after surgery, ctDNA-positive patients (38/119, 31.9%) were more than 9 times more likely to experience disease recurrence than ctDNA-negative patients (HR, 9.17, 95% CI, 2.60-32.42, P <0.001). Serial ctDNA detection preceded radiologic disease recurrence by a median lead time of 4.23 months (95% CI, 0.91-7.54 months). We also observed a positive correlation between the ctDNA detection rate and the disease stage. Conclusions: These results suggest that detection of ctDNA before and after surgery is associated with the identification of a high risk of disease recurrence of resectable NSCLC. Perioperative ctDNA analyses identify disease recurrence earlier than standard-of-care radiologic imaging, and thus could facilitate personalized cancer treatment at early time points. Clinical trial information: NCT03465241 and NCT03172156.
Validation of 4-marker protein panel for the early detection of lung cancer using PLCO samples.
Authors: Fahrmann Johannes , Irajizad Ehsan , Vykoukal Jody , Patel Nikul , Dennison Jennifer B , Murage Eunice , Ostrin Edwin Justin , Hanash Samir 
Published: May 2020

9024 Background: We have previously demonstrated that a protein panel consisting of ProSFTPB, CEA, CA125 and CYFRA21.1 may improve lung cancer risk assessment and has potential to define eligibility for computed tomography screening. Herein, we aimed to validate the classifier performance of the 4-marker protein panel using pre-diagnostic serum samples from the PLCO cohort. We additionally explored the additive value of diacetylspermine (DAS) with the 4-marker protein panel for identifying lung cancer cases. Methods: ProSFTPB, CEA, CA125 and CYFRA21.1 levels were measured in baseline sera of 537 lung cancer cases (76 SCLC/461 NSCLC) diagnosed within 6 years of baseline blood draw and 3772 cancer-free controls using bead-based immunoassays. DAS was measured using ultrahigh performance liquid chromatography mass spectrometry. Samples were analyzed in a double-blinded randomized fashion. Results: Overall classification performance (receiver operating characteristic area under the curve (ROAUC)) of the 4-marker panel for delineating lung cases diagnosed within 1 year and 1 to 2 years of baseline blood draw from cancer-free controls was 0.78 (95% CI: 0.74-0.82) and 0.73 (95% CI: 0.68-0.78), respectively. Classification performances of the 4-marker panel amongst lung cancer cases diagnosed within 1 year of baseline blood draw stratified into adenocarcinoma, squamous cell carcinoma and small cell lung cancer subtypes yielded ROAUCS of 0.78 (95% CI: 0.72-0.85), 0.76 (95% CI: 0.69-0.83) and 0.79 (95% CI: 0.68-0.90), respectively. Sub-analyses adjusting for smoking status yielded comparable ROAUC point estimates. Comparison of the 4-marker performance amongst non-NLST and NLST eligible lung cancer patients diagnosed within 1 year of baseline blood draw in comparison to matched cancer-free controls resulted in ROAUCs of 0.71 (95% CI: 0.63-0.79) and 0.74 (95% CI: 0.69-0.80), respectively. Analyses evaluating the additive classifier performance of serum DAS with that of the 4-marker protein panel revealed statistically significant improvement (McNemar Exact Test 2-sided p < 0.05) in sensitivity at high specificity derived from youden index for SCLC and squamous cell carcinoma cases diagnosed within 2 years from baseline blood draw, respectively, in comparison to the 4-marker protein panel alone. Conclusions: We have validated the performance of the 4-marker panel for early detection of lung cancer in the PLCO pre-diagnostic cohort. We further demonstrate that DAS can complement the 4-marker protein panel and identify more SCLC and squamous cell carcinoma cases.
The association between immune-related adverse events and efficacy outcomes with consolidation pembrolizumab after chemoradiation in patients with stage III NSCLC: an analysis from HCRN LUN 14-179.
Authors: Shukla Nikhil , Althouse Sandra K. , Sadiq Ahad Ali , Jalal Shadia Ibrahim , Jabbour Salma K. , Zon Robin , Kloecker Goetz H. , Fisher William B. , Reckamp Karen L. , Kio Ebenezer A. , Langdon Robert M. , Adesunloye Bamidele , Gentzler Ryan D. , Hanna Nasser H. , Durm Greg Andrew 
Published: May 2020

9032 Background: Consolidation checkpoint inhibitor therapy (CPI) for up to 1 year following chemoradiation (CRT) is a current standard of care for pts with inoperable stage III NSCLC. However, some pts are not able to complete 1 year of CPI due to immune-related adverse events (irAES). In multiple retrospective studies, pts with stage IV NSCLC treated with CPI who experience irAEs generally receive fewer cycles of CPI without a significant detrimental effect on efficacy. The association between irAEs and outcomes with consolidation CPI after CRT has never been reported. Here we report the association between irAEs and efficacy outcomes from the HCRN LUN 14-179, a single-arm phase II trial of consolidation pembrolizumab following concurrent CRT in pts with unresectable stage III NSCLC. Methods: After completion of CRT eligible pts with stage III NSCLC without PD received pembrolizumab 200 mg IV q 3 wks for up to 1 yr. Demographics, disease characteristics, and number of cycles of pembrolizumab received were reported in pts who had any grade irAEs (except pneumonitis which included grade >2 only) [Group A] and those without irAEs (except grade 1 pneumonitis) [Group B]. Chi-square test (or Fisher's Exact test) were used for comparisons for categorical variables and Wilcoxon test for continuous variables. The Kaplan-Meier method was used to analyze time to metastatic disease (TMDD), PFS, and OS. A log-rank test was used to compare groups. Results: 92 eligible pts for efficacy analysis were enrolled from March 2015 to November 2016. 4 yr OS estimate for all pts is 46.2%. Any grade irAEs (except grade I pneumonitis) (n = 37 pts) included pneumonitis (18.5%), colitis (3.3%), increased creatinine (5.4%), elevated transaminases (3.3%), hyperthyroidism (7.6%), hypothyroidism (13.0%). Grade ≥ 2 irAEs (n = 32 pts) included pneumonitis (18.5%), hypothyroidism (10.8%), and colitis (3.3%). Group A/B: male (21/38), female (16/17), current or former smoker (35/52), stage IIIA (20/35), stage IIIB (17/20), non-squamous (21/30), squamous (16/25). Median number of pembrolizumab cycles received in Group A/B pts were 9 vs 15 (p = 0.0942) respectively. 4 yr efficacy endpoints in Groups A/B were TMDD 35.3% vs 41.3% (p = 0.83), PFS 27.8% vs 28.7% (p = 0.97), OS 43.5% vs 47.9% (p = 0.99), respectively. Conclusions: Despite receiving fewer cycles of consolidation pembrolizumab, pts who experienced any grade irAEs (excluding grade 1 pneumonitis) did not have significantly reduced efficacy outcomes. Clinical trial information: NCT02343952.
I-SABR phase II randomized study of nivolumab immunotherapy and stereotactic ablative radiotherapy in early stage NSCLC: Interim analysis adverse effects.
Authors: Chang Joe Y. , Lin Steven H. , Yao Luyang , Gandhi Saumil , Liao Zhongxing X. , Chun Stephen G. , Jeter Melenda , Welsh James William , Lee Percy , Antonoff Mara , Feng Lei , Lee J. Jack , Heymach John 
Published: May 2020

9035 Background: Stereotactic Ablative Radiotherapy (SABR) provides > 95% local control and has become standard care of medically inoperable stage I NSCLC. However, cumulatively about 40% of patients develop recurrence in the regional lymph nodes, distant organs, or secondary lung cancer. Combined immunotherapy and SABR (I-SABR) may reduce these recurrences by stimulating stronger cancer specific immune response. Methods: This is an ongoing phase II randomized study (SABR vs. I-SABR) to evaluate the efficacy and toxicity of I-SABR in medically inoperable, early stage (T1-T3: < 7 cm, including multi-primary tumors), isolated recurrence NSCLC without lymph node or distant metastasis. The primary objective is event-free survival (any recurrence and/or death). Secondary objectives include rates of ≥Grade 2 toxicity. 4-D CT image guided SABR (50 Gy in 4 fractions or 70 Gy in 10 fractions) was delivered to all patients. Patients randomized to I-SABR received additional concurrent Nivolumab (240 mg, every two weeks for total of 7 doses or 480 mg every four weeks for total of 4 doses). 140 patients are anticipated to enroll. We report here interim analysis of toxicity. Results: 92 patients (median age: 72, range: 57 to 90) were enrolled and randomized (47 to SABR; 45 to I-SABR). With median follow up of 14.5 months (range 2 to 28 months), there were no treatment-related grade 4/5 adverse events. For the I-SABR arm, there was one case of possible related grade 3 dyspnea, skin rash and 2 cases of probable grade 3 fatigue. There were possible/probable treatment related 2 cases of grade 2 pneumonitis, fatigue, pruritus and 1 case of grade 2 hyperthyroidism and arthralgia. No patients discontinued treatment due to adverse effects. For the SABR arm, there were possible treatment related 1 case of grade 2 fatigue and pneumonitis. All symptoms resolved with or without treatment. Conclusions: Combined Nivolumab immunotherapy and SABR (I-SABR) appear to be well-tolerated in this fragile patient population with no grade 4/5 toxicity. All toxicities were tolerable and resolved. The major barrier for patient enrollment and/or randomization is patient’s perception of potential toxicities and additional clinic visits. Continued enrollment and additional follow up are needed to validate these findings. Clinical trial information: NCT03110978.
Artificial intelligence based on deep learning for differential diagnosis between benign and malignant pulmonary nodules: A real-world, multicenter, diagnostic study.
Authors: Xu Tao , Huang Chuoji , Liu Yaoqi , Gao Jing , Chang Huan , Yang Ronghua , Jiang Tianjiao , Cheng Zhaozhong , Yu Wencheng , Zhang Juncheng , Bai Chunxue 
Published: May 2020

9037 Background: Lung cancer is the most common cancer worldwide. Artificial intelligence (AI) platform using deep learning algorithms have made a remarkable progress in improving diagnostic accuracy of lung cancer. But AI diagnostic performance in identifying benign and malignant pulmonary nodules still needs improvement. We aimed to validate a Pulmonary Nodules Artificial Intelligence Diagnostic System (PNAIDS) by analyzing computed tomography (CT) imaging data. Methods: This real-world, multicentre, diagnostic study was done in five different tier hospitals in China. The CT images of patients, who were aged over 18 years and never had previous anti-cancer treatments, were retrieved from participating hospitals. 534 eligible patients with 5-30mm diameter pulmonary nodules identified by CT were planning to confirm with histopathological diagnosis. The performance of PNAIDS was also compared with respiratory specialists and radiologists with expert or competent degrees of expertise as well as Mayo Clinic’s model by area under the curve (AUC) and evaluated differences by calculating the 95% CIs using the Z-test method. 11 selected participants were tested circulating genetically abnormal cells (CACs) before surgery with doctors suggested. Results: 611 lung CT images from 534 individuals were used to test PNAIDS. The diagnostic accuracy, valued by AUC, in identifying benign and malignant pulmonary nodules was 0.765 (95%CI [0.729 - 0.798]). The diagnostic sensitivity of PNAIDS is 0.630(0.579 – 0.679), specificity is 0.753 (0.693 – 0.807). PNAIDS achieved diagnostic accuracy similar to that of the expert respiratory specialists (AUC difference: 0.0036 [-0.0426 - 0.0497]; p = 0.8801) and superior when compared with Mayo Clinic’s model (0.120 [0.0649 - 0.176], p < 0·0001), expert radiologists (0.0620 [0.0124 - 0.112], p = 0.0142) and competent radiologists (0.0751 [0.0248 - 0.125], p = 0.0034). 11 selected participants were suggested negative in AI results but positive in respiratory specialists’ result. 8 of them were malignant in histopathological diagnosis with tested more than 3 CACs in their blood. Conclusions: PNAIDS achieved high diagnostic accuracy in differential diagnoses between benign and malignant pulmonary nodules, with diagnostic accuracy similar to that of expert respiratory specialists and was superior to that of Mayo Clinic’s model and radiologists. CACs may be able to assist CT-based AI in improving their effectiveness but it still need more data to be proved. Clinical trial information: ChiCTR1900026233.
Clinical impact of targetable gene alterations on therapeutic outcomes in stage II/III locally advanced non-small cell lung cancer patients.
Authors: Zenke Yoshitaka , Matsumoto Shingo , Kato Terufumi , Miyamoto Shingo , Imakita Takuma , Mitsudomi Tetsuya , Aono Hiromi , Ushio Ryota , Furuya Naoki , Nishino Kazumi , Takata Saori , Nakao Mika , Hara Satoshi , Tachihara Motoko , Sekine Akimasa , Sakakibara-Konishi Jun , Toyozawa Ryo , Yoh Kiyotaka , Goto Koichi 
Published: May 2020

9038 Background: The clinical significance of genetic alterations in stage II/III non-small cell lung cancer (NSCLC) patients has not yet been clarified. We have prospectively analyzed NSCLC patients for cancer-related gene alterations and have followed up clinical course of the patients, establishing a large-scale clinico-genomic database in our nationwide genome screening project (LC-SCRUM-Japan). Methods: Submitted tumor samples were subjected to a targeted next-generation sequencing (NGS) system, Oncomine™ Comprehensive Assay. Therapeutic and prognostic data were collected and updated every year. Results: Since March 2015 to May 2019, 5166 non-squamous NSCLC patients from 263 institutions had been enrolled in the LC-SCRUM-Japan, and 754 of them were diagnosed as stage II/III. The median age of the 754 patients was 67 years (range, 21-92), and 503 (67%) were male, 595 (79%) smokers and 631 (84%) stage III. Of 640 available samples, 258 (40%) had targetable gene alterations, comprising 106 KRAS mut, 42 EGFR mut, 29 BRAF mut, 20 MET ex14skip/amp, 16 ALK fus, 12 ROS1 fus, 11 ERBB2 ex20ins, 8 RET fus, 7 EGFR ex20ins, 5 AKT1 mut, 1 NRG1 fus, 1 FGFR2/3 fus. In patients who received surgery (n = 159), 3-year disease-free survival rate was worse in patients with targetable gene alterations than in those without (40% vs 58% months; p = 0.03). In patients who received cytotoxic chemo-radiotherapy (n = 148), the response rate was similar in patients with targetable gene alterations and those without (70% vs. 77%); however, 3-year progression-free survival rate tended to be shorter in patients with targetable gene alterations than in those without (19% vs 35%; p = 0.08). Conclusions: In stage II/III NSCLC, the total frequency of targetable gene alterations was similar to that previously evaluated in our stage IV cohort (45%), and the current standard therapies showed early progression in the targetable gene-altered patients. A novel effective multimodality treatment in combination with targeted therapies is needed for this population.
Real-world survey of pneumonitis/radiation pneumonitis among patients with locally advanced non-small cell lung cancer treated with chemoradiotherapy after durvalumab approval: A multicenter retrospective cohort study (HOPE-005/CRIMSON).
Authors: Saito Go , Oya Yuko , Taniguchi Yoshihiko , Kawachi Hayato , Fujimoto Daichi , Matsumoto Hirotaka , Iwasawa Shunichiro , Suzuki Hidekazu , Niitsu Takayuki , Miyauchi Eisaku , Yokoi Takashi , Mitsui Miho , Uenami Takeshi , Sakata Yoshihiko , Arai Daisuke , Okada Asuka , Hara Satoshi , Teraoka Shunsuke , Kokubo Masaki 
Published: May 2020

9039 Background: Durvalumab was approved as a consolidation therapy after chemoradiotherapy (CRT) for locally advanced non-small cell lung cancer (NSCLC) and established as the standard of care. However, since the approval of durvalumab, little has been reported on the frequency, severity, or clinical course of pneumonitis/radiation pneumonitis throughout the course of CRT. Methods: We conducted a 17-center, retrospective cohort study of consecutive patients with locally advanced NSCLC who received concurrent chemoradiotherapy (CCRT) with platinum-based chemotherapy between May 2018 and May 2019. Results: A total of 275 patients were included; their median age was 69.9 (range, 40.3-87.5), mean V20 was 19.4% (range, 1.4-37.9), and mean "mean lung dose" was 10.9 Gy (range, 1.5-31.3). Of these, 204 patients received durvalumab consolidation therapy (74.2%). Median follow-up time from the initiation of CCRT was 8.4 months (range, 1.5-15.7). During follow-up, 225 patients (81.8%) developed any-grade pneumonitis/radiation pneumonitis. Of these, more than half (134 of 225) were asymptomatic (grade 1), 18 (6.5%) were ≥grade 3, and 4 patients (1.5%) had fatal pneumonitis/radiation pneumonitis. By the time of initial assessment of response to CCRT, 64 (23.3%) patients had developed radiation pneumonitis. Logistic regression revealed that only V20 ≥25 % was an independent risk factor of symptomatic (≥grade 2) pneumonitis/radiation pneumonitis (OR: 2.74, 95% CI: 1.35-5.53, p = 0.0045). Of the 275 patients, 67 were treated with corticosteroids for pneumonitis/radiation pneumonitis (24.7%), and 14 (5.1%) needed home oxygen therapy after the treatment of pneumonitis/radiation pneumonitis. Among patients treated with corticosteroids, 21 patients received durvalumab rechallenge. Of the 21 patients, 6 (29%) showed pneumonitis/radiation pneumonitis relapse, of which 3 (14%) resulted in suspension of durvalumab rechallenge, but none were fatal. Conclusions: Although over four-fifths of the patients treated with CCRT after the approval of durvalumab developed pneumonitis/radiation pneumonitis, more than half of them were asymptomatic, and ≥grade 3 events accounted for 6.5%. Sometimes patients needed corticosteroid therapy, which was in many occasions effective, and some also underwent durvalumab rechallenge. V20 was an independent risk factor of symptomatic pneumonitis/radiation pneumonitis.