bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of germ-line single nucleotide polymorphisms (SNPs) with pathologic response to neoadjuvant cisplatin-based chemotherapy in patients with resectable non-small cell lung cancers.
Authors: Chaft Jamie E. , Shah Sohela , Drill Esther N. , Sima Camelia S. , Joseph Vijai , Dutra-Clarke Ana Virginia Calogeras , Littman Jason , Kris Mark G. , Travis William D. , Rizvi Naiyer A. , Offit Kenneth 
Published: March 2020

7558 Background: Pathologic response to neoadjuvant chemotherapy correlates with survival in resected lung cancers. Predictive biomarkers of response are needed. Tumor-specific biomarkers have been hindered by reproducibility and specimen adequacy. Genome-wide association studies (most in SE Asia) have identified candidate SNPs that correlate with clinical outcomes after cisplatin-based chemotherapy. We evaluated whether these candidate SNPs are predictive of pathologic response to neoadjuvant chemotherapy in a US population. Methods: We aimed to correlate SNPs with near complete PR (ncPR) to neoadjuvant cisplatin + docetaxel in patients with resectable lung cancers. ncPR was defined as 90% necrosis, inflammation and fibrosis across serial 1cm sections of the resected tumor. Germline DNA was extracted and 50 candidate SNPs were genotyped by Sequenom Mass ARRAY iPLEX. SNPs were analyzed for correlation with ncPR using recessive (aa vs AA/aA) , dominant (AA vs aa/aA) and log-additive (linear increase in risk with each additional allele) genetic models. In this exploratory dataset, a p-value <0.1 was considered worthy of further study. Results: 60 patients were treated and had sufficient DNA for analysis. Nine patients had a ncPR. 7 of 50 SNPs (table) correlated with pathologic response in one of the three models. Conclusions: Of the candidate SNPs identified from the literature, 7 showed a promising correlation to ncPR to neoadjuvant chemotherapy. This expands upon the experience evaluating SNPs and chemotherapy sensitivity into a North American population. Study of these 7 SNPs is ongoing in our current multimodality trial as a validation cohort. This study was funded by the Lung Cancer Research Foundation. [Table: see text]
Prognostic impact of FGFR1 amplification in patients with early-stage resected squamous cell carcinomas of the lung (SQCLC).
Authors: Hellmann Matthew David , Wang Lu , Wynne Melissa , Sima Camelia S. , Kris Mark G. , Moreira Andre L. , Rekhtman Natasha , Paik Paul K. 
Published: March 2020

7559 Background: The spectrum and frequency of oncogenes in squamous cell lung cancers (SQCLCs) has recently been defined. Amplification of fibroblast growth factor receptor 1 (FGFR1) occurs in ~20% of SQCLCs; clinical trials of FGFR1 inhibitors for advanced SQCLCs are ongoing. The frequency, clinicopathologic features, and prognosis of FGFR1 amplification in early-stage, resected SQCLCs have been reported but with discrepant results (Kim et al, J Clin Oncol 2012, Heist et al, J Thorac Oncol 2012). Methods: A cohort of histopathologically-defined and clinically-annotated resected SQCLCs was tested for FGFR1 amplification by FISH (Zytovision Dual Color Probe). Amplification was defined by FGFR1 copy number ≥2.2x CEP8 control copy number and was assessed by two evaluators (MW, LW) who were blinded to clinical results. Disease-free survival (DFS) was defined as date of resection until relapse, recurrence, or death, whichever occurred first. We assessed association between FGFR1status and clinical features (Fisher’s exact test) and DFS (long-rank test). Multivariate DFS analysis was performed using Cox regression analysis. Results: 63 resected SQCLCs were evaluated. FGFR1 amplification was detected in 16 (24%). The median age of the cohort was 70 years (range 48-88). 15 (24%) currently smoked, 47 (75%) former, 1 (1%) never. 7 (11%) received neo-adjuvant therapy. 35 (56%) were stage I, 15 (24%) were stage II, and 13 (20%) were stage IIIA. There was no association between FGFR1 amplification and age (p>0.99), sex (p>0.99), smoking status (p=0.32), or stage of disease (p=0.18). 1-year and median DFS in FGFR1-amplified vs non-amplified cases were 86% vs 71% (p=0.022) and not reached vs 2.3 yrs (95% CI 1.1-3.4 yrs), respectively. Multivariate analysis (FGFR1 status, sex, and stage) found FGFR1amplification significantly associated with improved DFS (HR 3.2, 95% CI 1.1-9.4). Conclusions: In this cohort of resected SQCLCs FGFR1 amplification was associated with improved outcomes. There was no association between FGFR1 status and sex, age, smoking status, or stage. FGFR1 amplification is common in SQCLCs.
Computer-aided lung cancer screening with CT: A clinically usable nodule detection and assessment system.
Authors: Lo Pechin , Brown Matthew S. , Goldin Jonathan , Barnoy Eran , Kim Hyun J. , McNitt-Gray Michael F. , Aberle Denise R. 
Published: March 2020

7562 Background: The National Lung Screening Trial (NLST) recently demonstrated that lung cancer screening with low-dose CT reduces mortality. Current protocols use 4–8 mm nodules as positive screens. While there are some computer-aided nodule detection (CAD) systems currently available, they are rarely used in clinical practice because they generate too many false positives and lack reliable measurement tools. The purpose of this work is to develop a new CAD system to overcome these limitations and evaluate it against an expert panel of radiologists. Methods: The CAD system developed for lung nodule detection and measurement incorporates computer vision techniques including intensity thresholding, Euclidean Distance Transformation, and watershed segmentation. Rules pertaining to volume and shape were applied to automatically discriminate between nodules and bronchovascular anatomy. CAD system performance was assessed using 108 consecutive cases from the publically available Lung Imaging Database Consortium (LIDC), in which four radiologists reviewed each case. CT slice thickness ranged from 0.6–3.0 mm. Nodules were included that were: (a) ≥ 4mm, and (b) marked by a majority of the LIDC readers, and (c) ≥ 4 x CT slice thickness (to ensure adequate spatial resolution). Results: 44 of 108 subjects had one or more nodules meeting criteria. Median CAD sensitivity per subject for these 44 cases is reported for all nodules ≥ 4mm and the subset of nodules ≥ 8mm. The false positive (FP) rate per subject is reported for all 108 cases. The overall concordance correlation coefficient (CCC) between the CAD volume of each nodule and the LIDC reference volume was measured. Conclusions: Based on clinical CT screening protocols, a CAD system has been developed with high nodule sensitivity and a much lower false positive rate than previously reported systems. Automated volume measurements show strong agreement with the reference standard, providing a comprehensive detection and assessment workflow for lung cancer screening. [Table: see text]
Impact of environmental tobacco smoke (ETS) on ALK rearrangements in never smokers (NS) with non-small cell lung cancer (NSCLC): Analyses on a prospective multinational ETS registry.
Authors: Kubo Akihito , Ando Masahiko , Soo Ross A. , Kawaguchi Tomoya , Ou Sai-Hong Ignatius , Ahn Myung-Ju 
Published: March 2020

7565 Background: EGFR and ALK are important driver mutations in NS. While we reported the significant association of increased ETS with EGFR mutations in Japanese cohort (Kawaguchi, Clin Cancer Res, 2011), ETS association with ALK has not been reported. Methods: ETS exposure on NS with NSCLC was evaluated using the standardized questionnaire including exposure period, place, and duration. Cumulative dose of ETS (CETS) was defined as a sum of the number of the exposure years in childhood and in adulthood, and was treated as a continuous variable or quintile. EGFR mutations and ALK rearrangements were tested by PCR-based detection and fluorescence in situ hybridization, respectively. Multivariate analyses were done using the generalized linear mixed model (GLIMMIX procedure, SAS v9.3). Results: From March 2008 to December 2012, 498 NS with NSCLC were registered with the following patient characteristics: ethnicity (nationality) of Asian/ Caucasian/ others, 425 (Japanese 250, Korean 102, Chinese 46, others 2)/ 48/ 25; male/female, 114/384; age <65/>=65, 286/212. EGFR status was wild type 43.6%, exon 19 deletion 25.3%, L858R 21.5% and other mutations 9.6%. ALK status was wild type 52.0%, rearranged 10.6% and unknown 37.3%. Average CETS (years) of NS with EGFR (+), ALK (+) and wild type tumors were 45.4, 26.9 and 37.7, respectively. In multivariate generalized linear mixed model, incidence of activating EGFR mutations, not ALK rearrangements, was significantly associated with the increment of CETS in female, not in male gender. Odds ratios (OR) for EGFR mutations in female (n=384) were 1.084 (95% CI, 1.003-1.171; p=0.0422) for each increment of 10 years in CETS while OR in male (n=114) were not significant (OR 0.890; 95% CI, 0.725-1.093; p=0.2627). OR for ALK rearrangements in female (n=238) and those in male gender (n=74) were 0.930 (0.791-1.094; p=0.3814) and 0.854 (0.620-1.178; p=0.3319). Conclusions: Increased ETS exposure was closely associated with EGFR mutations in NS with female gender and NSCLC in the expanded multinational cohort. However, the association of ETS and ALK rearrangements in NS with NSCLC was not significant.
Dual intervention with a lymph node (LN) specimen collection kit and enhanced specimen dissection to improve staging of resectable non-small cell lung cancer (NSCLC).
Authors: Sareen Srishti , Ramirez Robert A. , Javed Ahmed Yasir , Miller Laura Elizabeth , Wang Christopher , Smeltzer Matthew , Khandekar Alim , Schoettle Glenn P , Robbins Samuel G , Gibson Jeffrey B , Wolf Bradley Aaron , Robbins Edward T , Osarogiagbon Raymond U 
Published: March 2020

7569 Background: LN metastasis impairs survival of resectable NSCLC, but routine pathologic nodal staging is suboptimal. We tested the impact of a dual intervention (a surgical specimen collection kit with specific, pre-labeled LN collection cups, to improve intraoperative hilar/mediastinal LN dissection; and a fastidious gross dissection of the resected lung specimen for perihilar/intrapulmonary LNs) on the rate of detection of LN metastasis. Methods: We matched dual intervention cases with controls performed with standard surgical specimen collection and pathology examination protocols. Controls were hierarchically matched for extent of resection, laterality, surgeon, pathologist and T-stage. All statistical comparisons were made with Exact Conditional Logistic Regression, to account for the matched case-control design. Results: Patient demographic, tumor histology, and size characteristics were similar between the groups. The impact of the dual interventions is shown in the Table. Conclusions: The dual interventions significantly increased retrieval of N1 and N2 LNs, the rate of detection of LN metastasis, and nodal up-staging. There were strong trends towards higher aggregate stage and increased adjuvant therapy eligibility. The interventions may improve stage-adjusted survival by improving stage accuracy, and improve aggregate survival by increasing the appropriate use of post-operative adjuvant therapy. A prospective randomized trial to test survival impact of the dual interventions is at an advanced planning phase. [Table: see text]
Clinical characteristics of patients with multiple primary lung cancers: Moving beyond the Martini and Melamed criteria.
Authors: Zauderer Marjorie Glass , Drilon Alexander Edward Dela Cruz , Sima Camelia S. , Lou Feiran , Finley David J. , Kris Mark G. 
Published: March 2020

7570 Background: Deciding to operate for lung cancer in patients with a prior lung cancer resection is influenced by the extent of disease at 1st resection and the certainty that the new lesion is a 2nd primary lung cancer. While the Martini and Melamed (M&M) criteria (J Thorac Cardiovasc Surg 1975) guide the decision whether a new lesion represents a 2nd lung cancer, improvements, incorporating detailed clinical and molecular analyses, are needed. Methods: From a prospective database, we identified 130 patients who underwent two curative resections from 1995 to 2009 for non-small cell lung cancers. We examined associations between clinical factors and patterns of recurrence/DFS/OS following 2nd surgery. Results: Patient characteristics: median age 66; 42% men; and 8% never smokers. See Table for stage, histology, and completeness of resection. DFS and OS were not associated with smoking status, surgical procedure, and histology. Stage at 1st resection was not associated with patterns of recurrence (none vs local vs distant, p=0.77), DFS (p=0.61), or OS (p=0.37). Earlier stage at 2nd resection was associated with improved DFS (p<0.001) and OS (p<0.001), as well as a trend toward less distant recurrence (p=0.06). As many surgeries predated routine genotyping, very few patients (5%) had genotyping from both resections. 38% of 2nd resection stage IA lung cancers recurred distantly. 20% had a third lung cancer and 47% had at least one other malignancy. Conclusions: Outcomes after 2nd primary lung cancers are unaffected by the stage of the 1st lung cancer. Pursuit of curative interventions should not be influenced by the stage of the 1st cancer. We need more detailed molecular analysis to help correctly identify new primaries. We also need additional features to help discriminate among those at most risk for another lung cancer vs local recurrence vs distant recurrence. [Table: see text]
Patient-reported symptom burdens in NSCLC patients undergoing proton, 3DCRT, or IMRT.
Authors: Wang Xin Shelley , Liao Zhongxing X. , Komaki Ritsuko , Cox James D. , Gomez Daniel Richard , Bokhari Raza H , Sailors Mary L , Cleeland Charles S. 
Published: March 2020

7574 Background: Concurrent chemoradiation (CXRT) for stage III non-small-cell lung cancer (NSCLC) patients is associated with the development of systemic self-reported symptom burden as well as radiation esophagitis (RE). This longitudinal study aims to provide a profile of the symptom burden among 3 radiation techniques concurrently used with chemotherapy: 3-dimensional conformal radiation therapy (3DCRT), intensity- modulated radiation therapy (IMRT) and proton beam therapy (PBT). Methods: NSCLC patients (N=164) treated at MD Anderson Cancer Center rated symptoms via the M. D. Anderson Symptom Inventory (MDASI) weekly from pre-therapy up to 20 weeks post-therapy. Descriptive analysis identified major symptom burden, and mixed effect modeling examined change over time in symptom outcomes among the 3 types of CXRT. Results: Average total radiation dose was higher (p=.0003) for PBT (N=30, 71.6 Gy) and IMRT (N=67, 66.3 Gy) than for 3DCRT (N=24, 62.1 Gy). Over time, all patients reported a cluster of symptoms that increased as the dose accumulated, including fatigue, drowsiness, pain, difficulty swallowing, poor appetite and sore throat; symptoms generally peaked at week 7-9 and returned to pre-therapy levels at week 13. The IMRT group had significant less-severe sore throat (p=.03), while there were no significant differences in symptom severity among the 3 types of CXRT for the other major symptoms before, during and after CXRT. However, there was a trend of more patients reporting moderate to severe sickness symptoms as a component score (fatigue, pain, sore throat, poor appetite and drowsiness) in the 3DCRT group than in the IMRT or PBT groups at end of CXRT (50% vs. 44%, 31%) and at 13 weeks (53% vs. 23%, 25%). Also, there was a trend of more patients under 3DCRT than IMRT or PBT had moderate to severe sore throat (RE symptom) by end of CXRT (60% vs. 44%, 46%) and no different by 13 weeks (27% vs. 25%, 31%). Conclusions: Although clinical studies have reported the toxicities of CXRT, this is the first longitudinal study that compared symptom profiles for NSCLC patients receiving PBT, IMRT and 3DCRT. There is an impression of more severe treatment-related symptoms for 3DCRT (although in lower radiation dose) than IMRT or PBT.
Genomic characterization and high-throughput therapeutic screening of malignant mesothelioma to reveal novel tumor dependencies.
Authors: Alifrangis Constantine , Quispel Janssen Josine , de Vries Hilda , Schunselaar Laurel , Bignell Graham , Garnett Mathew , Neefjes Jacques , Berns Anton , Baas Paul , McDermott Ultan 
Published: March 2020

7581 Background: Clinical trials of targeted therapeutics in mesothelioma have demonstrated limited efficacy. It has been suggested that combinations of targeted agents may be more effective in this disease, but given the unknown status of tractable oncogenic mutations it has been difficult to ascertain which key signalling nodes drive these tumours that may lend themselves to therapeutic intervention. We therefore aimed to characterise a representative panel of mesothelioma cell lines at the genomic level, and then determine critical “nodes” utilising a high throughput screen of targeted agents. Methods: 19 mesothelioma cell lines and 6 mesothelioma primary tumour early passage lines underwent Illumina whole exome sequencing and copy number analysis. In parallel a high throughput screen was performed utilising a panel of targeted therapeutics enabling each mesothelioma to be screened across 48 compounds. Efficacy was confirmed in 3D spheroid culture. Results: Exome sequencing of the mesothelioma panel revealed mutations in tumour suppressor genes previously described in mesothelioma including NF2, as well as previously unreported mutations in this disease affecting histone modifying genes MLL2 and SETD2. Notably an absence of mutated “driver” oncogenes was observed. High throughput screening demonstrated limited activity for most small molecule inhibitors as single agents. However, despite an absence of mutations in PIK3CAor related genes, PI3K/mTORC inhibition had the broadest single agent efficacy. Conclusions: We demonstrate that mutations in cell lines are similar to those found in patient-derived tumours implying fidelity at the genomic level. Mesotheliomas harbour multiple mutations in tumour suppressors, but lack commonly tractable oncogenic mutations which may explain poor efficacy seen in clinical trials to date. We further demonstrate that PI3K may represent a critical node therapeutically that may be useful in combinatorial approaches.
Platelet counts (PLT) at baseline and on treatment as predictor for progression free survival (PFS) in patients with advanced malignant pleural mesothelioma (MPM): EORTC 08052 study.
Authors: Gaafar Rabab Mohamed , Popat Sanjay , Van Meerbeeck Jan P. , Baas Paul , Fennell Dean , Pallis Athanasios G. , Hasan Baktiar , O'Brien Mary 
Published: March 2020

7585 Background: PLT values at baseline are considered as a negative prognostic factor in several different tumor types (lung, colorectal, renal and endometrial cancer) in both early and advanced disease settings. This is an exploratory analysis of PLT (baseline and changes during treatment) and their value in predicting PFS and overall survival (OS) in patients with stage IV MPM treated with cisplatin/bortezomib in the context of a single-arm phase II trial (EORTC 08052). Methods: Patients participating in the clinical trial were chemo-naïve with histological proven MPM and PS 0/1 (cisplatin 75 mg/m2 d1 and bortezomib 1.3 mg/m2 on d1, 4, 8, 11 q3wks). PLT analysis was pre-planned in the protocol and was recorded at baseline and at each cycle. Nadir of change in PLT was recorded at 8 and 18 weeks according to predefined cut off points (median PLT value). The association of the PLT with PFS and OS was analyzed. Results: 82 patients from EORTC-08052 study were analyzed with 1394 records of PLT. The cut off point for baseline was median PLT 374x103/mm3. We confirmed that patients with baseline PLT less than median had longer PFS compared to patients with counts higher than median (median PFS: 5.7 vs. 3.7 months [mo]; HR: 0.55; 95% CI: 0.34-0.88; p: 0.012). There was also a trend towards higher OS for patients with baseline PLT values less than median (median OS: 14.8 vs.10.6 mo; HR: 0.62; 95% CI: 0.38-1.02; p: 0.059). The median decrease of PLT values at 8 wks of treatment was 243 x103/mm3. Patients with decrease lower than median had higher PFS (median PFS: 7.5 vs. 5.7 mo; HR: 2.2; 95% CI: 1.3-3.8; p: 0.003) and a trend towards higher OS (median OS: 14.9 vs. 10.6 mo; HR: 1.6; 95% CI 1-2.7; p: 0.06). Changes at 18 weeks had no prognostic value. Conclusions: Besides low baseline PLT values we observed that a decrease in PLT at 8 weeks (but not 18 weeks) during treatment could predict PFS and to less extent OS. Validation of this observation is planned.
Interim outcome analysis of a prospective phase I trial of surgical resection with intracavitary hyperthermic cisplatin and gemcitabine for patients with resectable malignant pleural mesothelioma.
Authors: Richards William G. , Dasilva Marcelo C , Eisen Hannah M. , Barlow Julianne C , Bueno Raphael , Sugarbaker David 
Published: March 2020

7588 Background: We completed a phase I trial of cisplatin and dose-escalated gemcitabine in a hyperthermic intra-operative lavage (IOHC) following extrapleural pneumonectomy (EPP arm) or extended pleurectomy (PD arm). Primary and secondary endpoints including gemcitabine MTD (1000 mg/m2 with 175 mg/m2 cisplatin) and pharmacokinetics, toxicity and mortality were reported (IMIG congress, 9/11-14/2012, abstract IIB.4 [1]). To define phase II indications, we explored patient outcome in comparison to published phase II results of a similar trial using cisplatin IOHC alone following EPP (J Thorac Cardiovasc Surg 2009, 138:405 [2]). Methods: The protocol was registered and IRB approved. Informed consent was obtained. Overall survival was calculated from the date of surgery to the date of death or censored at the date of most recent contact. Patients who were treated on the EPP arm at 500 to 1000 mg/m2 gemcitabine dose levels were included, grouped by epithelial (E) or non-epithelial (NE) histological subtype. Median, 1-year and 2-year survival was estimated using Kaplan-Meier methods. Results: 141 patients were registered. Median age was 65 (43-85) and 22 (21%) were women. Histology was epithelial (63), biphasic (32), and sarcomatoid (8). Two patients died perioperatively (2%). 59 patients were treated on the EPP arm of which the 27 (13 censored) treated at 500 to 1000 mg/m2 gemcitabine were studied. Qualitative comparison with a prior phase II trial of cisplatin IOHC (ref [2]) suggests incremental survival benefit to adding gemcitabine for patients with epithelial but not non-epithelial tumor histology (Table). Conclusions: Patients with epithelial histology tumors who require EPP for macroscopic complete resection appear likely to benefit from the addition of gemcitabine and should be included in a phase II investigation of this combination. Patients with non-epithelial biopsy who require EPP should be considered for other treatment strategies. Clinical trial information: NCT00571298. [Table: see text]