bluuebunny/crossref_metadata_2025_split huggingface dataset:
Thymic carcinoma: A cohort study of prognostic factors after surgical resection from the European Society of Thoracic Surgeons database.
Authors: Ruffini Enrico , Detterbeck Frank C. , Van Raemdonck Dirk , Rocco Gaetano , Thomas Pascal Alexandre , Weder Walter , Brunelli Alessandro , Guerrera Francesco , Keshavjee Shaf , Altorki Nasser K. , Schutzner Jan , Toker Alper , Spaggiari Lorenzo , Arame Alex , Lim Eric Kian Saik , Venuta Federico ,   European Society of Thoracic Surgeons Thymic Group
Published: March 2020

7602 Background: Thymic carcinomas are rare tumors which have recently been separated from thymomas due to their different histologic/clinical characteristics. Most of the current literature is composed of small series spanned over extended time periods Methods: The European Society of Thoracic Surgeons (ESTS) developed a retrospective database collecting data on patients with thymic tumors submitted to surgery (1990-2011). Out of 2,265 incident cases, there were 229 thymic carcinomas. Clinical-pathologic characteristics were analyzed including age, gender, stage (Masaoka), histologic subtypes (squamous cell/others), type of resection (complete/incomplete), tumor size, induction and adjuvant therapy (chemotherapy-ChT/radiotherapy-RT), recurrence. Primary outcome was overall survival (OS); secondary outcomes were disease-free survival (DFS) and the cumulative incidence of recurrence. Survival analysis was performed using univariate and multivariate (Cox-shared frailty) competing-risk models. Missing data were analysed using multiple-imputation techniques Results: A multidisciplinary approach (surgery, ChT and RT) was used in most patients. Induction therapy was employed in 78 patients (ChT, 53; ChT/RT 23; RT, 2). Adjuvant therapy was employed in 150 patients (ChT, 19; ChT/RT, 72; RT, 59). Complete resection (R0) was achieved in 71% of the patients. Five and 10-year OS were 60% and 35%. Five and 10-year DFS were 62% and 43%. Cumulative incidence of recurrence was 0.25, 0.32 and 0.40 at 3, 5, and 10 years. Independent OS predictors (multivariate analysis) were young age (p=0.006), stage I/II (vs. III/IV, p=0.02), R0 resection (p<0.001), adjuvant therapy (ChT, RT or both) (p=0.02). Independent predictor of recurrence (univariate analysis) was tumor size (p=0.05). Conclusions: In thymic carcinomas submitted to surgical resection, increased age,Masaoka stages III-IV and incomplete resection had a significant impact in worsening survival. Larger tumors had an increased risk of recurrence. The administration of adjuvant ChT or RT was associated with improved overall survival. A multidisciplinary approach to these rare tumors remains essential.
Thymic epithelial tumors at University Federico II of Naples: A 30-year experience.
Authors: Buonerba Carlo , Federico Piera , Calabrese Filomena , Ottaviano Margaret , Nappi Lucia , Rescigno Pasquale , Matano Elide , Di Lorenzo Giuseppe , Damiano Vincenzo , Palmieri Giovannella 
Published: March 2020

7603 Background: According to the 2004 WHO classification, thymic epithelial tumors (TETs) comprise different histologies, including thymomas, thymic carcinoma, typical and atypical carcinoids. Histology classification of TETs has a dramatic impact on the prognosis and therapeutic strategy. We here review all TETs treated at our Institution over the past 30 years. Methods: Eligible patients had a pathologically confirmed TET and had at least one access at our Institution. Relevant demographic and clinical data were retrieved. An exploratory analysis was conducted using a step-wise model in patients with completely resected tumors to seek for factors predictive of recurrence after radical surgery. Results: One hundred and three patients with TETs were included in this retrospective analysis. Forty-three were female, sixty were male. Median age was 43 years (range 32-58). Forty-three patients had myasthenia gravis. Four had a thymic neuroendrocrine tumor, 19 had a thymic carcinoma, while the remaining had a thymoma. Forty-seven patients were alive at the time of analysis. Median overall survival was 5.85 years (range, 2.58-9.9). In the whole sample population, seventy-six patients had a completely resected tumor with clear pathological margins. In this sub-group of 76 patients (median age: 46, 35-55; 30 females, 46 males), 12 had a thymic carcinoma and 30 patients recurred after radical surgery. At multivariate analysis, which included age, sex, adjuvant chemotherapy, adjuvant radiotherapy, maximum tumor diameter, presence of myasthenia gravis and stage, the only factor significantly predictive of recurrence was tumor histology (odds ratio: 3,8182, 95% CI: 1,03 to 14,1; p = 0.04). Conclusions: We showed that patients with thymic carcinomas are at increased risk of recurrence after radical surgery independently on adjuvant chemotherapy/radiotherapy treatment. Additional therapeutic options are required in the adjuvant setting of completely resected thymic carcinomas.
Biomarkers (BM) France: Results of routine EGFR, HER2, KRAS, BRAF, PI3KCA mutations detection and EML4-ALK gene fusion assessment on the first 10,000 non-small cell lung cancer (NSCLC) patients (pts).
Authors: Barlesi Fabrice , Blons Helene , Beau-Faller Michele , Rouquette Isabelle , Ouafik L'houcine , Mosser Jean , Merlio Jean-Philippe , Bringuier Pierre Paul , Jonveaux Philippe , Le Marechal Cedric , Denis Marc G. , Penault-Llorca Frederique Madeleine , Debieuvre Didier , Soria Jean-Charles , Cadranel Jacques , Mazieres Julien , Missy Pascale , Morin Franck , Nowak Frederique , Zalcman Gerard ,   Intergroupe Francophone de Cancérologie Thoracique (IFCT)
Published: March 2020

8000 Background: Personalized medicine is now a reality for advanced NSCLC pts on the basis of routine screening for EGFR mutation and ALK gene fusion assessment. The French NCI (INCa) also decided to additionally fund the routine assessment of 4 additional BM (HER2, KRAS, BRAF, PI3KCA). Methods: Starting on April 2012, these BM analyses were prospectively collected into a database head by the IFCT (www.ifct.fr) with 15-20,000 analyses awaited after one year. The physicians prescribing each of these BM analyses were then connected to this database and were asked to regularly complete epidemiological, clinical and therapeutic data for each corresponding patient. Results: 10,000 BM analyses were collected and entered into the BM France database at the time of this first analysis (January 2013). On the basis of available data, the patients were mainly male (63.8%), (ex)smokers (83.3%) and stage IV pts (64%). The tumors were mainly adenocarcinomas (76.1%). The samples for BM analysis were collected under bronchoscopy, surgery or transthoracic biopsy in 27.4, 28.1 and 24.2%, respectively. The 10,000 molecular profiles were characterized by 9.4% EGFR (including 0.8% EGFR resistant), 0.9% HER2, 26.9% KRAS, 1.6% BRAF, and 2.6% PI3KCA mutated and 4.0% EML4-ALK fusion genes. Double mutations were seen in 0.9% of the tumors. On January 2013, data on treatment were available for 18.6% of patients among whom 56.9% of patients received a treatment according to their molecular profile (labeled drugs or bio-guided trials). Updated data will be presented during the meeting. Conclusions: Biomarkers France is the largest ever conducted biomolecular study on advanced NSCLC patients and provides solid data on the value of a nationwide BM screening policy for NSCLC patients.
Clinical activity of the ALK inhibitor LDK378 in advanced, ALK-positive NSCLC.
Authors: Shaw Alice Tsang , Mehra Ranee , Kim Dong-Wan , Felip Enriqueta , Chow Laura Quan Man , Camidge D. Ross , Tan Daniel Shao-Weng , Vansteenkiste Johan F. , Sharma Sunil , De Pas Tommaso , Wolf Juergen , Katayama Ryohei , Lau Yi-Yang Yvonne , Goldwasser Meredith , Boral Anthony , Engelman Jeffrey A. 
Published: March 2020

8010 Background: Lung cancers harboring anaplastic lymphoma kinase (ALK) gene rearrangements are sensitive to the tyrosine kinase inhibitor (TKI) crizotinib (CRZ), but invariably develop resistance. LDK378 is a novel, more potent ALK TKI than CRZ, with significant antitumor activity in preclinical models. Methods: In this multicenter phase I study, 131 patients (pts) with advanced malignancies harboring a genetic alteration in ALK, including 123 with ALK-rearranged (ALK+) NSCLC (as determined by FISH), were enrolled. LDK378 was administered orally at doses of 50–750 mg once daily. All pts were assessed for PK, response to therapy, and adverse events (AEs). In >20 pts with CRZ-resistant disease, tumor biopsy was performed before LDK378 treatment to identify CRZ resistance mutations. Results: As of November 8, 2012, 131 pts had been enrolled (38% male, median age 53 years), including 59 pts in the dose escalation phase, during which the MTD of 750 mg once daily was established, and 72 pts in an expanded cohort at the MTD. Among 88 evaluable NSCLC pts who received LDK378 at 400–750 mg daily, the overall response rate (ORR) was 70%, with 40 confirmed and 22 unconfirmed responses. In the subset of 64 CRZ-resistant pts, the ORR was 73%, with 31 confirmed and 16 unconfirmed responses. As of November 8, 2012 50% of pts with unconfirmed responses were ongoing. Responses were observed in pts with different CRZ resistance mutations as well as in pts without detectable mutation. Responses were also seen in pts with untreated CNS metastases. Among NSCLC pts with confirmed response, median duration of response (DOR) was 7.4 months (95% CI, 6.7 – NR), and 78% had a DOR of ≥6 months. In all 123 NSCLC pts, median PFS was 8.6 months (95% CI, 4.3 – 19.3). The most common AEs were nausea (72%), diarrhea (69%), vomiting (50%), and fatigue (31%). The most common Grade 3/4 AEs were ALT elevation (12%), diarrhea (7%), and AST elevation (6%). Conclusions: LDK378 induces durable responses in the majority of pts with advanced, ALK+ NSCLC, including CRZ-resistant pts with and without CRZ resistance mutations. These results suggest that more potent ALK inhibition by LDK378 represents a highly efficacious treatment strategy for ALK+ pts, particularly those who relapse on CRZ. Clinical trial information: NCT01283516.
Clinical next generation sequencing (NGS) to reveal high frequency of alterations to guide targeted therapy in lung cancer patients.
Authors: Ali Siraj M. , Palma Norma Alonzo , Wang Kai , Ross Jeffrey S. , Stephens Philip J. , Yelensky Roman , Palmer Gary A. , Lipson Doron , Miller Vincent A. 
Published: March 2020

8020 Background: Cancer genomic profiling via NGS in a clinical setting can reveal additional actionable genomic alterations (GA) in patients with lung cancer (LC) previously tested only by hotspot analysis and leading to unanticipated avenues of targeted treatment. Methods: We performed an NGS-based diagnostic test (FoundationOne) to characterize all classes of GA across 3,320 exons of 182 cancer-related genes and 37 introns of 14 genes frequently rearranged in cancer on 386 LC FFPE specimens in a CLIA-certified lab (Foundation Medicine). Specimens included fine needle aspirates, core needle biopsies, and malignant effusions. 95% of cases were NSCLC (367/386). Actionable GAs are defined as those linked to targeted anti-cancer therapies approved or being evaluated in clinical trials. NGS confirmed known hotspot results for EGFR, KRAS and EML4:ALK in 100% of cases. Results: Genomic profiles were generated from 364/386 (94%) of lung cancer cases, identifying 1205 GA, averaging 3.31 alterations per tumor (range 0 to 10). 85% of tumors (310) harbored at least one actionable GA, with a mean of 1.79 GA per tumor (range 0 to 6). In 68% of tumors (248), at least one GA was detected that would be missed by current ‘hotspot assays’. ERBB2 harbored base substitutions or indels in 1.3% of cases. BRAF and C-Kit were altered at frequencies of 2% and 1% respectively. The mTOR/PI3K pathway is likely to be activated via alterations in tumor suppressors STK11 (11%), NF1 (6%) and PTEN (4%), as well as by alterations of PIK3CA (10%) and in AKT1/2/3 (4%), suggesting possible benefit from mTOR/PI3K inhibitors. The Hedgehog pathway (PTCH1/SMO/SUFU) was altered in 2% of cases. ALK and RET were rearranged in 4% and 2% of cases, respectively, with several cases initially diagnosed negative by FISH testing. Conclusions: Profiling the tumor genomes of 364 LC patients led to the identification of a series of GA not detectable by hotspot testing that could significantly inform targeted treatment decisions. Moreover, actionable GA appeared in unexpected tumor type, i.e. an EGFR mutation in a SCLC, reinforcing the likely utility of clinical cancer genomic profiling for the personalized treatment of LC patients.
Comparison of the characteristics and clinical course of 677 patients with metastatic lung cancers with mutations in KRAS codons 12 and 13.
Authors: Yu Helena Alexandra , Sima Camelia S. , Shen Ronglai , Kass Samantha Lindsay , Kris Mark G. , Ladanyi Marc , Riely Gregory J. 
Published: March 2020

8025 Background: Patients (pts) with KRAS mutant lung cancers have a shorter survival compared to pts with KRAS/EGFR wild type tumors (Johnson et al, Cancer 2012). Whether outcomes for patients with KRAS mutant metastatic lung cancers differ by smoking status or specific amino acid substitution is unknown. In order to understand the impact of KRAS mutation subtype in the metastatic setting, we analyzed a large cohort of patients with KRAS mutant metastatic lung cancer. Methods: We identified all pts with KRAS mutant metastatic or recurrent lung cancers from Feb 2005 to Aug 2011. KRAS mutation type, clinical characteristics, and outcomes from diagnosis were obtained from the medical record. A multivariate cox proportion hazard model was used to identify factors associated with overall survival. Results: KRAS mutations were identified in 677 pts (53 at codon 13, 624 at codon 12). Median age: 66 (range 31-89), women: 62%, never smokers: 7%. Pts with transition mutations (n=157) were more likely to be never-smokers (p<0.0001). There was no difference in outcome for pts with KRAS transition versus transversion mutations (p=1) or when comparing current/former smokers to never smokers (p=0.33). There was no difference in overall survival (OS) when comparing specific amino acid substitutions (G12C=366, G12V=141, G12D=114, G12A=68, G13C=27, G13D=23, G12S=19, G12F=11)(p=0.20). Pts with KRAS codon 13 mutant tumors had inferior OS compared to pts with codon 12 mutant tumors, median 13 months (mo) (95% CI 13-17 mo) and 16 mo (95% CI 9-16 mo), respectively (p=0.009). There was no difference in frequency of receiving platinum-based chemotherapy or chemotherapy of any kind between pts with codon 12 and 13 mutant tumors. In a multivariate Cox model which included age, gender and smoking status, KRAS codon 13 mutation was associated with worse overall survival than KRAS codon 12 mutation (HR 1.52 95% CI 1.11-2.08 p=0.008). Conclusions: Among pts with KRAS mutant metastatic lung cancers, smoking history, and specific amino acid substitution do not affect outcome. Patients with KRAS codon 13 mutant metastatic lung cancer have shorter survival compared to pts with KRAS codon 12 mutant lung cancer.
MEK114653: A randomized, multicenter, phase II study to assess efficacy and safety of trametinib (T) compared with docetaxel (D) in KRAS-mutant advanced non–small cell lung cancer (NSCLC).
Authors: Blumenschein George R. , Smit Egbert F. , Planchard David , Kim Dong-Wan , Cadranel Jacques , De Pas Tommaso , Dunphy Frank , Udud Katalin , Ahn Myung-Ju , Hanna Nasser H. , Kim Joo-Hang , Mazieres Julien , Kim Sang-We , Baas Paul , Rappold Erica , Redhu Suman , Bellew Kevin M. , Streit Michael R. W. , Wu Frank S. , Janne Pasi A. 
Published: March 2020

8029 Background: KRAS mutations are detected in 25% of NSCLC, and there are no approved targeted therapies for this subset of NSCLC. D, an approved second-line treatment for NSCLC, has a response rate of < 10%. T is a reversible, highly selective allosteric inhibitor of MEK1/2 activation and kinase activity. This phase II trial (NCT01362296) evaluated the efficacy of T vs D in pts with advanced KRAS-mutant NSCLC who had received prior platinum-based chemotherapy. Methods: Pts were randomized 2:1 to T (2 mg QD) or D (75 mg/m2 IV every 3 weeks) and stratified by type of mutational status and gender. Crossover to the other arm after progressive disease was allowed. Primary endpoint was PFS in pts with KRAS-mutant NSCLC (modified ITT; mITT). Secondary endpoints were OS, ORR, duration of response, and safety. PFS and OS were compared using a stratified log-rank test. The trial was stopped early for futility at a planned interim analysis; 92 PFS events were reported at the time of study termination. Results: Between September 2011 and July 2012, 134 pts were randomized to T (89) or D (45); 129 pts had KRAS-mutant NSCLC. Mean age was 61.4 y and 53% were male. In the mITT, 61/86 pts (71%) on T and 31/43 (72%) on D had a PFS event. HR for PFS was 1.14 (95% CI, 0.75-1.75; P = .5197) with a median PFS of 11.7 vs 11.4 wk for T vs D. ORR was 12% for T (10/86) and for D (5/43). With 27 (31%) deaths on T and 15 (35%) on D, HR for OS was 0.97 (95% CI, 0.52-1.83; P= .934). Five fatal SAEs were reported during treatment with T but none with D; 1 unspecified death was considered related to T. Frequent AEs reported with T were rash (59%), diarrhea (47%), nausea (34%), hypertension (34%), and dyspnea (33%). Grade 3/4 AEs with T were hypertension (16%/0), dyspnea (7%/3%), rash (6%/3%), diarrhea (6%/0), and asthenia (6%/0). Rate of treatment related SAEs was 15% with T and 12% with D. Conclusions: T did not improve PFS in pts with KRAS-mutation–positive NSCLC compared with D. However, an ORR of 12% for T in KRAS-mutant NSCLC suggests that an effort to better identify responsive mutations is warranted. The safety profile did not favor T, but is, in general, consistent with the overall T safety profile. Clinical trial information: NCT01362296.
Survival and long-term follow-up of the phase I trial of nivolumab (Anti-PD-1; BMS-936558; ONO-4538) in patients (pts) with previously treated advanced non-small cell lung cancer (NSCLC).
Authors: Brahmer Julie R. , Horn Leora , Antonia Scott J. , Spigel David R. , Gandhi Leena , Sequist Lecia V. , Sankar Vindira , Ahlers Christoph Matthias , Wigginton Jon M. , Kollia Georgia , Gupta Ashok Kumar , Gettinger Scott N. 
Published: March 2020

8030 Background: The immune checkpoint receptor programmed death-1 (PD-1) negatively regulates T-cell activation. Nivolumab, a PD-1 receptor blocking antibody, was evaluated in a phase 1 study in pts with various tumors including NSCLC (Topalian et al, NEJM 2012;366:2443). Methods: Pts with ≥1 prior chemotherapy regimen received nivolumab (1-10 mg/kg IV Q2W) for ≤12 cycles (4 doses/8W cycle) or until discontinuation criteria were met. We report initial overall survival (OS) and updated safety and response data for NSCLC pts. Results: 127 pts evaluable for safety received nivolumab at 1, 3, or 10 mg/kg as of July 2012. Common drug-related AEs were decreased appetite (9%), anemia (8%), diarrhea, nausea, and pruritus (7% each). The most common G3/4 AEs were fatigue, pneumonitis, and elevated AST (2% each). Two drug-related deaths from pneumonitis occurred early in the trial and led to increased monitoring without further deaths from pneumonitis. Median OS (mOS) across all dose cohorts was 9.2 mo and 9.6 mo for squamous (sq) and non-sq NSCLC, respectively. mOS was not reached at the 3 mg/kg dose (phase 3 dose) for either histology. Sustained OS was observed, with 44%/ 41% and 44%/ 17% of pts (sq/non-sq) alive at 1 and 2 years, respectively (Table). Prolonged ORs occurred in both histologies (Table). Conclusions: In this long-term follow-up of a phase I trial, nivolumab had an acceptable safety profile and showed an encouraging sustained OS benefit across histologies in previously treated advanced NSCLC. Follow-up through a Feb 2013 data cut (≥1 yr follow-up for all pts) will be provided at presentation. Clinical trial information: NCT00730639. [Table: see text]
A phase I/II study with a highly selective ALK inhibitor CH5424802 in ALK-positive non-small cell lung cancer (NSCLC) patients: Updated safety and efficacy results from AF-001JP.
Authors: Nakagawa Kazuhiko , Kiura Katsuyuki , Nishio Makoto , Seto Takashi , Maemondo Makoto , Inoue Akira , Hida Toyoaki , Yamamoto Nobuyuki , Yoshioka Hiroshige , Harada Masao , Ohe Yuichiro , Nogami Naoyuki , Takeuchi Kengo , Shimada Tadashi , Tanaka Tomohiro , Tamura Tomohide 
Published: March 2020

8033 Background: Anaplastic lymphoma kinase (ALK) is a constitutively activated tyrosine kinase in a subset of NSCLC with ALK fusion gene derived from chromosomal rearrangement. Previously, CH5424802, a highly selective, second-generation ALK inhibitor, has demonstrated clinically meaningful antitumor activity and a favorable toxicity profile (ESMO 2012). Here we report the updated results of this study. Methods: Patients (Pts) with ALK-positive NSCLC and no prior ALK inhibitor therapy were treated with CH5424802 at 300 mg bid until progressive disease or intolerable toxicity to investigate the efficacy and safety. Results: As of the cut-off date of Dec. 14, 2012, 58 pts have been treated with CH5424802: median age 49.5 years, M/F 25/33, ECOG PS 0/1 26/32, never-smoker 60.3%, ≥2 prior chemotherapy regimens 62%. Among the 46 pts in phase II part of this study, the overall response rate was 93.5% (95% CI: 82.1%, 98.6%) with 2 CRs and 41 PRs. Tumor shrinkage by 30% (PR) was achieved quickly with 65% occurring within 3 weeks of treatment and 87% within 6 weeks. With a median follow-up period of 12.6 months, 47/58 pts (40/46 pts in phase II part) were still on study treatment, and the median treatment duration has passed 10.3 months. The major treatment-related AEs were dysgeusia (21/58, 36%), rash, AST increased, blood bilirubin increased (19/58, 33% each), constipation and blood creatinine increased (17/58, 29% each), mostly grade 1-2. The major treatment-related grade 3 AEs were neutrophil count decreased (4/58, 7%). No grade 4 or fatal AEs were observed. Treatment-related visual disorders, vomiting and nausea were rare and mild. Conclusions: In patients with ALK-positive NSCLC but naïve to any ALK inhibitor therapy, treatment with CH5424802 demonstrated generally mild toxicity and lead to high response rate of 93.5% and durable treatment beyond 10 months, expecting that treatment duration can be longer than that of crizotinib. CH5424802 is therefore a promising new ALK inhibitor for NSCLC. Clinical trial information: JapicCTI-101264.