bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety and activity of Combined AVElumab with Axitinib in unresectable or metastatic Thymomas B3 and Thymic carcinomas: The CAVEATT study.
Authors: Conforti Fabio , Pala Laura , Catania Chiara , Zucali Paolo Andrea , Della Vigna Paolo , Pirola Sara , Stucchi Sara , Pennacchioli Elisabetta , Queirolo Paola , Giaccone Giuseppe , De Pas Tommaso Martino 
Published: May 2020

e21114 Background: Patients (pts) with advanced B3 thymoma (B3T) and thymic carcinoma (TC) resistant to chemotherapy have limited treatment options. Treatment with Anti-PD1 showed not negligible toxicity and limited activity, and anti-VEGFR drugs obtained limited and short lasting antitumor responses. No data on combined anti-PD1/PD-L1 with antiangiogenic drugs are available in B3T/TC. We report preliminary results on safety and activity of avelumab combined with axitinib in this pts population. Methods: The CAVEATT is a single arm, multicentric, phase II trial in immunotherapy-naive pts with advanced B3T or TC, progressing after at least one line of platinum based chemotherapy. Prior therapy with antiangiogenic drugs is allowed. Pts received Avelumab 10 mg/kg iv every 2 weeks and Axitinib 5 mg twice a day until progression or toxicity. The primary objective of the study is overall response rate (ORR) by RECIST 1.1; secondary endpoints include ORR by irRC and ITMIG, and QoL by EORTC QLQ-C30. An interim futility analysis is planned after the enrollment of the first 18 patients. If at least 5 out of 18 patients will obtain a PR, the accrual will continue to reach the total number of 33 pts, according with a Simon’s minimax design. Tumor and blood samples are collected at baseline and whenever feasible at disease progression, to identify predictive biomarkers of response and mechanisms of resistance to treatment. Results: 1 pt with B3T and 12 with TC were enrolled from April 2019 to January 2020. Median age was 59 years (range 33-77). 8 pts received ≥2 previous line of therapies, and 6 pts were pretreated with an antiangiogenic drug. The median follow-up was 5.1 months. 10 pts were evaluable for response. The proportions of patients who achieved a partial response (PR) or a stable disease (SD) were respectively 40% (95% CI 17%–69%) and 60% (95% CI 30%–83%). The median PFS was 7.9 months (95% CI 2.5–NA) 12 pts were evaluable for toxicity. Treatment-related adverse events (AE) of grade 1 or 2 occurred in 7 (58%) pts, and the most common was diarrhea (3 pts). Grade ≥3 AEs occurred in 2 (17%) pts: 1 had G3 hyperthension and 1 G3 hand foot syndrome, both leading to axitinib drug reduction. No immune-related AEs (irAEs) were observed. No patient stopped treatment for toxicity, 5 pts stopped for progressive disease, and 8 pts are still on treatment. Conclusions: Preliminary results suggest promising antitumor activity and a good toxicity profile of the combination of axitinib and avelumab in pts with advanced B3T and TC. Accrual is ongoing to reach the target of 33 pts Clinical trial information: 2017-004048-38 .
Nivolumab for thymic epithelial tumors: Case series.
Authors: Aydiner Adnan , Ak Naziye 
Published: May 2020

e21115 Background: Metastatic and unresectable thymoma (T) or Thymic Carcinoma (TC) have limited treatment options, especially after first line. Methods: Patients with unresectable or recurrent thymic tumors who used minimum one dose of Nivolumab at any line of treatment were evaluated retrospectively. Even though standart dose of nivolumab is 3mg/kg dosage, due to financial concerns we used low dose regimen mostly. Results: 8 patients with TC (n = 3), T (n = 4) and mixt histology (n = 1) were included to study. Patients used nivolumab between April 2018 and August 2019, as median 3rd line of treatment. One patient used as first line treatment due to chemoresistant disease at neoadjuvant line. Three patients had previous myasthenia gravis that had to be controlled before treatment. Four patients showed moderate (n = 2) or severe (n = 2) adverse events with nivolumab treatment. Interestingly, two severe adverse events were occurred at first dose even with 40 mg nivolumab and required cessation of treatment permanently. Median follow-up time was 16.1 months (range: 12.7-165.4). The median number of nivolumab received was four (range: 1 – 18). Best response was partial response. Two patients progressed at the 3rd and 5th month of treatment. One of the patients with inoperable disease initially underwent surgery after nivolumab therapy. Duration of response for one patient with TC and one patient with T B2 were 9 and 14 months, respectively. Median survival time after nivolumab was 7.4 months (range: 2-22.1). Conclusions: Despite the small number of patients, nivolumab is an option for T and TC patients. Low dose nivolumab may also be very toxic for T, especially in patients with known myasthenia gravis history. [Table: see text]
Investigation of immune repertoires in thymoma.
Authors: Pathak Priyadarshini , Cox Mary , Dave Utpal P. , Loehrer Patrick J. 
Published: May 2020

e21117 Background: Paraneoplastic autoimmune manifestations are seen in 30 to 40% of thymoma cases. Thymus plays the main role in T- cell maturation with ‘negative selection’ of autoreactive T-cells. Due to reasons not well understood, this function is deranged in thymomas resulting in dysregulation of immune function, loss of ‘self-tolerance’ and autoreactivity. The low cost and high-throughput of next generation sequencing techniques now make it feasible to analyze extensive T-cell receptor(TCR) gene rearrangements in peripheral blood lymphocytes. Methods: 40 patients with thymoma were identified between December, 2010 and September, 2019 at Indiana University. Whole blood samples were collected after diagnosis of thymoma but prior to thymectomy. 20 patients developed paraneoplastic manifestations at some point during the disease course. Genomic DNA was isolated from whole blood samples and TCR analysis performed using a commercially available next generation sequencing assay. This was compared with the control population of 20 patients who did not demonstrate any paraneoplastic features during their disease course. Patients were matched based on age, clinical stage and WHO classification. Results: Paraneoplastic manifestations seen in the 20 patients included Myasthenia Gravis (n = 12), Good’s Syndrome (n = 2), immune mediated cytopenia (n = 3) including pure red cell aplasia, pure white cell aplasia and thrombocytopenia, neurologic manifestations such as encephalitis (n = 2), Autoimmune Autonomic Neuronopathy(n = 1) and Isaac’s Syndrome (n = 2). Some patients also demonstrated more than one paraneoplastic syndrome. The onset and course of these manifestations varied; onset prior to diagnosis of thymoma, onset after thymectomy and improving or worsening clinical features after thymectomy. Since the exact mechanism of autoimmunity is still unknown, we attempted to detect differences in TCR subsets between these two groups. Our study shows that it is technically feasible to interrogate the peripheral blood lymphocytes of thymoma patients for TCR gene clonality and diversity. Conclusions: Diverse autoimmune syndromes can be described in thymoma patients with varying clinical course and severity. Although our study is underpowered, TCR gene sequencing is efficient and may not only improve our understanding of these paraneoplastic syndromes but also identify biomarkers for their diagnosis. Our research could also potentially lead to development of targeted treatment options in the future based on TCR manipulation.
Clonal dominance of EGFR and efficacy of EGFR-tyrosine kinase inhibitors (EGFR-TKIs) in NSCLC.
Authors: Ai Xinghao , Chen Rongrong , Cui Jiuwei , Zhang Jiexia , Lin Wen , Xie Congying , HU Xiaohua , Zhang Junping , Jiao Xiaodong , Rao Chuangzhou , Yang Weihua , Chang Lianpeng , Xia Xuefeng , Yi Xin , Lu Shun 
Published: May 2020

e21501 Background: Though EGFR mutations in lung cancer are identified most often on the trunks of tumor phylogenetic trees in early stage, whether EGFR would always be the dominant clone in the advanced stage is unknown, as cancer evolution often follows a branched trajectory, with divergent subclones evolving simultaneously. The impact of clonal dominance of EGFR on outcomes with targeted therapies has not been explored. Methods: Paired tumor and plasma samples at diagnosis were obtained from systemic treatment naïve patients with advanced NSCLC in the clinical trial (NCT03059641). cfDNA and tumor DNA were sequenced by target-capture deep sequencing of 1021 genes related to solid tumors, with blood cells as the germline control. Clonal dominance analysis was performed on the basis of the CCF determined for SNVs and clustered in plasma or tumor sequencing data using a modified version of Pyclone. PFS was estimated using Kaplan-Meier method and compared using log-rank test. Results: From February 2017 to December 2019, 300 advanced NSCLC patients were enrolled prospectively from 14 centers cross China. One hundred and fourteen EGFR mutant patients treated with EGFR-TKI were followed until disease progression (PD). The medium follow-up time was 10 month (1-27 months) and 92 (80.7%) patients have reached PD, with the ORR of 74.6% (85/114), mPFS of 10.5 months. Clonal dominance analysis of EGFR showed 76 patients had EGFR as the dominant clone according to tissue NGS results, and 66 patients as the dominant clone according to plasma cfDNA NGS results (p = 0.04). The ORR was significantly higher for patients with EGFR as dominant clone according to plasma cfDNA NGS results (84.8% vs 60.9%, p = 0.016), and PFS was significantly longer (12 vs 8 months, HR = 2.58). There was no difference when using tissue NGS results to analyze EGFR clonal dominance. However, if comparing patients who were defined as EGFR dominant clone by both tissue and plasma (n = 44) with those defined as EGFR nondominant (n = 9), EGFR dominance was associated with higher ORR (84.1% vs 44.4%, p = 0.01), and longer PFS (11 vs 6 months, HR = 9.88) significantly. Moreover, multivariate Cox proportional hazard ratio analysis demonstrated it as an independent prognostic indicator of EGFR-TKIs. Conclusions: Clonal dominance of EGFR in the pretreatment plasma cfDNA is associated with the efficacy of EGFR-TKIs in NSCLC. This study indicated the importance of evaluating clonal dominance in the current clinical practice and future trial designs. Clinical trial information: NCT03059641.
Alterations in STK11 to limit response to immune checkpoint inhibitors in lung cancer.
Authors: Fricke Jeremy , Mambetsariev Isa , Pharaon Rebecca , Baroz Angel Ray , Zhao Dan , Massarelli Erminia , Koczywas Marianna , Salgia Ravi 
Published: May 2020

e21503 Background: The use of immune checkpoint inhibitors (ICIs) drastically transformed the treatment of lung cancer. However, a variety of response rates have been observed in patients due to intrinsic or acquired resistances. STK11 mutated patients represent a subgroup of lung cancer patients with diminished outcomes when given ICIs, with some of these patients developing hyperprogressive disease (HPD). Methods: In this study, a retrospective cohort of 384 lung cancer patients previously treated with ICIs was identified from the City of Hope Thoracic Registry (THOR) with a cutoff date of November 11, 2018. Next-generational sequencing (NGS) was performed on 246 patients. 24 of these patients were harboring an alteration in STK11. Data was collected on these patients until December 31, 2019. HPD was exclusively defined by time-to-treatment failure (TTF) < 2 months (TTF is defined as the time from the start of treatment with ICI to ICI discontinuation for any reason, including progression, patient preference, toxicity, or death). Overall survival (OS) and progression free survival (PFS) was started from the initiation of ICI therapy. OS and PFS was calculated between 2 groups (HPD vs non-HPD) using the Mantel-Cox Log-rank test. Results: Almost half (11/13; 45.8%) of the patients with STK11 developed HPD. There was a significant difference between HPD and non-HPD patients in median OS (2 vs 23 months; p = 0.0013) and median PFS (1 v 9 months; p < 0.0001). The median age was 66 (range, 41-90) years old with the majority of patients female (14/24; 58.3%). Most of the patients are deceased (16/24; 66.7%). 91.7% of STK11 patients histologically were adenocarcinoma and 91.7% were smokers with a median pack year history of 40 (range, 4-90). All of the patients had metastatic disease presenting with stage IV disease (21/24; 87.5%). ICI therapies used were pembrolizumab (11/24; 45.8%), Atezolizumab (8/24; 33.3%), nivolumab (4/24; 16.7%), and durvalumab (1/24; 4.2%). PD-L1 expression varied: negative (8/24; 33.3%), 1%- < 50% (7/24; 29.2%), ≥50% (4/24; 16.7%), and not reported (5/24; 20.8%). The most commonly occurring co-mutations were found in TP53 (14/24; 58.3%), KRAS (12/24; 50.0%), SMARCA4 (9/24; 37.5%), PRKDC (8/24; 33.3%) and LRP1B (8/24; 33.3%). Three patients had a pathological co-mutation that is targetable (1 ALK rearrangement, 1 EGFR exon 19 deletion, and 1 RET fusion). Conclusions: STK11 patients who developed HPD had worse OS and PFS compared to STK11 patients without HPD. These results are preliminary and additional analysis is needed to compare differences between various cohorts.
Liquid biopsy: Safety and efficacy in a tool for molecular profiling of advanced non-small cell lung cancer (NSCLC).
Authors: Rizwan Saleha , Otaibi Zachary , Lo Herman , Khan Talal , Wegner Rodney E. , Finley Gene Grant 
Published: May 2020

e21506 Background: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer with a broad spectrum of targeted therapies already available or in clinical trials. Among the NSCLC patients, 23% to 25% harbor a mutation in a gene associated with approved or emerging targeted therapy. These therapies have changed the therapeutic landscape of NSCLC with significantly improved clinical outcomes in advanced metastatic NSCLC patients. It is imperative to test for these gene alterations in order to identify patients who could potentially benefit from these efficacious targeted therapies and to avoid therapies unlikely to provide clinical benefit. A major limitation in obtaining molecular testing occurs when minimally invasive techniques are used to obtain tissue sample resulting in insufficient yield for testing. In such cases, the utilization of circulating tumor DNA (ctDNA), commonly known as liquid biopsy, has proven very beneficial. In a study utilizing ctDNA, increased detection rates were found when using ctDNA in addition to tissue testing and a > 98.2% concordance rate was found. We report results of 40 NSCLC patients from our institute who had liquid biopsy with or without tissue profiling done. Methods: We molecularly profiled 40 newly diagnosed advanced NSCLC patients using both tissue and liquid biopsies. Tissue was assayed using the John Hopkins university molecular panel and liquid biopsies were performed by Biocept. Results: 14 out of 40 (35%) patients had insufficient or no tissue for molecular testing. Concordant results were found in 17 out of the 26 (65.4%) patients who had both tissue and liquid molecular testing done. Liquid Biopsy detected additional mutations in 5 (19.2%) patients which were not picked up on tissue and led to change in management in 4 patients. 12 out of 40 (30%) patients had repeat liquid biopsies done at progression of disease with new mutations detected on 4 patients revealing resistance to current treatment and change in treatment. Conclusions: Liquid Biopsy reveals high concordance rates with tissue genotyping and increases rate of detection of targetable mutations in NSCLC. It offers a safe and effective alternative when additional tissue is needed to identify genetic mutations.
Could soluble levels of CD40L and galectin-9 be possible prognostic biomarkers and therapeutic targets in NSCLC?
Authors: Costa Guilherme Jorge , da Matta Marina Catena , Torres Leuridan Cavacante , Casarini Dulce Elena 
Published: May 2020

e21508 Background: Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all cases of lung cancer. The immune system is now recognized to have the potential to destroy cancer cells. TIM-3 binds to Galectin-9 (GAL9) causing suppression of cytokine production, cell cycle arrest and cell death. Soluble CD40L (sCD40L) that is released by activated T lymphocytes and platelets. Therefore, we hypothesized that soluble forms immune checkpoint receptors and their ligands, such as TIM-3, GAL9 and CD40L may also prognostic implications of NSCLC. Objectives: Evaluate the soluble levels of CD40L, TIM-3 and GAL9 in patients with NSCLC in III and IV stages of disease. Methods: Samples of blood were collected from a cohort prospective involving 32 patients between 50 and 80 years old (65 + 8,6 years). Enzyme-linked immunosorbent assay was used to quantify expression these receptors. A non-parametric test was used to compare all groups (Mann-Whitney U-test). Statistical significance was defined as p<0.05. Data analysis was performed using GraphPadPrism v8.3. Results: Our results showed higher levels GAL-9 and TIM3 in patients with stage III and IV than controls ( p<0.05). As also, higher expression of CD40L was identified in patients stage III than stage IV ( p<0.0001) and controls ( p=0.007). It wasn’t seen significant different expression of CD40L between stage IV patients and controls. Analyzing GAL9, it was identified higher level in patients stage III than stage IV ( p<0.0001). Expression of TIM-3 wasn’t significant difference between patients with stage III and IV. When analysing in ratio between CD40L/TIM3, TIM3/GAL9 and CD40L/GAL9 in all groups, only TIM-3/GAL9 ratio had a positive correlation in patients stage IV (r=0.688; p<0.0001). By histology, patients with squamous cell carcinoma had higher levels of CD40L than adenocarcionoma ( p=0.01), but no significant difference was identified between expression of TIM3 e GAL9 and histological subtypes. Conclusions: This study showed expression sCD40L and GAL9 were higher stage III than stage IV in patients NSCLC. It can be inferred that soluble CD40L and GAL9 receptors are possible prognostic biomarkers and potential therapeutic targets in NSCLC.
Comprehensive cross-platform comparison of methodologies for noninvasive EGFR mutation testing: Results of the RING observational trial.
Authors: Romero Atocha , Molina-Vila Miguel Angel , Jantus-Lewintre Eloisa , Insa Amelia , Cruz Patricia , Collazo Ana , Perez Altozano Javier , Juan-Vidal Oscar , Diz Pilar , Cobo Manuel , Hernandez Berta , Vazquez-Estevez Sergio , Benitez Gretel , Guirado Maria , Rodriguez-Festa Alejandro , Calabuig-Fariñas Silvia , Rosell Rafael , Camps Carlos , Royuela Ana , Provencio-Pulla Mariano 
Published: May 2020

e21518 Background: Several platforms for non-invasive EGFR testing are currently used in the clinical setting, with sensitivities ranging from 30 to 100%. Comparison studies in prospective cohorts remain limited and reports evaluating mutant allelic fractions (MAFs) are particularly scarce. The RING observational trial (ClinicalTrials.gov identifier NCT03363139) was designed to comprehensively analyze the concordance between methodologies for EGFR mutation detection in blood. Methods: Seventy-two EGFR mutant NSCLC patients were enrolled in the trial. Plasma samples were prospectively collected at progression to first line Tyrosine Kinase Inhibitor and tested for EGFR mutations by 7 methodologies; cobas EGFR Mutation Test v2, Therascreen EGFR Plasma RGQ PCR Kit, QuantStudio 3D Digital PCR System, a 5-nuclease real-time PCR assay in presence of PNA, OncoBEAM EGFR and NGS with two different gene panels, Ion Torrent Oncomine and GeneRead QIAact Lung DNA UMI Cancer Panel. Results: The agreement between all methodologies for was almost perfect for the detection of deletions in exon 19 (K = 0.86; 95%CI: 0.76-0.96) and substantial for exon 21 point mutations (K = 0.76; 95%CI: 0.63-0.89). Regarding the p.T790M resistance mutation, concordance was lower but still substantial (K = 0.68; 95%CI: 0.57-0.79). If only NGS-based technologies were considered, the agreement was almost perfect for sensitizing mutations and substantial for the resistance mutation (K = 0.84; 95%CI: 0.68-1.00, K = 0.86; 95%CI: 0.69-1.00 and K = 0.77; 95%CI: 0.60-0.95 for exon 19, exon 21 and p.T790M, respectively). Most discordant samples between methodologies had mutant allele fractions (MAFs) ≤0.5%. Sensitizing mutations were always present at higher MAFs than concomitant p.T790M, explaining the lower concordance observed for this variant. MAFs obtained by different methodologies showed an excellent reproducibility (intraclass correlation coeficients 0.85-0.97). Similarly, Passing–Bablok regression analysis showed a high correlation between methodologies when assessing MAFs. Conclusions: Our results support the use of liquid biopsies for non-invasive EGFR testing in the clinical setting and highlight the need to systematically report MAFs.
Evaluation of TKI toxicity according to inflammatory markers and body mass index in patients with non-small cell lung cancer (NSCLC) harboring an EGFR mutation: A retrospective observational study.
Authors: Runciman Thanya , Motta Guerrero Rodrigo , Aliaga Macha Carlos , Carracedo Carlos F. 
Published: May 2020

e21522 Background: The standard treatment for patients with advance EGFR mutated NSCLC are Tirosine Kinasa inhibitors (TKI), we face in our clinical practice a different profile of toxicity; there is limited data of Inflammatory markers in this especial population. The aim of our study is to determine whether neutrophil lymphocyte ratio (NLR), lymphocyte platelet ratio(PLR), RDW-CV and body mass index (BMI) are related to the develop of this toxicity. Methods: We retrospectively analyzed data of patients with EGFRm NSCLC at Aliada Clinic between January 2016 to December 2019. Inflammatory markers were obtained from laboratory tests performed during the first visit as outpatient. The BMI kg/m2 at the start of the treatment was defined as the weight (kg) divided by the height (m) squared. Adverse event (AE) were graded according CTCAE v5.0. Results: A total of 164 patients were diagnosed with advanced NSCLC, of these 50 patients were assessed, 29 women and 21 men. The average age was 58.9 years, median of 59.5 ( 38 to 83; SD: 11.7). The most frequent EGFR mutation was deletion 19 (59.6%) followed by L858R mutation ( 23.1%) . The median BMI was 25.18 (16.2 to 41.3 kg/m2) 46.2% were normal, 36.5% were overweight, and 11.5 % were obese. 80% present any grade of AE. The most frequent AE was skin related: 75% (90 % grade I or II) follow by gastrointestinal: 57.6% (74 % grade I or II). There were no significant differences between NLR according to toxicity grade I-II vs III-IV (media: 3.44 and 4.32; P = 0.46); PLR according toxicity grade I-II vs III-IV (media: 229.41 and 251-50; P = 0.78); and RDW-CV according to toxicity grade I-II vs III-IV (media: 14.17 and 14.4; P = 0.74). Similarly, no significant differences were observed among toxicity profiles in relation to BMI (p = 0.2). Finally, there was no impact of severity of toxicity on progression-free survival (p = 0.64) or overall survival 24,33 months (IC 95% 16,05 – 32,6; p = 0.9). Conclusions: There was no relation between inflammatory markers and the grade of toxicity in patients with EGFRm advance NSCLC receiving TKIs. We suggest increase the population to validate our results.