tbuckley/cabot-search huggingface dataset:
Comparative analysis of prognostic molecular signatures in Asian and Caucasian AML populations.
Authors: Miyoung Kim, S Dilhan Weeraratne, Jane Snowdon, Winnie Felix, Lionel Lim, Young Kyung Lee, Eunyup Lee, Kibum Jeon, Jiwon Lee, Dae Young Zang, Boram Han
Journal: Journal of Clinical Oncology (2019)

e13025 Background: Next generation sequencing (NGS) studies on various cancer types have revealed clinical insights on the molecular etiology of tumors and defined new treatment paradigms. However, the genomic landscape of a tumor type may be predicated on race. Application of broad-brush findings from one population to another may lead to erroneous treatment decisions. While the majority of published NGS cancer studies focus on Caucasian populations, few studies evaluate the molecular profiles of a tumor type between different demographies. In this study, acute myeloid leukemia (AML) patients of East Asian descent were sequenced at a South Korean hospital, interpreted, and compared with the Caucasian population from The Cancer Genome Atlas (TCGA). Methods: 23 South Korean AML patients were sequenced in 2018 using the 54 gene Illumina TruSight Myeloid Panel at Hallym University, College of Medicine. Orthogonal testing for FLT3-internal tandem duplication (ITD) was done by Sanger sequencing. Watsonä for Genomics (WfG), an artificial intelligence decision-support system, was used for variant interpretation and annotation. Additionally, 181 AML patients of Caucasian descent from the TCGA dataset were analyzed for comparison. Results: WfG identified at least 1 clinically actionable therapeutic alteration in 70% (16/23) of all Asian cohort cases. FLT3-ITD or tyrosine kinase domain (TKD) mutations were reported in 27% (49/181) of cases in the TCGA cohort but only 9% (2/23) of the Asian cohort. DNMT3A mutations were detected in 25% (45/181) and 74% (17/23) of the TCGA and Asian cohorts, respectively. Other oncogenic mutations in AML including NRAS, IDH1, IDH2, CEBPA, TET2, and NPM1 were represented at comparable frequencies between the two populations. Conclusions: Tumor biomarkers that affect prognosis can be informative in the clinical setting. In our study, FLT3 and DNMT3A, predictors of poor prognosis in AML, demonstrated decreased and increased respective frequencies in South Koreans compared to Caucasians, suggesting that some mutational signatures that predict cancer outcome may vary by race.
Cachexia in head and neck squamous cell carcinoma (HNSCC) patients (pts) after cisplatin-based chemoradiation (CRT): A cross-sectional study.
Authors: Gilberto Castro, Willian das Neves, Thomás Giollo Rivelli, Eduardo Furquim Simao, Renata Eiras Martins, Marco Aurelio Vamondes Kulcsar
Journal: Journal of Clinical Oncology (2019)

e23138 Background: Cachexia is a wasting syndrome that may affect HNSCC pts, contributing to their dismal prognosis. We aimed to study the frequency of cachexia in HNSCC survivors treated with CRT with curative intent. Methods: Cross-sectional study that included 120 consecutive pts from Jan/2014 to Feb/2017, over 18 y.o. and who were previously treated with definitive or adjuvant CRT for HNSCC (nasopharynx, oropharynx [OP], oral cavity [OC], hypopharynx and larynx [L]). Eligible pts were in regular follow-up for at least 2 years in the multidisciplinary team, with no evidence of disease. Medical history, body weight, height, mid-arm muscle circumference (MAMC) and muscle strength (MS, handgrip dynamometer) were measured, and laboratory tests (hemoglobin [Hb], albumin and C-reactive protein [CRP]) were obtained. Cachexia was diagnosed when there was any weight loss in the previous year, and at least 3 of the following: reduced grip muscle strength, fatigue, anorexia, low lean body mass, or laboratorial alterations (Hb &lt; 12 g/dL, serum albumin &lt; 3.2 g/dL or CRP &gt; 5.0 mg/L). A subjective assessment of nutritional status was made based on the Patient-Generated Subjective Global Assessment (PG-SGA) in its short form. Results: Median age 59 y.o. (21-78), 88 male (73%). Most common primary sites were OP (42%), L (24%) and OC (19%). Median follow-up was 42 mo. (24-125). There was a predominance of locally advanced disease at diagnosis: 73% T3/T4 and 72% N+. The mean weight was 64.5 kg (±14.6) pre-CRT, 57.8 kg (±12.2) post-CRT (p 0.02) and 63 kg (±11.8) in the present evaluation (p NS). Dysphagia was a complaint in 88 pts (73%). Cachexia was diagnosed in 42 pts (35%). As expected, cachectic pts (CP) presented lower MAMC (25.1 vs. 27.2 cm, p 0.0002) and MS (24.3 vs. 29.5 kgf, p 0.004). Higher mean CRP (12.7 vs. 4.2 mg/L, p 0.0001) and lower Hb (13.1 vs.13.9 g/dL, p 0.01) were also seen in CP. The PG-SGA score was higher in CP (7.9 vs. 5.7, p 0.006). Conclusions: Cachexia was frequently diagnosed in HNSCC pts with NED after CRT in a long-term follow-up, without evident weight loss. More effective preventive and therapeutic strategies are warranted. Supported in part by FAPESP grant 2014/00172-9.
Baseline cfDNA characteristics and evolution of cfDNA profile during treatment with selective FGFR inhibitor TAS-120.
Authors: Tyler J. Moss, Jordi Rodon Ahnert, Holly D. Oakley, Michael Kahle, Daniel D. Karp, Shubham Pant, Jeena Jacob, Victoria M. Raymond, Richard B. Lanman, Lawrence Kwong, Mark Routbort, Nital Soni, Jerry Huang, Milind M. Javle, Funda Meric-Bernstam
Journal: Journal of Clinical Oncology (2019)

3056 Background: There is an increasing role for cfDNA in monitoring response and mechanisms of resistance. We performed cfDNA analysis in a subset of patients enrolled on a Phase I trial with an irreversible, selective FGFR1-4 inhibitor, TAS-120. Methods: 58 plasma samples from 17 patients (13 with cholangiocarcinoma) were analyzed on a 73-gene, next-generation sequencing panel. Selected patients(pts) had longitudinal samples. Results: At least one alteration was detected in 46 cfDNA samples, in 16 (94%) of 17 pts – a pt with GBM had no alterations detected. 14 pts had alterations in FGFR2/3 by genomic testing of archival tumor samples, comprising 20 total alterations (18 unique). 10 of 20 FGFR2/3 alterations were also detected by cfDNA testing: 4/5 SNVs, 1/2 amplifications, 5/13 fusions. Three pts had FGFR/FGF alterations not included (thus not detected) in the cfDNA panel: 2 with FGF ligand amplification, and one FGFR4 mutation. 6 pts (35%) had PR, 5 (29%) had SD and 6 (35%) PD as a best response to TAS-120. Four pts had prior FGFRi: 2 had a PR, 1 SD, and 1 PD on TAS-120. Baseline cfDNA mutations became undetectable during treatment in 4/6 pts with PR. 4 of 6 PD pts had other driver mutations at baseline including mutations in PIK3CA, KRAS, IDH1, BRCA2, or amplifications in PIK3CA, PDGFR. 9 pts with cfDNA available at progression after SD/PR: 3 had acquired FGFR2 mutations (one each of V564L, V564F, or N549K). Two also acquired alterations in other candidate resistance genes ( PTEN and MAP2K1). Another pt had low variant allele frequency (VAF) NRAS G12D and BRAF A694T pretreatment and had SD. At progression, cfDNA revealed an increase in NRAS VAF and mutations acquired in the MAPK pathway . One pt with prior FGFRi acquired FGFR2 V564I and V564K detected by cfDNA prior to initiation of TAS-120, and had a PR on TAS-120. There was a drop in FGFR2 V564I VAF with response that subsequently increased with progression. The patient also acquired a FGFR2 V564L mutation at progression. Conclusions: FGFR alterations can be detected by cfDNA. cfDNA may detect potential resistance mechanisms, including PI3K or MAPK pathway alterations and acquired FGFR2 mutations. Patients with gatekeeper mutations in cfDNA at baseline may still respond to TAS-120. Further study is needed to determine the impact of FGFR2 mutations and co-alterations on TAS-120 sensitivity.
THU0221 DRY EYE IN SJÖGREN’S SYNDROME: CHEMOKINE AND CYTOKINE TEAR SPECTRUM
Authors: Gabriela Hernandez-Molina, Narlly Ruiz-Quintero, Guadalupe Lima, Diego Hernández-Ramírez, Amaya Llorente-Chavez, Vanessa Saavedra-González, Rodolfo Jimenez-Soto, Luis Llorente
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Previous studies have linked the participation of multiple chemokines and cytokines in the physiopathology of primary Sjögren's syndrome (PSS), however data regarding their presence in tears is scarce <h3>Objectives:</h3> To evaluate a panel of chemokines/cytokines in the tears of patients with PSS and correlate them with ocular symptoms as well as objective ocular tests. <h3>Methods:</h3> We included 21 patients with PSS (EULAR/ACR criteria). A single expert ophthalmologist in dry eye evaluated the patients and assessed the tear film break-up time, Schirmer-I test, tear meniscus height, the<i> Van Bijsterveld</i> staining score and the SICCA Ocular Staining Score (OSS). We classified lacrimal dysfunction severity in two categories (1=mild, mild/moderate or moderate, and 2= moderate/severe and severe). We scored the ESSPRI, and ocular dryness VAS as well as the Ocular Surface Disease Index (OSDI), a 12-item scale for the assessment of symptoms related to dry eye disease and their effect on vision. Tear samples were collected using sterile tear flow strips, that were immediately frozen at -86°C until assayed. Once defrosted, the tears were extracted from the strips using a buffer containing 0.5 M NaCl and 0.5% Tween-20. We tested IFN-γ, IL-10, IL-12, IL-17A, IL-1β, IL-2, IL-21, IL-23, IL-5, IL-6, IL-8, TNF-α, BAFF, CXCL10 and CCL2 by Luminometry. We also included 21 healthy controls without dry eye, to test chemokines/cytokines that after our initial screening were meaningful. <h3>Results:</h3> Most patients were females (90.4%), mean age 59.3±13 years and median disease duration 7.9 years (0.5-27). All of them had ocular and oral symptoms. The median tear film break-up time was 6 seconds (2-9), median Schirmer-I test 6 mm (1-25), median lacrimal meniscus height 1.5 mm (0.5-2), median Van Bijsterveld staining score 10 points (2-18), median OSS 7 points (2-11), median ESPPRI score 6.7 points (2-9.2) and median ocular dryness EVA score 9 points (1-10). We did not detect most of the evaluated chemokines/cytokines with the exception of IL-8, CXCL10, and CCL2. The former was similar in both, patients and controls. PSS patients had lower levels of CXCL10 (472.8 pg/μL vs 1652 pg/μL, p=0.01) and CCL2 (1.08 pg/μL vs 9 pg/μL) than controls. Indeed, patients with worst lacrimal dysfunction severity had the lowest levels of CXCL10 (239.3 pg/μL vs. 646.2 pg/μL, p=0.02). We found correlations among CXCL10 and CCL2 (T=0.30, p=0.02) and lacrimal meniscus height (T=0.55, p=0.005), as well as with CCL2 and lacrimal meniscus height (T=0-57, p=0.01). None of the other variables were correlated. <h3>Conclusion:</h3> We identified CXCL10 and CCL2 as the main chemokines in tears of patients with PSS. CXCL10 seems to participate in the normal eye homeostasis. <h3>Disclosure of Interests:</h3> None declared
Impact of IDO1 expression and inhibition on the sensitivity of anti-PD-1.
Authors: Jian Zhu, Rebecca L Zhu
Journal: Journal of Clinical Oncology (2019)

e14094 Background: Concurrent inhibition of IDO1 and PD-1 may have enhanced anti-tumor effects. However, inhibition of IDO1 failed to enhance efficacy of anti-PD-1 in late phase clinical trials. In this study, computational models were established to identify factors involved in interactions between these two types of agents. Methods: Abstracts published on IDO1, PD-1, PD-L1, anti-PD1/PD-L1 were downloaded from PubMed, and analyzed by text mining. The information on interactions among gene, compound/therapy, cell/animal model, pathway/disease, and clinical study was extracted. Networks were constructed to simulate effects of IDO1 inhibition on anti-PD-1. Results: The IDO1/anti-PD-1 network consists of 79 nodes, 227 interactions with 1277 possible regulatory paths from IDO1 to anti-PD-1. 675 paths are associated with agonism and 602 with antagonism between IDO1 inhibition and anti-PD-1. Up-regulation of [TNF-alpha, IFN-gamma, type I immunity &amp; CD8+ T cells], and down-regulation of [Tregs, MDSC, JAK/STAT pathway, IL-6 and PD-L1] are associated with enhancement of anti-PD-1 by IDO1 inhibition. Besides, treatments with PARP inhibitor, EGFR inhibitor or radiation may enhance the combination efficacy of IDO1 and PD-1 inhibitors. Up-regulation of TIM-3 and NK cells are associated with reduced activities of anti-PD-1 upon IDO1 inhibition. PD-L1 is a predictive biomarker for anti-PD-1 response and its expression can be regulated by IDO1. The IDO1/PD-L1 network consists of 83 nodes, 204 interactions and 318 paths. Up-regulation of IL-6, AhR, MDSC, JAK/STAT, HIF1A, IL10, NF-kappaB &amp; MYC was associated with induction of PD-L1 by IDO1. Conclusions: As the network analyses revealed, inhibition of IDO1 could either up- or down-regulate PD-L1, and enhance or reduce efficacy of anti-PD-1. Multiple factors, other than PD-L1, play roles in determining the efficacy of combining IDO1 and PD-1 inhibitors.
Molecular mechanism of chemoresistance and restoration in human gastric cancer cells.
Authors: Hye Jung Chang, Moon Young Choi, Min-Hee Cho, Kyoung Eun Lee, Soon-Nam Lee
Journal: Journal of Clinical Oncology (2019)

e15544 Background: Gastric cancer is characterized by a high rate of relapse and failure of chemotherapy because of the emergence of drug resistant cells. Hence, resistance to chemotherapy is a major obstacle for the management of gastric cancer. It might be related with the development of cancer stem cells (CSCs). The aim of this study is to investigate the characteristics of the 5-fluorouracil (FU) resistant gastric cancer and to study how to restore the chemosensitivity. Methods: We used the AGS gastric cancer cell line (AGS) and transformed it into a 5-FU resistant cell line (AGS-R). AGS-R was established by continuous exposure of the cells to progressively increasing concentrations of 5-FU for about 1 year and modulating mRNA expression levels of four genes associated with thymidylate synthase (TS). The research methods used were MTT assay, flow cytometry analysis, luciferase reporter assay, western blotting, and siRNA transfection. Results: 5-FU-resistant gastric cancer cell, AGS-R was established by continuous exposure to 5-FU with gradual increase of its concentration for about 1 year. Comparing with AGS, thymidylate synthase (TS) expression in AGS-R was highly increase at transcriptional and translational level. And decreased transcriptional activity of β-catenin in AGS-R was confirmed by Western blotting and luciferase assay. Even though treatment with ICG-001, an inhibitor of β-catenin, showed growth inhibition of AGS in a dose- and time-dependent manner, but it could not in AGS-R. The expression of CD44, well-known CSCs marker, was significantly higher on AGS-R compared to AGS. And the Notch pathway was remarkably up-regulated. Flow cytometry analysis revealed that CD44 expression was reduced on AGS-R transfected with specific siRNA for notch intracellular domain (NICD). Conclusions: This study suggests that chemoresistance of gastric cancer against continuous exposure to 5-FU is associated with decrease of β-catenin activity and development of stemness via the activation of Notch pathway. Therefore, the inhibition of Notch pathway might be a potential therapeutic target in 5-FU-resistant gastric cancer.
Association of state Medicaid expansion with timeliness of cancer care delivery.
Authors: Samuel U Takvorian, Justin E. Bekelman, Ronac Mamtani, Lawrence N. Shulman, Rachel M. Werner
Journal: Journal of Clinical Oncology (2019)

e18126 Background: The Affordable Care Act (ACA) expanded Medicaid eligibility to nonelderly adults with incomes at or below 138% of the federal poverty level in participating states. Medicaid expansion has been associated with earlier cancer stage at diagnosis; however, its impact on cancer treatment is unknown. Methods: We assembled retrospective cohorts of adult nonelderly patients (ages 40-64) with newly diagnosed breast, colon and lung cancer from January 2011 to December 2015, using data from the National Cancer Database (NCDB). We conducted a quasi-experimental, difference-in-differences analysis to compare Medicaid expansion and non-expansion states on timeliness of cancer therapy, stage at diagnosis, and insurance status for the years before (2011-2013) and after ACA Medicaid expansion (2014-2015). Results: There were 466,314 patients in expansion states (mean age, 54.7 years; 81.5% women) and 487,958 patients in non-expansion states (mean age, 54.9 years; 78.5% women). In expansion states relative to non-expansion states, there was no significant difference in the proportion of patients initiating cancer therapy within 30 days (adjusted difference-in-difference (DID) estimate -0.1%; 95% CI -0.8 to +0.7%, p = 0.868) or within 90 days of diagnosis (adjusted DID estimate -0.1%; 95% CI -0.3 to +0.1%, p = 0.501), before and after expansion. Among those with early-stage cancers undergoing definitive therapy, there was similarly no significant difference in time to treatment. Relative to non-expansion states, the proportion of early stage cancer diagnoses increased more (adjusted DID estimate +0.7%; 95% CI +0.3 to +1.2%, p = 0.002), and the proportion of advanced stage cancers decreased more (adjusted DID estimate -0.4%; 95% CI -0.7 to -0.1%, p = 0.008) in expansion states. The proportion uninsured at diagnosis decreased more in expansion states (adjusted DID estimate -0.8%; 95% CI -1.2 to -0.4%, p &lt; 0.001). Conclusions: Among nonelderly patients with common cancers, ACA Medicaid expansion was associated with an increase in the proportion of cancers diagnosed at early stage, a decrease in the proportion of cancers diagnosed at advanced stage, and a decrease in the proportion of uninsured. There was no significant effect on the timeliness of treatment.
Relation between dexamethasone (DEX) usage, preventive trimetprim/sulfametoxazole (ST), and pneumocystis pneumonia (PCP) for patients with breast cancer receiving dose-dense AC followed by dose-dense paclitaxel (ddAC-ddP): Preplanned analysis of WJOG9016B.
Authors: Koji Matsumoto, Meiko Nishimura, Yukinori Ozaki, Manabu Futamura, Toshikio Miyaki, Junji Tsurutani, Shigeru Imoto, Mihoko Doi, Shinya Tokunaga, Kenjiro Aogi, Kenichi Yoshimura, Hideaki Okada, Yasuaki Sagara, Motoi Baba, Shigenori E. Nagai, Toshimi Takano
Journal: Journal of Clinical Oncology (2019)

e12022 Background: PCP is rare complication of ddAC-ddP. DEX is plausible risk factor for PCP. Dose and duration of DEX against CINV is changing over time as other anti-emetic drugs (5HT3 RA, NK1 RA, and olanzapin) became available. Then DEX usage varies widely in each hospitals. ASCO/IDSA guideline recommends preventive ST for patients receiving 20 mg or more predonisone equivalents daily for more than one month, although evidence is lacking in patients receiving ddAC-ddP. This study is to investigate relation between DEX usage, preventive ST, and risk of PCP for patients receiving ddAC-ddP. Methods: This study is preplanned analysis of WJOG9016B (UMIN000024992) which investigated relative dose intensity of ddAC-ddP supported by 3.6 mg (approved dose in Japan) of pegfilgrastim. Eligible pts were HER2 negative PBC with stage I to IIIc, going to start ddAC-ddP and younger than 65 y.o.. DEX usage and preventive ST usage were discrete to treating physicians. Results: From Jan. 2017 to Jan. 2018, 92 pts were registered and 91 pts were in the FAS set, because one patients turned out be ineligible after registration. All patients received DEX for prevention of delayed CINV. Median total dose of DEX during ddAC was 112 mg (range; 80 to 212 mg), which was equal to 13.3 mg (9.52 mg–24.76 mg) predonisone equivalents daily. Only five of them (5.4%) received more than 20 mg predonisone equivalents daily. Twenty patients received preventive ST. Three patients developed PCP. None of them with preventive ST developed PCP (0%), whereas three of patients without ST developed PCP (4.2%). These three patients received total DEX dose during ddAC at 80 mg, 112 mg, and 112 mg, respectively. Conclusions: ST was highly effective for PCP prevention for patients receiving ddAC-ddP, if DEX used against delayed CINV. Without ST prevention, the risk of PCP was 4.2 %, which was higher than threshold (3.5%) proposed in ASCO/ IDSA guidelines. The threshold of steroid dose leading to the risk of PCP might be lower than 20 mg or more predonisone equivalents daily in patients receiving ddAC-ddP. Clinical trial information: UMIN000024992.
Prognostic value of monocyte to lymphocyte ratio (MLR) in epithelial ovarian cancer (EOC).
Authors: Marc Cucurull, Eudald Felip, Juan Jose Garcia, Carlos Erasun, Laura Angelats, Iris Teruel, Sergi Martinez-Román, Joaquin Hernández, Anna Esteve, Sofia España, Margarita Romeo
Journal: Journal of Clinical Oncology (2019)

e17066 Background: Identifying high-risk early-stage EOC patients (p) is a major issue. Also, controversy about the role of neoadjuvant chemotherapy prior to surgery in advanced EOC is still ongoing. A high MLR is related to poorer outcomes in several cancers, and also in ovarian cancer according to limited retrospective series. We explored the clinical value of MLR in a cohort of EOC p. Methods: We included all EOC p diagnosed in our center, from January 2008 to April 2017, who had undergone radical treatment. Overall survival (OS) was assessed by Kaplan Meyer. Maximally selected rank statistics was used to determine the MLR cut-off value for the greatest OS discrimination. The hazard ratio (HR) of death of MLR was explored by multivariate Cox regression models, adjusted by age at diagnosis, stage I/II versus (vs) III/IV, high grade serous carcinomas (HGSC) vs other, primary surgery vs interval surgery after neoadjuvant chemotherapy (PS, IS), residual disease &lt; 1 vs &gt; 1cm, year of diagnosis, and hemoglobin, neutrophils, platelets and MLR at diagnosis. Results: 124 p were included. Median age at diagnosis was 58.7 years; 55.6% were HGSC;67.7% stage III/IV; 69.3% received PS; 14.3% had residual disease &gt; 1cm. Median OS was 75 months. MLR was the laboratory parameter that more significantly impacted on OS in our model (p = 0.02). Optimal MLR cut-off was 0.38. The MLR &gt; 0.38 group (MLR-hi) had a higher-risk of death (HR = 2.9; 95% IC: 1.3–6.5) with respect to those with MLR &lt; = 0.38 (MLR-lo). Median OS were 100 and 35 months, respectively. In the MLR-lo group, median age at diagnosis was 56.9 years (vs 61.9 in the MLR-hi, p 0.047), 44.8% were HGSC (vs 61.2%, p 0.134), and 49.97% were stages I/II (vs 14.2%, p 0.001). MLR-hi p who had undergone PS or IS had similar OS (p = 0.63). In contrast, among MLR-lo p, PS showed significantly higher OS than IS (p &lt; 0.0001). Conclusions: In our cohort, MLR was an independent prognostic factor in EOC. Its potential role to identify high-risk early-stage p and to predict worse outcomes after PS among advanced-stage p need to be explored in larger cohorts.