tbuckley/cabot-search huggingface dataset:
National Comprehensive Cancer Network (NCCN) guideline compliance for lung cancer in a community teaching hospital.
Authors: Sufana Shikdar, Sarthak Sahu, Gaurav Jadhav, Simple Modi, Joseph Alukal, Gurwinder Singh, Peter Lambert, Shoaib Sheikh, Michael Rachshtut
Journal: Journal of Clinical Oncology (2018)

e18860 Background: Multiple studies have demonstrated that compliance to National Comprehensive Cancer Network (NCCN) guidelines, though complex, promotes better outcomes in a clinical oncology practice. Evaluation of key deficiencies in compliance with the NCCN guidelines provides health systems with effective strategies to improve on evidence-based practice in the management of lung cancer. Methods: Patients with histological or cytological confirmed diagnosis of primary lung cancer patients who was seen by medical oncologist in the Mercy Catholic Medical Center were identified. Mercy Catholic Medical Center is a conglomeration of two community teaching hospitals in greater Philadelphia. The guideline based eleven quality indicators were developed based on the Thoracic Oncology Network and Quality Improvement Committee of the American College of Chest Physicians (CHEST) and recent NCCN guidelines (2018). Frequency tables were provided to determine the proportion of adherence to the quality indicators. Results: We identified 101 cases of primary lung cancer in between June 1, 2015 and July 31, 2017. > 90% adherence was achieved for adequate tissue sample for molecular testing (96%) and clinical documentation of cancer stage by the physician (92%). Rates of brain imaging were 74%, 70% for smoking cessation counseling, 44% for biopsy confirmation for metastasis, 44% for mediastinal lymph node sampling, 52% for performance status documentation, 74% for PET imaging, 42% for lung function test and 39% for bronchoscopy within three months of initiation of treatment. NCCN treatment guideline was followed for 72% of patients. Overall, 60% (7/11) adherence of quality indicators was met for 46% (47/101) of patients. Conclusions: Guideline adherence by the medical oncologists is suboptimal. Possible explanations include unawareness or disagreement with the guidelines, resource restrictions in the community setting and premorbid and functional status of the patients. Our results recommend effective strategies to improve rates of adherence, and investigating underlying causes of nonadherence.
Impact of age on utilization and prognostic value of FLT3 and NPM1 testing in acute myeloid leukemia.
Authors: Claudio A Mosse, Fern Fitzhenry, Michele LeNoue-Newton, Julie Ann Lynch, Kristine E. Lynch, Jiwon Chang, Amy M Perkins, Michael Matheny, Mia Alyce Levy
Journal: Journal of Clinical Oncology (2018)

e19008 Background: In acute myeloid leukemia (AML) patients, FLT3 mutations (FLT3 mt) are associated with worse prognosis, while NPM1 mutations (NPM1 mt) have better prognosis. There have been conflicting reports on the prognostic value of these tests among older patients. We examined FLT3 and NPM1 test utilization and their prognostic value among Veterans Administration patients. Methods: We identified 20,141 Veterans diagnosed with AML from 2006-2015 using ICD9 and ICD10 diagnosis codes. We assessed rates of FLT3 and NPM1 testing, and analyzed OS for each age cohort by mutation status with Cox proportional hazards models adjusted for age, site of care, Charlson Comorbidity Index (CCI), and race. Results: Median age of patients was 71 years with a median follow-up of 12.2 months. When stratified by age, younger patients (median 59.3, range 18.1-64.9) had significantly higher testing rates (NPM1 2.7% vs. 1.7%; FLT3 2.8% vs. 1.6%; Both 2.1% vs. 1.3%) (p < 0.001) than older patients (median 76.8, range 65.0-101.6). Median OS for patients with FLT3 and NPM1 testing was 12.9 months. The median OS (unadjusted) for the younger cohort was 11.6 months longer than the older cohort. In both cohorts, FLT3mt was a poor prognostic factor, while NPM1mt was a good prognostic factor. Of note, the prognostic utility of FLT3 and NPM1 was comparable in the younger and older cohorts. In all subgroups, older patients had a lower median OS compared to younger patients with the best prognostic group (NPM+/FLT3-) in older patients having lower median OS than the worst prognostic group (NPM-/FLT3+) in younger patients. Conclusions: FLT3 and NPM1 are prognostic factors in patients regardless of age, although older AML patients generally have worse outcomes across all subgroups. The data suggest that testing for FLT3 and NPM1 should be more widespread in the VA population. Table 1: Outcomes By Mutation Younger Cohort (n = 117) Older Cohort (n = 141) Age (years) (HR, 95% CI) 0.14 (0.01-2.81) 1.22 (0.70-2.14) Median OS 19.3 7.7 Median OS NPM1+ (HR, 95% CI) 27.9 (0.72, 0.33-1.57) 6.2 (0.70, 0.41-1.19) Median OS FLT3+ (HR, 95% CI) 23.0 (1.26, 0.65-2.43) 3.5 (1.90, 1.11-3.27) OS NPM1+/FLT3- 30.4 10.6 OS NPM1+/FLT3+ 23.0 3.5 OS NPM1-/FLT3+ 14.5 2.8 OS NPM1-/FLT3- 19.2 8.0
Intestinal luminal putrescine is produced by collective biosynthetic pathways of the commensal microbiome
Authors: Atsuo Nakamura, Takushi Ooga, Mitsuharu Matsumoto
Journal: Gut Microbes (2018)

The intestinal microbiome produces various metabolites that may harm or benefit the host. However, the production pathways of these metabolites have not been well characterised. The polyamines putrescine and spermidine required for physiological process are also produced by intestinal microbiome. The production and release of these polyamines by microbiome are poorly understood, though we have confirmed that intestinal bacteria produced putrescine from arginine. In this study, we characterised polyamine synthesis by analysing the collective metabolic functions of the intestinal microbiome. In particular, we analysed polyamines and their intermediates in faecal cultures, as well as the colonic contents of rats injected with isotope-labelled arginine through a colon catheter, using mass spectrometry. Isotope-labelled putrescine was detected in faecal cultures and colonic contents of rats injected with isotope-labelled arginine. Putrescine is produced through multiple pathways, and its extracellular intermediates are exchanged between bacterial species. Additionally, we demonstrated that the collective metabolic pathway depends on a complex exchange of metabolites released into the colonic lumen. This study demonstrates the existence of putrescine biosynthetic pathways based on the collective metabolic functions of the intestinal microbial community. Our findings provide knowledge to manipulate the levels of intestinal microbial products, including polyamines, that may modulate host health.
Abstract 16484: The Transcriptional Repressor NR1D2 is Associated With Congenital Heart Disease and Plays an Evolutionarily Conserved Role in Cardiac Development
Authors: James R Priest, Georg Vogler, Sylvia Nurnberg, Michael Portman, Bruce D Gelb, Euan A Ashley, Rolf Bodmer, Thomas Quertermous
Journal: Circulation (2015)

Title: The Transcriptional Repressor NR1D2 is Associated with Congenital Heart Disease and Plays an Evolutionarily Conserved Role in Cardiac Development. Introduction: Congenital heart disease (CHD) is a leading cause of morbidity and mortality in young children and the underlying genetic etiology is complex and poorly defined. Recent genetic studies of mixed cardiac phenotypes focusing on de novo events have identified novel disease loci in up to 10% of participants and uncovered new functional categories of genes related to cardiac development. Hypothesis: We hypothesize that exome sequencing of patients with CHD will uncover novel genes related to cardiac disease and development. Methods: To identify disease-associated mutations, we analyzed exome sequencing data in a multi-institutional discovery cohort of 59 trios with a novel analytical pipeline. We phenotyped knockout animals for orthologous genes across multiple genetic phyla (mouse and fruit fly) for aspects of cardiac development. Additionally we performed Chromatin Immuno-Precipitation Sequencing (ChIP-seq) in a HL-1 mouse atrial cell line. Results: Exome sequencing uncovered a de novo missense variant R175W in the highly conserved DNA binding domain of NR1D2 a key component of the molecular clock. Knockout mice for Nr1d2tm1-Dgen display atrioventricular septal defects and related malformations, while knockdowns of the drosophila homolog Eip75B displays abnormal heart tube fusion during late embryonic development. ChIP-seq data for Nr1d2 suggests transcriptional repression at key loci controlling differentiation into both valve development (Twist1, Twist2, Bmpr1b) and atrial left-right patterning (Pitx2, Cited2). Conclusions: A patient with a deleterious de novo mutation in NR1D2 and knockout in multiple model organisms show cardiac defects, while genomic analysis of ChIP-seq data supports a modulatory role for this transcriptional repressor in the complex 3-dimensional process of cardiac morphogenesis. In conclusion, these data suggest that NR1D2 plays an evolutionarily conserved role in cardiac development and congenital heart disease. Further experiments are needed to understand the mechanism by which NR1D2 might link the molecular clock to cardiac development.
TCT-619 Comparison of one-dimensional (1D) and three-dimensional (3D) models for the estimation of coronary fractional flow reserve through cardiovascular imaging
Authors: Cristiano Bezerra, Pedro A. Lemos, Fábio A. Pinton, Lucas Müller, Carlos Bulant, Gonzalo Maso Talou, Raul A. Feijóo, Antonio Esteves Filh Esteves, Pablo Blanco
Journal: Journal of the American College of Cardiology (2018)
Randomized phase II study of pembrolizumab after stereotactic body radiotherapy (SBRT) versus pembrolizumab alone in patients with advanced non-small cell lung cancer: The PEMBRO-RT study.
Authors: Willemijn Theelen, No Firstname H.Peulen@Nki.Nl, Ferry Lalezari, Jeltje de Vries, Joop De Langen, Joachim Aerts, Kim Monkhorst, Paul Baas
Journal: Journal of Clinical Oncology (2018)

9023 Background: High dose radiation can lead to increased tumor antigen release, improved antigen presentation and T-cell infiltration. It may therefore enhance the effects of checkpoint inhibition. We evaluated if stereotactic body radiation therapy (SBRT) on a single metastasis preceding pembrolizumab treatment in patients with NSCLC is well tolerated and leads to an increased tumor response. Methods: Patients (n = 74) with advanced NSCLC (≥2nd line) regardless of PD-L1 status were randomized (1:1) between pembrolizumab (200mg q3w) alone (control arm) or pembrolizumab preceded by SBRT (3x8Gy within 7 days prior to the first cycle) on a single metastasis (experimental arm). Sequential biopsies were obtained from the same, non-irradiated tumor site at baseline and after two cycles of pembrolizumab. The primary endpoint was improvement in overall response rate (ORR) at 12 weeks from 20% in the control arm to 50% in the experimental arm according to RECIST 1.1. Results: From July 2015 until the time of writing, 72 patients had been randomized and 64 patients who received at least one cycle of pembrolizumab could be evaluated for the primary endpoint. ORR at 12 weeks was 19% in the control arm (n = 32) vs 41% in the experimental arm (n = 32); the number of patients with a CR, PR, SD and PD were 0/6/7/19 and 1/12/6/13, respectively. Median PFS was 1.8 months in the control arm vs 6.4 months in the experimental arm; HR 0.55 (CI 0.31 – 0.98, p = 0.04). Grade ≥3 toxicity was experienced in 22% of patients in the control arm vs 17% in the experimental arm. The most common AEs were fatigue, nausea, fever and hypothyroidism. No increase in treatment related toxicity was observed in the experimental arm. Conclusions: With 86% of patients evaluable, we conclude that pembrolizumab preceded by SBRT resulted in a doubling of the ORR without increase in toxicity. The primary endpoint of 50% DCR was not (yet) met. This is a well-tolerated and promising treatment strategy to augment the anti-tumor immune response with checkpoint blockade. Definitive results as well as correlations with PD-L1 expression will be available and discussed at ASCO. Clinical trial information: NCT02492568.
Investigation of PD-L1 expression and response to pembrolizumab (pembro) in gastric cancer (GC) and cervical cancer (CC) using combined positive score (CPS) and tumor proportion score (TPS).
Authors: Karina Kulangara, Lindsay Guerrero, Alex Posch, Scott Boyer, Debra Ann Hanks, Josette Carnahan, Jiangdian Wang, Jared Lunceford, Mary Savage, Matthew John Marton, Scott K. Pruitt, Jonathan Wes Juco, Kenneth Emancipator
Journal: Journal of Clinical Oncology (2018)

4065 Background: TPS, the percentage of viable tumor cells with partial or complete membrane staining at any intensity, has been invaluable for assessing PD-L1 expression in non–small cell lung cancer (NSCLC) and identifying patients (pts) likely to respond to anti-PD–1/PD-L1 therapy. However, TPS has limited utility beyond NSCLC. We investigated the predictive value of TPS and CPS and their association with response to pembro in pts with GC and CC. Methods: Tumor samples from pts with previously treated GC (KEYNOTE-059, NCT02335411) or CC (KEYNOTE-158, NCT02628067) were analyzed for PD-L1 expression per an investigational-use-only-labeled version of the PD-L1 IHC 22C3 pharmDx assay (Agilent Technologies). Response was assessed per RECIST v1.1 by independent review. External reproducibility of CPS, the number of PD-L1–staining cells (tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells, multiplied by 100, was assessed. Results: Response, prevalence, positive predictive value (PPV), and negative predictive value (NPV) for CPS and TPS at cutoffs of 1 (TPS1, CPS1) and 10 (TPS10, CPS10) are shown in the table. Response to pembro was significantly associated with CPS (P= 0.002) but not TPS (P= 0.224) in GC, whereas response to pembro was significantly associated with CPS (P= 0.008) and TPS (P= 0.023) in CC. Intersite and interobserver overall agreement assessments of external reproducibility for CPS were 92.0% (95% CI, 87.4-96.3) and 96.6% (95% CI, 94.0-98.7), respectively, in GC and 95.0% (95% CI, 90.3-99.2) and 99.7% (95% CI, 99.7-100.0), respectively, in CC. Conclusions: CPS is a robust, reproducible scoring method that identified more responders than did TPS in GC and CC. Further investigation of CPS in cancers beyond NSCLC is warranted. Clinical trial information: NCT02335411 and NCT02628067.Scoring and Cutoff Responders/Total n/N Prevalence of PD-L1 Expression, % PPV, % NPV, % Odds ratio for Tumor Response All Patients, N PD-L1 Positive PD-L1 Negative Gastric cancer CPS1 257 24/148 7/109 58 16 94 2.8 TPS1 5/32 26/225 12 16 88 1.4 Cervical cancer CPS1 96 13/81 0/15 84 16 100 ∞ TPS1 10/50 3/46 52 20 93 3.6 CPS10 10/45 3/51 47 22 94 4.6 TPS10 6/26 7/70 27 23 90 2.7
Correlating whole blood AR-V7 and AR-V9 with therapy response to AR-targeted therapies in metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Edmond Michael Kwan, Sarah Q To, Heidi C Fettke, Andrew Michael Mant, Maria M Docanto, Patricia Bukczynska, Nicole Ng, Lisa-Jane K Graham, Phillip Parente, Carmel Jo Pezaro, Kate Lynette Mahon, Lisa Horvath, Tilman Todenhöfer, Arun Azad
Journal: Journal of Clinical Oncology (2018)

e17070 Background: The expression of androgen receptor splice variants (AR-V) in mCRPC patients has widely been regarded as a predictive biomarker for non-response to AR-targeted therapies. However, recent data from our group and others has questioned this association. We report new data from our whole blood assay, correlating baseline and end-of-treatment (EOT) AR-V7 and AR-V9 expression with clinical outcomes in mCRPC patients treated with abiraterone or enzalutamide. Methods: We have previously developed a whole-blood, quantitative polymerase chain reaction assay for detecting circulating AR-V7 and AR-V9. The assay was applied to samples prospectively collected from 48 mCRPC patients immediately prior to commencing abiraterone or enzalutamide, and where available, at treatment cessation. Patients positive for either AR-V7 or AR-V9 were defined as AR-V-positive, and AR-V-negative if neither variant was detected. All AR-V-positive samples underwent confirmatory DNA sequencing to confirm variant expression. AR-V expression was correlated with PSA response rate (chi-square test) and PSA progression-free survival (PSA-PFS) (log-rank test). Results: The median follow-up was 10.6 mo. Twelve out of 48 patients (25%) were AR-V-positive, with no samples positive for both variants at baseline. Similar response rates were observed in AR-V-positive (7/12) and AR-V-negative (23/36) patients (50% vs. 64%, p = 0.7). PSA-PFS did not differ significantly between groups (8.1 mo vs. not reached, p = 0.5). EOT samples were available in nine patients, with four exhibiting AR-V-positivity. Of these, two (50%) patients were AR-V-positive at baseline, and two (50%) patients converted from AR-V-negative to AR-V-positive at treatment cessation (PSA-PFS 3.4 and 2.6 mo respectively). One of the conversion patients transitioned from V7–/V9– to V7+/V9+. Neither AR-V7 nor AR-V9 were detected in any of 13 normal male controls. Conclusions: With extended follow-up, whole blood expression of AR-V7 and AR-9 continues to not correlate with treatment response in mCRPC patients commencing AR-targeted therapies. Dynamic changes in AR-V expression were detectable with this assay.
Mutational and immune gene expression profiling at relapse in patients (pts) treated with adjuvant dabrafenib plus trametinib (D + T) or placebo (pbo) in the COMBI-AD trial.
Authors: Reinhard Dummer, Axel Hauschild, Mario Santinami, Victoria Atkinson, Mario Mandalà, Vanna Chiarion-Sileni, James M. G. Larkin, Marta Nyakas, Caroline Dutriaux, Andrew Mark Haydon, Caroline Robert, Dirk Schadendorf, Paola Aimone, Bijoyesh Mookerjee, Catarina D. Campbell, James Garrett, Jan C. Brase, Richard Kefford, John M. Kirkwood, Georgina V. Long
Journal: Journal of Clinical Oncology (2018)

9574 Background: In the COMBI-AD trial, adjuvant D + T resulted in a significant relapse-free survival benefit (HR, 0.47 [95% CI, 0.39-0.58]; P < .001) vs pbo in pts with resected stage III BRAF V600E/K–mutant melanoma. At a median follow-up of 2.8 y, 37% of pts in the D + T arm and 57% in the pbo arm had relapsed. Resistance mechanisms are largely unknown in the adjuvant setting. We report mutational and immune gene expression profiling at relapse in COMBI-AD. Methods: COMBI-AD (NCT01682083) randomized pts with resected stage III BRAF V600E/K–mutant melanoma to receive D + T or pbo. DNA and RNA were extracted from the same relapse sample. Mutational landscape and immune gene expression signature were examined by sequencing 570 genes (mean depth ≈ 500×) and gene expression profiling using a customized NanoString panel. Plasma samples were subjected to ctDNA profiling (73 genes). Results: At relapse, 66 tissue samples (D + T, n = 24 [n = 4 relapsed on treatment]; pbo, n = 42) were collected (20 distant, 43 local/regional, 3 secondary primary melanoma). Paired baseline samples were available in most cases (n = 57). A BRAF V600E/K mutation was detected in all relapse samples except in 1 secondary primary melanoma. The genomic landscape was as expected for melanoma: the most common non–BRAF V600 genetic aberrations were CDKN2A (38%), CDKN2B (24%), PTEN (23%), TP53 (18%), and ARID2 (14%), and median tumor mutation burden (TMB) was ≈ 10 SNVs/Mb. No substantial differences in mutation frequency, TMB, or BRAF copy number were noted in relapse vs baseline samples or between treatment arms. Putative genetic resistance mechanisms in the MAPK (eg, MAP2K1, NRAS mutations) and non-MAPK (eg, PI3K pathway mutations) pathways were found in a small subset of relapse samples from pts treated with D + T. No significant differences in T-cell–specific/immune gene expression signatures were observed between arms. Conclusions: Although mutations in MAPK and non-MAPK pathways were found in a few relapse samples, no uniform adaptations were observed, suggesting that resistance to adjuvant D + T is caused by various genetic/epigenetic mechanisms. Clinical trial information: NCT01682083.
Circulating tumor cells enumeration (CTCs) and circulating tumor DNA (ctDNA): Clinical and molecular features of “rapidly progressing” stage IV disease (Stage IV<sub>prog</sub>).
Authors: Lorenzo Gerratana, Qiang Zhang, Andrew A. Davis, Youbin Zhang, Giovanna Rossi, Kimberly Strickland, Zhaomei Mu, Lisa E. Flaum, Cesar Augusto Santa-Maria, Hushan Yang, William John Gradishar, Leonidas C Platanias, Massimo Cristofanilli
Journal: Journal of Clinical Oncology (2018)

12040 Background: Liquid biopsy technologies, including CTCs and ctDNA, have a growingly paramount role in the management of advanced breast cancer (ABC) and are potentially capable to convey different types of information. Methods: This retrospective study analyzed 62 ABC patients (pts), characterized with paired CTCs and ctDNA assessments. CTCs were isolated through CellSearch and ctDNA was analyzed using the Guardant360 NGS assay. The previously reported cut-off of 5.7 was used for ctDNA percentage (%ctDNA) (Gerratana et al 2018), while 5 count was used for CTCs. Matched pairs variations in %ctDNA and CTCs at baseline (BL), at the 1st evaluation (E1) and at progression (PD) were tested through Wilcoxon test and associations with clinical variables were tested through Kruskal-Wallis test. Their prognostic impact was explored through Cox regression for progression-free survival (PFS), overall survival (OS) and PFS after E1 (E1_PFS). Results: CTCs and %ctDNA were comparable in respect to age at BL, while CTCs were marginally higher in luminal ABC (P = 0.07). Pairwise %ctDNA varied significantly between BL and E1 (P = 0.0012) and E1 and PD (P = 0.0016), but not between BL and PD. No significant variations were observed regarding CTCs, apart from triple negative ABC (P = 0.035). Both BL %ctDNA and CTCs had an impact in terms of PFS (HR 1.9, P = 0.02 and HR 3.4, P = 0.003 respectively) and OS (HR 3.5, P = 0.021 and HR 16.6, P = 0.011; respectively) but only BL CTCs retained its impact on E1_PFS (HR 3.5, P = 0.015). On the other hand, both E1 %ctDNA and CTCs had a prognostic impact on E1_PFS (HR 3.2, P = 0.009 and HR 3.2, P = 0.012; respectively). Pts with an increased ≥5.7 %ctDNA or stable ≥5.7 %ctDNA between BL and E1, experienced a worse E1_PFS in respect to pts with stable %ctDNA < 5.7 (HR 9, P = 0.009 and HR 3.1, P = 0.043; respectively); with a median time to progression after E1 of 22 days and 2.53 months each. Conclusions: The study suggests that both CTCs and ctDNA provide non-overlapping information about prognosis and treatment benefit. CTCs describes the underlying metastatic biology, while ctDNA gives a more, quantitative, real-time assessment of tumor burden and treatment benefit.