tbuckley/cabot-search huggingface dataset:
Genome-wide nucleotide patterns and potential mechanisms of genome divergence following domestication in maize and soybean
Authors: Jinyu Wang, Xianran Li, Kyung Do Kim, Michael J. Scanlon, Scott A. Jackson, Nathan M. Springer, Jianming Yu
Journal: Genome biology (2019)

Plant domestication provides a unique model to study genome evolution. Many studies have been conducted to examine genes, genetic diversity, genome structure, and epigenome changes associated with domestication. Interestingly, domesticated accessions have significantly higher [A] and [T] values across genome-wide polymorphic sites than accessions sampled from the corresponding progenitor species. However, the relative contributions of different genomic regions to this genome divergence pattern and underlying mechanisms have not been well characterized.Here, we investigate the genome-wide base-composition patterns by analyzing millions of SNPs segregating among 100 accessions from a teosinte-maize comparison set and among 302 accessions from a wild-domesticated soybean comparison set. We show that non-genic part of the genome has a greater contribution than genic SNPs to the [AT]-increase observed between wild and domesticated accessions in maize and soybean. The separation between wild and domesticated accessions in [AT] values is significantly enlarged in non-genic and pericentromeric regions. Motif frequency and sequence context analyses show the motifs (PyCG) related to solar-UV signature are enriched in these regions, particularly when they are methylated. Additional analysis using population-private SNPs also implicates the role of these motifs in relatively recent mutations. With base-composition across polymorphic sites as a genome phenotype, genome scans identify a set of putative candidate genes involved in UV damage repair pathways.The [AT]-increase is more pronounced in genomic regions that are non-genic, pericentromeric, transposable elements; methylated; and with low recombination. Our findings establish important links among UV radiation, mutation, DNA repair, methylation, and genome evolution.
Radiomics-based identification of peritumoral infiltration in de novo glioblastoma imaging presents targets amenable for potential targeted extended resection: A neurosurgical survey.
Authors: Andrew E. Sloan, Gaurav Shukla, Saima Rathore, Hamed Akbari, Vinai Gondi, Christos Davatzikos
Journal: Journal of Clinical Oncology (2019)

e13573 Background: Radiomics-based machine learning tools have been developed to analyze preoperative multiparametric MR images of patients with glioblastoma (GBM) to predict various outcomes of clinical interest, such as survival, molecular mutation status, and subclinical peritumoral infiltration, all before initial surgical resection. Preoperative identification of regions containing the highest probability of subclinical tumor infiltration presents an opportunity for targeted extended resection in the setting of a clinical trial, but the willingness of neurosurgeons to perform such a procedure is not known. Methods: We selected five neurosurgeons from high volume centers ( &gt; 20 GBM surgeries per year) and performed an in silico study of anonymized preoperative images of patients with GBM, with radiomics-based infiltration maps depicting high probabilities of peritumoral infiltration. With regards to these regions beyond the enhancing tumor, we surveyed them on their willingness to attempt biopsy, and asked them to rate whether they felt such a region could be resected. Results: Preoperative maps of 20 patients with GBM, containing 26 regions of interest depicting high-risk peritumoral infiltration regions (distributed among frontal, temporal, occipital, parietal, cerebellar, and deep loci) were presented to five expert neurosurgeons from different institutions. Of the 20 patients, a median of 90% were deemed to be safe to biopsy; a median of 55% were felt to be definitely resectable, and median 35% to be possibly resectable. 85% of the 20 subjects were felt to be good candidates for participation in a clinical trial assessing the feasibility, safety, and efficacy of targeted extended resection. Conclusions: In selected patients, experienced neurosurgeons are willing to attempt targeted extended resection using radiomics-based maps of peritumoral infiltration in the context of a clinical trial. Proceeding with development of such a trial is warranted.
Abstract 18127: Automated Physician Notifications to Improve Guideline-Based Anticoagulation in Atrial Fibrillation
Authors: Jeffrey M Ashburner, Steven J Atlas, Shaan Khurshid, Lu-Chen Weng, Olivia Hulme, Yuchiao Chang, Daniel E Singer, Patrick T Ellinor, Steven A Lubitz
Journal: Circulation (2017)

Introduction: Oral anticoagulants (OAC) are effective for stroke prevention in patients with atrial fibrillation (AF). However, many AF patients with an elevated stroke risk are not treated with OA...
Characteristics of POLE and POLD1 gene variations in Chinese cancer patients.
Authors: Jianfei Yao, Shiying Dang, Lifeng Li, Xinyi Liu, Guifeng Liu, Shifu Chen, Lele Song
Journal: Journal of Clinical Oncology (2019)

e14031 Background: POLE and POLD1 gene variations have been suggested as potential markers for immunotherapy due to their significant association with the tumor mutation burden (TMB), an effective indicator for response prediction in immunotherapy. Methods: In this study, we systematically studied the spectrum and characteristics of POLE and POLD1 gene variations from 1,392 Chinese cancer patients, and their correlation with existing immunotherapeutic markers and cancer associated genes. Results: We found that the frequency of POLE variations was not statistically different from that in COSMIC database, while the frequency of POLD1 variations in Chinese lung cancer patients was significantly higher than that in COSMIC database. Variations frequency analysis showed that c.857C &gt; G and c.2091dupC were potential high frequency variations in Chinese cancer patients. Patients carrying POLE damaging variations were significantly younger, and patients carrying POLD1 damaging variations exhibited significantly higher frequency of MSI than POLE/POLD1 WT patients. Further studies found that patients carrying POLE exonuclease domain damaging variations, POLD1 exonuclease and non-exonuclease domain damaging variations exhibited significantly higher TMB than POLE/POLD1 WT patients, while no such difference was found in patients carrying POLE and POLD1 neutral variations. Moreover, patients with POLE exonuclease domain damaging variations showed significantly higher frequency of MMR gene and driver gene variations than POLE/POLD1 WT patients, including genes associated with RTK/RAS/RAF pathway. Patients with damaging POLD1 variations also exhibited higher frequency of MMR gene variations than POLE/POLD1 WT patients. The high frequency variant genes in patients with POLE exonuclease domain damaging variations or POLD1 damaging variations were associated with MMR, RTK/RAS/RAF, TGFβ, WNT, PI3K-Akt and TP53 pathways. Conclusions: This study identified key characteristics and domains of POLE and POLD1 gene variations that related to TMB, MSI, MMR gene variations and key driver gene variations, and provided theoretical and practical basis for patient selection based on POLE or POLD1 gene status in immunotherapy.
Identifying anti-EGFR (EGFRi) response subgroups using evidence of ctDNA selective pressure.
Authors: Christine Megerdichian Parseghian, Jason Willis, Van K. Morris, Kanwal Pratap Singh Raghav, Arvind Dasari, Victoria M. Raymond, Richard B. Lanman, Michael J. Overman, Scott Kopetz
Journal: Journal of Clinical Oncology (2019)

3587 Background: Metastatic colorectal cancers (mCRC) that respond to EGFRi display a robust circulating tumor DNA (ctDNA) signature that reflects selective pressure and clonal evolution. Conversely, non-responding tumors do not exhibit this signature. On this basis, we developed a novel method that defines EGFRi sensitivity with improved biological confidence with fewer patients (pts), and does not rely on clinical trial outcomes where responses may be confounded by concurrent chemotherapy. We used this method to further elucidate the association of several features that have been previously reported to be associated with EGFRi resistance, namely tumor sidedness, BRAF, PIK3CA, or ERBB2 ( HER2) MTs, and the absence of APC/ TP53 MT . Methods: We analyzed 112 pts with baseline tissue based RAS WT mCRC who had progressed following EGFRi, and with plasma samples available for ctDNA sequencing using a blood based NGS assay. Using our previously validated EGFRi exposure signature, we identified pts with evidence of selective pressure. Results: Post EGFRi ctDNA found 37% and 33% of pts with left sided and transverse tumors displayed evidence of selective pressure, respectively. 0 pts with right sided tumors displayed evidence of selective pressure; p= 0.01. Similarly, BRAFV600E MT displayed no evidence of selective pressure vs 30% of WT pts; in contrast, selective pressure was evident in pts with PIK3CA MT , ERBB2 MT and pts with absence of APC/TP53 MT (42% vs 28%, 67% vs 28%, 24% vs 43%, respectively for MT vs WT, p= NS for all). BRAF, PIK3CA, ERBB2, and APC/TP53 MT were present in 4/117, 12/108, 3/118 and 30/91 pts, respectively. ctDNA shedding was similar for all subgroups, as was time from previous EGFRi, indicating that these factors were not confounders. Conclusions: Consistent with prior large randomized studies, no pts with right sided tumors or BRAF MT had evidence of biologic benefit as assessed by presence of selective pressure. In contrast a number of pts with transverse tumors, ERBB2 MT , PIK3CA MT or absence of APC/TP53 MT had evidence of EGFR selective pressure, confirming that these are not absolute predictors of EGFR resistance and suggesting a subset of these pts were deriving benefit from EGFR inhibition. This biology based approach has the potential to more efficiently evaluate biomarkers of targeted therapy in the future without reliance on large randomized datasets.
Evaluation of the patient-reported outcomes common terminology criteria for adverse events (PRO-CTCAE) with abiraterone acetate plus prednisone (AAP), degarelix (D), or the combination in men with biochemically recurrent prostate cancer (BCRPC).
Authors: Karen A. Autio, Emmanuel S. Antonarakis, Raymond Baser, Mark N. Stein, Daniel H. Shevrin, Ulka N. Vaishampayan, Tina M. Mayer, Michael J. Morris, Susan F. Slovin, Elisabeth I. Heath, Scott T. Tagawa, Dana E. Rathkopf, Matthew I. Milowsky, Michael Roger Harrison, Tomasz M. Beer, Arjun Vasant Balar, Andrew J. Armstrong, Channing Judith Paller, Ethan M. Basch, Howard I. Scher
Journal: Journal of Clinical Oncology (2019)

5080 Background: Patient-reported symptoms using the PRO-CTCAE provide insights into the patient experience with care. Earlier use of AAP (an androgen biosynthesis inhibitor plus prednisone) with androgen deprivation therapy in castration sensitive disease may lead to increased symptoms. We previously reported a randomized phase 2 trial of intermittent AAP, D, or AAP+D in BCRPC (NCT01751451) and now share the PRO-CTCAE results. Methods: Men were randomized 1:1:1 to AAP, D, or AAP+D for 8 months, then entered follow up with PSA, testosterone, and safety monitoring. PRO-CTCAE was elicited from patients monthly for hot flashes (HF), fatigue, arthralgias, myalgias, anxiety, depression, sexual function, plus overall QOL. Changes from baseline to end of treatment were compared between groups. AUCs were calculated for each item as a measure of symptom severity over time. Results: 110 men were included. Compliance with PRO-CTCAE reporting from baseline to EOT was 93%. HF did not differ between AAP+D and D, but were increased relative to AAP (all p &lt; 0.05). These differences were consistent when HF were measured as an AUC (all p &lt; 0.01). Fatigue severity did not differ between groups however men receiving AAP reported a small worsening in activity interference from fatigue as compared to AAP+D (p &lt; 0.05). Overall QOL scores were high and did not differ with AAP+D relative to AAP or D. Conclusions: Collection of PRO-CTCAE was feasible and did not demonstrate differences in fatigue, HF, or QOL between AAP+D and D. Comparisons of PRO-CTCAE to matched clinician-reported AEs, and changes in PRO-CTCAE with testosterone recovery during follow up are planned. Clinical trial information: NCT01751451.
Emergency oncology: The situation of acute general hospital in Japan.
Authors: Yoshitaka Onishi, Takashi Miyakawa, Mari Minematsu, Shimpei Natsuaki, Masari Ogawa, Toshinori Nagata
Journal: Journal of Clinical Oncology (2019)

e18069 Background: The need for supportive and palliative care services for cancer patients is well established. Our hospital is acute general hospital with 602 beds, 20 ICU beds, radiation unit, chemotherapy unit and with emergency department(ED) 24hours and 365 days open, locates close to one of the national cancer center. In this situation, we have many acutely unwell patients with newly diagnosed cancer in emergency department(emergency oncology). Methods: We reviewed the records of the patients with newly diagnosis of cancer and treated by surgery, radiation and or chemotherapy and of the patients transfered by ambulance at ED in 2017, 2018 and 2019, retrospectively and consecutively. Results: In this three years, we have 1626 patients with first diagnosis of cancer, 268 patients visited after clinic-hour and 130 patients needed ambulance with critical symptoms. Of those, 145 had gastro-intestinal, 34 hepato-billiary, 25 urological, 24 lung, 16 gynecology, 9 breast and 23 other cancer. During this period, total 30027 patients were transported by ambulance to our ED. Conclusions: Although there are many cancer centers in Japan, there are only one unit in Japan.(National Cancer Center Hospital(Tokyo) )that provide urgent care to cancer patients. In this situation, acute hospitals have to have a role for emergency oncology. We need varying models of emergency and acute care development (e.g., acute cancer net-work system, regionalization, education for the physicians and patients, organize the emergency oncology unit in acute hospital or cancer center) with cooperation of oncologist and non-oncology emergency physicians in Japan as they are trying and developing in the USA and UK.
FDA analysis of depth of response (DpR) and survival across 10 randomized controlled trials in patients with previously untreated unresectable or metastatic melanoma (UMM) by therapy type.
Authors: Christy Osgood, Flora Mulkey, Pallavi Shruti Mishra-Kalyani, Steven Lemery, Ashley Ward, Patricia Keegan, Rajeshwari Sridhara, Marc Robert Theoret, Richard Pazdur
Journal: Journal of Clinical Oncology (2019)

9508 Background: Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 may not capture the full spectrum of benefit that patients with melanoma derive from targeted kinase inhibitors (TKI) or immunotherapies. We explored the relationship between DpR and overall survival (OS) in patients treated with TKI (BRAF, MEK inhibitors), immunotherapy (antibodies targeting PD-1 or CTLA-4), or chemotherapy (dacarbazine or paclitaxel). Methods: Ten randomized controlled trials of patients with previously untreated UMM were pooled and evaluated by type of therapy. DpR was grouped by maximal tumor shrinkage (G0 = no shrinkage or increase, G1 = ≤25%, G2 = 26-50%, G3 = 51-75%, G4 = 76- &lt; 100%, and G5 = 100%). We performed an exploratory analysis evaluating the association between DpR and OS using hazard ratios (HR) generated from a Cox proportional hazards model where maximal tumor shrinkage category was included as a time varying covariate. Results: There were 3778 patients evaluable for tumor response. The table displays the HR for OS by DpR group and therapy type. Estimated OS at 24m in patients with deep response ( &gt; 75%; G4+G5) treated with TKI and immunotherapy was 69% and 92%, respectively, although many patients were censored. Conclusions: For patients with previously untreated UMM a larger DpR correlates with a longer OS, regardless of therapy type. Deep response ( &gt; 75%) is associated with a high rate of estimated OS at 24 months in patients treated with immunotherapy. Analysis of DpR provides additional granularity of response data and may provide a more nuanced prediction of clinical outcome. [Table: see text]
Clinicopathologic features and prognostic analysis of stage I ovarian clear cell cancer.
Authors: Tian Tian Wang, Ning Li, Lingying Wu
Journal: Journal of Clinical Oncology (2019)

e17090 Background: Ovarian clear cell carcinoma is one kind of Epithelial ovarian carcinoma and is considered high-grade tumor. This retrospective analysis aimed to evaluate the clinical and pathologic features and to determine prognostic variables in patients with stage I ovarian clear cell cancer. Methods: 378 patients with ovarian clear cell cancer were treated in National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, from February 1999 to December 2018. And 214(56.6%) had stage I disease. We retrospectively analyzed the prognostic relevance of different clinicopathological variables in 102 patients underwent surgery treatment, specifically including age, initial symptom, endometriosis, stage, tumor size, serum CA125 and CA199, chemotherapy regimens and treatment course. Results: The median age was 51 years old. 64(62.7%) patients presented with large pelvic mass (median diameter:12.0cm). 82.4% patients had no more than 200U/ml elevation of serological CA125(median: 50.76U/ml). 81.8% patients had no more than 100U/ml elevation of serological CA199(median: 24.8U/ml). The median follow-up time was 40.5 months. The 5-year disease-free survival was 82.8%. All patients were restaged using the 2014 FIGO staging system. 31(30.4%), 17(16.7%), 25(24.5%), 17(16.7%)patients had stage IA, IC1, IC2, IC3, respectively. Univariate analysis showed that tumor size(P = 0.045) and serum CA199(P = 0.025) were related with poor disease-free survival. 5-year disease-free survival (86.9%) of patients with four course chemotherapy was comparable to that (80.2%) with five or more. Patients at stage IC1 or IC2/IC3(rupture before surgery) had the similar outcomes compared with patients at stage IA. And the results of multivariate statistical analysis showed there was no independent, statistically significant prognostic variable. Conclusions: Tumor size and serum CA199 were related with prognosis. Disease-free survival at stage IC1 or IC2/IC3 was comparable to that at stage IA. Five course chemotherapy or more may not improve the 5-year disease-free survival than four.
Impact of EGFR amplification status in newly diagnosed glioblastoma treated with Stupp protocol.
Authors: Addison Barnett, Anas Saeed Bamashmos, Assad Ali, Xuefei Jia, Wei (Auston) Wei, Soumya Sagar, Gene H. Barnett, Lilyana Angelov, Alireza Mohammad Mohammadi, David M. Peereboom, Glen Stevens, John H. Suh, Erin Sennett Murphy, Jennifer S. Yu, Manmeet Singh Ahluwalia
Journal: Journal of Clinical Oncology (2019)

e13569 Background: Standard post-surgical glioblastoma (GBM) treatment, per Stupp protocol, includes six-weeks of concurrent Temozolomide chemoradiation followed by at least six cycles of adjuvant-Temozolomide. Previous investigations into epidermal growth factor receptor (EGFR) amplification as a prognostic factor in GBM have yielded contradicting results, requiring further investigation. The primary aim of this study was to determine the degree to which EGFR amplification, in newly diagnosed GBM, impacted progression free survival (PFS) and overall survival (OS). Methods: Data from 582 patients who underwent surgical intervention for GBM at a tertiary care institution between 2012 and 2018 were analyzed. Only adult patients who underwent treatment per Stupp protocol and had pathological analysis on EGFR and CEP7 were included. Amplification and non-amplification status was calculated by a ratio of EGFR/CEP7 &gt; 2 and &lt; 2, respectively. PFS and OS outcomes were compared using Cox proportional hazard models stratified by surgery type and sex. Results: Of the original 582 patients, 122 were treated per Stupp protocol and had documented EGFR analysis. Of patients who were EGFR amplified, 41 (58.5%) were male and 25 (48.1%) were female (p = 0.38) and median amplification was 1.07 and 1.16 (p &lt; 0.001), respectively. EGFR non-amplified patients had a PFS hazard ratio, HR = 0.70 (95% CI = 0.44 – 1.12, p = 0.14); and an OS HR = 0.60 (95% CI = 0.35 – 1.03, p = 0.065). When the EGFR/CEP7 ratio was stratified by quartile, it was found that Q4 compared to Q1 (Q4 &gt; 6.50 vs 0 &lt; Q1 ≤ 1.06) had a PFS HR = 2.1 (95% CI = 1.11 – 4.07, p = 0.024); and an OS HR = 2.48 (95% CI = 1.10 – 5.60, p = 0.028). Conclusions: There was no statistical difference in prevalence of EGFR amplification by sex. However, despite statistical significance, there was minimal difference in median degree of amplification by sex (0.09). Trends begin to show that patients who were EGFR non-amplified had better PFS and OS outcomes than patients who were EGFR amplified, although this was not statistically significant. Patients with very high EGFR amplification (Q4) had significantly poorer PFS and OS outcomes than patients with very low EGFR amplification (Q1).
Plasma proteomic analyses and treatment predictive biomarker candidates in melanoma patients receiving immune checkpoint blockade or targeted therapy.
Authors: Hanna Eriksson, Haris Babacic, Janne Lehtio, Maria Pernemalm
Journal: Journal of Clinical Oncology (2019)

9574 Background: The introduction of immune checkpoint inhibitors (ICIs) or therapies targeting the MAPK-pathway (MAPKis) has significantly improved clinical outcomes in metastatic melanoma patients. Still, a large proportion of the patients become resistant to therapy and there is a need for treatment predictive biomarkers. The aim of this study was to analyze the treatment predictive biomarkers based on the plasma proteome of patients with metastatic melanoma treated with ICIs or MAPKis. Methods: We analyzed serial plasma samples from 48 patients with metastatic melanoma collected; 24 patients were treated with ICIs and with MAPKis, respcetively. A non-biased, high-resolution isoelectric focusing of peptides-liquid chromatography-mass spectrometry (HiRIEFLC-MS/MS)-based method, and with proximity ligation assays (PEA) targeting 92 immuno-oncology-related proteins were used.We analyzed the change in protein levels during treatment with a paired t-test, and their association with progression free survival (PFS) with Cox proportional hazards models. Results: HiRIEFLC-MS/MS detected 1,835 proteins.We detected statistically-significant log2-fold-changes in 109 protein levels out of 1,160 proteins tested (not corrected for multiple testing). PDCD-1 had the highest log2-fold change (FC = 1.27) after treatment (p = 0.02). After stratifying for treatment type, PDCD-1 levels increased in patients treated with ICIs (FC = 2.13, p= 0.0008), but not in MAPKis-treated patients. PEA analyses confirmed this observation. The PEA panel showed association between 44 proteins and shorter PFS (pcoefficient &lt;0.05, pLRT&lt;0.05, qLRT&lt;0.05), among them: LGALS1, CSF1, VEGFA, CASP8, CCL2, TNFSF14, ANGPT2, IL10, IL6, and ADGRG1. Of these, increase in plasma levels during treatment of LGALS1, CCL2 and ADGRG1 were associated with longer PFS. HiRIEF LC-MS/MS detected 69 proteins associated with PFS (pcoefficient&lt; 0.05, pLRT&lt; 0.05, qLRT &lt; 0.05). Conclusions: By using HiRIEFLC-MS/MS, we could detect putative treatment predictive proteins in plasma from patients with metastatic melanoma treated with ICIs or MAPKis. Our findings require further validation.