tbuckley/cabot-search huggingface dataset:
Intragenic Meiotic Crossovers Generate Novel Alleles with Transgressive Expression Levels
Authors: Sanzhen Liu, James C Schnable, Alina Ott, Cheng-Ting “Eddy” Yeh, Nathan M Springer, Jianming Yu, Gary Muehlbauer, Marja C P Timmermans, Michael J Scanlon, Patrick S Schnable
Journal: Molecular Biology and Evolution (2018)

Meiotic recombination is an evolutionary force that generates new genetic diversity upon which selection can act. Whereas multiple studies have assessed genome-wide patterns of recombination and specific cases of intragenic recombination, few studies have assessed intragenic recombination genome-wide in higher eukaryotes. We identified recombination events within or near genes in a population of maize recombinant inbred lines (RILs) using RNA-sequencing data. Our results are consistent with case studies that have shown that intragenic crossovers cluster at the 5′ ends of some genes. Further, we identified cases of intragenic crossovers that generate transgressive transcript accumulation patterns, that is, recombinant alleles displayed higher or lower levels of expression than did nonrecombinant alleles in any of ∼100 RILs, implicating intragenic recombination in the generation of new variants upon which selection can act. Thousands of apparent gene conversion events were identified, allowing us to estimate the genome-wide rate of gene conversion at SNP sites (4.9 × 10−5). The density of syntenic genes (i.e., those conserved at the same genomic locations since the divergence of maize and sorghum) exhibits a substantial correlation with crossover frequency, whereas the density of nonsyntenic genes (i.e., those which have transposed or been lost subsequent to the divergence of maize and sorghum) shows little correlation, suggesting that crossovers occur at higher rates in syntenic genes than in nonsyntenic genes. Increased rates of crossovers in syntenic genes could be either a consequence of the evolutionary conservation of synteny or a biological process that helps to maintain synteny.
P01.107 Resection of supratentorial lesions employing a combined surgical aspiration and monopolar stimulationdevice
Authors: N Thakur, C Senft, V Seifert, M Forster
Journal: Neuro-Oncology (2018)

Intraoperative neurophysiological monitoring and mapping are indispensable during surgery close to the corticospinal tract (CST). Assuming a nearly 1:1 distance-to-current relationship, a combined surgical aspiration and monopolar stimulation (cSAMS) device has recently been introduced. The present study investigates the results of the use of the cSAMS device focusing on both, postoperative motor deficits and the extent of lesion resection (EoR) Between January 2015 and September 2017, a cSAMS device (short train stimulation, interstimulus interval 4 msec, pulse duration 500 µsec) was used in 89 patients during resection of supratentorial lesions in the vicinity of the CST. Motor function was assessed preoperatively, on the first day after surgery, at discharge and at 3 months. The lowest motor thresholds evoking motor evoked potentials were as follows (mA, number of patients): 10-20mA n = 25; 5–9 mA n = 23; 2 to 4 mA, n = 16; and <2 mA, n = 3. In 22 patients, no MEPs could be evoked at stimulation intensities ≤ 20 mA. Thus, data of 67 patients were used for further evaluation. Immediately after surgery, a worsening of preoperative symptoms or new motor deficits were observed in 27 patients (40.3%), persisting at discharge in 10 patients (14.9%) and at the follow-up visit in four patients (6.0%). Gross total resection of lesions near the CST could be achieved in 52 patients (77.6%), whereas tumor removal had to remain subtotal or partial in 13 and 2 patients (19.4% and 3.0%), respectively. The cSAMS device is safe, reliable and facilitates surgery, because tumor resection does not need to be interrupted for subcortical mapping. Thanks to continuous mapping, EoR can be maximized while minimizing the risk of permanent neurological deficits.
Potential cost savings by dose rounding monoclonal antibodies (mAB) in a community cancer center.
Authors: Mehmet Sitki Copur, Curtis Gnewuch, Megan Schriner, Mithat Gonen, Monica McDonald, Jami Kezeor, Mark Tharnish, Ryan C. Ramaekers, Dron Gauchan, Douglas Clark, Lois Greenwalt, Katie Kuhl, Mary Mickey, Max Norvell
Journal: Journal of Clinical Oncology (2016)

6616 Background: Increasing new cancer cases and approval of expensive drugs extending survival has led to unsustainable cancer care costs. Potential cost savings by a dose rounding practice for mABs is presented. Methods: Using EHR, Oct 2014 - Oct 2015, metastatic cancer patients receiving mABs at CHI-Health St Francis in Grand Island Nebraska were identified. Trastuzumab, ofatumumab, obinutuzumab did not require dose rounding and excluded. Available vial size(s) and cost/mg (per acquisition costs) for each mAB recorded. Costs of actual amount prescribed compared to hypothetical ≤ 5% and ≤ 10% reduced doses rounded to nearest vial sizes. Doses resulting in decreased number of used vials qualified and included in analysis. Average actual dose reduction (%) resulting in cost-savings for both groups was also calculated. Results: 728 doses of 8 mABs identified. Vial sizes of pembrolizumab and ipilimumab did not allow meaningful dose rounding. At ≤ 5% dose rounding 255/728 doses (35%) qualified, with potential annual cost savings(PACS) of $ 220,793. At ≤ 10% dose rounding 526/728 doses (72%) qualified, with a PACS s of $ 454,461.The average actual dose reduction was 2.4% and 4.9% at 5 and 10 % groups respectively. Overall average cost savings per qualifying dose reduction was around $ 865.Significant differences among different mABs for dose rounding at either 5% (p = 0.002) or 10% (p < 0.001) were observed. Overall more doses qualified for cost savings at 10%. Conclusions: A pragmatic dose rounding project may reduce cost in metastatic cancer when cure is not the goal. Drug waste may be avoided/eliminated by convenient vial sizes or lyophilized forms like in trastuzumab. Our data reflect mAB use and potential cost savings in a community cancer setting. Drug ≤ 5% Reduction # % Savings ≤ 10% Reduction # % Savings Reduction 5% vs 10% P Cost 5% vs 10% P Bev 136/323 42 $ 113,288 250/323 77 $ 208,250 < 0.001 < 0.001 Ritux 62/232 26 $ 55,614 169/232 72 $ 151,593 < 0.001 < 0.001 Cetux 12/46 26 $ 7,632 18/46 39 $ 11,448 0.267 0.017 Panitum 19/40 47 $ 23,465 26/40 65 $ 32,110 0.176 0.089 Ramu 13/42 31 $ 13,312 33/42 78 $ 33,792 < 0.001 < 0.001 Ipi 0/7 0 $ 0 0/7 0 $ 0 Pembro 0/2 0 $ 0 0/2 0 $ 0 Nivo 13/36 36 $ 7,482 30/36 83 $ 17,268 < 0.001 0.001 Total 255/728 35 $ 220,793 526/728 72 $ 454,461
The prognostic impact of proinflammatory markers (NLR, PLR) in biliary cancer.
Authors: Leslie Jane Padrnos, Komal Thind, Brandon Barrett, Taofic Mounajjed, Heidi Kosiorek, Dora Lam-Himlin, Mitesh J. Borad
Journal: Journal of Clinical Oncology (2016)

e15621 Background: Laboratory based inflammatory markers such as neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR) have been shown to be associated with worse prognosis in some solid malignancies. Evaluating simple lab-based ratios in biliary cancer may provide improved prognostication and classification. Methods: Individuals with biliary cancer (resected cholangiocarcinoma (rCCA), unresected (uCCA) or resected gallbladder carcinoma (rGBC)) were retrospectively identified through a cancer registry query. Clinical and laboratory data were collected through medical record review. Individuals with laboratory data collected within 2 weeks of surgical intervention/ biopsy were included. Analysis was conducted separately in the three groups. Cutoff values of NLR and PLR were determined by ROC curves. Median overall survival (mOS) was estimated by Kaplan-Meier and comparison by logrank test. Results: In 98 patients with rGBC, univariate analysis revealed the high PLR > 242 group (N = 38) demonstrated mOS of 10.4 months (mts) compared to low PLR ( < 242) (N = 68) [mOS 19.8 mts (p-value 0.01)]. High NLR was associated with lower hemoglobin (p < 0.01) and lower albumin (p < 0.05) than low NLR, but was not prognostic. In 142 patients with rCCA, univariate analysis revealed the high NLR ( > 1.76) group (N = 122) demonstrated mOS 46.1 mts compared to low NLR ( < 1.76) (N = 20) [mOS 27.4 mts (p = 0.10)]. High PLR > 310 was associated with mOS 35.8 mts compared to low PLR [mOS 45.7 mts (p = 0.35)]. High PLR was associated with positive margin status, lung metastasis, lower albumin, and higher CA 19-9 than low PLR (p < 0.05). In 89 patients with uCCA, univariate analysis revealed high NLR > 5.66 (N = 30) with mOS of 3.6 months, and low NLR (N = 59) mOS of 8.9 month (p = 0.017). High PLR ( > 188) (N = 36) was associated with higher carcinoembryonic antigen verses low PLR ( < 188)(N = 53) (p < 0.05), but was not prognostic. Conclusions: In this study the use of proinflammatory laboratory ratios do not prognosticate in rCCA . PLR, but not NLR, is associated with prognosis in rGBC. In uCCA, NLR, but not PLR, is prognostic. Further study of proinflammatory markers is necessary to better delineate the prognostic ability of these ratios within the biliary cancers.
Durvalumab in ≥ 3rd-line advanced NSCLC: Updated results from the phase 2 ATLANTIC study.
Authors: Marina Chiara Garassino, Byoung Chul Cho, Joo-Hang Kim, Julien Mazieres, Jhanelle Elaine Gray, Paul Wheatley-Price, Keunchil Park, Ross A. Soo, Yifan Huang, Catherine Wadsworth, Phillip A. Dennis, Naiyer A. Rizvi
Journal: Journal of Clinical Oncology (2018)

9058 Background: The Phase 2 ATLANTIC study investigated the anti-PD-L1 antibody durvalumab in heavily pretreated pts with advanced NSCLC. Here we report updated results for two of the three pt cohorts (defined by tumor PD-L1 expression and EGFR/ALK mutation status) for which data have reached further maturity. Methods: ATLANTIC (NCT02087423) is an open-label, single-arm trial of advanced NSCLC pts who had progressed after ≥2 regimens. After initially enrolling all-comers, the study was restricted to pts with PD-L1-expressing tumors (≥25% of tumor cells [TC]). Pts received durvalumab 10 mg/kg IV every 2 weeks ≤12 months. The primary endpoint was ORR by independent central review (ICR) using RECIST v1.1 in pts with TC ≥25%. Pts in Cohort 1 were EGFR+/ALK+ and pts in Cohorts 2 (not reported) and 3 (TC ≥90% only) were EGFR−/ALK−. Interim results were reported for a prior data cutoff (DCO; June 3, 2016). Results: As of the latest DCO (November 7, 2017), 444 pts had received durvalumab, 111/68 in Cohorts 1/3. Median age was 61.0 years in both cohorts, 0.9%/29.4% had squamous histology, and the mean number of prior therapies in each cohort was 3.8/2.6. Median OS was 13.3/13.2 months, with a 1-year OS rate of up to 53%, in pts with higher PD-L1 expression (Table). Grade ≥3 treatment-related AEs (CTCAE v4.03) occurred in 5.4%/19.1%. Immune-mediated AEs were manageable, occurring with similar incidences as that reported previously for the earlier DCO. Clinical trial information: NCT02087423. Conclusions: These findings demonstrate durable efficacy and a promising effect on OS with durvalumab in a subset of heavily pretreated, advanced NSCLC pts. Cohort 1 (EGFR+/ALK+) Cohort 3* (EGFR−/ALK−; TC≥90%) TC < 25% (n = 28) TC ≥25%† (n = 74) (n = 68) Confirmed ORR,‡ n (%) [95% CI] 1 (3.6) [0.1–18.3] 9 (12.2) [5.7–21.8] 21 (30.9) [20.2–43.3] Median DoR (IQR),‡ months 7.9 (7.9–7.9) 7.4 (5.6–9.2) NR (NR–NR) n = 30¶ n = 77¶ n = 67¶ Median PFS (95% CI),‡ months 1.9 (1.8–1.9) 1.9 (1.8–3.6) 2.4 (1.8–5.5) Median OS (95% CI), months 9.9 (4.2–13.3) 13.3 (6.3–24.5) 13.2 (5.9–NC) 1-year OS (95% CI), % 40.4 (22.5–57.6) 53.3 (40.6–64.4) 51.8 (39.2–63.1) *Includes pts with unknown EGFR/ALK status; †Includes pts with TC ≥90%; ‡Evaluable per ICR (based on the prior DCO); ¶Full analysis set. NC, not calculated; NR, not reached.
Abstract 18828: Association Between Serum Uric Acid Level and Metabolic Syndrome in a Rural Japanese Population
Authors: Yuki Nakao, Shinske Mikami, Hajime Takemoto, Hitoshi Susawa, Kengo Kobayashi, Haruki Tanaka, Kouichi Tanaka, Yasuki Kihara
Journal: Circulation (2015)

Objective: Several reports have showed associations between serum uric acid (UA) levels and metabolic syndrome (MetS). Limited information, however, is available concerning the prospective relation between UA and the risk of developing MetS. Hypothesis: The aim of this study was to evaluate whether hyperuricemia or their combination predicts MetS. Methods: We evaluated 1468 subjects (783 male subjects, 685 female subjects; mean age 48.3 years) who underwent health examination programs in 2008 and 2013, who were free of MetS. Results: At baseline, hyperuricemia was detected in 86 male subjects (11%) and 14 female subjects (2%). Male subjects with baseline hyperuricemia had significantly higher MetS prevalence in 2013 than those without (male subjects: 17.9 vs. 8.4%, P&lt;0.0001; female subjects: 6.1 vs. 1.8%, P=0.143). Compared with subjects in the first quintile of uric acid levels at baseline, the age-adjusted odds ratios (ORs) for MetS cumulative incidence among subjects in the second, third, and fourth quintiles were, 1.2 (95% confidence interval (CI): 0.4-2.8: P=0.07), 2.1 (95% CI: 0.9-4.7: P=0.81) and 1.2 (95% CI: 0.3-4.8: P=0.81), for male subjects. Multivariable logistic analysis revealed that hyperuricemia was significantly associated with MetS cumulative incidence in male subjects (OR 1.9: 95% CI: 1.1-3.1, P=0.013) and not in female (OR 3.8: 95% CI: 0.2-18, P=0.1). Conclusion: Hyperuricemia is a significant predictor of MetS in rural Japanese male subjects.
Real-world study to quantify the symptom and disease burden of central nervous system (CNS) metastases (mets) in non-small-cell-lung cancer (NSCLC).
Authors: Gracy Crane, Tom Karagiannis, Nasreen Khan, Samuel Gally, Vlatka Smoljanovic, Pascale Tomasini, Nuria Lara, Adam Gondos, Stefan Hammerschmidt
Journal: Journal of Clinical Oncology (2018)

e14019 Background: Many lung cancer patients (pts) with CNS mets are excluded from clinical trials. To better understand the symptomatic and disease burden in such pts, we designed a prospective real-world study to quantify differences in health-related quality of life (HRQoL) and healthcare resource use (HRU) between pts with metastatic NSCLC with/without CNS mets. Methods: 163 pts were recruited (n = 81 CNS; n = 82 non-CNS). To approximate clinical trial inclusion criteria pts had ECOG performance status 0–2, metastatic NSCLC diagnosis 2–8 months previously, and ≥12 weeks life expectancy at enrollment. Three study visits were planned: baseline and 2 follow-up visits, approx. 6 weeks apart. HRQoL data were collected via validated questionnaires (EORTC QLQ-C15-PAL, QLQ-BN20, EuroQoL EQ-5D-5L) and HRU and clinical data via clinical charts. Student’s T-test, chi-square test, or Fisher's exact tests were used for group comparisons. In this cross-sectional analysis, baseline data are presented. Results: Baseline demographics were similar between cohorts, except pts with CNS mets were younger (62.0 vs 65.7 years, p = 0.018) with a lower body mass index (BMI) (13.6% underweight [BMI <18.5] vs 3.7%, p = 0.047). NSCLC history and presence of mets at NSCLC diagnosis were similar between cohorts. In the CNS cohort, 64.2% of pts had CNS mets at initial NSCLC diagnosis; in the remaining 35.8% of pts, median time from initial diagnosis to CNS mets diagnoses was 3.4 (± 1.5) months, vs 3.6 (± 1.5) months in the non-CNS cohort. Symptom burden, mean baseline physical, functioning, and symptom scores were similar between cohorts. Baseline HRU was similar between cohorts, except more pts with CNS mets had surgery, radiotherapy and longer duration of hospitalization; as expected. Conclusions: We used clinical trial inclusion criteria in a real-world study to quantify disease burden of pts with CNS mets. Baseline data suggest pts with CNS and non-CNS mets have similar disease burden in terms of symptoms and HRU, which may assist prospective planning for broader inclusion of pts with CNS mets in clinical trials, as recommended by the ASCO-FoCR brain mets working group.
Abstract 18103: Community Trends in Incidence and Mortality of Hospitalized Acute Decompensated Heart Failure: The ARIC Study
Authors: Patricia P Chang, Lisa M Wruck, Marina Bessell, Eyal Shahar, Joseph S Rossi, Laura R Loehr, Stuart D Russell, Sunil K Agarwal, Suma H Konety, Carlos J Rodriguez, Wayne D Rosamond
Journal: Circulation (2015)

Introduction: Understanding population-based trends in heart failure incidence is important to evaluation and planning of prevention and treatment strategies. Hypothesis: Community trends of acute decompensated heart failure (ADHF) in racially diverse populations may differ by race and sex. Methods: The Atherosclerosis Risk in Communities (ARIC) Study conducted continuous and comprehensive surveillance of hospitalized ADHF events (age ≥55 years) in four US communities between 2005-2012 and estimated hospitalized ADHF incidence and survival by race and sex. 17,651 hospitalizations for ADHF were identified by ICD-9-CM codes, then validated by standardized physician review of hospital records, yielding a weighted sample of 31,006 hospitalizations after accounting for sampling design. HF with reduced EF (HFrEF) was defined as EF&lt;50%. Results: Of the ADHF hospitalizations, 16259 (52.4%) were HFrEF, 11835 (38.2%) were HF with preserved EF (HFpEF), and 2912 (9.4%) were HF with unknown EF. HFrEF (both incident and recurrent ADHF) was more common in men (black men 70.4%, white men 61.4%), whereas HFpEF was more common in women (white women 50.0%, black women 39.5%). Compared to whites, blacks were younger, with less coronary heart disease and atrial arrhythmias, and more hypertension, diabetes, and chronic kidney disease. Between 2005-2012, the incidence of hospitalized ADHF increased, which mostly reflected the increase in rates of HFpEF (average annual percent change of incident HFpEF: black women 16.6%, black men 13.2%, white women 8.0%, white men 8.3%), with higher age-adjusted average incident HFpEF rates in women (black women 6.2 per 1000 persons, white women 5.9/1000, black men 4.6/1000, white men 4.2/1000). Changes in HFrEF incidence and changes in 28-day and 1-year case fatality for HFpEF and HFrEF were modest and generally not statistically significant. Age-adjusted 1-year case fatality was similar across all race-sex groups (~30% after any incident ADHF). Similar trends were seen for recurrent ADHF (HFpEF and HFrEF). Conclusions: Incident ADHF rates increased between 2005 and 2012 in the ARIC Study communities, primarily because of incident HFpEF in women and blacks. Further study is needed to understand the differences by race and sex.
Precision and reproducibility of automated computer‐guided Psoriasis Area and Severity Index measurements in comparison with trained physicians
Authors: C. Fink, C. Alt, L. Uhlmann, C. Klose, A. Enk, H.A. Haenssle
Journal: British Journal of Dermatology (2018)

BackgroundThe Psoriasis Area and Severity Index (PASI) represents the gold standard for psoriasis severity assessments but is limited by its subjectivity and low intra‐ and inter‐rater consistency.
Irf7 as a novel marker for predicting bone metastases of primary prostate cancer.
Authors: Zhao Yang, Chen Wenxia, Zhu Weiliang, Meng Hui, Wei Ting, Zhang Jian
Journal: Journal of Clinical Oncology (2016)

e16581 Background: There has not yet been an efficient marker for predicting bone metastases of primary prostate cancer. Irf7, a potent transcription factor and has been proven to be associated with breast cancer metastasis. Here we investigate the clinical features of Irf7 protein in bone metastases of primary PCa. Methods: Ninety-seven prostate specimens (10 nodular hyperplasia, 82 PCa and 5 bone metastases) were obtained from ZhuJiang Hospital between 2006 and 2009. For PCa patients, the exclusion criteria were included: (1) metastatic disease at presentation; (2) any type of treatment against PCa; (3) prior history of any malignant tumor; (4) insufficient tumor tissues. Clinical information was obtained from ZhuJiang Hospital with up to the 60 months of follow-up. Irf7 expression was analyzed in nodular hyperplasia, primary and metastatic tumors using Immunohistochemistry technique. Meanwhile, IFN-β expression was tested as the control of Irf7. Results: Irf7 expressed in 9 of 10 hyperplasia and 64 of 82 PCa samples, however, only 1 of 5 cases with bone metastases. For 82 PCa patients, 26 cases developed bone metastases, and 5 non-bone metastases. In metastasis group, more specimens (83.9%) showed lower expression levels of Irf7 as compared with the non-metastasis group (62.7%, P = 0.041). Kaplan-Meier analysis showed the predictive value of Irf7 for metastasis (P = 0.043).Notably, after excluding the non-bone metastases, patients with lower expression levels of Irf7 had increased risk of developing bone metastasis (P = 0.030). There was no significant relationship between Irf7 and the Gleason score, PSA level. Low-level of IFN-β was more often expressed in metastasis specimens (61.3%) as compared with the non-metastasis (41.2%, P = 0.077), but it alone could not predict development of bone metastasis (p =0.055).Additional, far more specimens in metastasis group had low-level of both Irf7 and IFN-β (61.3%) as compared with the non-metastasis (25.5%, P = 0.001), which further identified the development of bone metastasis (P = 0.001). Conclusions: Our findings suggested that Irf7 alone or combination with IFN-β signaling might be a useful biomarker for bone metastasis of primary PCa.
Second primary tumors in a cohort of more than 1,000 renal cancer patients treated at Instituto Oncológico Henry Moore (IOHM).
Authors: Dario Niewiadomski, Claudia Lorena Acuna, Leonardo Smolje, Gaston Martin Reinas, Cesar Gonzalez, Diego Juarez, Ernesto Gil Deza, Eduardo L. Morgenfeld, Edgardo G. J. Rivarola, Felipe G. Gercovich
Journal: Journal of Clinical Oncology (2018)

e13631 Background: Murphy and col (Jama Oncol. 2017.30605. Nov 2017) demonstrated a 3.5% to 36.9% prevalence range of second primary tumors (SPT) in cancer patients.This paper aims to show the incidence of SPT in a cohort of 1023 patients (Pt) with renal cancer diagnosis (RCDx). Methods: Between 1/1/2001 and 12/31/2017, 37,506 new Pt with histological diagnosis of cancer were incorporated to the IOHM database. All those coded under the WHO ICD10 code C64 and presenting SPT were selected. The temporal relation between the appearance of SPT and RCDx was categorized as: antecedent (more than 90 days before RCDx), synchronous (90 days before to 90 days after RCDx) or subsequent (more than 90 days after RCDx) (Murray et al World J Urol. 2016 December ; 34(12): 1667–1672). Results: A total of 114 Pt out of 1,024 Pt (11%) with RCDx presented SPT. Characteristics of population: Sex: F = 30/M = 84. Median age: 61y (r = 38-87). Median Follow Up: 50m (r = 1-204). Antecedent SPT= 41Pt, synchronous SPT= 15Pt, subsequent SPT= 58Pt. Most antecedent SPT were: Prostate(14) Breast(4), Lymphoma(2), Colorectal(2), Larynx(2). Most synchronous SPT were: contralateral renal cancer(7), bladder(2), prostate(2). Most subsequent SPT were: prostate(14), contralateral renal cancer(12), bladder(6), breast(5) and lung(5), Colon(3). The median time for antecedent SPT was 49,1m; and 42,1m for subsequent SPT. (T test p = 0.12) Conclusions: 1) To our knowledge, this cohort of 1024 renal cancer Pt is the largest in Argentina. 2) The incidence of SPT is 11 % and the median detection time is 45 months. 3) For both sexes, the most common synchronous or subsequent tumor was contralateral kidney cancer, highlighting the importance of Nephron Sparing Surgery.