tbuckley/cabot-search huggingface dataset:
MBCL-11. TIME TO RADIOTHERAPY IMPACTS SURVIVAL IN PEDIATRIC AND ADOLESCENT NON-METASTATIC MEDULLOBLASTOMA TREATED BY UPFRONT RADIOTHERAPY – A REPORT FROM THE HIT 2000 TRIAL
Authors: Stefan Dietzsch, Felix Placzek, Klaus Pietschmann, André O von Bueren, Christiane Matuschek, Albrecht Glück, Matthias Guckenberger, Volker Budach, Jutta Welzel, Christoph Pöttgen, Heinz Schmidberger, Frank Heinzelmann, Frank Paulsen, Montserrat Pazos, Rudolf Schwarz, Dagmar Hornung, Carmen Martini, Anca Ligia Grosu, Frank Michael Meyer, Karolina Jablonska, Juergen Dunst, Karin S Kapp, Karin Dieckmann, Beate Timmermann, Torsten Pietsch, Monika Warmuth-Metz, Robert Kwiecien, Martin Benesch, Nicolas U Gerber, Stefan M Pfister, Steven C Clifford, Katja von Hoff, Sabine Klagges, Stefan Rutkowski, Rolf-Dieter Kortmann, Martin Mynarek
Journal: Neuro-Oncology (2020)

Abstract PURPOSE To evaluate prognostic factors and impact of participation in a randomized trial in non-metastatic medulloblastoma. METHODS AND PATIENTS 382 patients with non-metastatic medulloblastoma aged 4–21 years with primary neurosurgical resections between 2001 and 2011 were enrolled into the HIT 2000 trial and centrally reviewed. Between 2001 and 2006, 176 of these patients participated in the randomized trial HIT-SIOP PNET 4. Three different radiotherapy protocols were applied. Molecular subgroup was available for 157 patients. RESULTS Median follow-up was 6.35 [0.09–13.86] years. The 5-year progression-free (PFS) and overall survival (OS) rates were 80.3 % ± 2.1 % and 86.5 % ± 1.8 %, respectively. On univariate analysis, there was no difference in PFS and OS according to radiotherapy protocols or in patients who participated in the HIT-SIOP PNET 4 trial or not, while histology, molecular subgroup and postoperative residual tumor influenced PFS significantly. Time interval between surgery and irradiation (≤48 days vs. ≥49 days) failed the significance level (p=0.052). On multivariate analyses, molecular subgroup (WNT activated vs. Group3 HR 5.49; p=0.014) and time interval between surgery and irradiation (HR 2.2; p=0.018) were confirmed as independent risk factors. CONCLUSION Using a centralized review system, multiprofessional and multiinstitutional collaboration as established for pediatric brain tumor patients in Germany, and risk-stratified therapy, outcome for non-metastatic medulloblastoma treated within HIT-SIOP PNET4 could be maintained outside the randomized trial. Prolonged time to radiotherapy negatively influenced survival.
Abstract 15761: Risk-Reclassification of Patients With Suspected Coronary Artery Disease Using an Acoustic Score
Authors: Samuel E Schmidt, Simon Winther, Mette H Grønhøj, Louise Nissen, Bjarke S Larsen, Jelmer S Westra, Niels R Holm, Lars Frost, Hans Erik Boetker, Axel Diederichsen, Johannes J Struijk, Morten H Boettcher
Journal: Circulation (2018)

Background: Conventional risk stratification for suspected coronary artery disease (CAD) results in a low proportion of positive findings in patients referred to non-invasive tests. The novel steth...
TAMI-20. POLY(ADP-RIBOSE) GLYCOHYDROLASE INHIBITION SEQUESTERS NAD+ TO POTENTIATE THE METABOLIC LETHALITY OF ALKYLATING CHEMOTHERAPY IN IDH MUTANT TUMOR CELLS
Authors: Hiroaki Nagashima, Christine Lee, Kensuke Tateishi, Fumi Higuchi, Megha Subramanian, Seamus Rafferty, Lisa Melamed, Julie Miller, Hiroaki Wakimoto, Daniel Cahill
Journal: Neuro-Oncology (2020)

Abstract Mutations in IDH1 or IDH2 characterize the majority of diffuse infiltrative gliomas of younger adulthood. DNA alkylator chemotherapy has proven to be an effective treatment for IDH mutant glioma, yet recurrences remain frequent and improved treatments are needed. Upon exposure of cancer cells to DNA alkylating agents, poly(ADP-ribose) polymerases (PARPs) catalyze the transient oligomerization of nicotinamide adenine dinucleotide (NAD+) into poly-ADP-ribose (PAR) chain-assemblies, which stimulate the DNA damage response. Here, we find that, in IDH mutant glioma cells, alkylator-induced cytotoxicity is dramatically augmented by pharmacologic inhibition or genetic knockout of the PAR breakdown enzyme poly(ADP-ribose) glycohydrolase (PARG). Mechanistically, we show this augmentation is driven by a metabolic state pairing amplified alkylator-induced DNA damage with catastrophic depletion of NAD+. IDH mutant cancer cells have low basal levels of NAD+, rendering them vulnerable to prolonged NAD+ depletion. Either of two clinically-utilized monofunctional alkylators, procarbazine (PCZ) or temozolomide (TMZ), when exposed to multiple IDH mutant lines, activated PARP conversion of cellular NAD+ monomers into polymerized PAR. Subsequent PAR breakdown and recycling of NAD+ monomers was then halted by concomitant PARG inactivation, amplifying PARylation-mediated DNA damage signaling and critically depleting free NAD+, resulting in profound cytotoxicity. This effect was partially reversed by NAD+ rescue supplementation, confirming the key contribution of metabolic stress. Combined alkylator treatment and PARG inhibition in vivo maximized both NAD+ depletion and cytotoxicity in an endogenous IDH mutant cancer model. Thus, alkyating DNA damaging agents expose a metabolic liability in IDH mutant cancers, and subsequent targeted blockade of PAR breakdown and NAD+ metabolite recovery can exploit this vulnerability to provide genotype-specific therapeutic benefit.
CTNI-36. TREATMENT AND PROGNOSTIC FACTORS FOR PEDIATRIC GLIOBLASTOMAS--THE 10 YEARS EXPERIENCE FROM ONE SINGLE CENTER
Authors: Juan Li, Mingyao Lai, Qingjun Hu, Zhaoming Zhou, Xing Zhang, Linbo Cai
Journal: Neuro-Oncology (2020)

Abstract OBJECTIVE We retrospectively analyzed the clinical features of pediatric glioblastoma patients in our center in the past 10 years. METHODS From November 2009 to December 2018, patients with glioblastoma under 18 years were admitted to Guangdong Sanjiu Brain Hospital. Clinical and pathological features were summarized, and the curative effect was evaluated. RESULTS A total of 31 pediatric patients were enrolled. The median age is 13.8 years (range 0.8–18), including 19 males and 12 females. To Sep, 2019, the median follow-up time was 18 months(Range 4–80 months). Among them, 2 were lost to follow-up, 13 died, 16 still survived, and the longest survivor survived for 80 months. The median survival time was 16.4 months, the 2-year survival rate was 38%. In the prognostic factor analysis, the median survival time of patients with surgical resection ≥90% was 18 months (95% CI 15.9–20 months), and for children with resection 90% was 11 months (95% CI 9.9–12 months), P=0.027, with significantly statistically difference. Multivariate analysis showed that tumor resection rate was an independent prognostic factor for survival. CONCLUSION The prognosis of pediatric glioblastoma is still dismal. This study demonstrates that prognosis of such patients with GTR or near GTR is better.
Knockout of aminopeptidase A in mice causes functional alterations and morphological glomerular basement membrane changes in the kidneys
Authors: Benedikt Marahrens, Arndt Schulze, Jan Wysocki, Meei-Hua Lin, Minghao Ye, Yashpal S. Kanwar, Michael Bader, Juan Carlos Q. Velez, Jeffrey H. Miner, Daniel Batlle
Journal: Kidney International (2020)
Epidemiological characteristics of COVID-19 cases and estimates of the reproductive numbers 1 month into the epidemic, Italy, 28 January to 31 March 2020
Authors: Flavia Riccardo, Marco Ajelli, Xanthi D Andrianou, Antonino Bella, Martina Del Manso, Massimo Fabiani, Stefania Bellino, Stefano Boros, Alberto Mateo Urdiales, Valentina Marziano, Maria Cristina Rota, Antonietta Filia, Fortunato D'Ancona, Andrea Siddu, Ornella Punzo, Filippo Trentini, Giorgio Guzzetta, Piero Poletti, Paola Stefanelli, Maria Rita Castrucci, Alessandra Ciervo, Corrado Di Benedetto, Marco Tallon, Andrea Piccioli, Silvio Brusaferro, Giovanni Rezza, Stefano Merler, Patrizio Pezzotti
Journal: Eurosurveillance (2020)

Background On 20 February 2020, a locally acquired coronavirus disease (COVID-19) case was detected in Lombardy, Italy. This was the first signal of ongoing transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the country. The number of cases in Italy increased rapidly and the country became the first in Europe to experience a SARS-CoV-2 outbreak. Aim Our aim was to describe the epidemiology and transmission dynamics of the first COVID-19 cases in Italy amid ongoing control measures. Methods We analysed all RT-PCR-confirmed COVID-19 cases reported to the national integrated surveillance system until 31 March 2020. We provide a descriptive epidemiological summary and estimate the basic and net reproductive numbers by region. Results Of the 98,716 cases of COVID-19 analysed, 9,512 were healthcare workers. Of the 10,943 reported COVID-19-associated deaths (crude case fatality ratio: 11.1%) 49.5% occurred in cases older than 80 years. Male sex and age were independent risk factors for COVID-19 death. Estimates of R 0 varied between 2.50 (95% confidence interval (CI): 2.18–2.83) in Tuscany and 3.00 (95% CI: 2.68–3.33) in Lazio. The net reproduction number R t in northern regions started decreasing immediately after the first detection. Conclusion The COVID-19 outbreak in Italy showed a clustering onset similar to the one in Wuhan, China. R 0 at 2.96 in Lombardy combined with delayed detection explains the high case load and rapid geographical spread. Overall, R t in Italian regions showed early signs of decrease, with large diversity in incidence, supporting the importance of combined non-pharmacological control measures.
EXTH-22. THE CNS PENETRATING TAXANE TPI 287 AND THE AURKA INHIBITOR ALISERTIB IMPROVE SURVIVAL IN VIVO
Authors: Brian Williams, Cory Zumbar, Muge Sak, Norman Lehman
Journal: Neuro-Oncology (2020)

Abstract Glioblastoma is the most common primary malignant brain tumor in adults and has a poor prognosis with current standard of care. The AURKA inhibitor alisertib exhibits antiproliferative activity against glioblastoma in vitro including our previous work. Unlike current clinically used taxane drugs, the novel taxane TPI 287 penetrates the CNS. In this study we stereotactically implanted human GB9 xenografts into nude mice brains and tested the activity of alisertib alone, TPI 287 alone and both together compared to control. Five days after implantation treatment was started using twice daily 20 mg/kg alisertib orally administered 5 days per week and/or 18 mg/kg TPI-287 administered intravenously every 4 days for a total of 3 treatments. Survival was assessed as well tumor volume using MR imaging at 2 weeks and 4 weeks after tumor implantation. Monotherapy with alisertib improved survival, which was further improved with the addition of TPI 287 (p=0.0058). TPI 287 alone did not significantly improve survival. Tumor volume was significantly decreased in all treatment groups at 2 weeks compared with control. At 4 weeks the alisertib and TPI 287 groups showed a trend toward decreased tumor volume with a significant decrease in the combination therapy group. This data supports the potential use of this combination therapy in human trials.
The cannabinoid WIN55212‐2 restores rhinovirus‐induced epithelial barrier disruption
Authors: Alba Angelina, Mar Martín‐Fontecha, Beate Rückert, Paulina Wawrzyniak, Mario Pérez‐Diego, Jacobo López‐Abente, Mübeccel Akdis, Cezmi A. Akdis, Oscar Palomares
Journal: Allergy (2020)

Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
mrMLM v4.0.2: An R Platform for Multi-locus Genome-wide Association Studies
Authors: Ya-Wen Zhang, Cox Lwaka Tamba, Yang-Jun Wen, Pei Li, Wen-Long Ren, Yuan-Li Ni, Jun Gao, Yuan-Ming Zhang
Journal: Genomics Proteomics & Bioinformatics (2020)

Previous studies have reported that some important loci are missed in single-locus genome-wide association studies (GWAS), especially because of the large phenotypic error in field experiments. To solve this issue, multi-locus GWAS methods have been recommended. However, only a few software packages for multi-locus GWAS are available. Therefore, we developed an R software named mrMLM v4.0.2. This software integrates mrMLM, FASTmrMLM, FASTmrEMMA, pLARmEB, pKWmEB, and ISIS EM-BLASSO methods developed by our lab. There are four components in mrMLM v4.0.2, including dataset input, parameter setting, software running, and result output. The fread function in data.table is used to quickly read datasets, especially big datasets, and the doParallel package is used to conduct parallel computation using multiple CPUs. In addition, the graphical user interface software mrMLM.GUI v4.0.2, built upon Shiny, is also available. To confirm the correctness of the aforementioned programs, all the methods in mrMLM v4.0.2 and three widely-used methods were used to analyze real and simulated datasets. The results confirm the superior performance of mrMLM v4.0.2 to other methods currently available. False positive rates are effectively controlled, albeit with a less stringent significance threshold. mrMLM v4.0.2 is publicly available at BioCode (https://bigd.big.ac.cn/biocode/tools/BT007077) or R (https://cran.r-project.org/web/packages/mrMLM.GUI/index.html) as an open-source software.
LINC-31. TREATMENT OUTCOME IN CHILDREN WITH MEDULLOBLASTOMA IN MEDIUM-INCOME COUNTRY: AN EXPERIENCE FROM A SINGLE TERTIARY CENTRE IN KUALA LUMPUR, MALAYSIA
Authors: C-Khai Loh, Hamidah Alias, Doris Lau
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Medulloblastoma is the most common malignant brain tumour in children. The overall outcome has improved however, this was not translated to developing nations. METHOD This was a retrospective review of patients from January 2000 to December 2017. Treatment was given using modified SIOP PNET 4 protocol: cranio spinal irradiation (CSI), a total of 54G with vincristine followed by 8 cycles of adjuvant chemotherapy. Prior to year 2007, patients had CSI with or without adjuvant chemotherapy. Those &amp;lt;3 years old received modified UKCCSG/SIOP CNS protocol with 2 weekly chemotherapy for a duration of 392 days followed by CSI when required. All patients had MRI brain and spine, and tissue histopathological examination but without molecular subtype. RESULTS Medulloblastoma comprised of 30% (n=31) out of total 103 brain tumour cases. Mean age at presentation was 7.6 years old (SD 4.4) with male to female ratio of 2:1. Average time of symptoms was 4.8 weeks. Majority, 77.4% was high risk and 19.4% was standard risk. There was high treatment abandonment rate (35.5%, n=11). Three patients returned and completed treatment after multiple surgeries in an average of 9 months. Three years OS and EF were 69.6% and 74.8%, respectively. Six patients aged &amp;lt; 3years; half had advance disease on palliative care post surgery. Other survivors had severe learning difficulty and two had second malignancy (meningioma and thyroid carcinoma) at average 15.5 years after diagnosis. CONCLUSION Strategy to reduce treatment abandonment is crucial. Moreover, multidisciplinary management and molecular stratification are important in improving the outcome.
EPID-33. PRACTICE VARIATION OF STEROID DOSING AND TAPERING SCHEDULES AMONG THE NEURO-ONCOLOGY COMMUNITY
Authors: Charissa Jessurun, Alexander Hulsbergen, Rishi Nandoe Tewarie, Timothy Smith, Marike Broekman
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Steroids are commonly used for treatment of peritumoral edema and increased intracranial pressure in brain tumor patients. However, despite the widespread use of steroids, relatively little evidence is available about the optimal dosing scheme in brain tumor patients. PURPOSE The aim of this study is to increase insight in the practice variation of steroid dosing and tapering schedules among the neuro-oncology community. METHODS An electronic survey consisting of 27 questions regarding dosing and tapering schedules and adverse events of steroids was conducted among neurosurgeons internationally between 6 December 2019 and 1 June 2020. The survey was distributed by the electronic mailing lists of the Europeans Association of Neurosurgical Societies and via social media platforms. Collected data was assessed for quantitative and qualitative analysis using the Kruskal-Wallis test. RESULTS The survey obtained 175 responses. 87% of respondents answered all questions. Steroids are prescribed routinely perioperatively by 80% of respondents. Prescribed doses range from 2 to 64 mg/day in dosing schedule ranging from one to four times a day. The most prescribed steroid is dexamethasone in a dose of 16 mg/day. No significant association is seen between the prescribed dose and frequency of adverse events, years of experience, country, type of institution or having an institutional guideline. CONCLUSION Steroids are routinely prescribed perioperatively in brain tumor patients. However, there is a great practice variation in steroid dosing and tapering schedules among neurosurgeons. Future investigation is needed to identify an optimal dosing scheme and implement (inter)national guidelines for the dosing of steroids.
PATH-11. PROGNOSTIC SIGNIFICANCE OF EPIGENETIC SUBTYPES AND CpGs ASSOCIATED WITH PROGRESSION TO G-CIMP LOW IN THE EORTC RANDOMIZED PHASE III INTERGROUP CATNON
Authors: C Mircea S Tesileanu, Martin van den Bent, Thais Sabedot, Marc Sanson, Alba Brandes, Wolfgang Wick, Paul Clement, Sarah Erridge, Michael Vogelbaum, Anna Nowak, Jean Baurain, Warren Mason, Helen Wheeler, Michael Weller, Iris de Heer, Hendrikus Dubbink, Johan M Kros, Kenneth Aldape, Pieter Wesseling, Vassilis Golfinopoulos, Thierry Gorlia, Brigitta Baumert, Houtan Noushmehr, Pim French
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Uncontrolled studies have suggested that methylation-based epigenetic subtypes can be used for prognostication of glioma. We used the prospective randomized CATNON trial to validate the clinical relevance of these epigenetic subtypes. METHODS The phase III CATNON trial randomized 751 adult patients with newly diagnosed 1p/19q non-codeleted anaplastic glioma to 59.4 Gy radiotherapy +/- concurrent and/or adjuvant TMZ. CNV data and methylation data were derived from Infinium MethylationEPIC arrays. Epigenetic subtyping and risk of progression to G-CIMP low were determined from random forest models and 7 specific CpGs (PMID: 29642018). IDH1/2 status was determined with a glioma-tailored NGS panel. Overall survival (OS) was measured from date of randomization. RESULTS Methylation analysis was performed on 654 tumors: 440 were IDH1/2mt, 204 IDH1/2wt and of 10 IDH1/2 status was unknown; 8 IDH1/2mt were 1p/19q codeleted. Based on methylation, tumors were classified as G-CIMP high (n=409), G-CIMP low (n=19), codel-like (n=18), mesenchymal-like (n=107), classic-like (n=48), and PA-like tumors (n=53). Median OS between these epigenetic subtypes varied considerably: codel-like 9.1 yrs, G-CIMP high 9.5 yrs, G-CIMP low 2.8 yrs, mesenchymal-like 1.3 yrs, classic-like 1.6 yrs, and PA-like 2.8 yrs. The difference in OS of the IDH1/2mt astrocytoma subgroup patients was prominent [G-CIMP low vs G-CIMP high: HR 4.12, 95% CI 2.37-7.19, p &amp;lt; 0.001]. Within the IDH1/2mt G-CIMP high astrocytoma patients, 115 tumors were predicted to have risk of progression to G-CIMP low and patients with such tumors indeed had poorer survival [risk vs no-risk: HR 1.59, 95% CI 1.10-2.31, p = 0.02]. Median OS in G-CIMP high tumors with (n=37) and without (n=366) CDKN2A/B HD was 3.3 yrs versus not reached [p&amp;lt; 0.001], in G-CIMP low tumors it was 1.2 yrs (n=6) versus 4.4 yrs (n=12) [p=0.008]. CONCLUSIONS In IDH1/2mt anaplastic astrocytoma, G-CIMP status and CDKN2A/B HD are of independent prognostic value.
74P Pivotal trial 201 data on outpatient administration of naxitamab (Hu3F8), a humanized GD2 targeted immunotherapy for the treatment of refractory/relapsed (R/R) high-risk (HR) neuroblastoma (NB)
Authors: D.A. Morgenstern, J. Mora, G.C. Chan, K. Nysom, M. Bear, L. Worsaae Dalby, S. Lisby, B.H. Kushner
Journal: Annals of Oncology (2020)
Extrapulmonary SARS-CoV-2 manifestations
Authors: Thiago Carvalho
Journal: Nature Medicine (2020)

saw the declaration of a global pandemic in March, by the World Health Organization, of a coronavirus, SArS-CoV-2, that causes the disease COVID-19.Studies undertaken this year have advanced the understanding of the clinical characteristics, viral entry and immune response, and have made inroads into vaccine development, among other advances.
Molecular subtyping of hepatocellular carcinoma: A step toward precision medicine
Authors: Yichao Wu, Zhikun Liu, Xiao Xu
Journal: Cancer Communications (2020)

Abstract Hepatocellular carcinoma (HCC) is one of the most prevalent and fatal digestive tumors. Treatment for this disease has been constraint by heterogeneity of this group of tumors, which has greatly limited the progress in personalized therapy. Although existing studies have revealed the genetic and epigenetic blueprints that drive HCCs, many of the molecular mechanisms that lead to HCCs remain elusive. Recent advances in techniques for studying functional genomics, such as genome sequencing and transcriptomic analyses, have led to the discovery of molecular mechanisms that participate in the initiation and evolution of HCC. Integrative multi‐omics analyses have identified several molecular subtypes of HCC associated with specific molecular characteristics and clinical outcomes. Deciphering similar molecular features among highly heterogeneous HCC patients is a prerequisite to implementation of personalized therapeutics. This review summarizes the current research progresses in precision therapy on the backbone of molecular subtypes of HCC.
IMG-18. ASSESSMENT OF SUSPECTED DISEASE PROGRESSION USING MULTIPARAMETRIC 18F-CHOLINE PET/MRI IN CHILDHOOD AND TEENAGE-YOUNG ADULT GLIOMAS
Authors: Valentina Ferrazzoli, Ananth Shankar, Julia Cockle, Christine Tang, Ahmed Al-khayfawee, Benjamin Thomas, Anna Barnes, Jamshed Bomanji, Francesco Fraioli, Harpreet Hyare
Journal: Neuro-Oncology (2020)

Abstract OBJECTIVES Evaluation of post-treatment glioma burden remains a significant challenge in children, teenagers and young adults (TYA). The aim of this study was to evaluate the utility of ChoPET/MRI for evaluation of suspected disease progression in childhood and TYA gliomas. METHODS 27 patients (mean age 14 years, range 6–21 years) with suspected glioma disease progression were evaluated with ChoPET/MRI (n=59). Relative cerebral blood volume (rCBV), apparent diffusion coefficient (ADC) and maximum standardised uptake values (SUVmax) in enhancing (enh) and non-enhancing (ne) tumour and normal-appearing white matter (wm) were calculated (rCBVenh, rCBVne, rCBVwm, ADCenh, ADCne, ADCwm, SUVenh, SUVne, SUVwm). 2 blinded radiologists scored tumour probability (1 = unlikely; 5 = definitely). Sensitivity and specificity calculated with gold standard histopathology or clinical follow-up. RESULTS Accuracy for the detection of residual/recurrent tumour on conventional MRI was 96.3% (91.7% ≤14 years, 100% ≥15 years) and ChoPET was 73.1% (66.7% ≤14 years, 80.0% ≥15 years). Lack of agreement was observed in 9/27 patients, with ChoPET superior to MRI in 1 case of a posterior fossa tumour. Tumour component analysis demonstrated significantly higher SUVenh and SUVne than SUVwm (SUVenh: p&amp;lt;0.001; SUVne: p=0.004, equivalent to results were observed for ADV and rCBV (ADCenh, ADCne: p&amp;lt;0.001 vs ADCwm; rCBVenh, rCBVne: p&amp;lt;0.001 vs rCBVwm). CONCLUSIONS MRI is more sensitive than ChoPET in the evaluation of suspected disease progression in TYA gliomas. However, quanititative ChoPET is able to detect enhancing and non-enhancing tumour and may be helpful in evaluating posterior fossa disease where MRI is equivocal.